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Accurate identification of intermediate risk (Gleason 3 + 4 = 7) prostate cancer patients with low risk of disease progression is an unmet challenge in treatment decision making. Here we describe a gene signature that could guide clinicians in the selection of patients with intermediate stage clinically localized prostate cancer for active surveillance. We examined six major drivers of aggressive disease – PTEN, MYC, RB1, TP53, AURKA, AR – by immunohistochemistry in a focused (N = 69) cohort predominantly consisting of intermediate risk prostate cancer. Fuzzy clustering and unsupervised hierarchical clustering were utilized to determine the correlation of gene expression and methylation values with immunohistochemical expression. From the immunohistochemistry observation, we found that intermediate risk prostate cancer cases could be classified as ‘complex’ (differential expression of more than one driver) or ‘simple’ (differential expression of only one). Focussing on the ‘simple’ cases, expression and methylation profiling generated signatures which correlated tightly only with differential PTEN expression and not with any of the other drivers assessed by immunohistochemistry. From this, we derived a geneset of 35 genes linked to high PTEN expression. Subsequently we determined its prognostic significance in intermediate‐risk cases extracted from three publicly available clinical datasets (Total N = 215). Hence, this study shows that, by using immunohistochemistry as an upfront stratifier of intermediate risk prostate cancers, it is possible to identify through differential gene expression profiling a geneset with prognostic power across multiple cohorts. This strategy has not been used previously and the signature has the potential to impact on treatment decisions in patients for whom decision making is currently empirical at best.

Background: Malnutrition leads to poor cognitive performance and physical growth in children and is a major component of school health services. Imbalanced nutrition in adolescence can put them at high risk of chronic diseases particularly if combined with adverse lifestyle. Aims & Objectives: This study was designed to assess and compare the nutritional status of government and private school children of Muzaffarnagar city. Material and Methods: School based, comparative Cross-sectional study. One private and one government school was selected using unistage stratified random sampling. A total of 1960 (980 each from private school and government school) school children of class 6-12 were studied for socio-epidemiological details, dietary habits, and physical activity. Information on education status, occupation, monthly income of their parents was also collected. Required anthropometric measurements were taken. Results: Of 980 children from private school, 90 (9.18%) were underweight,138 (14.08%) were overweight, and 137 (13.97%) were obese. Majority of children from government school were underweight 215 (21.94%) except for 24 (2.45%) overweight children. Conclusion: This study shows the dual nature of nutritional problem, under-nutrition among the lower socioeconomic class of govt. school at one side and worrisome epidemic of obesity among the affluent of private school

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.

On the basis of first-principles density functional theory calculations, we propose a new molecular photoswitch which exploits a photochemical [1,3]-silyl(germyl) shift leading from a silane to a silene (a Si=C double bonded compound). The silanes investigated herein act as the OFF state, with tetrahedral saturated silicon atoms disrupting the conjugation through the molecules. The silenes, on the other hand, have conjugated paths spanning over the complete molecules and thus act as the ON state. We calculate ON/OFF conductance ratios in the range of 10-50 at a voltage of +1 V. In the low bias regime, the ON/OFF ratio increases to a range of 200-1150. The reverse reaction could be triggered thermally or photolytically, with the silene being slightly higher in relative energy than the silane. The calculated activation barriers for the thermal back-rearrangement of the migrating group can be tuned and are in the range 108-171 kJ/mol for the switches examined herein. The first-principles calculations together with a simple one-level model show that the high ON/OFF ratio in the molecule assembled in a solid state device is due to changes in the energy position of the frontier molecular orbitals compared to the Fermi energy of the electrodes, in combination with an increased effective coupling between the molecule and the electrodes for the ON state.