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Background: Environmental modification of genetic information (epigenetics) is often invoked to explain interindividual differences in the phenotype of schizophrenia. In clinical practice, such variability is most prominent in the symptom profile and the treatment response. Epigenetic regulation of immune function is of particular interest, given the therapeutic relevance of this mechanism in schizophrenia. Methods: We analyzed the DNA methylation data of immune-relevant genes in patients with schizophrenia whose disease duration was less than 3 years, with previous lifetime antipsychotic treatment of no more than 2 weeks total. Results: A total of 441 patients met the inclusion criteria. Core symptoms were consistently associated with 206 methylation positions, many of which had previously been implicated in inflammatory responses. Of these, 24 methylation positions were located either in regulatory regions or near the CpG islands of 20 genes, including the SRC gene, which is a key player in glutamatergic signalling. These symptom-associated immune genes were enriched in neuronal development functions, such as neuronal migration and glutamatergic synapse. Compared with using only clinical information (including scores on the Positive and Negative Syndrome Scale), integrating methylation data into the model significantly improved the predictive ability (as indicated by area under the curve) for response to 8 weeks of antipsychotic treatment. Limitations: We focused on a small number of methylation probes (immune-centred search) and lacked nutritional data and direct brain-based measures. Conclusion: Epigenetic modifications of the immune system are associated with symptom severity at onset and subsequent treatment response in schizophrenia., Introduction Schizophrenia is characterized by its heterogeneity in both clinical symptoms and treatment response. It affects 24 million individuals around the world, resulting in substantially reduced life expectancy and a [...]

* Context.--Recent genome-wide sequencing studies have identified a subset of pancreatic ductal adenocarcinomas (PDACs) harboring significant alterations in epigenetic regulation genes, including the COMPASS-like complex genes. Whether this subset of PDACs has specific histologic characteristics or carries prognostic or therapeutic implications is unknown. Objective.--To determine the specific clinicopathologic and molecular features of PDACs carrying mutations in COMPASS-like complex genes. Design.--We analyzed a series of 103 primary and metastatic PDACs with comprehensive molecular profiling, including 13 PDACs carrying loss-of-function COMPASS-like complex gene alterations (study cohort). Another 45 patients carrying PDACs with wild-type COMPASS-like complex genes were used as the control group. Results.--PDACs within the study cohort were smaller, harboring frequent areas of poor differentiation and concurrent alterations in KRAS, TP53, SMAD4, and CDKN2A. A subset of metastatic PDACs from the study cohort showed squamous differentiation. There was a trend toward decreased survival in the study group. We further interrogated 2 public data sets and found that PDACs with COMPASS-like complex gene alterations have increased rates of TP53 mutation, body-tail location, poor differentiation or undifferentiated histology, and a higher death rate. Conclusions.--COMPASS-like complex gene alterations likely represent a subset of more aggressive PDACs with poor or squamous differentiation histologically and increased concurrent TP53 mutations. These findings may have potential prognostic and therapeutic implications., Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related morbidity and mortality, with an estimated 5-year survival rate of just 9%-10%, (1,2) and accounts for a significant portion of [...]

Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity and dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor- Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders., Introduction Prescription opioids, such as morphine, are the most effective clinical analgesics. However, their clinical utility is limited by analgesic tolerance and reinforcing effects (1, 2). Opioids exert potent euphoric [...]

Background: Psoriasis (PS), vitiligo (VT), and Pityriasis rosea (PR) are chronic skin diseases often occurring as a consequence of exaggerated immune responses. These skin manifestations can be triggered as a result of the molecular mimicry between viral protein (s) and host protein (s), which could generate auto-antibodies. In addition, it can be hypothesised that skin diseases are manifestations of the reduced immunity that is observed in chronic hepatitis B virus (HBV)-infected individuals. Aims and Objective: To investigate the presence of HBV in PS, VT, and PR cases and Human Herpes Virus (HHV) 6 and 7 in PR cases. Materials and Methods: DNA extracted from healthy controls (n = 20), PS (n = 10), VT (n = 11), and PR (n = 12) were subjected to HBV-S gene-specific polymerase chain reactions (PCRs) and HHV 6-UL57 and HHV7-UL10 gene-specific PCRs. PCR products of positive samples (HBV and HHV 6 and 7 DNA) of expected length were bi-directionally sequenced using overlapping primers. Sequence identification was performed by NCBI BLAST and analysed by multiple sequence alignment. HBV DNA copy number was determined through quantitative real-time PCR. The blood samples were also tested for HBV serological markers and Interferon gamma (IFN-γ) by enzyme immunoassays. Results: The PCR data and Immunoassay study revealed that seven out of 12 PR, six out of 10 PS, and six out of 11 VT cases had signs of HBV infection. HHV 6 DNA was detected in four, whereas HHV 7 DNA was found in two of the 12 PR blood samples. PR6 presented the evidence of both HHV 6 and 7 co-infections. Conclusion: Observing the correlation of HBV with skin diseases, albeit at the pilot level, a larger study is warranted to identify HBV infection in skin disease patients. The evidence of HHV 6 and HHV 7 DNA in PR cases supports the HHV infection linkage with PR. Keywords: Co-infection, Pityriasis rosea, psoriasis, vitiligo, KEY MESSAGES: Underlying viral infections may be linked to chronic skin disease manifestations. Evidence of high frequency of HBV infection in PS, VT, and PR cases and the presence of HHV 6 and/or 7 infections in PR draw a diagnostic perspective for screening these subjects for these viruses as well., Author(s): Ruchi Supekar [1,2]; Subrata Roy [2]; Abhishek De [3]; Subhajit Biswas (corresponding author) [1,2] Introduction Psoriasis (PS), vitiligo (VT), and Pityriasis rosea (PR) are chronic skin diseases that often [...]

Background The conventional means of controlling the recurring pandemics of Type A Influenza Virus (IAV) infections remain challenging primarily because of its high mutability and increasing drug resistance. As an alternative to control IAV infections, the prophylactic use of cytokines to drive immune activation of multiple antiviral host factors has been progressively recognized. Among them, Type III Interferons (IFNs) exhibit a pivotal role in inducing potent antiviral host responses by upregulating the expression of several antiviral genes, including the Interferon-Stimulated Genes (ISGs) that specifically target the virus replication machinery. To harness the immuno-adjunctive potential, we examined whether pre-treatment of IFN[lambda]3, a Type III IFN, can activate antiviral host responses against IAV infections. Methods In the present study, we bioengineered a food-grade lactic acid-producing bacteria (LAB), Lactococcus lactis (L. lactis), to express and secrete functional murine IFN[lambda]3 (MuIFN[lambda]3) protein in the extracellular milieu. To test the immune-protective potential of MuIFN[lambda]3 secreted by recombinant L. lactis (rL. lactis), we used murine B16F10 cells as an in vitro model while mice (BALB/c) were used for in vivo studies. Results Our study demonstrated that priming with MuIFN[lambda]3 secreted by rL. lactis could upregulate the expression of several antiviral genes, including Interferon Regulatory Factors (IRFs) and ISGs, without exacerbated pulmonary or intestinal inflammatory responses. Moreover, we also showed that pre-treatment of B16F10 cells with MuIFN[lambda]3 can confer marked immune protection against mice-adapted influenza virus, A/PR/8/1934 (H1N1) infection. Conclusion Since the primary target for IAV infections is the upper respiratory and gastrointestinal tract, immune activation without affecting the tissue homeostasis suggests the immune-adjunctive potential of IFN[lambda]3 against IAV infections. Keywords: Murine IFN[lambda]3 (MuIFN[lambda]3), Lactococcus lactis (L. lactis), Type A Influenza Virus (IAV), Immune protection, Author(s): Sandeep Yadav[sup.1], Aparna Varma[sup.1], Aparna Odayil Muralidharan[sup.1], Sucharita Bhowmick[sup.1], Samiran Mondal[sup.2] and Amirul Islam Mallick[sup.1] Background Frequent outbreaks of Type A Influenza Virus (IAV) and their significant impact on [...]

Purpose Transport of secretory immunoglobulin A (SIgA) through the airway epithelial cell barrier into the mucosal lumen by the polymeric immunoglobulin receptor (pIgR) is an important mechanism of respiratory mucosal host defense. Identification of immunomodulating substances that regulate secretory immunity might have therapeutic implications with regard to an improved immune exclusion. Thus, we sought to analyze secretory immunity under homeostatic and immunomodulating conditions in different compartments of the murine upper and lower respiratory tract (URT&LRT). Methods Pigr gene expression in lung, trachea, and nasal-associated lymphoid tissue (NALT) of germ-free mice, specific pathogen-free mice, mice with an undefined microbiome, as well as LPS- and IFN-[gamma]-treated mice was determined by quantitative real-time PCR. IgA levels in bronchoalveolar lavage (BAL), nasal lavage (NAL), and serum were determined by ELISA. LPS- and IFN-[gamma]-treated mice were colonized with Streptococcus pneumoniae and bacterial CFUs were determined in URT and LRT. Results Respiratory Pigr expression and IgA levels were dependent on the degree of exposure to environmental microbial stimuli. While immunostimulation with LPS and IFN-[gamma] differentially impacts respiratory Pigr expression and IgA in URT vs. LRT, only prophylactic IFN-[gamma] treatment reduces nasal colonization with S. pneumoniae. Conclusion Airway-associated secretory immunity can be partly modulated by exposure to microbial ligands and proinflammatory stimuli. Prophylactic IFN-[gamma]-treatment modestly improves antibacterial immunity in the URT, but this does not appear to be mediated by SIgA or pIgR., Author(s): Alexander Pausder [sup.1] [sup.2] [sup.3], Jennifer Fricke [sup.4] [sup.9], Klaus Schughart [sup.4] [sup.5] [sup.6], Jens Schreiber [sup.7], Till Strowig [sup.8], Dunja Bruder [sup.1] [sup.2], Julia D. Boehme [sup.1] [sup.2] [...]

Byline: M. H.A. Mohamed and I. M. El-Sabagh Keywords: IBH, Hexon gene, Fiber gene, Phylogenetic analysis, Fowl aviadenoviruses INTRODUCTION The fowl adenovirus (FAdV) is the etiology of IBH in poultry. [...]

Introduction New, potent androgen receptor (AR) pathway inhibitors (ARPIs) have improved overall survival in men with metastatic prostate cancer (PCa) (1, 2). However, more aggressive subtypes of castrate-resistant prostate cancer [...], Therapy-induced neuroendocrine prostate cancer (t-NEPC) is a highly aggressive subtype of prostate cancer with poor patient survival. Emerging evidence indicates that t-NEPC can develop when prostate adenocarcinoma cells acquire cancer stem-like cell signaling in the presence of androgen receptor inhibition, followed by redifferentiation toward neuroendocrine lineage and subsequent t-NEPC progression. Whether the stem-like signaling is controlled by the core pluripotency stem cell genes (e.g., LIN28 and SOX2) remains unknown. Here, we report that the transcription of the LIN28B isoform and SOX2 were co-upregulated in t-NEPC patient tumors, patient-derived xenografts, transgenic mice, and cell models. Immunohistochemistry validated that LIN28B and SOX2 protein expression were elevated in t-NEPC patient biopsies. Using prostate adenocarcinoma and t-NEPC cell models, we demonstrated that LIN28B induced a stem-like gene network, neuroendocrine biomarkers, and neuroendocrine cell morphology. LIN28B depletion by CRISPR inhibited t-NEPC tumorigenesis and xenograft growth. These LIN28B functions were mediated mainly through the suppression of let-7 miRNA expression, resulting in de-repression of the transcription factor HMGA2 and HMGA2-mediated SOX2 expression. This study revealed a mechanism by which t-NEPC can develop through the LIN28B/let-7/SOX2 axis that regulates a cancer cell stem-like gene network, highlighting LIN28B as a potential therapeutic target in t-NEPC.

Introduction Accumulation of aggregated misfolded proteins is a pathologic hallmark of many neurodegenerative diseases, including Alzheimer disease (AD), the most predominant form of dementia. Accompanying the formation of [beta]-amyloid (Ap) [...], Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated a potent IFN immunogenicity of nucleic acid-containing (NA-containing) amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with [beta]-amyloidosis inside the brain and contributes to neuropathology. An IFN-stimulated gene (ISG) signature was detected in the brains of multiple murine Alzheimer disease (AD) models, a phenomenon also observed in WT mouse brain challenged with generic NA-containing amyloid fibrils. In vitro, microglia innately responded to NA-containing amyloid fibrils. In AD models, activated ISG-expressing microglia exclusively surrounded NA* amyloid p plaques, which accumulated in an age-dependent manner. Brain administration of rIFN-[beta] resulted in microglial activation and complement C3-dependent synapse elimination in vivo. Conversely, selective IFN receptor blockade effectively diminished the ongoing microgliosis and synapse loss in AD models. Moreover, we detected activated ISG-expressing microglia enveloping NA-containing neuritic plaques in postmortem brains of patients with AD. Gene expression interrogation revealed that IFN pathway was grossly upregulated in clinical AD and significantly correlated with disease severity and complement activation. Therefore, IFN constitutes a pivotal element within the neuroinflammatory network of AD and critically contributes to neuropathogenic processes.

In some salmonid populations, multiple smolt age classes co-emigrate owing to variation in the duration of freshwater residence. While it is assumed that smolts prolong freshwater residence to maximize survival, infectious agent profiles and host gene expression (GE) have not been compared between concurrently migrating age classes. We coupled molecular assays of gill samples from nonlethally biopsied Chilko Lake sockeye salmon smolts with acoustic telemetry to study variation in infectious agent profiles and GE between age classes and survival groups. Although neither infectious agent profiles or GE were associated with survival, age-2 smolts exhibited higher mortality in the first 14 km of the downstream migration. There were measurable differences between the age classes in GE and the prevalence and load of 'Candidatus Branchiomonas cysticola', a bacterium commonly found in British Columbia salmonids. Relative to age-1 smolts, age-2 smolts displayed elevated GE related to inflammation and a molecular-based mortality-related signature. Although not associated with migration failure in this study, these patterns of GE are suggestive of mortality and could have implications for smolt survival. Dans certaines populations de salmonides, des saumoneaux de differentes classes d'age emigrent ensemble en raison de variations du temps de residence en eau douce. S'il est presume que les saumoneaux prolongent leur residence en eau douce afin de maximiser leur survie, les profils d'agents infectieux et l'expression genetique (EG) d'hotes de differentes classes d'age migrant ensemble n'ont pas ete compares. Nous avons jumele des analyses moleculaires d'echantillons de branchies preleves de maniere non letale de saumoneaux de saumon rouge du lac Chilko a la telemetrie acoustique afin d'etudier les variations des profils d'agents infectieux et de l'EG entre classes d'age et groupes de survie. Bien que ni les profils d'agents infectieux ni l'EG ne soient associes a la survie, les saumoneaux de 2 ans presentaient une mortalite plus grande dans les premiers 14 km de la devalaison. Il y avait des differences mesurables entre les classes d'age sur le plan de l'EG et de la prevalence et de la charge de << Candidatus Branchiomonas cysticola >>, une bacterie repandue dans les salmonides en Colombie-Britannique. Par rapport aux saumoneaux de 1 an, les saumoneaux de 2 ans presentaient une EG elevee associee a l'inflammation et une signature reliee a une mortalite a base moleculaire. Bien qu'ils ne soient pas associes a l'echec de la migration dans la presente etude, ces motifs d'EG indiqueraient une mortalite et pourraient etre importants pour la survie des saumoneaux. [Traduit par la Redaction], Introduction The seaward migration of juvenile anadromous Pacific salmon smolts (Oncorhynchus spp.) is an impressive annual event in which millions of fish travel from freshwater rearing areas to marine environments. [...]

Lynch Syndrome (LS) is a highly variable entity with some patients presenting at very young ages with malignancy whereas others may never develop a malignancy yet carry an unequivocal genetic predisposition to disease. The most frequent LS malignancy remains colorectal cancer, a disease that is thought to involve genetic as well as environmental factors in its aetiology. Environmental insults are undeniably associated with cancer risk, especially those imparted by such activities as smoking and excessive alcohol consumption. Notwithstanding, in an inherited predisposition the expected exposures to an environmental insult are considered to be complex and require knowledge about the respective exposure and how it might interact with a genetic predisposition. Typically, smoking is one of the major confounders when considering environmental factors that can influence disease expression on a background of significant genetic risk. In addition to environmental triggers, the risk of developing a malignancy for people carrying an inherited predisposition to disease can be influenced by additional genetic factors that do not necessarily segregate with a disease predisposition allele. The purpose of this review is to examine the current state of modifier gene detection in people with a genetic predisposition to develop LS and present some data that supports the notion that modifier genes are gene specific thus explaining why some modifier gene studies have failed to identify associations when this is not taken into account. Keywords: Lynch syndrome, MSH2, MLH1, Modifier genes, Incidence, Survival, Author(s): Rodney J. Scott[sup.1] Introduction LS is defined as a person who presents with a cancer related to a deficiency in DNA mismatch repair. Approximately 15% of all colorectal cancers [...]

The ability of swine to support replication of phylogenetically diverse influenza A virus (IAV) strains from avian and mammalian origin poses a public health risk because of the potential for [...]

Introduction Arsenic is the 20th most abundant element and a toxic metalloid that is present in the Earth's crust. Its average concentration is 2-5 mg/kg (Moore 1991). Because of its [...], Arsenic is a widespread toxic metalloid that is classified as a class I carcinogen known to cause adverse health effects in humans. In the present study, we investigated arsenic accumulation potential and comparative gene expression in Indian mustard. The amount of arsenic accumulated in shoots varied in the range of 15.99-1138.70 mg/kg on a dry weight basis among five cultivars. Comparative expression analysis revealed 10 870 significantly differentially expressed genes mostly belonging to response to stress, metabolic processes, signal transduction, transporter activity, and transcription regulator activity to be up-regulated, while most of the genes involved in photosynthesis, developmental processes, and cell growth were found to be down-regulated in arsenic-treated tissues. Further, pathway analysis using the KEGG Automated Annotation server (KAAS) revealed a large-scale reprogramming of genes involved in genetic and environmental information processing pathways. Top pathways with maximum KEGG orthology hits included carbon metabolism (2.5%), biosynthesis of amino acids (2.1%), plant hormone signal transduction (1.4%), and glutathione metabolism (0.6%). A transcriptomic investigation to understand the arsenic accumulation and detoxification in Indian mustard will not only help to improve its phytoremediation efficiency but also add to the control measures required to check bioaccumulation of arsenic in the food chain. Key words: arsenic, Brassica juncea, phytoremediation, transcriptome, pathway analysis. L'arsenique est un metalloïde toxique repandu qui est classifie comme un cancerogene de classe I connu pour entraîner des effets nefastes sur la sante des humains. Dans le present travail, les auteurs ont etudie le potentiel d'accumulation de l'arsenique et l'expression differentielle chez la moutarde brune. La quantite d'arsenique accumulee dans les tiges variait entre 15,99 et 1138,70 mg/kg sur la base de la matiere seche parmi cinq cultivars. Une analyse comparative de l'expression genique a permis d'identifier 10 870 genes presentant une expression differentielle significative. La plupart de ceux qui etait exprimes a la hausse suite a un traitement a l'arsenique etaient annotes comme etant lies a la reponse aux stress, a des processus metaboliques, a la transduction de signaux, a divers types de transport ainsi qu'a des facteurs de transcription. Ceux exprimes moins abondamment etaient annotes comme etant associes a la photosynthese, aux processus developpementaux et a la croissance cellulaire. De plus, une analyse de sentiers a l'aide du <> (KAAS) a revele une reprogrammation globale des genes impliques dans la reponse aux informations genetiques et environnementales. Les principaux sentiers presentant le plus d'orthologues KEGG incluaient le metabolisme du carbone (2,5 %), la synthese des acides amines (2,1 %), la transduction des signaux hormonaux (1,4 %) et le metabolisme du glutathion (0,6 %). Une analyse transcriptomique visant a comprendre l'accumulation et la detoxication de l'arsenique chez la moutarde brune permettra non seulement d'ameliorer son efficacite en matiere de phytoremediation, mais pourra aussi contribuer aux mesures de contrôle visant a etablir la bioaccumulation de l'arsenique dans la chaîne alimentaire. [Traduit par la Redaction] Mots-cles : arsenique, Brassica juncea, phytoremediation, transcriptome, analyse des sentiers.

Suppressors of cytokine signaling (SOCS) family members can inhibit multiple biological functions of cytokines, hormones, and growth factors. In this study, a SOCS6 gene homolog from triangle sail mussel Hyriopsis cumingii (HcSOCS6) was cloned and characterized. The full-length cDNA of HcSOCS6 was 1,823 bp and encoded 458 amino acid residues. No introns were found in the genomic sequence. The deduced HcSOCS6 protein possesses highly conserved functional domains, including the Src homology 2 domain and the SOCS box. Phylogenetic analysis showed that HcSOCS6 was clustered with other molluscan genes. Transcripts of HcSOCS6 were constitutively expressed in all examined tissues, at high levels in the hepatopancreas and gills and low levels in hemocytes. Transcription of HcSOCS6 was significantly upregulated in hemocytes and the hepatopancreas after injecting with lipopolysaccharide, but it was only upregulated in hemocytes after Aeromonas hydrophila stimulation. The expression of HcSOCS6 in mantle significantly increased during wound healing, especially on the third day. These results suggested that HcSOCS6 was involved in the immune response and wound healing in the triangle sail mussel. KEY WORDS: mussel, Hyriopsis cumingii, SOCS6, immune response, mRNA expression, wound healing, INTRODUCTION Suppressors of cytokine signaling (SOCS) proteins, part of a classical negative feedback system, are important in regulating cytokine signal transduction. These SOCS proteins may modulate the function, strength, and [...]

Introduction The androgen receptor (AR) regulates cellular programs that promote the survival and proliferation of prostate cancer (PC) cells. Consequently, first-line treatment for metastatic PC centers on inhibiting AR activity [...], Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with diverse drivers of disease progression and mechanisms of therapeutic resistance. We conducted deep phenotypic characterization of CRPC metastases and patient-derived xenograft (PDX) lines using whole-genome RNA sequencing, gene set enrichment analysis, and immunohistochemistry. Our analyses revealed 5 mCRPC phenotypes based on the expression of well-characterized androgen receptor (AR) or neuroendocrine (NE) genes: AR-high tumors (ARPC), AR-low tumors (ARLPC), amphicrine tumors composed of cells coexpressing AR and NE genes (AMPC), double-negative tumors (i.e., [AR.sup.-]/[NE.sup.-]; DNPC), and tumors with small cell or NE gene expression without AR activity (SCNPC). RE1 silencing transcription factor (REST) activity, which suppresses NE gene expression, was lost in AMPC and SCNPC PDX models. However, knockdown of REST in cell lines revealed that attenuated REST activity drives the AMPC phenotype but is not sufficient for SCNPC conversion. We also identified a subtype of DNPC tumors with squamous differentiation and generated an encompassing 26-gene transcriptional signature that distinguished the 5 mCRPC phenotypes. Together, our data highlight the central role of AR and REST in classifying treatment-resistant mCRPC phenotypes. These molecular classifications could potentially guide future therapeutic studies and clinical trial design.

Introduction Lineage plasticity, a process by which differentiated cells lose their identity and acquire an alternative lineage program, has recently been identified as an emerging mechanism of resistance to targeted [...], Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration-resistant prostate cancers become androgen receptor (AR) signaling independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome, and interactome using in vivo, in vitro, and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR cofactors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage- defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for enhancer of zeste homolog 2 (EZH2) inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights into how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

Introduction Most of the identified plant resistance (R) proteins against pathogens/pests belong to a superfamily of intracellular immune receptors, which are structural with nucleotide binding site (NBS) and leucine-rich repeat [...], Proteins with nucleotide-binding site (NBS) and leucine-rich repeats (LRRs) have been reported to play important roles in plant disease resistance, growth, and development. However, no comprehensive analysis of this protein family has been performed in conifers. Here we report that the Pinus monticola PmTNL2 gene is a member of the NBS-LRR superfamily. Quantitative reverse transcription-PCR (qRT-PCR) analysis revealed that the PmTNL2 transcript was expressed in a tissue-specific pattern with extensive regulation by various environmental stimuli in western white pine seedlings, suggesting its wide involvement in stress defense and diverse developmental processes. In silico analysis of the PmTNL2 promoter region revealed multiple cis-regulatory elements characterized with potential functions for development-, light-, and stress-regulated transcript expression. Expression patterns were largely confirmed by PmTNL2 promoter-directed reporter gene expression using stable transgenic Arabidopsis plants. Notably, the PmTNL2 promoter activity was highly expressed in shoot apical and floral meristems and was induced strongly with vascular specificity by pathogen infection. Our data has provided a fundamental insight into both expression regulation and putative functions of the PmTNL2 gene in the context of plant growth and development, as well as in responses to environmental stressors. Promoter application as a potential tool for tree improvement was further discussed. Key words: cis-elements, Cronartium ribicola, Pinus monticola, promoter activity analysis, tree improvement. Il est rapporte que les proteines qui comptent un domaine de liaison de nucleotides (NBS) et des repetitions riches en leucine (LRR) jouent des roles importants dans la resistance aux maladies, la croissance et le developpement. Cependant, aucune analyse exhaustive de cette famille de proteines n&apos;a ete realisee chez les coniferes. Dans ce travail, les auteurs rapportent que le gene PmTNL2 chez le Pinus monticola est un membre de la superfamille NBS-LRR. Une analyse en PCR quantitative (qRT-PCR) a revele que le transcrit de PmTNL2 est exprime de maniere tissus-specifique et qu&apos;il presente une regulation considerable par divers stimuli environnementaux chez les plantules du pin argente, ce qui suggere un large role dans la defense aux stress et dans divers processus developpementaux. Une analyse in silico du promoteur du gene PmTNL2 a revele de nombreux motifs de regulation en cis connus comme etant associes a la regulation de l&apos;expression en reponse au developpement, a la lumiere et aux stress. Les profils d&apos;expression ont ete largement confirmes chez transformants stables d&apos;Arabidopsis dotes d&apos;une construction liant le promoteur de PmTNL2 a un gene rapporteur. Notamment, l&apos;activite du promoteur etait elevee chez les meristemes apicaux et floraux et elle etait fortement induite de maniere specifique chez les tissus vasculaires suite a une infection par un agent pathogene. Ces donnees ont fourni un apercu fondamental a la fois de la regulation de l&apos;expression que des fonctions putatives du gene PmTNL2 dans le contexte de la croissance des plantes, du developpement et en reponse a des stress environnementaux. Les auteurs discutent egalement des applications possibles de ce promoteur dans le contexte de l&apos;amelioration des arbres. [Traduit par la Redaction] Mots-cles: elements en cis, Cronartium ribicola, Pinus monticola, analyse de l&apos;activite d&apos;un promoteur, amelioration des arbres.

Background Clostridioides difficile infection (CDI) is an infectious nosocomial disease caused by Clostridioides difficile, an opportunistic pathogen that occurs in the intestine after extensive antibiotic regimens. Results Nine C. difficile strains (CBA7201-CBA7209) were isolated from nine patients diagnosed with CDI at the national university hospital in Korea, and the whole genomes of these strains were sequenced to identify their genomic characteristics. Comparative genomic analysis was performed using 51 reference strains and the nine isolated herein. Phylogenetic analysis based on 16S rRNA gene sequences confirmed that all 60 C. difficile strains belong to the genus Clostridioides, while core-genome tree indicated that they were divided into five groups, which was consistent with the results of MLST clade analysis. All strains were confirmed to have a clindamycin antibiotic resistance gene, but the other antibiotic resistance genes differ depending on the MLST clade. Interestingly, the six strains belonging to the sequence type 17 among the nine C. difficile strains isolated here exhibited unique genomic characteristics for PaLoc and CdtLoc, the two toxin gene loci identified in this study, and harbored similar antibiotic resistance genes. Conclusion In this study, we identified the specific genomic characteristics of Korean C. difficile strains, which could serve as basic information for CDI prevention and treatment in Korea. Keywords: Clostridioides difficile, Clostridioides difficile infection, Comparative genomics, Pathogenic features, Toxin A and toxin B, Antibiotic resistance gene, Author(s): Seung Woo Ahn[sup.1], Se Hee Lee[sup.1], Uh Jin Kim[sup.2], Hee-Chang Jang[sup.2], Hak-Jong Choi[sup.1], Hyon E. Choy[sup.3], Seung Ji Kang[sup.2] and Seong Woon Roh[sup.1] Background Clostridioides difficile is a major [...]

Author(s): Balakrishnan N. V. Premkrishnan[sup.1], Cassie E. Heinle[sup.1], Akira Uchida[sup.1], Rikky W. Purbojati[sup.1], Kavita K. Kushwaha[sup.1], Alexander Putra[sup.1], Puramadathil Sasi Santhi[sup.1], Benjamin W. Y. Khoo[sup.1], Anthony Wong[sup.1], Vineeth Kodengil Vettath[sup.1], [...], Background Bacillus cereus is ubiquitous in nature, found in environments such as soil, plants, air, and part of the insect and human gut microbiome. The ability to produce endospores and biofilms contribute to their pathogenicity, classified in two types of food poisoning: diarrheal and emetic syndromes. Here we report gap-free, whole-genome sequences of two B. cereus strains isolated from air samples and analyse their emetic and diarrheal potential. Results Genome assemblies of the B. cereus strains consist of one chromosome and seven plasmids each. The genome size of strain SGAir0260 is 6.30-Mb with 6590 predicted coding sequences (CDS) and strain SGAir0263 is 6.47-Mb with 6811 predicted CDS. Macrosynteny analysis showed 99% collinearity between the strains isolated from air and 90.2% with the reference genome. Comparative genomics with 57 complete B. cereus genomes suggests these strains from air are closely associated with strains isolated from foodborne illnesses outbreaks. Due to virulence potential of B. cereus and its reported involvement in nosocomial infections, antibiotic resistance analyses were performed and confirmed resistance to ampicillin and fosfomycin, with susceptibility to ciprofloxacin, tetracycline and vancomycin in both strains. Conclusion Phylogenetic analysis combined with detection of haemolytic (hblA, hblC, and hblD) and non-haemolytic (nheA, nheB, and nheC) enterotoxin genes in both air-isolated strains point to the diarrheic potential of the air isolates, though not emetic. Characterization of these airborne strains and investigation of their potential disease-causing genes could facilitate identification of environmental sources of contamination leading to foodborne illnesses and nosocomial infections transported by air. Keywords: Bacillus cereus, Food poisoning, Antibiotic resistance, Enterotoxins

Author(s): Daekeun Hwang[sup.1,2], Seung Min Kim[sup.3] and Hyun Jung Kim[sup.1,2] Background Acid treatment is commonly used for the control or elimination of pathogenic microorganisms on the surface of medical devices [...], Background Acid treatment is commonly used for controlling or killing pathogenic microorganisms on medical devices and environments; however, inadequate acid treatment may cause acid tolerance response (ATR) and offer cross-protection against environmental stresses, including antimicrobials. This study aimed to characterise an Escherichia coli strain that can survive in the acidic gastrointestinal environment. Results We developed an acid-tolerant E. coli O157:H7 ATCC 43889 (ATCC 43889) strain that can survive at pH 2.75 via cell adaptation in low pH conditions. We also performed RNA sequencing and qRT-PCR to compare differentially expressed transcripts between acid-adapted and non-adapted cells. Genes related to stress resistance, including kdpA and bshA were upregulated in the acid-adapted ATCC 43889 strain. Furthermore, the polymyxin resistance gene arnA was upregulated in the acid-adapted cells, and resistance against polymyxin B and colistin (polymyxin E) was observed. As polymyxins are important antibiotics, effective against multidrug-resistant gram-negative bacterial infections, the emergence of polymyxin resistance in acid-adapted E. coli is a serious public health concern. Conclusion The transcriptomic and phenotypic changes analysed in this study during the adaptation of E. coli to acid environments can provide useful information for developing intervention technologies and mitigating the risk associated with the emergence and spread of antimicrobial resistance. Keywords: E. coli O157:H7, Polymyxin resistance, Acid adaptation, Whole genome sequencing, Transcriptome analysis

Introduction Arsenic (As) exposure through drinking water is a global public health concern affecting at least 140 million people (World Health Organization 2012). In 2001, the U.S. Environmental Protection Agency [...], BACKGROUND: Chronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes. OBJECTIVES: We investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, mean ([+ or -]SD) [micro]g/g creatinine: 11.7 (10.6)]. METHODS: DNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species. RESULTS: In adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (FDR < 0.05). After Bonferroni correction, 5 CpGs remained associated with total urinary As ([p.sub.Bonferroni] DISCUSSION: This is one of the first epigenome-wide association studies to investigate As exposure and locus-specific DNA methylation using the Illumina MethylationEPIC array and the largest epigenome-wide study of As exposure. The top DMP was located in SLC7A11A, a gene involved in cystine/glutamate transport and the biosynthesis of glutathione, an antioxidant that may protect against As-induced oxidative stress. Additional DMPs were located in genes associated with tumor development and glucose metabolism. Further research is needed, including research in more diverse populations, to investigate whether As-related DNA methylation signatures are associated with gene expression or may serve as biomarkers of disease development. https://doi.org/10.1289/EHP6263