Vowel recognition using Kohonen\u27s self-organizing feature maps

An important organizing principle observed in the sensory pathways in the brain is the orderly placement of neurons. Although the neurons are structurally identical, the specialized role played by each unit is determined by its internal parameters that are made to change during early learning processes. In the human auditory system, the nerve cells and fibres are arranged in a manner that would elicit maximum response from the neurons when they are activated. Although most of this organization is genetically determined, some of the high level organization is created due to algorithms that promote self-organization. Kohonen\u27s self-organizing feature map is a neural net model that produces feature maps similar to the ones produced in the brain. These maps are capable of describing topological relationships of input signals using a one or two dimensional representation. This technique uses unlabeled data and requires no training as in supervised learning algorithms. It is hence immensely useful in speech and vision applications. This neutral net has been implemented for the recognition of vowels in the American English language. The net has been trained and tested with vowel data. The formation of internal clusters or categories has been observed and closely reflects the tonotopic relationships between the vowels. An analysis of the results has been carried out and the performance has been compared to other classification techniques. A graphical user interface has also been developed using Xview to help visualize the formation of the maps during the training and testing processes

Cancer is a Preventable Disease that Requires Major Lifestyle Changes

This year, more than 1 million Americans and more than 10 million people worldwide are expected to be diagnosed with cancer, a disease commonly believed to be preventable. Only 5–10% of all cancer cases can be attributed to genetic defects, whereas the remaining 90–95% have their roots in the environment and lifestyle. The lifestyle factors include cigarette smoking, diet (fried foods, red meat), alcohol, sun exposure, environmental pollutants, infections, stress, obesity, and physical inactivity. The evidence indicates that of all cancer-related deaths, almost 25–30% are due to tobacco, as many as 30–35% are linked to diet, about 15–20% are due to infections, and the remaining percentage are due to other factors like radiation, stress, physical activity, environmental pollutants etc. Therefore, cancer prevention requires smoking cessation, increased ingestion of fruits and vegetables, moderate use of alcohol, caloric restriction, exercise, avoidance of direct exposure to sunlight, minimal meat consumption, use of whole grains, use of vaccinations, and regular check-ups. In this review, we present evidence that inflammation is the link between the agents/factors that cause cancer and the agents that prevent it. In addition, we provide evidence that cancer is a preventable disease that requires major lifestyle changes

SAMHD1 promotes DNA end resection to facilitate DNA repair by homologous recombination

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV- 1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

INNODIA Master Protocol for the evaluation of investigational medicinal products in children, adolescents and adults with newly diagnosed type 1 diabetes

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers

Young v adult cirrhotics: a prospective, comparative analysis of the clinical profile, natural course and survival.

In order to assess the frequency and profile of cirrhosis in the young, 169 consecutive patients with cirrhosis were studied. Sixty three (37%) patients of less than or equal to 35 years age were defined as young and the remaining 106 (63%) patients (greater than 35 years) as adult cirrhotics. Men predominated significantly (p less than 0.01) in the young cirrhotic group. The aetiology, the frequency of positive hepatitis B markers and initial clinical presentation were similar in the two groups. During the follow up period (30.6 +/- 29.7 months for the young and 25.8 +/- 21.7 months for the adult group), except for abdominal distension and pedal oedema which occurred significantly more often in the adult compared with the young cirrhotics, no difference was noted in the two groups. Twenty seven (39.7%) deaths (40% as a result of hepatic failure and 52% due to variceal bleeding) occurred in the young and 47 (44.3%) deaths (63.8% because of hepatic failure and 26% because of variceal bleeding) occurred in the adult cirrhotics during the follow up (difference NS). The five year survival (61.9% v 55.7%) and the probability of survival within the same Child's grade of liver disease were comparable. In both the groups, however, the probability of survival was significantly higher in Child's A compared with Child's B and C and in Child's B compared with Child's C grade of liver disease. Survival was not influenced by sex of the patient and aetiology of cirrhosis. Results of this prospective study indicate that cirrhosis is not uncommon in young adults. The aetiology, clinical presentation, natural history of the disease and the survival rates in young cirrhotics do not differ significantly from adult cirrhotics

Structure-Activity Relationship and Mode of Action of a Frog Secreted Antibacterial Peptide B1CTcu5 Using Synthetically and Modularly Modified or Deleted (SMMD) Peptides.

All life forms are equipped with rapidly acting, evolutionally conserved components of an innate immune defense system that consists of a group of unique and diverse molecules known as host defense peptides (HDPs). A Systematic and Modular Modification and Deletion (SMMD) approach was followed to analyse the structural requirement of B1CTcu5, a brevinin antibacterial peptide amide identified from the skin secretion of frog Clinotarsus curtipes, India, to show antibacterial activity and to explore the active core region. Seventeen SMMD-B1CTcu5 analogs were designed and synthesised by C and N-terminal amino acid substitution or deletion. Enhancement in cationicity by N-terminal Lys/Arg substitution or hydrophobicity by Trp substitution produced no drastic change in bactericidal nature against selected bacterial strains except S. aureus. But the sequential removal of N-terminal amino acids had a negative effect on bactericidal potency. Analog B1CTcu5-LIAG obtained by the removal of four N-terminal amino acids displayed bactericidal effect comparable to, or in excess of, the parent peptide with reduced hemolytic character. Its higher activity was well correlated with the improved inner membrane permeabilisation capacity. This region may act as the active core of B1CTcu5. Presence of C-terminal disulphide bond was not a necessary condition to display antibacterial activity but helped to promote hemolytic nature. Removal of the C-terminal rana box region drastically reduced antibacterial and hemolytic activity of the peptide, showing that this region is important for membrane targeting. The bactericidal potency of the D-peptide (DB1CTcu5) helped to rule out the stereospecific interaction with the bacterial membrane. Our data suggests that both the C and N-terminal regions are necessary for bactericidal activity, even though the active core region is located near the N-terminal of B1CTcu5. A judicious modification at the N-terminal region may produce a short SMMD analog with enhanced bactericidal activity and low toxicity against eukaryotic cells

Effect of peptides against biofilm formation by <i>S</i>. <i>aureus</i> strains.

<p>Biofilm formed by <i>S</i>. <i>aureus</i> at 12 h were treated with 100μg/ml of peptides for 12 h and the biofilm formation was determined by measuring the absorbance at 570 nm.</p

Primary sequences of SMMD B1CTcu5 analogs.

<p>Primary sequences of SMMD B1CTcu5 analogs.</p

Cytotoxicity in human cells.

<p>The values represent averages ± s.d from three separated experiments.</p><p>Cytotoxicity in human cells.</p