Proteases perform numerous vital features in flatworms, a lot of which

Proteases perform numerous vital features in flatworms, a lot of which will tend to be conserved through the entire phylum hybridization (Desire) confirmed the fact that full-length and dynamic types of SmedCB are located in secretory cells surrounding the planaria intestinal lumen. The family members contains around 25,000 types, like the free-living planaria genome continues to be sequenced and these worms are extremely amenable to the usage of RNAi, producing them a perfect flatworm for research [3,4]. While is often used being a model for regeneration, it has been proposed being a model for parasitic flatworms, similar to the free-living can be used being a model for various other parasitic nematodes [5]. More than half Foretinib IC50 from the known people of are individual or veterinary parasites, including worms from the genus as well as the parasite talk about several similarities Foretinib IC50 within their reproductive systems, protonephridia, and stem cell populations [7]. Both are triploblastic, bilaterally symmetric metazoans and contain anxious, digestive, and secretory systems [8]. Furthermore, these organisms talk about over 85% of their forecasted proteome, including many groups of proteases [9]. For digestive function, and also have a blind-end, bifurcated gut that distributes digested meals through the entire body [10]. Mature feminine worms will make use of several specific proteases to quickly digest red bloodstream cells for a price of 500 each and every minute [11]. While vertebrates depend on serine proteases through the trypsin family members (clan PA) for proteins digestive function, invertebrate helminths generally make use of cysteine proteases through the clan CA (papain-like proteases) and aspartic proteases through the clan AA. Cysteine and aspartyl proteases may also be key to digestive function in various other invertebrates like nematodes and arthropods. It would appear that the choice for digestive serine proteases happened during the advancement of arthropods or mollusks [12, 13, 14]. Three cysteine cathepsin proteases perform nearly all digestion of food in helminths: cathepsins B, C, and L. These clan CA proteases are located in lots of flatworm parasites, like the trematodes [11, 15]. Immunohistochemistry shows that cathepsins B, C, and L are linked strongly using the gastrodermis, vitellaria, and tegument [15]. These proteases function in concert to degrade hemoglobin and albumin in the acidic helminth gut [16]. Inhibition of cysteine proteases provides been proven to eliminate parasites both and flatworms could be induced to regurgitate their gut items as well as the cysteine proteases cathepsin B, C, and L, aswell as an aspartyl protease (cathepsin D) and an asparaginyl endopeptidase (legumain), have already been determined [19, 10]. Cathepsin B1, or SmCB1, represents one of the most abundant cysteine peptidase activity measurable in both adult schistosomes and gastrointestinal articles (GIC) ingredients. Along with degrading web host hemoglobin and albumin, SmCB1 provides been proven to degrade many immunoglobulins gut proteases in digestive function, we looked into the role of the enzymes in the gut of gastrointestinal items. Using RNAi and particular protease inhibitors, we probed the function of many protease families to look for the roles of the enzymes in proteins digestive function. We further analyzed a cathepsin B-like cysteine protease and its own localization in [24] was found in all tests. Worms were managed as explained previously at space heat (20C22C) in 1x Montju?c salts (worm drinking water), pH 7.2, and were given every fourteen days with organic meat liver organ [25]. Unless normally stated, animals had NF1 been starved for 14 days Foretinib IC50 prior to make use of in tests. Era of worm regurgitant Worms had been starved for just one week and cleaned many times in 1x Montju?c salts prior to the addition of 3% EtOH for just one hour to induce regurgitation. Treatment with low-percentage ethanol will not result in long-term harm of worms [26]. Control examples had been treated with drinking water. Worm regurgitant was gathered and filtered utilizing a 50mm Filter Device (Nalgene), then focused 50-fold using at an Amicon Ultra 10K MWCO Centrifugal Filtration system at 8,000 x and 4C. The focused vomit was kept at -80C. Proteomic evaluation of S. mediterranea regurgitant Proteins id in regurgitant was performed using.

Advanced prostate cancer continues to be recognized as becoming attentive to

Advanced prostate cancer continues to be recognized as becoming attentive to androgen deprivation because the 1940s when Charles Huggins 1st explained the role of medical castration in controlling these patients. Recently, several next-generation androgen-directed brokers (e.g. abiraterone and enzalutamide) are also proven to result in a survival advantage in males with CRPC. With a lot of new treatment plans available, several questions remain. Included in these are: how exactly to greatest series chemotherapy with these newer hormonal brokers, the medical implication of cross-resistance between taxanes and androgen-directed brokers and which subsets of individuals may advantage most from early usage of chemotherapy. This review provides an overview from the growing part of chemotherapy in the administration of advanced prostate malignancy in today’s period. 12%; = 0.01). Nevertheless, the prostate-specific antigen (PSA) response prices (i.e. 50% PSA declines) between organizations had not been different (33% 22%, = 0.11) no difference in OS was observed either. A second evaluation of QoL on that research was consequently reported by Osoba and co-workers.22 QoL HA130 IC50 was assessed using two studies: the Western Organization for Study and Treatment of Malignancy Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the grade of Existence Module-Prostate 14 (QOLM-P14). General, those in the mitoxantrone-prednisone organizations were HA130 IC50 discovered to possess significant improvements in global QoL in comparison to settings (= 0.009). Provided these motivating palliative benefits and having less alternative therapeutic choices in those days, mitoxantrone (provided as well as prednisone) was authorized for males with mCRPC. These trial had not been powered to identify differences in success between those getting mitoxantrone versus the ones that do not. A more substantial trial (= 242) carried out by the Malignancy and Leukemia Group B (CALGB), the CALGB 9182 research, was developed so that they can see whether mitoxantrone created improvements in Operating-system.23 While PSA reactions (i.e. 50% PSA decrease) were more prevalent (38% 22%, = 0.008) and there is a significant hold off in progression-free success (PFS) using the mix of mitoxantrone in addition hydrocortisone in comparison to hydrocortisone alone (median PFS 3.7 2.three months, = 0.022), zero difference in Operating-system between the organizations was observed (median Operating-system 12.7 12.three months, 0.05). Furthermore, when the mitoxantrone group was set alongside the placebo group there have been no variations in objective radiographic reactions (i.e. total response plus incomplete response price; 7% 4%, = 0.375) or in global QoL as assessed using the Functional Living Index-Cancer (FLIC). There have been differences between your two organizations in the psychological state subscale, family members disruption subscale and two discomfort items. Having less obvious objective benefits reported in both of these tests illustrated the serious need for more efficient treatment options during this time period period. At the existing time, regardless of the lack of success advantage with mitoxantrone, this chemotherapy may still possess a job in the second-line (post-docetaxel) establishing in particular individuals. Although the book taxane agent cabazitaxel Rabbit Polyclonal to GAK is usually more advanced than mitoxantrone with this establishing (observe TROPIC trial, below), mitoxantrone is usually connected with lower prices of myelosuppression and could be a affordable chemotherapy choice in an individual with poor bone tissue marrow reserves or overall performance status 2C3. Due to its palliative results, mitoxantrone could be specifically useful in docetaxel-pretreated individuals with symptomatic bone tissue discomfort who might not tolerate cabazitaxel. Cyclophosphamide Another chemotherapeutic choice commonly employed in the pre-docetaxel period to treat males with mCRPC was dental cyclophosphamide. A small number of researchers possess reported response prices in the number of 20%C40% when provided as monotherapy or in conjunction with other brokers (both PSA and HA130 IC50 goal response requirements).24,25,26,27,28,29,30 In another of the early research, Raghavan and colleagues given cyclophosphamide at 100 mg daily orally on times 1C14 of the 28-day time cycle. Thirty individuals were treated altogether, plus they reported a median Operating-system of 12.7 months from your day of cyclophosphamide initiation, partial responses (per the Country wide Prostatic Cancer Project criteria) in six (20%) subject matter and disease stabilization in 13 (43%) subject matter.24 Furthermore, 18 (60%) individuals experienced a significant decrease in tumor-associated symptoms and 21 (70%) had significant discomfort reductions. Another statement by Nicolini and co-workers (= 8) examined continuously-dosed dental cyclophosphamide at a dosage of 100C150 mg daily.26 They reported two partial responses and three individuals with steady disease as the other three topics progressed (per Prostate-Specific Antigen Functioning Group requirements). In those that taken care of immediately treatment (= 5), the median Operating-system from enough time of cyclophosphamide commencement was 17 weeks and period of clinical advantage was reported at 9 weeks..

Here we report the rescue of a recombinant porcine reproductive and

Here we report the rescue of a recombinant porcine reproductive and respiratory syndrome virus (PRRSV) carrying an enhanced green fluorescent protein (EGFP) reporter gene as a separate transcription unit. neutralising antibodies and antiviral compounds, but also for fundamental research on the LDE225 biology of the virus. Introduction Porcine reproductive and respiratory syndrome (PRRS), characterized by respiratory diseases in nursery pigs and reproductive failure in sows [1,2], LDE225 has become one of the most economically important infectious diseases in the global swine industry [3]. PRRS virus (PRRSV), the causative agent of PRRS, is a member of a group of enveloped RNA viruses from the genus Arterivius of the family within the order I, I, I, I, I, and I was introduced between the viral sequences and used to construct the full-length viral cDNA. Figure 1 Construction of plasmids for PRRSV rescue. A. The cDNA fragments F1, F2, F3, F4, LATS1 and F5 were reversely transcribed and amplified from HP-PRRSV/SD16 genomic RNA. The CMV promoter was introduced to the 5 end of HP-PRRSV/SD16 and the hepatitis delta … HP-PRRSV/SD16 was propagated in Marc-145 cells and total RNA was isolated from the infected cells using TRIZOL reagent (Invitrogen, Carlsbad, CA, USA). The entire viral genome of HP-PRRSV/SD16 except for the 5 and 3 ends was amplified by RT-PCR using Phusion? High-Fidelity PCR Master Mix (NEB, Ipswich, MA, USA) in five distinct overlapping regions (named F1 to F5) (Figure?1a). Each amplicon was inserted into the pEASY?-blunt simple cloning vector and after sequencing, introduced into the pBAC-SD16-5-3 vector to generate the pBAC-SD16FL (Figure?1a). The unique restriction sites inserted into pBAC-SD16FL between nt 15 170 and 15 171 of the HP-PRRSV/SD16 genome cDNA sequence were used for the cloning of EGFP under the control of the TRS6. To this end, fragment Fa (ending at the N gene with I and I sites introduced at the 3 end) and Fm (starting from the 3-UTR with I and I sites introduced at the 5 end) were amplified from pBAC-SD16FL and ligated together to generate fragment Fam, which was used to replace the fragment used in the original construction of pBAC-SD16FL to LDE225 generate plasmid pBAC-SD16FL-AM (Figure ?(Figure1b).1b). The sequence analysis revealed that two unique restriction sites (I and I) were correctly inserted into pBAC-SD16FL between nt 15 170 and 15 171 of the HP-PRRSV/SD16 genome. The EGFP gene was amplified from the pEGFP-N1 Vector (Clontech, Mountain View, CA, USA) using Phusion? High-Fidelity PCR Professional Combine (NEB, Ipswich, MA, USA) with primers 5-GCGATCGCTGATGGTTCCGCGGCAACCCCTTTAACCAGAGTTTCAGCGGAACAATGGTGAGCAAGGGCGAGG -3 (the I site is normally underlined), filled with a duplicate of the TRS6 series (in vivid), and 5- CGACGCGTCGTTACTTGTACAGCTCGTCCA -3 (the I site is normally underlined). The amplified item was placed into the pEASY?-straight-forward basic cloning vector to generate plasmids pEASY-TRS6-EGFP, and following sequencing, cloned into We / I-cut pBAC-SD16FL-AM to generate plasmid pBAC-SD16FL-TRS6-EGFP (Figure?1c). All primer sequences used in this scholarly research are obtainable from the matching writer upon demand. Recovery and Transfection of recombinant infections To recovery the recombinant HP-PRRSV/SD16 and HP-PRRSV/SD16/TRS6-EGFP, 80% confluent Marc-145 cells cultured in 6-well plate designs had been transfected with the plasmids pBAC-SD16FM and pBAC-SD16FL-TRS6-EGFP using Attractene Transfection Reagent LDE225 (Qiagen, Valencia, California, USA) regarding to the producers guidelines. After 4C5?times of incubation in 37 C, the cells and supernatants were collected and freeze-thawed for 3 situations and the supernatants were then used to infect Marc-145 cells to propagate the rescued trojan. The comprehensive genomic sequences of the rescued infections had been verified by sequencing. The rescued infections of HP-PRRSV/SD16/TRS6-EGFP and HP-PRRSV/SD16 had been called rHP-PRRSV/SD16 and rHP-PRRSV/SD16/TRS6-EGFP, respectively. Distribution of recombinant infections Because rHP-PRRSV/SD16/TRS6-EGFP is normally very much less complicated for analyzing the invert hereditary program than that for rHP-PRRSV/SD16, rHP-PRRSV/SD16/TRS6-EGFP was utilized in the pursuing trials. To determine whether the recovery method or.

Imprinted genes play important roles in placenta development and function. facilitating

Imprinted genes play important roles in placenta development and function. facilitating the derivation of PTSCs. Our results show that PTSCs reactivate several paternally expressed genes, including the PcG gene is lethal when inherited paternally, and results in severely reduced extra-embryonic tissues at early post-implantation stages of development. Finally, to test if the 81422-93-7 supplier observed defects are due to a diminished pool of TSCs, we show that lentiviral delivery of shRNA against to fertilized preimplantation embryos reduces TSC derivation significantly. RESULTS Parthenogenetic embryos are impaired in TSC production The failure of parthenogenetic embryos to sustain trophoblast development beyond early post-implantation stages (Varmuza et al., 1993) suggested that their TSC compartment may be impaired due to absence of one or more paternally expressed, early post-implantation-acting imprinted gene(s). To test this hypothesis, a series of paired experiments was performed to determine the frequency with which parthenogenetic TSCs (PTSC) could be generated in comparison with fertilized TSCs (FTSC) (Table 1). Fertilized blastocysts were efficient at producing TSCs; 60% of outgrowths generated at least one colony, and 81422-93-7 supplier in most cases, more than one TSC colony was found in each well. Parthenogenetic embryos were 97.5% less efficient at generating TSCs than fertilized blastocysts, with only 4.6% of blastocysts yielding colonies, and fewer colonies per blastocyst, in most cases only one. Most parthenogenetic outgrowths contained only small clusters of giant cells after 3-4 days in culture. Table 1. PTS cell derivation We compared five PTSC cell lines with four FTSC cell lines for a number of features. In addition to displaying a characteristic epithelial appearance with defined edges to the colonies (Fig. 1A,B), the identity of TSCs was confirmed by cell-type marker analysis, including the TSC-specific markers and (Fig. 1G). Removal of FGF4 resulted in differentiation of both FTSCs and PTSCs into trophoblast giant cells (not shown). Fig. 1. Fertilized and parthenogenetic TS cells show similarities in morphology and gene expression. (A,B) Phase-contrast images of fertilized (A) and parthenogenetic (B) TSC colonies. (C-F) FISH showing (C,D) and (E,F) expression in FTSC (C,E) and … PTSCs reactivate 81422-93-7 supplier some paternally expressed imprinted genes (PEGs) Three PTSC lines derived from MI oocytes (PTS1-PTS3) and two lines derived from MII oocytes (PTS4, PTS5) were examined for expression of several known imprinted genes by RT-PCR. In addition, four FTSC lines, including F1-FTS, were assayed to evaluate consistency of expression across a range of cell lines (Fig. 81422-93-7 supplier 1G). The analysis resulted in the categorization of these genes into two classes: those with consistent expression across all TSC lines, such as (- Mouse Genome Informatics), and (- Mouse Genome Informatics), (not shown), and was assayed but not detected in any TSC lines. Genes with consistent expression across all 81422-93-7 supplier PTSC lines were assayed for monoallelic expression TNR in F1-FTS. SNP analysis in F1-FTS cell line revealed paternal expression of and showed biallelic expression, indicating lack of imprinting of this gene in TSCs. We were unable to assess allelic expression of due to lack of polymorphisms. Fluorescent hybridization reveals that PTSCs undergo normal X-inactivation and express from one allele The paternal X chromosome is preferentially inactivated in murine extra-embryonic tissues. Previous studies have shown that parthenogenetic embryos, despite lacking a paternal genome, appear to inactivate one of their X-chromosomes (Nesterova et al., 2001). We tested PTS2 and PTS5 cell lines for expression of by fluorescent hybridization (FISH). Both PTSC lines showed a distribution of RNA characteristic of X chromosome silencing, indicating that X-inactivation can occur in PTSCs (Fig. 1C,D). In addition, only one allele of is active, as revealed by the presence of only one RNA FISH signal (Fig. 1E,F), indicating that reactivation is restricted to one of the grandparental alleles. Together, these results indicate.

In an effort to improve antigen-specific T cell reputation of cancer

In an effort to improve antigen-specific T cell reputation of cancer cells, we have analyzed several modulators of antigen-expression. recommend that iHsp90 improve reputation of growth cells by Capital t cells particular for a melanoma-associated antigen as a result of raising the indicated intracellular antigen pool obtainable for refinement and 187389-53-3 manufacture demonstration by MHC Course I, along with improved amounts of MHC Course I itself. As these Hsp90 inhibitors perform not really get in the 187389-53-3 manufacture way with Capital t cell function, they could possess potential for make use of in immunotherapy of tumor. Intro While there can be popular curiosity in mobilizing anti-tumor defenses, there stay obstacles to immunotherapy [1] [2]. Restorative success possess been accomplished through adoptive transfer of both Compact disc8+ tumor-reactive cytotoxic Capital t cells (CTL) [3] and Compact disc4+ growth infiltrating lymphocytes (TIL) [3], [4]. Lately, there offers been significant improvement using adoptive transfer of cells that are designed to communicate Chimeric Antigen Receptors (CAR), permitting for therapy with extremely described effector populations [5]. In addition, there can be raising recognition that Compact disc4+ regulatory Capital t cells (Tregs) play an essential part in suppressing anti-tumor defenses [6]. Nevertheless, actually when tumor-specific Capital t cells are overflowing within growth sites, this immune system response will not really always business lead to control of growth development [6]. Remarkably, producing effective defenses can become limited by several suppressive elements in the growth microenvironment, including antigen regulatory elements created by the growth cells [7]. Some of the down-regulatory results on the sponsor immune system response possess been inhibited therapeutically via neutralization of Treg cells, blockade of the PD-1/PD-L path, or inhibition of myeloid-based immunosuppressive substances [8], including focusing on of Capital t cell service checkpoints such as CTLA-4, but such therapies may become limited by significant part results [9]. In addition to results on immune system cells, heterogeneity within the growth itself also takes on an essential part in restricting the effectiveness of the immune system response. This conversation concentrates on techniques to conquering the reduction of growth antigen appearance [7], [10]C[12], to address this path of growth get away from Capital t cell-mediated defenses [13]. 187389-53-3 manufacture While antigen reduction may become the result of ongoing immune system stresses, including immune system editing [14], we possess proven that there are many methods to restore antigen appearance, including MAP-kinase (MAPK)- inhibitors [11], Interferon-beta (IFN-) [10], topoisomerase inhibitors [15], and most lately iHsp90 [16]. Centered on a display for real estate agents that enhance Capital t cell reputation of Melan-A/MART-1, the iHsp90 17-Allylamino-17-demethoxygeldanamycin (17-AAG) was identified as a powerful incitement of most cancers antigen appearance [16]. By suppressing 187389-53-3 manufacture Hsp90, 17-AAG causes the destabilization of the items of many mutant oncogenes, including BRAF, NRAS and CRAF [17]. Cxcl12 Through its part in controlling the conformation, balance and function of many essential oncogenic customer protein, Hsp90 can be important in keeping cancerous modification and in raising the success, development, and intrusive potential of tumor cells, including melanomas [18] [19]. Many people of this medication course possess been examined in human being medical tests [20], and while the medicines may sluggish growth development, to day non-e possess been successful as solitary real estate agents [21]. Remarkably, iHsp90s possess been demonstrated to boost Capital t cell reputation of both Her-2 [22] and EphA2 [23] antigens. Both of these onco-proteins are known customer protein of Hsp90, and while the amounts of intracellular appearance of these antigens had been after Hsp90 treatment, the improved CTL-recognition of the treated growth cells was credited to improved turnover of the protein, mixed with increased peptide demonstration on MHC substances. In comparison, proof suggests that the difference antigens and MHC Course I protein that boost in response to iHsp90 are not really Hsp90 customer protein, and.

Previous studies provided substantial evidence of a striking suppressive effect of

Previous studies provided substantial evidence of a striking suppressive effect of hepatocyte nuclear factor 4 (HNF4) on hepatocellular carcinoma (HCC). kinases (MAPKs), c-Jun N-terminal kinases (JNKs), and p38 MAPKs in response to numerous cellular stresses [17, 18]. In particular, ASK1 has been identified as a key determiner of cell death via triggering cell apoptosis. Interestingly, ASK1 has also been reported to promote cellular differentiation. Recent studies revealed that ASK1 may be involved in differentiation process in diverse cell types, including keratinocytes [19], chondrocytes [20] and stem cells [21]. On the other hand, substantial evidence demonstrate that a quantity of cancers are intimately related to ASK1 mediated cascades [22C24]. However, the role of ASK1 in malignances remains controversial [25C30]. Rabbit Polyclonal to ADCK5 Nakagawa and expression was particular interesting because it is a key mediator of MAPK signaling and is reported to be involved in the pathogenesis of many tumors. We then validated the effect of HNF4 on expression by real-time polymerase chain reaction (RT-PCR) and Western blotting. ASK1 expression appeared to be sensitive to the level of HNF4. It was increased by HNF4 overexpression and decreased by HNF4 knockdown (Physique ?(Physique1B1B and Supplementary Physique S2). Consistently, Western blot analysis showed that phosphorylation of the JNK and p38 (MAPKs downstream of ASK1) were also increased after HNF4 overexpression (Physique ?(Physique1C).1C). This result confirmed that MAPKs can be activated by HNF4. We then used the JASPAR database [34] to predict the site of HNF4 response element (HNF4-RE) in the promoter region of gene. One HNF4-RE was recognized when the profile score threshold was set to 80% (Supplementary Physique S3); this was confirmed by chromatin immunoprecipitation (ChIP) assay. As shown in Physique ?Determine1D,1D, the binding of HNF4 to promoter was highly enriched in Hep3B cells with HNF4 overexpression. In contrast, knockdown of HNF4 by small interfering RNA (siRNA) in Hep3B cells substantially decreased the binding enrichment. These data suggest direct binding between endogenous ASK1 and HNF4 in HCC cells. To further determine the effect of HNF4 on transactivation, luciferase reporter plasmids made up of the promoter with the HNF4-RE were transfected into AdHNF4-infected Hep3B and Huh7 cells. The reporter assay showed that ectopic HNF4 expression increased the transcriptional activity of promoter, and that this effect was significantly impaired by mutation of the HNF4-RE (Physique ?(Physique1E1E and Supplementary Table S1). Together, these data reveal that HNF4 activates transcription by binding to its promoter. Physique 1 HNF4 regulates the MAPK signaling pathway and activates buy 199113-98-9 ASK1 by binding to its promoter Reduced ASK1 expression is associated with aggressive clinicopathological features and poor prognosis for human HCC We next examined ASK1 and HNF4 mRNA levels in HCC tissue specimens and their surrounding noncancerous tissue (NT) from 60 patients (defined as Group 1) by RT-PCR. Compared with NT, HNF4 mRNA was downregulated in 45 of 60 cases (75%) and ASK1 mRNA was downregulated in 44 of 60 cases (73.33%; Physique ?Physique2A).2A). buy 199113-98-9 Moreover, ASK1 expression was positively correlated with HNF4 levels in HCC patients (= 0.605, < 0.0001; Physique ?Physique2B).2B). The clinicopathological significance of ASK1 and buy 199113-98-9 HNF4 expression was further analyzed. The median mRNA level of ASK1 and HNF4 was chosen as the cutoff point, leaving 30 cases in each group (Supplementary Furniture S2CS3). ASK1 and HNF4.

Introduction We have recently described an increased lymphocytic infiltration rate in

Introduction We have recently described an increased lymphocytic infiltration rate in breast carcinoma tissue is a significant response predictor for anthracycline/taxane-based neoadjuvant chemotherapy (NACT). for pCR in multivariate analysis (LPBC: OR 2.7, p?=?0.003, strLy: OR 1.2, p?=?0.01). The amount of intratumoral lymphocytes was significantly predictive for pCR in univariate (OR 1.2, p?=?0.01) but not in multivariate logistic regression analysis (OR 1.2, p?=?0.11). Conclusion Confirming previous investigations of our group, we have prospectively validated in an independent cohort that an increased immunological infiltrate in breast tumor tissue is predictive for response to anthracycline/taxane-based NACT. Patients with LPBC and increased stromal lymphocyte infiltration have significantly increased pCR rates. The lymphocytic infiltrate Rabbit polyclonal to LRRC15 is a promising additional parameter for histopathological evaluation of breast cancer core biopsies. Introduction Primary systemic therapy is the treatment of choice in locally advanced breast cancer. Besides the well-established adjuvant therapy regimens neoadjuvant chemotherapy (NACT) is increasingly used 503612-47-3 IC50 in patients with operable cancers [1], [2]. While NACT of early stages of breast cancer leads to high clinical response rates [3], [4], a pathological complete remission (pCR) is achieved in only one-fourth of the patients, with variable rates in different subtypes. The adaptive immune system is thought to play an important role in suppressing the progression of malignant cancers [5]C[9]. The presence of infiltrating lymphocytes within the tumor tissue has been shown for numerous tumor entities and high lymphocyte infiltration rates correlated with improved outcome [10]C[13]. For breast cancer patients 503612-47-3 IC50 older than 40 years a high degree of infiltrating lymphocytes was correlated with increased survival [14]. In rapidly proliferating breast cancer tissues, a lymphocytic infiltrate demonstrated to be an independent predictive indicator for recurrence-free survival [15]. Furthermore, we and others have shown that a high lymphocyte infiltration is predictive for response to NACT in breast cancer patients [16]C[19]. Using core biopsies of untreated breast carcinomas for the analysis of predictive markers, NACT regimen can be used as in vivo chemotherapy-sensitivity test with pCR as indicator of beneficial outcome from chemotherapy [20]. In previous retrospective investigations we could demonstrate that an increased immunological infiltrate is predictive for response after anthracycline/taxane NACT. We showed that lymphocyte-predominant breast cancer (LPBC), defined as tumors with >60% lymphocyte infiltrate of either stromal (strLy) 503612-47-3 IC50 or intratumoral (iTuLy) lymphocytes had a significantly increased pCR rate after NACT [16]. Using pretherapeutic core biopsies of HER2 negative patients randomized for the PREDICT study, a substudy of the neoadjuvant GeparQuinto trial, we prospectively analysed the immunological infiltration rate as independent predictor for response to NACT. Methods Study Population A total of 313 FFPE primary tumor core biopsies were evaluated in the prospective PREDICT study, a substudy of the GeparQuinto trial. The GeparQuinto trial (“type”:”clinical-trial”,”attrs”:”text”:”NCT 00567554″,”term_id”:”NCT00567554″NCT 00567554) was a prospective, randomized, open label, multicentre phase III trial program exploring the integration of Bevacizumab, Everolimus (RAD001) and Lapatinib into current neoadjuvant chemotherapy regimes for primary breast cancer. Chemotherapy consisted of 4 cycles of epirubicine, cyclophosphamide followed by taxane. The PREDICT study was designed as a substudy of GeparQuinto for prospective validation of molecular biomarkers in HER2 negative tumors in the neoadjuvant setting. Only HER2-negative patients in setting 1 that did not receive Bevacizumab were included in the PREDICT study. 93 centers (of a total of 127 GeparQuinto centers) have participated in the Predict substudy and have provided tumor samples in parallel to the randomization. Everolimus was administered to the non-responders in a second randomization, at that time the lymphocyte analysis had already been performed. 37 patients investigated for lymphocyte parameters were randomized to the Everolimus arm of GeparQuinto. Written informed consent for use of biomaterials was obtained from all patients, ethic committee approval was obtained for all centres participating in the clinical study and from the 503612-47-3 IC50 institutional review board of the Charit hospital. Data analysis approach All clinical data, including the immunohistochemical data on estrogen receptor, progesterone receptor and HER2 status were extracted from the clinical study databases and represent the local assessment. This was predefined in the prospective statistical analysis plan for the PREDICT study. Tumor samples and inclusion criteria All samples were formalin-fixed, paraffin-embedded pretherapeutic core biopsies collected before randomization, with written informed consent. Samples were stored in the GBG tumor bank at the Institute of Pathology, Charit Hospital, Berlin, Germany. The following inclusion criteria were used: 1) HER2 negative patients that were randomized to setting 1 of.

Background VEGF-regulated genes in the cervices of pregnant and non-pregnant rodents

Background VEGF-regulated genes in the cervices of pregnant and non-pregnant rodents (rats and mice) were delineated by DNA microarray and Real Time PCR, after locally altering levels of or action of VEGF using VEGF agents, namely siRNA, VEGF receptor antagonist and mouse VEGF recombinant protein. levels of VCAM-1, a key molecule in leukocyte recruitment, endothelial adhesion, and subsequent trans-endothelial migration, were elevated about 10 folds by VEGF. Further, VEGF brokers also altered mRNA levels of decorin, which is involved in cervical collagen fibrillogenesis, and expression of eNO, PLC and PKC mRNA, crucial downstream mediators of VEGF. Of notice, we show that VEGF may regulate cervical epithelial proliferation, as revealed by SEM. Conclusion These data are important in that they shed new insights in VEGF’s possible roles and mechanisms in cervical events near-term, including cervical remodeling. Background Cervical remodeling is considered a chronic inflammatory-like process regulated by numerous factors, and its dysfunction can potentially lead to birth-related complications [1-4]. Because the vasculature plays a crucial role in inflammatory reactions, we have previously hypothesized that factors that regulate the cervical vasculature are likely to play a critical role in cervical remodeling, notably VEGF and its associated molecules, such as nitric oxide. For instance, local microvascular alterations during cervical remodeling may be essential for delivery of cells and factors to the connective tissues for remodeling. In turn, vascular-derived factors, such as leukocytes, play a critical role in cervical remodeling by invading cervical tissue and releasing catabolic enzymes and cytokines [5]. Thus, recruitment or mobilization of leukocytes into the cervical connective tissue buy 545-47-1 may require structural changes to the vasculature, and this process may be regulated, directly and/or indirectly, by several factors. VEGF is usually a member of a family of closely related growth factors that include VEGF-A, -B, -C, -D, -E and placenta growth factor (PIGF) [6]. VEGF-A has well-established biological effects and exists as several splice variants [6]. Biological effects of VEGF are largely mediated by two receptors: KDR (kinase domain region) and Flt-1 (fms-like tyrosine kinase-1) [7,8]. The role of VEGF in female reproductive biology is best known PLZF in the ovarian and uterine events. VEGF is essential for a variety of ovarian and uterine endometrial functions by mediating cyclical growth of blood vessels. For instance, treatment with a VEGF inhibitor (mFlt- [1-3]-IgG) virtually blocks corpus luteum angiogenesis and maturation of endometrium [9]. VEGF signaling pathways for microvascular regulation have been extensively analyzed to date, mostly in human umbilical vein endothelial cells [HUVECs]. In spite of this, very little is known about VEGF function in the cervix in general and buy 545-47-1 cervical remodeling in particular. We recently reported that only VEGF variants 120 and 164 exist in the rat cervix [10]. In general, VEGF 164 is the most abundant and best characterized of all VEGF variants in the body. We also exhibited that there exist two VEGF receptors in the cervix of pregnant rats, buy 545-47-1 namely KDR and Flt-1, and that VEGF, its receptors, and some of its important signaling molecules are altered in the cervix during pregnancy [10]. Even though mechanisms mediating specific vascular effects of VEGF are beginning to be unraveled, they are not fully elucidated and vary between vascular beds. A global or genome-wide view of VEGF-related genes in the “ripening” cervix and knowledge of the specific VEGF/VEGF receptor pathway mediating their cellular effects, is essential for obtaining a comprehensive evaluation of the processes (vascular and non-vascular) regulated by VEGF. In this study, we alter VEGF action by either over-expressing, down regulating or blocking VEGF action in the cervix of non-pregnant and pregnant rodents (rat and mice) using recombinant VEGF-protein, -siRNA generating pDNA or -receptor antagonist (PTK787), respectively. Tissues were analyzed using DNA microarray, gel-based PCR, Real-Time PCR, SEM, and histology. Methods Animals and treatment with VEGF brokers a) Timed-pregnant Sprague Dawley.

Background The prevention of persistent human immunodeficiency virus type 1 (HIV-1)

Background The prevention of persistent human immunodeficiency virus type 1 (HIV-1) infection requires the clarification of the mode of viral transduction into resting macrophages. to the IN-CACindependent viral infection of macrophages, which is resistant to RAL. Thus, the ATM-dependent cellular pathway and Vpr-induced DNA damage are novel targets for preventing persistent HIV-1 infection. proposed that DNA-dependent protein kinase was a cellular factor involved in gap-repair [9], and then ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), Nijmegen breakage syndrome 1 (NBS1), and poly(ADP-ribose) polymerase 1 (PARP1) have also been nominated as cellular proteins involved in efficient viral transduction [10-13]. Using KU55933, a specific ATM inhibitor, Lau proposed that ATM is also involved in HIV-1 transduction [14], whereas Sakurai demonstrated that DNA damage repair enzymes are involved in multiple steps of retroviral infection [15]. These observations support the importance of DNA double-strand breaks (DSBs) in viral transduction, although their roles are controversial [16-19]. A possible explanation for discrepancies in reported observations is that the single-strand gaps are repaired in a redundant fashion by DNA damage repair enzymes, the expression of which varies among cells [20]. It is also possible that DSBs have modest effects on viral transduction, which may be overwhelmed by the infectivity of the wild-type (WT) virus. This suggests that it is important to evaluate the effects of DSBs using more sophisticated experimental approaches. Here we focused on the role of DNA damage (DSBs), particularly in integration of viral DNA. Interestingly, HIV-1 DNA integrated into artificially induced DSBs in an IN-CACindependent manner and DNA damaging agents upregulated the infectivity of IN-CACdefective virus. The positive effects of DSBs on viral integration were resistant to raltegravir (RAL), an IN-CA inhibitor. Moreover, Vpr, an accessory gene product of HIV-1, mimicked DNA damaging agents and increased IN-CACindependent viral transduction into monocyte-derived macrophages (MDMs). Even when the catalytic activity of IN was impaired, infectious secondary virus was generated without any mutations that yielded phenotypes resistant to RAL. Based on these observations, we propose that the ATM-dependent mode of DSB-specific integration of viral DNA and the Vpr-induced DSBs are novel CASP12P1 targets for anti-HIV compounds that inhibit viral transduction into MDMs, a persistent reservoir of HIV-1 infection. Results HIV-1 integrates into the sites of artificially induced DSBs To understand the roles of DSBs in integration of viral DNA into macrophages, we established a system using THP-1 cells, a human monocytic leukemia cell line that differentiates into macrophage-like cells A 438079 hydrochloride manufacture after treatment with phorbol myristate acetate (PMA) (Figure?1A) [21]. We transfected THP-1 cells with plasmid DNA that contained the recognition sequence for I-hybridization (FISH) analysis, which detected provirus DNA in a single locus in the genome (Figure?6E). Sequence analysis of the provirus DNA of clone A 438079 hydrochloride manufacture #2413 finally identified an intact viral DNA structure with the flanking nucleotide sequence of the I-reported that the integration rate of the IN-CACdefective virus was enhanced by DNA damaging agents such as x-ray irradiation or hydrogen peroxide [48], whereas we showed that DSBs upregulated IN-CACindependent viral integration and promoted the production of secondary viruses, which were competent for subsequent viral infection. Importantly, analysis of the nucleotide sequences of the viral RNA from the secondary viruses showed that there were no revertants to WT virus. Most of the viruses analyzed also A 438079 hydrochloride manufacture had no reported mutations linked to RAL-resistant phenotypes [29-32]. Taken together with observation that RAL could reduce A 438079 hydrochloride manufacture the infectivity of WT virus at a similar level to D64A virus, our data also suggest that currently available IN inhibitors cannot completely block productive viral infection, which.

Background Globally, on the subject of 20% of cultivated land is

Background Globally, on the subject of 20% of cultivated land is now affected by salinity. gene might be used like a potentially encouraging transgene to improve abiotic stress tolerances in crop vegetation. Introduction Ground salinity is one of the major abiotic tensions leading to major depression of crop yields [1]. This problem is definitely becoming more severe because of ground degradation, water shortage and global warming. Clearly, the development of transgenic plants that can tolerate high salt stress would offer a practical contribution to solving this urgent problem. Considerable efforts have been made to increase the salt tolerance of plants, not only by exploitation of natural genetic variation, but also by transferring foreign genes into plants [2], [3]. Genes used in the transgenic approach possess Rabbit polyclonal to SMAD3 included those encoding practical and regulatory proteins [4], [5]. Functional proteins, including enzymes required for biosynthesis of various osmoprotectants, ion transporters for keeping high K+ and low Na+ homeostasis and detoxification enzymes, directly protect against environmental tensions. Regulatory proteins were shown to be involved in control of gene manifestation and transmission transduction in response to multiple tensions. They include transcription factors, protein kinases and enzymes involved in phosphoinositide rate of metabolism. However, due to the fact that salt tolerance is definitely a complex trait and that the underlying molecular mechanisms are not well-understood, such strategies have met with only limited success [6]. The finding of genes involved in various stress reactions provides new focuses on for improvement 89-25-8 supplier of stress tolerance in crop vegetation. The genus R1 and [9], [10]. Genetic analysis of a DNA damage-sensitive strain of R1 led to the discovery of a novel regulatory protein (DR0167, also named PprI) [11], [12]. The IrrE protein can stimulate transcription of and using a shuttle plasmid under the control of a GroESL promoter promotes DNA restoration and offers oxidative damage safety [13]. [17], [18]. This model organism may consequently become well-suited to investigating rules by IrrE. is one of the most important oilseed plants cultivated worldwide, and it is sensitive to salt stress throughout the growing time of year. Transgenic vegetation overexpressing AtNHX1, a vacuolar Na+/H+ antiporter from gene can be utilized to improve tolerance to additional abiotic tensions and, in particular, tolerance to high salinity. We shown here that manifestation of IrrE, a global regulator for intense radiation resistance in and cells against numerous abiotic tensions To study the effect of IrrE in control strain carrying only the pMG1 vector and a transformant strain expressing 89-25-8 supplier IrrE. Using LB plate assays, as demonstrated in Number 1A, IrrE safeguarded cells against salt shock and additional abiotic tensions such as oxidative, osmotic and thermal shocks. The effect of salt stress on the growth of control strain and IrrE-expressing strain was examined in M9 minimal medium. When the IrrE-expressing strain was inoculated into M9 minimal medium, it also displayed better growth than the control strain with higher maximal cell denseness (Number 1B). In the presence of 0.65 M NaCl, the IrrE-expressing strain reached a maximum OD600 of 0.88 after 60 h of incubation, while the control strain displayed significantly impaired growth (Figure 1C). Number 1 Effects of abiotic tensions on growth of strains. IrrE-overexpressing transgenic vegetation display significantly improved salt tolerance To assay the effect of IrrE manifestation on salt tolerance inside a crop flower, we generated transgenic vegetation overexpressing the gene (Number 2). As demonstrated in Number 2A, a construct 89-25-8 supplier comprising the full-length cDNA of the gene under the control of the cauliflower mosaic computer virus 35S promoter was launched into the genome of cultivar Shuanzha no.9 using an gene fragment. Seven homozygous lines from these transgenic vegetation were acquired in the T2 generation. Southern blot analysis suggested that seven transgenic lines experienced one or more copies of the gene (data not shown). Western blot analysis confirmed the manifestation of IrrE in four self-employed transgenic lines, but not in the wild-type control.


Danielle is a full-time model, qualified nutritionist (dip), food writer and chef based in London. She has been modelling for five years and since the job depends heavily on the way you look, feel and act, has become increasingly aware of the importance of her dietary choices. Following plenty of research, studying part-time and learning through personal experience, Danielle began to understand and experience the benefits that come with eating natural, wholesome ingredients, and cutting out processed and refined foods from her diet completely.

Giving up sugar and grains meant giving up traditional granolas and the lack of it left her feeling lost in the mornings, and in search of a healthy alternative - something which, at this point, didn't exist on the market. She began to make her own gluten-free granola using different seeds such as buckwehat, amaranth and quinoa, and when friends, family and Instagram followers loved it, they encouraged her to create it for the masses. The recipe has developed a lot from the first experiment in her kitchen, and contains her favourite superfoods and a nutritious selection of nuts and seeds, to make a range of honest, reliable breakfast goods.

No buzzwords or unreliable health claims - just real food, made with real ingredients, providing real energy and real health benefits.


An Essay on the Roots of Morality

Where does morality come from? How can we know which actions are good and which are bad? How do we recognize a good person, a good life? Are there moral rules or standards that apply to everyone, everywhere, all the time? Or are moral standards merely rules of behaviour and customs adopted by a given culture, so that what is right in one society can be wrong in another, and vice-versa.

Since René Descartes and succeeding generations of rationalist thinkers, we have attempted to answer questions like these in terms of reason, which Enlightenment philosophers (aggressively rejecting many centuries of religious authority) insisted was the only true route to certain knowledge of any kind—more certain, even, than the senses, which sometimes deceive. What we can demonstrate to be an axiom in logic or mathematics, we can be sure is true, always and everywhere.

Rationalist moral systems can draw up lists of rules to be consulted and obeyed, or they can be focused on the outcomes of actions, which are to be calculated prior to acting. The first approach is called deontological (Gk. deont: being necessary) and it proposes that morally relevant actions are always either good or bad, regardless of their consequences, and further that it is possible to draft rules that have broad if not universal application. The second system, called Utilitarian (or consequentialist), deems those actions good which result in the greatest happiness for the greatest number. A third approach was adopted by Immanuel Kant, perhaps the most influential of all modern moral philosophers. Kant attempted to establish a handful of fundamental rational principles upon which all moral judgment could be based. In this famous “categorical imperative” he argued that “I ought never to act except in such a way that I could also will that my maxim should become a universal law.” In other words, the test of whether a moral precept is true or valid is whether we can assert it to be true in all imaginable circumstances. Only under these conditions can a rational person act in good faith.

Kant proposed a step-by-step process of moral deliberation or testing in connection with the categorical imperative:

1)   State the principle guiding your action (or proposed action).

2)   Then restate the principle as a universal law that applies to all rational people.

3)   Carefully and systematically examine the universal principle in the light of the best current knowledge about the world and its rational inhabitants. Move to stage 4.

4)   Ask the question: given the evidence, should I act on this principle?

5)   If the answer to (4) is “yes, then the action is morally permissible.

The Kantian categorical imperative bears an important epistemological relationship to scientific truth as it has been explored in the last century by philosophers of science. This is nowhere more striking than in the work of Karl Popper and his notion of “falsifiability.” For Popper, establishing scientific fact is a process of deriving a hypothesis and then repeatedly testing it against evidence in a continuous series of attempts to prove it wrong, or to falsify it. Our confidence in a scientific “fact” grows with our inability to prove it false. A corollary to this is that there is no absolutely certain knowledge in science, only degrees of confidence.

Rational moral knowledge is similarly capable of confirmation through the process of falsifiability, which is essentially the process Kant employs in his examples of moral dicta which can and cannot rationally be universalized— which do, and do not, meet the criteria for categorical imperatives. Kant’s categorical imperatives  (categorical because universal; imperative because they are commands) are written as demands for action: save the child! stop the murderer! help the weak! and so on. It is these demands that are to be tested against universal applicability, to see if they are falsifiable.

In current academic thought, this approach to establishing fact in the realm of the normative is called critical moral realism. The moral realist position implicit in what follows is broadly in agreement with the position taken on social constructionism by critical realists such as Roy Bhaskar and Margaret Archer, Andrew Collier, and Zygmunt Bauman among others. It has echoes of the pragmatist philosophy of William James, the moral implications of which are expressed eloquently in The Will to Believe and The Varieties of Religious Experience. Broadly speaking, critical moral realism proposes that reality is both socially constructed and objective (absolute). Society is a human product, but it is also an objective reality. People as individuals are products of that social reality. In other words, humans not only construct a social world, but we are also shaped and produced by what we and others have created. This is not a deterministic process, because if we are all co-producers of reality, then we cannot entirely be its passive creatures (or ideological dupes). Ours is a fate which we ourselves collaborate in producing. Nevertheless, social realities do become objective realities. They are our realities: stabilized, solidified, made “real” through ideology (systems of representation) and institutions (schools, juridicial processes, etc). Made real, in other words, through  everyday material practice.

From the perspective of the early 21st century, the Enlightenment contention that reason alone can provide reliable knowledge about the world, and that there is no limit to that knowledge, is no longer tenable. As Popper understood, science itself does not accept this claim. Nor should it, given the 20th century discoveries of Kurt Gödel and Werner Heisenberg (among others) who established that science and mathematics, as formal systems, are in principle unable to know everything there is to know. Twentieth century physics and mathematics has taught us that it is axiomatic that there will always be knowledge that is true, to which reason has no access. We are condemned by our finite intelligence to lives lived in the midst of rationally inaccessible mystery.

But this does not mean that our moral lives need be lived without anchors. One such anchor, I would suggest, is what Zygmunt Bauman calls “the moral impulse,” and what earlier generations of moral philosophers have variously referred to as conscience and moral sense.[1] It is the innate human impulse to what Emmanuel Levinas terms “being-for-the-other.” How this impulse is interpreted in the construction of both value systems and social institutions (to the extent that these are value-based) is only in part socially contingent; social contingency cannot fly in the face of this fundamental reality of human existence.

The other anchor is also, apparently, a fact of our psychological existence as homo sapiens. Some of the strongest academic support for the existence of an intrinsic moral sense has come from the American linguist, social critic and philosopher Noam Chomsky, whose hypothesis of the existence of an innate grammar in humans that permits them to learn language has been widely (though not universally) accepted. Chomsky’s ideas have effectively displaced earlier earlier behaviourist theory across a wide spectrum of interests.

In his famous review of B.F. Skinner’s Verbal Behavior, he pointed out that much of behaviourist ‘science’ was meaningless at its core. Rather than explaining phenomena it examines, as it claims to do, it merely names them. To describe a painting, for example, as a ‘controlling stimulus’ that evoked an individual’s ‘verbal response’ tells us nothing useful, since the individual might respond in an almost infinite number of ways, his response being determined as much by internal disposition as external stimulation. It was similarly absurd to claim that behaviourist stimulus-response-style training, rather than native endowment, was the key to language development. Children of varying intelligence and cultures acquire language at much the same rate, Chomsky observed, despite the fact that few of them are systematically taught, or rewarded. Furthermore, children use grammar in ways that suggest they are following rules, rather that merely imitating what they hear. Virtually all English-speaking children, for example, initially make the mistake of generalizing the grammatical rule that to form a plural one adds ‘s’, saying ‘foots’ and ‘sheeps’ instead of ‘feet’ and ‘sheep’. Nor could even the richest learning environment account for the apparently unlimited variety of wholly novel sentences small children are able to devise on their own, and understand.

Chomsky has concluded that if it is the case that the human mind is in a sense hard-wired with basic grammatical information, it is likely that it is also equipped, at birth, with other fundamental structures of thought through which it interprets the world. Among these, Chomsky believes, may be an ethical sense. As have other moral theorists, Chomsky sees an analogy between aesthetic sense and moral sense: “Work of true aesthetic value follows canons and principles that are only in part subject to human choice; in part, they reflect our fundamental nature. The result is that we can experience deep emotion—pleasure, pain, excitement, and so on—from certain creative work, though how and why remains largely unknown.” The aesthetic sense also, necessarily, excludes some possibilities. But those limits on artistic creativity, Chomsky says, should be “a matter of joy, not sorrow, because they follow from the fact that there is a rich domain of aesthetic experience to which we have access.”[2] The same is true, he says, of moral judgment:

 What its basis may be we do not know, but we can hardly doubt that it is rooted in fundamental human nature. It cannot be merely a matter of convention that we find some things to be right, others wrong…..The acquisition of a specific moral and ethical system, wide ranging and often precise in its consequences, cannot simply be the result of  ‘shaping’ and ‘control’ by the social environment. As in the case of language, the environment is far too impoverished and indeterminate to provide this system to the child, in its full richness and applicability. Knowing little about the matter, we are compelled to speculate; but it certainly seems reasonable to speculate that the moral and ethical system acquired by the child owes much to some innate human faculty. The environment is relevant, as in the case of language, vision, and so on; thus we can find individual and cultural divergence. But there is surely a common basis, rooted in our nature.[3]

When faced with moral problems, people are able to call on a basic ethical grammar within which to construct and articulate solutions. Unethical actions are thus performed against the grain of individual insight. One could speculate, on the basis of observation, that this is usually for institutional reasons: human instincts favour moral behaviour, but social institutions, structures, and contingencies sometimes provoke anti-human behaviour. An optimistic, though not unreasonable, corollary is that if we change the institutions, we can permit basic human moral instincts to prevail. Where the moral sense comes from, as Chomsky confesses, remains a mystery. But that need not undermine its claim to authenticity. Chomsky himself suggests that there may be absolute limits to human understanding, just as there are limits to human physical potentialities.[4] We cannot become birds; it may be that we are incapable of understanding or solving certain intellectual problems simply by virtue of being human and limited by inbuilt human capabilities.

Chomsky’s speculative insight invites the further conjecture, that behaviourist approaches to morality suffer the same flaw as Skinner’s approach to language. It would suggest that the notion that ethics is constituted by observable bodily behaviour—by actions—is mistaken. To shift the conceptual framework slightly, we can say that in the same way that behaviourism errs in failing to understand that Mind is not merely a word we use to talk about physical actions, but has a real existence and a real location, ‘in the head,’ so to speak, behaviorist approaches to ethics fail to acknowledge that the ‘moral sense’ is real. In Chomsky’s terms, they fail to acknowledge the existence of a hardwired ethical grammar common to all (healthy) human beings, which provides a syntax within which moral choices and decisions can be made.

Similarly, to argue that an individual’s moral responses are dictated by the external stimulus of institutional and cultural rules is to ignore the rich variety of those responses—many of which will find solutions entirely outside the structure of institutional rules. (The saintly, as Emmanuel Lévnas observes, typically respond in ways that entirely transcend local cultural standards of Good.) Further, the fact that ethical behaviour occurs within given social structures in no way proves that the behaviour is caused by the structures. It could as easily be the case, as Chomsky argues, that ethical behaviour stems from innate impulses, though it may be shaped by cultural constraints.

In short, human activities are no doubt deterministic to some degree, meaning that our evolutionary biological makeup, along with the constraints imposed by our cultural institutions, mechanically determine what actions we take in any given circumstance. But as Stuart Kauffman has put it, the biological world is a world of doings as well as happenings. Even very simple living organisms make choices, exhibit agency, or a freedom to act. And with agency, preferences emerge (preference being the choice between one thing or another), and with preferences, value—that which makes one choice preferable over another. And “with value comes meaning…in the sense of mattering to some entity.”[5] At every level of life, but in particular in human beings, agency, intentionality, free will, exist and help to determine actions and their outcomes.

One might also call upon evidence from sociology and psychology, citing psychopathy as an example of ‘missing’ moral sense, or the work of child psychologists in locating the origins of ethical behavior. The distinguished child psychologist Jerome Kagan, for instance, has been quoted as saying that his own research on children in diverse societies (American, Vietnamese and Fijian) has led him to conclude that there is an innate moral sense. “I did not begin my research with that in mind, but it was imposed on me after examining the data.”[6] However it is not clear whether these scientists are talking about morality or evolutionary strategies. Chomsky himself prefers to leave the question open.

There are other approaches to deriving the real existence of moral values. For example, Robert Kane proposes a comprehensive approach to establishing, as an absolute value, a variation of Kant’s categorical imperative that people should be viewed only as ends, never as means. Kane sees absolute values as a form of “objective worth.” To help define objective worth he proposes a mind experiment in which we are asked to imagine a painter who has been ill and depressed because his work is not selling. A wealthy friend and benefactor plots a scheme to have agents purchase several paintings from the gallery and high prices and in the name of knowledgeable and respected collectors. The painter mistakenly believes that his paintings have been recognized for their worth and his spirits rise. Kane now asks us to imagine another world in which circumstances are similar, including the painter’s depression and the fact that he considers himself to be a great talent. In this world, legitimate collectors actually do recognize the merit of his work and purchase his paintings at high prices. Finally, we are to imagine that in both worlds, the painter dies a happy man, in the belief that his talent has been recognized and acknowledged. But only in the second world is his belief correct: in the first, he was deceived. The notion of objective worth begins to come into focus, Kane says,

 when we ask whether it would make any difference to [the painter] which of these two worlds he lives in, given that he believes he is a great artist in both and does not feel less happy subjectively in one world than in the other. To say that there is an important difference in value in the two worlds for [the painter] even though he would not know it and would feel equally happy in both, is to endorse the notion of objective worth.[7]

Kane suggests, correctly, I think, that the painter, if asked, would certainly prefer the world in which he is not deceived. The reason is because there is objective value to the worth of genuine artistic merit, which he is able to recognize. One could also argue that the objective worth resides in truth versus falsity. In any case, the painter’s judgment does not rely solely on his subjective impressions, but takes into account objective values.

Again, however, we are left with the unanswered question: what is it that enables him to recognize these absolutes?

It seems to me that a partial solution to this puzzle can be found in the moral impulse, which is both a necessary and sufficient condition for proving the existence of moral absolutes, that is, values that are applicable in all cases, at all times, in all places. (Or, alternatively, values that are recognizable from all social, cultural and temporal perspectives.) The very fact of the existence of the moral impulse certainly denies the validity of moral relativism as a coherent philosophy. The knowledge that we all possess a moral consciousness or impulse (empirically verifiable, I would argue), and that, in its authentic voice, it speaks to each of us in much the same way, would certainly seem to be strong evidence that there must be some acts that are universally ‘good’ and others that are universally ‘bad.’ The taking of an innocent life is one such universal; others deal with respect for human dignity. Even terrorists, who make a career of killing the innocent, consistently justify their actions with the argument that their victims only appear to be innocent, and are actually complicit at some level in objectionable policies of the offending group or state. Alternatively, or sometimes in the same breath, they claim that the taking of innocent life was necessary to advance some greater normative good. These are of course moral arguments, that implicitly recognize the sanctity of innocent life.

Kane proposes as a fundamental moral precept what he calls ‘the ends principle,’ which is Kantian in its origin and which he describes this way: “Treat every person as an end and not as a means (to your or someone else’s ends) whenever possible. When it is not possible, strive to sustain this ideal to the degree possible, by choosing those actions that will best restore and preserve moral spheres (in which everyone can be treated as an end).” [8]

Zygmunt Bauman’s description of the moral impulse as the innate disposition to be ”for the Other”, can be seen as a thumbnail version of this precept. How can we know what is required of us in being “for the Other?” Our own experience informs us. In its prescriptive form this knowledge is expressed in a number of moral constructs, including the following:

Christianity: “All things whatsoever ye would that men should do to you, do you even so to them: for this the Law and the Prophets.” (Mathew 7:12)

Judaism: “What is hateful to you, do not to your fellow men. This is the entire law: all the rest is commentary.”(Talmud, Shabbat 31a)

Hinduism: “This is the sum of duty: Do naught unto others which would cause you pain if done to you.” (Mahabharata 5:1517)

Buddhism: “Hurt not others in ways that you yourself find hurtful.” (Udana-Varga, 5:18)

Confucianism: “Surely it is a maxim of loving kindness: Do not unto others that you would not have them do unto you.” (Analects, 15:23)

Taoism: “Regard you neighbour’s gain as your own gain and your neighbour’s  loss as your own loss.” (T’ai Shang Kan Ying P’ien)

Zoroastrianism: “That nature alone is good which refrains from doing unto another whatsoever is not good for itself.” (Dadistan-I-dinik, 94:5)

The suggestion is sometimes made that these examples of the so-called ‘golden rule’ are merely expressions of an innate selfishness, in that they are a behavioural means to avoiding personal harm. The empirical/historical evidence does not seem to support this position. We might well ask why there is no hint of reciprocity in any of these precepts; why, for example, in the Christian context the rule is not “Do unto others as you would have them do unto you, so that they will do the same.” Or, “Do unto others as you would have them do unto you, unless there are large gains or small costs in doing otherwise.” The entire purpose of these prescriptions for behaviour is to eliminate the prospect of such reciprocity from behavioural motivation. Clearly, the ‘authors’ thought this was a realistic possibility at least some of the time for some people, and most of us would agree, based on our personal life experience.

Thomas Nagel’s response to the reductionist, behaviourist position that denies the existence of genuine moral motivation is as follows: it might be argued that racism is an innate, biological disposition among humans. Or scientific research might claim to show that one race is intellectually superior to another. We must then ask, should racism thus be exempt from moral criticism? And if “of course not” is the obvious and correct response, where does this idea come from? It cannot determined by biology—that would be contradictory. As Nagel says, moral thought cannot be escaped in reductionism. Nor can its existence be denied. It remains mysterious, but (like gravitational attraction) no less real for its inexplicability. Kant wrote: “Two things fill the heart with renewed and increasing awe and reverence the more often and the more steadily that they are meditated on: the starry skies above me and the moral law within me.”[9]

It seems a mystery that is in principle unsolvable. Religion provides one answer in affirming that humans are made in (a moral) God’s image. The American cosmologist Brian Swimme, bases an ethical theory on the most up-to-date scientific knowledge.[10] Swimme observes that we can now reconstruct the evolution of the universe in considerable detail, from the Big Bang 13.8 billion years ago to an expanding, homogenous broth of hydrogen, to star clusters and galaxies, to the emergence of life, consciousness, and with human life, self-consciousness. Noting that humans are made up of the same constituent material as everything else in the universe and are thus literally one with the universe, he draws a fascinating conclusion: we are the universe thinking. If that is the case, what sort of ethical thought might we be expected to exhibit?

Swimme notes that the universe appears to be consistently evolving in the direction of increasing complexity.Or, as Aristotle might have said, the universe and its constituents are flourishing. For Aristotle, it is in that flourishing (Gk. eudaimonia) that we can locate good. A careful observer of natural world, whom some call the first biologist, Aristotle believed that the undeveloped or immature in nature is best explained in terms of the developed or mature. The adult is prior to the child, the oak tree is prior to the acorn (and, yes, the chicken comes before the egg!). It is an entirely reasonable point of view, for how can we explain the undeveloped if not by understanding its relationship to the thing that it is to become? In Aristotle, ethics is embedded in science in every entity, in every process. To study nature was in a very real sense to study ethics, since in growing, moving, becoming what it truly is, reaching its full potential, each entity in the world is approaching good. It is as if good were a kind of gravitational force, causing all natural motion, drawing everything toward it the way an object of love attracts lovers.

Knowing what science now tells us about the evolving complexity around us, it is difficult to escape the conclusion that ethical behaviour consists in supporting this fundamental trend in all things. Why? Because it is impossible to believe that the observed behaviour of the universe is wrong, or bad. Could it be simply morally neutral? Well, it could be, but Swimme, like Kant, like Aristotle, finds this impossible to square with his own, and other humans, sense of awe and wonder in the face of nature’s evolving power and beauty.

In the end it requires a leap of faith to arrive at the conclusion that nature and its processes are in some essential way, good. But having arrived there, the world makes a good deal more sense. Ethically, it becomes clear that acts that favour complexity, or flourishing, are good, and those that thwart it, bad—a morality we might expect of “the universe thinking.”

An elaborate prescription for both social behaviour and conduct toward the natural environment can be drawn from this single precept: to honour diversity and to encourage flourishing.

[1] Johnathan Glover notes that the attribution of a moral impulse or “ethical disposition” to people as an element of their “humanity is only partly an empirical claim. It remains also partly an aspiration.”  Johnathan Glover, Humanity: A Moral History of the Twentieth Century (London, Pimlico, 2001), 25. A.W. Wood asserts that there must, however, be some connection between the positive and the normative: “[E]thics must be grounded in a knowledge of human beings that enables us to say that some modes of life are suited to our nature, whereas others are not.” A.W. Wood, Hegel’s Ethical Thought (Cambridge, Cambridge University Press, 1990), 17. Bauman proposes a link in the “moral impulse.”

[2] Noam Chomsky, Language and Problems of Knowledge (Cambridge, MIT Press, 1988), 152. And later (p 161): “The evidence seems compelling, indeed overwhelming, that fundamental aspects of our mental and social life, including language, are determined as part of our biological endowment, not acquired by learning, still less by training, in the course of our experience.”

[3] Ibid., 152-3.

[4] Ibid, 156 ff.

[5] Stuart Kaufman, Reinventing the Sacred (New York, Basic Books, 2008).

[6] Kagan, Jerome, “Interview with Jerome Kagan,” by C. Hall, Psychology Today, July1982, 55-6.

[7] Robert Kane, Through the Moral Maze: Searching for Absolute Values in a Pluralistic World (New York, Paragon House, 1994), 74-5.

[8] Compare to Kant: “Act in such a way that you always treat humanity, whether in your own person or in the person of any other, never simply as a means, but always at the same time as an end.” (Foundations of the Metaphysics of Morals, 1785)

[9] Critique of Practical Reason (1788).

[10] Swimme Canticle of the Cosmos and other works, published in a variety of media.

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Why is it needed ?

As outlined in the sections on support to the culture sector and cultural and creative industries, despite the potential of the culture sector, it remains poorly exploited and at risk, both from an environmental and human perspective.

Culture subprogramme Opportunities


Your search for "machine learning" returned 437 results.

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Making improvements to user experience with ML

How machine learning is changing the travel industry

Machine learning’s growth continues as it permeates into unrelated industries. Travel booking might not seem like a good fit at first, but Wilco van Duinkerken of trivago explains how ML is innovating the way you find and book your next holiday.

Interview with Vish Abrams, Architect, Cloud Development at Oracle

GraphPipe makes deploying a machine learning model easy and comfortable

Oracle has just released a new open source tool: GraphPipe is designed to simplify and standardize the deployment of machine learning models. We talked to Vish Abrams, Architect, Cloud Development at Oracle about the new tool, its benefits, challenges and more.

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Does your company have a machine learning strategy?

Are you ready for machine learning? Do you have a plan? In this article, Atakan Cetinsoy from BigML goes over six things that every organization needs to be aware of when they’re devising their own machine learning strategy.

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Applying machine learning to DevOps

How can developers learn to utilize machine learning in their DevOps practice? In this article, Prasanthi Korada goes over some basic approaches that can help developers apply cutting edge tech like machine learning to their everyday work.

Watch Sumanas Sarma and Rob Hinds' JAX London 2017 session

Agile machine learning: From theory to production

With artificial intelligence and machine learning becoming increasingly relevant for modern enterprises, many companies might be feeling the pressure to invest in an AI strategy, before fully understanding what they are aiming to achieve. In this session, Sumanas Sarma and Rob Hinds explain how you can go from theory to production in adopting machine learning solutions.

Minimizing machine learning risks

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Machine learning inevitably adds black boxes to automated systems and there is clearly an ethical debate about the acceptability of appropriating ML for a number of uses. The risks can be mitigated with five straightforward principles.

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The state of machine learning in 2018

The future of digital technology is here. 2017 saw incredible progression for things like data science, artificial intelligence, and machine learning. Where will they go in 2018? In this article, Maria Thomas explores the future of data science and how well it can be combined with predictive analysis.

Open source makes everything better

Why are so many machine learning tools open source?


The book is now available! 97313179
(another Prime Pages' Curiosity)
Prime Curios!
Curios: Curios Search:

+ 97:31:31:79 is the longest emirp duration that along with its reversal (97:13:13:79) can both be timed on a seven-segment digital chronometer stopwatch simultaneously in emirp hours, emirp minutes, emirp seconds, and emirp hundredths of a second. [Beedassy]


Q. 459 The Unbridgeable Gap

(Question answered by Martin, Ramesam, Charles and Dennis)

Q. 429 Discussion on ‘I am That’

Q: I have a couple of questions about ‘I Am That’.

As I understand it, this essentially says: Atman = brahman. So the ‘I’ is not the ahaMkAra ‘I’, rather the Atman ‘I’.

1. Did I get that right?

2. When one begins to reflect upon ‘I Am That’, is one expected to feel the I as the ahaMkAra I? And then move, gradually, towards realizing the I is in fact Atman?

3. The reason I ask (2) is because I have a great deal of difficulty ‘feeling’ my ahaMkAra I. It just doesn’t ‘compute’ with me. Does this brain/body sense things, have feelings, emotions, thoughts; am I aware of external and internal things? Yes! All the time. But are these sensations, feelings, thoughts, etc. = ahaMkAra ‘I-me’? No. They’re just… stuff that happens, electrochemical dances in a brain in a skull in a body that is identified as ‘Jack’ Is this a problem – that I can’t consciously/directly feel my ahaMkAra I? That when I look for it, I see mithyA, nothing of essential substance? Could my not being able to directly experience my ahaMkAra I be a stumbling block? Continue reading

Q.401 – Who is the doer/enjoyer?

Q: Who is the doer and enjoyer of action if not brahman and ego?

A (Dennis): In reality (pAramArthika viewpoint), there is no doer, enjoyer, ego or action. From the point of view of the person in the world (vyAvahArika viewpoint), you can use whatever ‘explanation’ you feel happy with! The usually accepted way of explaining it is that brahman enables the action to take place through the jIva (Consciousness is ‘reflected’ in the mind).

Q.395 – Person vs Consciousness

Just to keep alive the thoughts on eka Jiva vAda…

Q: If we are just a ‘Stream of Consciousness’, how is it possible to introspect and know Reality? It is akin to the dreamer knowing that he is dreaming while still being in the dream. Also, the SOC’s suffering is really Brahman’s sufferring as Brahman alone exists. So is the SOC doing Brahman a favour by realizing the “Reality”? That doesn’t sound right!

A (Dennis): What do you (think you) mean when you say ‘I am a Stream of Consciousness’? In reality, there is only brahman (or Consciousness if you prefer). So it is correct to say ‘who-I-really-am is Consciousness’. But, if you are saying such things as ‘I know’, ‘I introspect’, ‘I dream’ etc, then you are speaking of the person. This is the level of the seeming world – vyavahAra. In reality (paramArtha), there is no world, no persons. I, the person, may suffer but  brahman does not suffer.

Q: My terminology is wrong but I meant ‘the thread of consciousness within Brahman’ which seems to be creating this impression of a ‘Creation’. This thread is running within Brahman and there are feelings of suffering. Since nothing exists but Brahman, Brahman is the sufferer through this thread. Suffering need not be physical it could be just psychological or some other means of pain.

A: There is no separate thing inside or outside of brahman; there is only brahman. The concepts that you are using are only of value to the extent that they help you to realize that truth. If they are not helping, discard them!

Overview of Western Philosophy – Part 10

(Read Part 9 of the series.)

Rousseau and Kant

Continuing Reflections (on reflections)

Back in April I wrote an article which looked into the concept of chidAbhAsahttps://www.advaita-vision.org/chidabhasa/. This is the idea that the ‘notion of I’ is a reflection, in the mind, of the non-dual consciousness. The theory is called pratibimba vAda in advaita. It says that there is only one ‘real’, pAramArthika or witnessing Consciousness, although there are many jIva-s; one ‘original’ (bimba) and many ‘reflections’ (pratibimba-s).

But of course, reality is non-dual, so it makes no sense to talk of a ‘Consciousness’ and a ‘reflected Consciousness’! So how do we explain this? In order for there to be a reflection, there have to be two things: an original thing, and some medium in which a reflection can take place. This is obvious in the case of the mirror. We cannot see our face in order to be able to shave or apply make up by looking into empty space. We cannot even do it by looking at a blank wall. There has to be a mirror or some reflecting medium which can serve as a mirror. Here, we seem to be saying that there is Consciousness and a reflecting medium – the mind. But of course if we have these two things, then we’re talking about dvaita not advaita.

Shankara’s Advaita introduces the concept of mAyA to provide a sort-of explanation for the world-appearance but the dvaitin may argue that, pedantically, brahman and mAyA are still two things. Only if we can explain everything in terms of paramArtha alone, he might say, can we establish non-duality. Of course, we can be pedantic too – you cannot explain anything in paramArtha, only in vyavahAra! But we acknowledge that mAyA is mithyA. In reality, there are no jIva-s, no world, no reflections. So, the bottom line is that reality is non-dual, so that we do not really have to justify the theory at all! Continue reading

Q. 393 – Idealism or Realism?

Q. 390 – karma and judgement

Q: On the subject of karma please could you explain who or what decides on the destination of the “stamp/soul/” to a higher or lower life form. It would seem to be a judgmental decision based on our behaviour so presumably cannot be “Self” which is unaffected and affects nothing?

A (Dennis): You have to distinguish between paramArtha and vyavahAra. The absolute reality is that there is only brahman – non-dual Consciousness. There is no world separate from Consciousness, no people separate from Consciousness. The world and people are mithyA. So, in reality karma has to be mithyA also; there is no birth, no death, no reincarnation, no one who acts and no one to be reborn as a cockroach.

Explanations at the level of vyavahAra are interim explanations for the benefit of someone who does not yet appreciate the above. At this level, there seems to be cause and effect and all the apparent scientific laws that operate in the world. Ishvara is the name given to the ‘entity’ of ‘brahman + mAyA’ who lays down these laws. But the laws are not operated by Him on an individual basis; they are simply the ‘rules’ that are necessarily followed by everything in creation (such as gravity, Newton’s Laws etc). There is no ‘judgement’ involved at all.

Wave and Ocean


If traditional art isn't quite to your tastes, you might want to consider the relaunched Emporium 53 - a collection of the most unique and talented artists.

Everything from exotic handmade chocolates to skateboards made out of reclaimed wood is available from 22 different local artists.

"We've made it as quirky and outrageous as we possibly can," the owner John Clay said.

"It's a celebration of local talent - we think it's important to support the obvious talent we have in this area."

Customers can follow a yellow brick road through the amazing wares in the shop's four rooms.

John's partner Trace, an artist who creates handmade chocolates in unusual flavours and colours, was looking for a place to display her work. John got the idea to buy the Emporium, which opened last September.

The shop in Cambridge Street, Cleethorpes is now open under the new management, and is still looking for artists to join its ranks.

"We put out a call for local artists to join us, and the response has been amazing. We could probably fill another shop and we're already in touch with exciting artists to show in the future."

Owners Trace Clay and John Clay (left) celebrate with artists outside their new business Emporium53 in Cambridge Street, Cleethorpes

So, who will you find there?

Reclaimed craftsman

Damian George has been skateboarding nearly 20 years, since he was 13, so perhaps it was inevitable he would get interested in making them.

What's less likely is his choice of material - reclaimed or repurposed pieces of wood that were going to be thrown out.

Owner Trace Clay and John Clay (left) look on as 'pirate' Damien George cuts the ribbon

Damian - who attended the opening as pirate Captain Jack Sparrow to continue the salvage theme - has his own woodworking business.

He gets most of his materials from a wood yard in Lincoln, and spends half a day fashioning each one into a working skateboard, or sometimes a coffee table or a mirror.

"I use my imagination and try and see what abandoned materials could be reused for. I also incorporate wheels from agricultural vehicles into my work."

Most people enjoy chocolate, but not everyone considers it an artform. Trace Clay has always been fascinated with the possibilities of it though.

"Chocolate was one type of art I hadn't worked with before, so I decided to give it a go," she said.

Trace Clay of the Chocolat Story at Emporium 53's relaunch

"I have 25 different flavours people probably won't have tried before, like passion fruit and grated coconut or milk chocolate creme infused with spices.

"I use cocoa paint on the moulds to create the colours and patterns on the chocolates."

Her chocolates are also interwoven with fairytales and classic children's stories, so if you've ever wanted to know what chocolate inspired by the Cheshire Cat or Captain Hook tastes like, Trace has your answer.

Lasting memories

Pam first learnt the skills of casting working with children at St Andrew's Hospice, however she's developed it into a business which captures memories of all stages of life.

Casting Memories takes imprints of hands, feet, pregnancy bumps and even pets to help people remember loved ones, whether they're still around or not.

Pam French of Casting Memories with a touching memento she's created

"People want something to physically hold onto after a death, especially if it's sudden or tragic. I often work with funeral parlours to give family something to remember them by, whether it's a hand to hold or a face to touch.

"Lately, we've found symbolic babies are very popular for people who've had a miscarriage. It gives them something to touch, even though they've never got to hold their baby."

She also helps to immortalise happy moments, such as newborn babies' hands or an expectant mum's bump.

It takes just 20 minutes for Pam to create an impression, which are often decorated in a style that represents the person.

Urban artist

Lynsey Powles has always enjoyed spray paint - but don't call her a grafitti artist.

"We prefer aerosol artist or urban artist so people don't get the wrong idea," she explained.

"It takes a lot of dedication to get good at it - I've been doing it for 14 years."

You have probably seen some of Lynsey's art around Cleethorpes, as the council often enlists her to brighten up walls and car parks with her colourful work.

The weird and wonderful artwork on display

She also decorates Damien's skateboards, and will soon be giving Emporium 53's shutters a new lick of paint.

"A college student won a competition to pick the design for them, so I'll be helping her to put it on and teach her the basics of aerosol art," she said.


February 9th, 2013

Gove’s plans to scrap certain GCSEs in return for the English Baccalaureate were apparently lacking in quality this week as he announced his failure in the House of Commons.

Calling them a “bridge too far”, we saw another U-turn in Government policy and a fortunate concession to Labour and teaching Unions who rightfully expressed concerns and fear at the proposals. Unfortunately, however, this is just one change of many that was being pushed through the Houses of Parliament. Alongside this, there are plans to make GCSEs and A-Levels much more rigorous and demanding whilst changing the curriculum dramatically. Schools are being told that the current system for exams are too easy and that students need to be pushed harder and harder; the stress is on the outcomes of exams.

At a recent lecture at the University of Birmingham, Anthony Seldon, author of famous biographies of Blair, argued that the Government (and schools) focus far too much on the measurable factor of qualifications gained rather than the personal development of the individual who spends up to seven years in their institution. Tested solely on their ability to soak up knowledge and regurgitate it on a piece of paper (perhaps in a certain style), schools seem lacking in building up confidence skills, creativity and that flair of determination that you would hope to see in every student as a result. Instead, like battery hens, students are pushed through a system of education where their sole purpose is to gain good grades so their school can demonstrate their “excellence” whilst the student is then pushed along on the factory line for the next institution.

Ironically, it would seem, this kind of approach to pushing children through education is one that causes demotivation, dissatisfaction and, in some cases, anti-establishmentarianism. Simply being pushed by their “superiors” to achieve A-grades in the core subjects, it is often heard that a lack of A-grades simply translates to a lack of success. Hence, if you don’t achieve A-grades, you are a failure and you will get nowhere in your life. Yet, this could just end up as a self-fulfilling prophecy; being told you will achieve nothing means you will achieve nothing. You might be putting your all into it, but being told that there’s no point because you’ll get nowhere – why not just give up?

Meanwhile, the different learning styles of individuals are overlooked; alternative qualifications such as BTECs and apprenticeships are deemed inferior, “for stupid people”. Apprenticeships are not accepted on UCAS, and many universities and employers overlook or do not display the criteria in any other form than A-Levels. Despite being more specialised in their area, those with BTEC or similar qualifications are told their qualifications are not of equal worth to A-Levels. This is quite simply outrageous.

Of course, this article is not true of every educational institution. There are many across the country that do realise the full potential of individuals and do accept the qualifications that others are too elitist to do so; those whom do give people a chance without judgement. These are the places we should be drawing inspiration for. It is argued that those who are given a chance to strive for something and work at their rate learn better and faster than those are forced into a strict schedule and discipline. Surely, these children would become passionate about a certain field, develop for that field and become better workers.

In the current British system of education, there are many flaws that do need fixing. You can argue that exams may be too easy and that different exam boards are competing for schools by offering lower boundaries for grades, but the truth is that full potential can be realised through the self-development of individuals. Rather than focusing on exam grades, focus on their passions, their skills and their needs.

Additionally published by Backbench.


My sculptures have a ranging degree of physical accuracy that allows a viewer to discover a subjective meaning between figure and expression. The figure and anatomical exactness have always been a powerful focus in traditional sculpture. We naturally look for ourselves in a work of art and create a story as soon as we find forms that relate. In contrast, as we sacrifice a sense of accuracy for a form of expression, the work demands a subjective relationship with the viewer. When rational and seemingly irrational decisions are placed together, an individual wants to discover a meaning for why they relate. This expressiveness can be the medium’s physical limitation, a contrasting sensation of color, or a conceptual connection between symbols. I do not worry about creating a likeness in a sculpture. Instead, I focus on what makes a medium unique and how a believable figure can emerge. Whether it is wood, clay, resin, or found object, the most important aspect of my work is the interaction with a medium. That said, I passionately learn from tradition, historical reference, and natural sciences to see beauty from different perspectives. This acceptance of physical inaccuracy and curiosity of meaning becomes an intimate reflection of a viewer’s experiences.

To get into contact with me please fill in the form below.

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Reinvent Your Space

  De-cluttering and Organization

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After nearly 30 years at the same address, we unexpectedly sold our home and had to downsize quickly to move to a smaller home. I was completely overwhelmed since every closet, cabinet and garage storage space was full of "stuff." Alice helped me keep my sanity while we decided on what to keep, what to donate, and what to sell. She also helped me prepare for a huge garage sale. She has a very calm and cool demeanor, which was so helpful during that stressful time. Alice takes the initiative to research what items may be worth so that the client can make a decision on what to do. She even knew where to recycle things that I would have put in the trash! Since the move, Alice has continued to help me by posting and selling items on eBay and relieving me of that chore. Thanks, Alice, for all your help!

- HL, Santa Ana, CA


Eric Jones MD came up with an idea in "Hamlet and Oedipus".

Furthermore, there is also a relationship between Oedipus’ armed entrance into the bedroom in which Jocasta hanged herself, and Hamlet’s confrontation of Gertrude in her bedroom....

Hamlet Compare and contrast Oedipus and Hamlet

What is the difference between Oedipus the King and Hamlet

Comparison Of Oedipus The King vs. Hamlet vs. …

This is also a principal theme of classical mythology, and to fully understand Hamlet as a tragic hero, a comprehension of the mythological references at the beginning of the play must be foremost in the reader's mind....

In both the common tragedies, “Oedipus Rex” and “Hamlet”, both main characters are generally good.

It can also be argued that Hamlet suffers from an Oedipus complex; ..

Theory #4: Hamlet suffers from an Oedipus Complex

Lawrence Danson in the essay “Tragic Alphabet” discusses the hesitation in action by the hero; this is related to his hesitation in speech: To speak or act in a world where all speech and action are equivocal seeming is, for Hamlet, both perilous and demeaning, a kind of whoring.

Finally Teiresias gives in,says Oedipus is the killer, and adds that he is "living in shamewith his closest relative."Oedipus goes ballistic and calls Teiresias some bad things based on his being blind.

Sophocles’ Oedipus the King and Shakespeare’s Hamlet

reality issue and especially about the character of Polonius, see by Ian Johnston; search for "Appearance and Reality.")

Hamlet acts harshly towards Rosencrantz and Guildenstern but (1) they were commoners who didn't really count in Hamlet's world and (2) even if they were imprisoned for a time in England, it is possible that if they were not killed they would somehow get word to the King about what Hamlet had done.

Free hamlet as a tragic hero Essays and Papers - …

Others apply the Oedipal analysis in a different way and suggest that Hamlet can't kill Claudius while his mother is alive because Claudius has stepped into the role of the father in Hamlet's Oedipal fantasy.

Free Oedipus the King Fate Essays and Papers - …

The "Hamlet" directed by Kenneth Brannagh (1996), while excellent and encompassing the full text of the play, is less accessible to children than the Zeffirelli/Gibson version.

Oedipus and Hamlet essay topics, buy custom Oedipus …

8. Some commentators argue that the force of Hamlet's hatred of Claudius stemmed not from the fact that Claudius killed Hamlet's father but because Claudius has acted out Hamlet's own long-repressed Oedipal fantasy, i.e., to eliminate the father and marry the mother.