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Abstract The colubrid snakes of the genera Gongylosoma Fitzinger, 1843 and Liopeltis Fitzinger, 1843 are distributed across south and southeast Asia with five and eight nominate species, respectively. Despite their wide distribution, members of these genera are among some of the least-known colubrids. The two genera were considered synonymous in the past only to be separated later, and are defined on rather nebulose characters with a lack of support from molecular data. To test the monophyly of the two genera, we generated molecular data for the type species of Gongylosoma and species representing the two genera, including samples of Liopeltis rappii (Günther, 1860) from the western Himalayas. Results recovered paraphyly of Liopeltis, especially with regard to the genus Gongylosoma. Morphological data supports recognizing the western and eastern populations of L. rappii as two distinct species. The findings from our integrative taxonomic approach advocate establishing a new genus to embody Liopeltis rappii and a new allied species from the central and western Himalayas. A rediagnosis and revised classification of the genera Gongylosoma and Liopeltis is presented. The results further hint at cryptic diversity across members of the two genera, warranting scrutiny of the most widespread members of the group.

Abstract Oncogene-induced replication stress is a crucial driver of genomic instability and one of the key events contributing to the onset and evolution of cancer. Despite its critical role in cancer, the mechanisms that generate oncogene-induced replication stress remain not fully understood. Here, we report that an oncogenic c-Myc-dependent increase in cohesins on DNA contributes to the induction of replication stress. Accumulation of cohesins on chromatin is not sufficient to cause replication stress, but also requires cohesins to accumulate at specific sites in a CTCF-dependent manner. We propose that the increased accumulation of cohesins at CTCF site interferes with the progression of replication forks, contributing to oncogene-induced replication stress. This is different from, and independent of, previously suggested mechanisms of oncogene-induced replication stress. This, together with the reported protective role of cohesins in preventing replication stress-induced DNA damage, supports a double-edge involvement of cohesins in causing and tolerating oncogene-induced replication stress.

Objective To evaluate co-prescribing of sedatives hypnotics and opioids.Design Retrospective study evaluating the association of patient characteristics and comorbidities with coprescribing.Setting and participants Using the national Merative MarketScan Database between 2005 and 2018, we identified patients who received an incident sedative prescription with or without subsequent, incident opioid prescriptions within a year of the sedative prescription in the USA.Outcome measures Coprescription of sedative-hypnotics and opioids.Results A total of 2 632 622 patients (mean (SD) age, 43.2 (12.34) years; 1 297 356 (62.5%) female) received incident prescriptions for sedatives over the course of the study period. The largest proportion of sedative prescribing included benzodiazepines (71.1%); however, z-drugs (19.9%) and barbiturates (9%) were also common. About 557 845 (21.2%) patients with incident sedatives also received incident opioid prescriptions. About 59.2% of these coprescribed patients received opioids coprescription on the same day. Multivariate logistic regression findings showed that individuals with a comorbidity index score of 1, 2 or ≥3 (aOR 1.19 (95% CI 1.17 to 1.21), 1.17 (95% C 1.14 to 1.19) and 1.25 (95% C 1.2 to 1.31)) and substance use disorder (1.21 (95% C 1.19 to 1.23)) were more likely to be coprescribed opioids and sedatives. The likelihood of receiving both opioid and sedative prescriptions was lower for female patients (aOR 0.93; 95% CI 0.92 to 0.94), and those receiving a barbiturate (aOR 0.3; 95% CI 0.29 to 0.31) or z-drugs (aOR 0.67; 95% CI 0.66 to 0.68) prescriptions at the index date.Conclusions Coprescription of sedatives with opioids was associated with the presence of comorbidities and substance use disorder, gender and types of sedatives prescribed at the index date. Additionally, more than half of the coprescribing occurred on the same day which warrants further evaluation of current prescribing and dispensing best practice guidelines.

The natricine snake genus Smithophis Giri, Gower, Das, Lalremsanga, Lalronunga, Captain, and Deepak, 2019, is represented by four species, three of which are distributed in northeast India and Bangladesh, and a single species in Yunnan and Myanmar. In the past, S. bicolor (Blyth, 1855) was said to be widespread across northeast India and Myanmar; however, recent studies have shown it to be a species complex. Here, we describe a new species of the complex from the Indian state of Mizoram that resembles S. bicolor. The new species differs in bearing a patterned dorsum, a darker venter, and moderately keeled sacral scales. Re-examination of types of S. arunachalensis Das, Deepak, Captain, Wade, and Gower, 2020, shows the presence of strongly keeled sacral keels in males, which is an important diagnostic character. A revised key to members of the genus is presented with notes on S. arunachalensis.

Hebius beddomei (Günther, 1864) is an endemic natricine colubrid snake species from the biodiverse Western Ghats, India. A recent molecular phylogeny provided evidence for the paraphyly of the genus Hebius, with Hebius beddomei recovered as sister to a clade containing Fowlea and Atretium. Freshly collected specimens and existing museum material allowed us to elucidate the generic status of the species and identify two distinct populations, one of which is described as a new species. A new genus, Sahyadriophis gen. nov., is proposed to accommodate Sahyadriophis beddomei gen. et. comb. nov., and Sahyadriophis uttaraghati gen. et. sp. nov. is described as a new species from the northern part of the range. The discovery of a new Oligocene divergent lineage, Sahyadriophis gen. nov., highlights the role of the Western Ghats as a source of relic lineages.

The pit viper snake genus Trimeresurus Lacépède, 1804 sensu lato, is a diverse group of nocturnal serpents comprising over 61 species. The genus is morphologically heterogeneous and has been divided into several subgenera. We present an updated phylogeny of Asian pitvipers and propose a revised classification. Additionally, we revise the taxonomy of T. popeiorum Smith, 1937 and propose taxonomic changes with support from molecular and morphological data. We restrict T. popeiorum sensu stricto to northeastern India, Bangladesh, southern China, and northern Myanmar; populations beyond these areas require further assessment. We also synonymize T. yingjiangensis Chen et al., 2019 with T. popeiorum based on overlapping morphological characters, molecular data, and distribution. The findings shed new light on the taxonomy of T. popeiorum, warranting the need for assessing the population of T. popeiorum from southeast Asia.

Chromatin remodelers direct the cohesin loader to nucleosome depleted regions where cohesin accesses chromosomes. Muñoz et al. now show that the cohesin loader in turn is a biochemical activator of a chromatin remodeler, helping to clear nucleosomes

N6-methyladenosine (m6A), the most abundant mRNA modification, is deposited in mammals/insects/plants by m6A methyltransferase complexes (MTC) comprising a catalytic subunit and at least five additional proteins. The yeast MTC is critical for meiosis and was known to comprise three proteins, of which two were conserved. We uncover three novel MTC components (Kar4/Ygl036w-Vir1/Dyn2). All MTC subunits, except for Dyn2, are essential for m6A deposition and have corresponding mammalian MTC orthologues. Unlike the mammalian bipartite MTC, the yeast MTC is unipartite, yet multifunctional. The mRNA interacting module, comprising Ime4, Mum2, Vir1, and Kar4, exerts the MTC’s m6A-independent function, while Slz1 enables the MTC catalytic function in m6A deposition. Both functions are critical for meiotic progression. Kar4 also has a mechanistically separate role from the MTC during mating. The yeast MTC constituents play distinguishable m6A-dependent, MTC-dependent, and MTC-independent functions, highlighting their complexity and paving the path towards dissecting multi-layered MTC functions in mammals.

A new species of bent-toed geckos of the genus Cyrtodactylus is described from western Arunachal Pradesh. The new species is a member of the Indo-Burma clade and is embedded within the “peguensis” group, a relationship deduced contingent on a partial fragment of mitochondrial NADH subunit 2 gene. Cyrtodactylus kamengensis sp. nov. is morphologically similar to C. himalayicus from which it differs in bearing a distinct ventrolateral fold and 6–8 basal lamellae on digit IV of pes. Genetically, the new species is sister to the Indian lineage of the “peguensis” group containing C. bhupathyi and C. gubernatoris. The Indian lineage of the “peguensis” group diverged from its Burmese relatives during the mid-Oligocene likely followed by the beginning of the Himalayan uplift, highlighting the role of the Himalayas in the diversification of biota.

Introduction: Blood pressure transient spikes have been considered to be noise and only a hindrance to a proper assessment of typical blood pressure, which is defined as the actual underlying average blood pressure over a long period of time. The current study aimed to see if the highest Self measured Systolic blood Pressure could be utilized to forecast the occurrence of Target organ damage and evaluate the independent association between the maximum Self measured Systolic blood Pressure and Target organ damage in individuals with untreated hyper-tension. Method: We evaluated the urine albumin/creatinine ratio (UACR) and carotid intima-media thickness (IMT) us-ing ultrasonography in 462 hypertensive individuals who had never taken treatment for their hypertension. Resi-dential blood pressure was recorded. Result: The maximal Self measured Systolic blood Pressure had considerably higher association coefficients with left ventricular mass index (LVMI) and carotid intima-media thickness than the mean Self measured Systolic blood Pressure. Irrespective of the mean Self measured Blood pressure level, multivariate regression studies showed that the maximal Self measured Systolic blood Pressure was independently related with left ventricular mass index and carotid intima-media thickness. Conclusion: Transiently high blood pressure measurements recorded at Self measured shouldn't be dismissed as noise but rather taken seriously as significant warning signs of hypertensive Target organ damage in the heart and arteries.

Fibroblast growth factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress, FGF signalling must decline. Why these signalling dynamics are required has not been determined. Here, we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly increases chromatin accessibility at neural genes in mouse embryos, and, using ATAC-seq in human embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs genome-wide across neural genes. Importantly, ERK1/2 inhibition induces precocious neural gene transcription, and this involves dissociation of the polycomb repressive complex from key gene loci. This takes place independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. Transient ERK1/2 inhibition is sufficient for the dissociation of the repressive complex, and this is not reversed on resumption of ERK1/2 signalling. Moreover, genomic footprinting of sites identified by ATAC-seq together with ChIP-seq for polycomb protein Ring1B revealed that ERK1/2 inhibition promotes the occupancy of neural transcription factors (TFs) at non-polycomb as well as polycomb associated sites. Together, these findings indicate that ERK1/2 signalling decline promotes global changes in chromatin accessibility and TF binding at neural genes by directing polycomb and other regulators and appears to serve as a gating mechanism that provides directionality to the process of differentiation.

A new species of Oligodon Fitzinger, 1826 is described based on specimens collected from Churah Valley of Himachal Pradesh. The new species is related to O. arnensis based on molecular as well as morphological data, however differs from it in several aspects. The new species shows a pairwise sequence divergence of 6–20% from congeners for mitochondrial cytochrome b gene. Lack of pterygoid and palatine teeth of the new species suggests that the diet may largely comprise of eggs. Discovery of the new species is not surprising, as the Western Himalayas has been poorly explored in terms of its herpetofaunal diversity. Considerable genetic divergence in the sampled sequence suggests Oligodon arnensis is a species complex, likely represents multiple species and a revision of the group would be desirable.

The tumour microenvironment (TME) may change in response to cancer treatments such as KRAS G12C inhibition, with potential implications for combination therapies. Here, the authors provide an antibody panel and workflow for analysing the TME with imaging mass cytometry in pre-clinical mouse models.

N6- methyladenosine (m6A) RNA modification impacts mRNA fate primarily via reader proteins, which dictate processes in development, stress, and disease. Yet little is known about m6A function in Saccharomyces cerevisiae, which occurs solely during early meiosis. Here, we perform a multifaceted analysis of the m6A reader protein Pho92/Mrb1. Cross-linking immunoprecipitation analysis reveals that Pho92 associates with the 3’end of meiotic mRNAs in both an m6A-dependent and independent manner. Within cells, Pho92 transitions from the nucleus to the cytoplasm, and associates with translating ribosomes. In the nucleus Pho92 associates with target loci through its interaction with transcriptional elongator Paf1C. Functionally, we show that Pho92 promotes and links protein synthesis to mRNA decay. As such, the Pho92-mediated m6A-mRNA decay is contingent on active translation and the CCR4-NOT complex. We propose that the m6A reader Pho92 is loaded co-transcriptionally to facilitate protein synthesis and subsequent decay of m6A modified transcripts, and thereby promotes meiosis.

We here describe a new species of bent-toed geckos from the northeastern Indian state of Arunachal Pradesh, which is widespread across the Dafla and Mishmi hills, occurring at elevations ranging from 179 m to 1400 m. The new species is recovered as sister to the Cyrtodactylus khasiensis clade based on a molecular phylogeny inferred from mitochondrial NADH-ubiquinone oxidoreductase, subunit 2 gene. Intraspecific uncorrected pairwise sequence divergence (p-distance) for the new species was found to be between 0 and 5%, whereas the interspecific divergence from the closely-related congeners was between 19 and 30%. The new species can be differentiated from members of the C. khasiensis clade using a suite of morphological characters: moderate body size (SVL 64.9–81.7); 8–11 supralabials; 8–10 infralabials; 24–26 bluntly conical, feebly keeled dorsal tubercles; 50–60 paravertebral tubercles; ~38 ventral scales between ventrolateral folds; no precloacal groves; 6–10 precloacofemoral pores in a continuous series; 10–16 distal subdigital lamellae on IV of pes; subcaudal scalation of original tail without enlarged plates. This is the fourth reptile species described from Arunachal Pradesh from the expedition led by the team, and this further highlights the need for further herpetological investigations into the region.

Lycodon deccanensis Ganesh, Deuti, Punith, Achyuthan, Mallik, Adhikari, Vogel, 2020 was recently described from the Mysore plateau of Karnataka based solely on morphology but lacking in-depth descriptions and comparisons. A scrutiny of the description reveals that the type series, of two specimens, comprise specimens of two different species along with discrepancies throughout the paper. Surveys conducted near the type locality of the species led to the discovery of additional specimens, which allow us to provide an elaborate description of the species and present data on its phylogenetic relationship with members of the genus and comments on the systematics of Lycodon of India. Results from molecular phylogenetics suggest that Lycodon deccanensis is a member of the L. aulicus clade based on molecular data for mitochondrial cytochrome b gene and shows an un-corrected p-distance (sequence divergence) of 14–17% from other members of the Lycodon aulicus clade.

Targeting self-renewing cancer cells without deleterious side effects in normal tissues has proven challenging. Here, the authors show that the well-tolerated HDAC inhibitor Quisinostat safely inhibits tumor maintenance and disease relapse by restoring high levels of histone H1.0.

A new species of green pit vipers of the genus Trimeresurus Lacépède, 1804 is described from the lowlands of western Arunachal Pradesh state of India. The new species, Trimeresurus salazar, is a member of the subgenus Trimeresurus, a relationship deduced contingent on two mitochondrial genes, 16S and ND4, and recovered as sister to Trimeresurus septentrionalis Kramer, 1977. The new species differs from the latter in bearing an orange to reddish stripe running from the lower border of the eye to the posterior part of the head in males, higher number of pterygoid and dentary teeth, and a short, bilobed hemipenis. Description of the new species and T. arunachalensis Captain, Deepak, Pandit, Bhatt & Athreya, 2019 from northeastern India in a span of less than one year highlights the need for dedicated surveys to document biodiversity across northeastern India.

The Himalayas represent a renowned biodiversity hotspot and an important biogeographic realm that has influenced origin and diversification of multiple taxa. A recent herpetological investigation of the eastern Himalayas of the Indian state of Arunachal Pradesh led to the discovery of a unique lineage of ablepharine skink, which is herein described as a new genus along with a new species. The findings are based an integrated taxonomic approach incorporating data from external morphology, microCT scans of the skull and molecular data. The molecular phylogeny of ablepharine skinks is also presented that suggests taxonomic amendments. Discovery of this unique lineage of skinks further highlights the biogeographic importance of the eastern Himalayas as a source for origin of several relic biota.

We report the first record of a snake, Ahaetulla laudankia Deepak, Narayanan, Sarkar, Dutta & Mohapatra, 2019 (Colubridae, Ahaetullinae) and confirm the occurrence of Lycodon travancoricus (Beddome, 1870) (Colubridae, Colubrinae) from Gujarat state based on reptile surveys conducted in South, Central, and Saurashtra regions of the state. We also provide new information on the morphology, microhabitat, diet, and behaviour of these species.

A new species of snail-eating snakes of the genus Pareas Wagler, 1830 is described from the eastern Himalayas. The species Pareas kaduri sp. nov. differs from all known species of the genus in bearing the following suite of characters: SVL 455–550 mm, TaL/TL 0.184–0.207, brown dorsum with black transverse bands throughout the body, 15 dorsal scale rows throughout the body and mid-dorsal vertebral scale rows enlarged, 8 rows keeled in males, loreal not touching orbit, ventrals 160–183, subcaudals 65–70 in males, 52 in one female specimen, hemipenis short, unilobed and 6–7 maxillary teeth. Molecular data for mitochondrial 16S rRNA and cytochrome b genes further attest the distinctness of the new species, which was recovered as a member of the Pareas hamptoni clade. Our work brings the total number of species recognized within the genus Pareas to 20.

Study DesignThis is a prospective study.PurposeThe aim of this study was to investigate the results of single-staged posterior decompression and circumferential fusion using a transpedicular approach to correct a kyphotic deformity due to thoracolumbar spinal tuberculosis.Overview of LiteratureSurgical management is frequently an imperative choice to achieve spinal decompression and deformity correction due to tuberculosis to relieve pain, improve neurology, and reconstruct the spine stability. Since the time anterior radical debridement and noninstrumented fusion was described, it has become apparent that even anterior debridement and bone grafting was often unsatisfactory in correcting or preventing the progression of kyphosis deformity. With the advent of modern segmental spinal instrumentation systems, isolated posterior instrumentation; combined anterior and posterior fusion; and single-staged posterior decompression and circumferential fusion have been described by many authors for correcting angular deformity and stabilizing the spine; however, there is a lack of consensus regarding the most effective means of correcting the deformity due to thoracolumbar spinal tuberculosis.MethodsThis is a prospective study of 20 patients with thoracolumbar spinal tuberculosis who underwent surgery at our institute.ResultsTwenty patients who were started on antituberculosis treatment underwent surgery using a single-staged posterior approach involving fixation, decompression, and kyphosis correction. Preoperatively, all patients had varying degrees of neurological deficit and a 27.45° average kyphotic angle, which improved. At the 1-year follow-up, correction was maintained at 6.9°, and 55% of patients showed neurological improvement. None of the patients experienced neurological deterioration. Two patients with lumbar spine tuberculosis underwent revision surgery because of nonunion.ConclusionsThe procedure of posterior decompression, fixation, and circumferential fusion using a transpedicular approach performed for thoracolumbar spinal tuberculosis is effective, safe, and excellent in correcting and maintaining kyphosis.

Background: Infections cause the production of inflammatory cytokines such as Interferon gamma (IFNγ). IFNγ in turn prompts the upregulation of a range of host defence proteins including members of the family of guanylate binding proteins (Gbps). In humans and mice alike, GBPs restrict the intracellular replication of invasive microbes and promote inflammation. To study the physiological functions of Gbp family members, the most commonly chosen in vivo models are mice harbouring loss-of-function mutations in either individual Gbp genes or the entire Gbp gene cluster on mouse chromosome 3. Individual Gbp deletion strains differ in their design, as some strains exist on a pure C57BL/6 genetic background, while other strains contain a 129-derived genetic interval encompassing the Gbp gene cluster on an otherwise C57BL/6 genetic background. Methods: To determine whether the presence of 129 alleles of paralogous Gbps could influence the phenotypes of 129-congenic Gbp-deficient strains, we studied the expression of Gbps in both C57BL/6J and 129/Sv mice following in vivo stimulation with adjuvants and after infection with either Toxoplasma gondii or Shigella flexneri. Results: We show that C57BL/6J relative to 129/Sv mice display moderately elevated expression of Gbp2, but more prominently, are also defective for Gbp2b (formerly Gbp1) mRNA induction upon immune priming. Notably, Toxoplasma infections induce robust Gbp2b protein expression in both strains of mice, suggestive of a Toxoplasma-activated mechanism driving Gbp2b protein translation. We further find that the higher expression of Gbp2b mRNA in 129/Sv mice correlates with a gene duplication event at the Gbp2b locus resulting in two copies of the Gbp2b gene on the haploid genome of the 129/Sv strain. Conclusions: Our findings demonstrate functional differences between 129 and C57BL/6 Gbp alleles which need to be considered in the design and interpretation of studies utilizing mouse models, particularly for phenotypes influenced by Gbp2 or Gbp2b expression.

The gekkonid lizard genus Hemidactylus Oken is the second most species-rich genus of geckos with greatest diversity in the tropical regions of the world. Some species of the genus are commensal and widespread; however, there are several endemic lineages with restricted distribution. India is home to at least 35 species, with 20 endemic species and the number is steadily increasing with exploration of new habitats and integrated taxonomic approach including molecular data. We made investigations into the molecular and morphological variation throughout the distribution of Hemidactylus triedrus Daudin, 1802 based on fresh specimens, literature review, museum material and molecular data. Results from morphological, molecular and micro-CT based anatomical data are unequivocal and show that H. triedrus is a species complex represented by three species, H. triedrus sensu stricto and two undescribed taxa. H. subtriedrus Jerdon, 1854 syn. nov. was found to be morphologically similar to the type specimen of H. triedrus, and genetically embedded in a clade containing H. triedrus sensu stricto and is here treated as a junior synonym of H. triedrus, whereas H. lankae Deraniyagala is referred to as nomen dubium given that the types are presently not traceable and the original description is inadequate in diagnosing the taxon. The populations from western-central India and parts of Pakistan, and from southern Karnataka are distinct and diagnosable, and are herein described as two new species, respectively. Morphological and molecular data support the distinctiveness of the new species. The present work resolves a taxonomic turmoil that lasted over two centuries highlighting the need for studies that integrate morphological and molecular data.

T cell receptor–major histocompatibility complex (TCR–MHC) affinities span a wide range in a polyclonal T cell response, yet it is undefined how affinity shapes long-term properties of CD8 T cells during chronic infection with persistent antigen. Here, we investigate how the affinity of the TCR–MHC interaction shapes the phenotype of memory CD8 T cells in the chronically Toxoplasma gondii-infected brain. We employed CD8 T cells from three lines of transnuclear (TN) mice that harbor in their endogenous loci different T cell receptors specific for the same Toxoplasma antigenic epitope ROP7. The three TN CD8 T cell clones span a wide range of affinities to MHCI–ROP7. These three CD8 T cell clones have a distinct and fixed hierarchy in terms of effector function in response to the antigen measured as proliferation capacity, trafficking, T cell maintenance, and memory formation. In particular, the T cell clone of lowest affinity does not home to the brain. The two higher affinity T cell clones show differences in establishing resident-like memory populations (CD103+) in the brain with the higher affinity clone persisting longer in the host during chronic infection. Transcriptional profiling of naïve and activated ROP7-specific CD8 T cells revealed that Klf2 encoding a transcription factor that is known to be a negative marker for T cell trafficking is upregulated in the activated lowest affinity ROP7 clone. Our data thus suggest that TCR–MHC affinity dictates memory CD8 T cell fate at the site of infection.

NODAL/Activin signaling orchestrates key processes during embryonic development via SMAD2. How SMAD2 activates programs of gene expression that are modulated over time however, is not known. Here we delineate the sequence of events that occur from SMAD2 binding to transcriptional activation, and the mechanisms underlying them. NODAL/Activin signaling induces dramatic chromatin landscape changes, and a dynamic transcriptional network regulated by SMAD2, acting via multiple mechanisms. Crucially we have discovered two modes of SMAD2 binding. SMAD2 can bind pre-acetylated nucleosome-depleted sites. However, it also binds to unacetylated, closed chromatin, independently of pioneer factors, where it induces nucleosome displacement and histone acetylation. For a subset of genes, this requires SMARCA4. We find that long term modulation of the transcriptional responses requires continued NODAL/Activin signaling. Thus SMAD2 binding does not linearly equate with transcriptional kinetics, and our data suggest that SMAD2 recruits multiple co-factors during sustained signaling to shape the downstream transcriptional program.

Protein synthesis can be segmented into distinct phases comprising mRNA translation initiation, elongation, and termination. Translation initiation is a highly regulated and rate-limiting step of protein synthesis that requires more than 12 eukaryotic initiation factors (eIFs). Extensive evidence shows that the transcriptome and corresponding proteome do not invariably correlate with each other in a variety of contexts. In particular, translation of mRNAs specific to angiogenesis, tumor development, and apoptosis is altered during physiological and pathophysiological stress conditions. In cancer cells, the expression and functions of eIFs are hampered, resulting in the inhibition of global translation and enhancement of translation of subsets of mRNAs by alternative mechanisms. A precise understanding of mechanisms involving eukaryotic initiation factors leading to differential protein expression can help us to design better strategies to diagnose and treat cancer. The high spatial and temporal resolution of translation control can have an immediate effect on the microenvironment of the cell in comparison with changes in transcription. The dysregulation of mRNA translation mechanisms is increasingly being exploited as a target to treat cancer. In this review, we will focus on this context by describing both canonical and noncanonical roles of eIFs, which alter mRNA translation.

T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2b haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 Ld-restricted epitope, derived from the Rop7 protein of Toxoplasma gondii. We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro. Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.

A distinctive early Miocene-divergent lineage of Old world racer snakes is described as a new genus and species based on three specimens collected from the western Indian state of Gujarat. Wallaceophis gen. et. gujaratenesis sp. nov. is a members of a clade of old world racers. The monotypic genus represents a distinct lineage among old world racers is recovered as a sister taxa to Lytorhynchus based on ~3047bp of combined nuclear (cmos) and mitochondrial molecular data (cytb, ND4, 12s, 16s). The snake is distinct morphologically in having a unique dorsal scale reduction formula not reported from any known colubrid snake genus. Uncorrected pairwise sequence divergence for nuclear gene cmos between Wallaceophis gen. et. gujaratenesis sp. nov. other members of the clade containing old world racers and whip snake is 21-36%.

[This corrects the article DOI: 10.1371/journal.pone.0148380.].

A growing body of evidence suggests that Polycomb group (PcG) proteins, key regulators of lineage specific gene expression, also participate in the repair of DNA double-strand breaks (DSBs) but evidence for direct recruitment of PcG proteins at specific breaks remains limited. Here we explore the association of Polycomb repressive complex 1 (PRC1) components with DSBs generated by inducible expression of the AsiSI restriction enzyme in normal human fibroblasts. Based on immunofluorescent staining, the co-localization of PRC1 proteins with components of the DNA damage response (DDR) in these primary cells is unconvincing. Moreover, using chromatin immunoprecipitation and deep sequencing (ChIP-seq), which detects PRC1 proteins at common sites throughout the genome, we did not find evidence for recruitment of PRC1 components to AsiSI-induced DSBs. In contrast, the S2056 phosphorylated form of DNA-PKcs and other DDR proteins were detected at a subset of AsiSI sites that are predominantly at the 5' ends of transcriptionally active genes. Our data question the idea that PcG protein recruitment provides a link between DSB repairs and transcriptional repression.

Screening a library of drugs with known safety profiles in humans yielded 30 drugs that reliably protected mammalian neurons against glucose toxicity. Subsequent screening demonstrated that 6 of these 30 drugs increase lifespan in C. elegans: caffeine, ciclopirox olamine, tannic acid, acetaminophen, bacitracin, and baicalein. Every drug significantly reduced the age-dependent acceleration of mortality rate. These protective effects were blocked by RNAi inhibition of cbp-1 in adults only, which also blocks protective effects of dietary restriction. Only 2 drugs, caffeine and tannic acid, exhibited a similar dependency on DAF-16. Caffeine, tannic acid, and bacitracin also reduced pathology in a transgenic model of proteotoxicity associated with Alzheimer's disease. These results further support a key role for glucose toxicity in driving age-related pathologies and for CBP-1 in protection against age-related pathologies. These results also provide novel lead compounds with known safety profiles in human for treatment of age-related diseases, including Alzheimer's disease and diabetic complications.

How dietary restriction (DR) increases lifespan and decreases disease burden are questions of major interest in biomedical research. Here we report that hypothalamic expression of CREB-binding protein (CBP) and CBP-binding partner Special AT-rich sequence binding protein 1 (SATB-1) is highly correlated with lifespan across five strains of mice, and expression of these genes decreases with age and diabetes in mice. Furthermore, in Caenorhabditis elegans, cbp-1 is induced by bacterial dilution DR (bDR) and the daf-2 mutation, and cbp-1 RNAi specifically in adults completely blocks lifespan extension by three distinct protocols of DR, partially blocks lifespan extension by the daf-2 mutation but not of cold, and blocks delay of other age-related pathologies by bDR. Inhibiting the C. elegans ortholog of SATB-1 and CBP-binding partners daf-16 and hsf-1 also attenuates lifespan extension by bDR, but not other protocols of DR. In a transgenic Abeta42 model of Alzheimer's disease, cbp-1 RNAi prevents protective effects of bDR and accelerates Abeta42-related pathology. Furthermore, consistent with the function of CBP as a histone acetyltransferase, drugs that enhance histone acetylation increase lifespan and reduce Abeta42-related pathology, protective effects completely blocked by cbp-1 RNAi. Other factors implicated in lifespan extension are also CBP-binding partners, suggesting that CBP constitutes a common factor in the modulation of lifespan and disease burden by DR and the insulin/IGF1 signaling pathway.