The role of MscL amphipathic N terminus indicates a blueprint for bilayer-mediated gating of mechanosensitive channels

The bacterial mechanosensitive channel MscL gates in response to membrane tension as a result of mechanical force transmitted directly to the channel from the lipid bilayer. MscL represents an excellent model system to study the basic biophysical principles of mechanosensory transduction. However, understanding of the essential structural components that transduce bilayer tension into channel gating remains incomplete. Here using multiple experimental and computational approaches, we demonstrate that the amphipathic N-terminal helix of MscL acts as a crucial structural element during tension-induced gating, both stabilizing the closed state and coupling the channel to the membrane. We propose that this may also represent a common principle in the gating cycle of unrelated mechanosensitive ion channels, allowing the coupling of channel conformation to membrane dynamics

Phosphorylated IκBα predicts poor prognosis in activated B-cell lymphoma and its inhibition with thymoquinone induces apoptosis via ROS release

Activated B-cell lymphoma (ABC), one of the three subtypes of Diffuse Large B-cell Lymphoma (DLBCL) has the worst survival rate after upfront chemotherapy and is characterized by constitutively activated NFκB. We therefore studied the role of NFκB In a cohort of clinical DLBCL samples and ABC cell lines. In our clinical tissue microarray cohort of DLBCL samples, p-IκBα was detected in 38.3% of ABC DLBCL and was an independent prognostic marker for poor survival. In vitro, we found that Thymoquinone (TQ), a natural compound isolated from Nigella sativa caused release of ROS in ABC cells. TQ-mediated release of ROS in turn inhibited NFκB activity by dephosphorylating IκBα and decreased translocation of p65 subunit of NFκB in the nuclear compartment in ABC cell lines. This led to inhibition of cell viability and induction of mitochondrial dependent apoptosis in ABC-DLBCL cell lines. Additionally, TQ treatment also caused up-regulation of death receptor 5 (DR5), however, up-regulation of DR5 did not play a role in TQ-induced apoptosis. Finally, combination of sub-optimal doses of TQ and TRAIL induced efficient apoptosis in ABC-DLBCL cell lines. These data show that p-IκBα can be used as a prognostic marker and target for therapy in this aggressive sub-type of DLBCL and TQ may play an important role in the management of DLBCL in the future

Role of leptin and its receptors in the pathogenesis of thyroid cancer

Leptin is a multifunctional adipose-derived cytokines that play a critical role in bodyweight homeostasis and energy balance. Recently, leptin and leptin receptor dysreulation have been reported in variety of malignant cells including thyroid. Leptin modulates growth and proliferation of cancer cells via activation of various growth and survival signaling pathways including JAK/STAT, PI3-kinase/AKT and/or Map kinases. In this review, current understanding of leptin\u27s role in the pathogenesis of thyroid cancer has been described

Frequency of OBI among patients with autoimmune hepatitis

Autoimmune hepatitis (AIH) is recognized as a serious disease in which the body's immune system attacks liver cells so untreated patients may consequently suffer from liver cirrhosis, hepatocellular carcinoma (HCC) and liver failure. The role of viral infection may be involved in AIH. Presence of anti-HBc alone is a predictive signal of potential OBI. Thus, this study was conducted to evaluate the rate OBI among the patients with AIH. Methods: The sera of 20 consecutive patients with AIH were collected and tested for LFT (ALT, AST, ALP elevation), Immunoglobulin (IgG) level, bilirubin, anti-LKM-1, ASMA, ANA in titer, HBsAg, HBcIgG. The patients' sera were also tested for HBV DNA by nested PCR and Real-time PCR. Results: Out of 20 patients, 10 (50) were males and 10 (50) females. The patients' ages ranged from 25 to 71 years with the mean age of 44.5±13.4. All patients' had elevated abnormal ALT and AST but their level of alkaline phosphatase was normal among the patients. All patients had IgG level>1.5 times upper than the normal limit. The patients' sera were negative for HBsAg and HBV DNA (by nested PCR and real-time PCR). Only 2 (10) females with AHI type 1 (positive ANA, ASMA in titers >1:100 were positive for HBcIgG while no OBI detection was found among the males (p=0.005). All diagnosis of the AHI was confirmed by pathologist. The level of ALT, AST among the cases with positive and negative OBI were (p=0.000) and (p=0.003), respectively. Conclusion: In the present study, two OBI female patients with type 1 AIH were positive for anti-HBc but negative for HBsAg and HBV DNA. With regard to the consequences of OBI, prior to prophylactic treatment, it is recommended to screen HBV markers including anti-HBc in all diagnosed patients with AIH. © 2020 Asian Pacific Organization for Cancer Prevention

The role of MscL amphipathic N terminus indicates a blueprint for bilayer-mediated gating of mechanosensitive channels

The bacterial mechanosensitive channel MscL gates in response to membrane tension as a result of mechanical force transmitted directly to the channel from the lipid bilayer. MscL represents an excellent model system to study the basic biophysical principles of mechanosensory transduction. However, understanding of the essential structural components that transduce bilayer tension into channel gating remains incomplete. Here using multiple experimental and computational approaches, we demonstrate that the amphipathic N-terminal helix of MscL acts as a crucial structural element during tension-induced gating, both stabilizing the closed state and coupling the channel to the membrane. We propose that this may also represent a common principle in the gating cycle of unrelated mechanosensitive ion channels, allowing the coupling of channel conformation to membrane dynamics

Molybdenum (Mo) increases endogenous phenolics, proline and photosynthetic pigments and the phytoremediation potential of the industrially important plant Ricinus communis L. for removal of cadmium from contaminated soil.

Cadmium (Cd) in agricultural soil negatively affects crops yield and compromises food safety. Remediation of polluted soil is necessary for the re-establishment of sustainable agriculture and to prevent hazards to human health and environmental pollution. Phytoremediation is a promising technology for decontamination of polluted soil. The present study investigated the effect of molybdenum (Mo) (0.5, 1.0 and 2.0 ppm) on endogenous production of total phenolics and free proline, plant biomass and photosynthetic pigments in Ricinus communis plants grown in Cd (25, 50 and 100 ppm) contaminated soils and the potential for Cd phytoextraction. Mo was applied via seed soaking, soil addition and foliar spray. Foliar sprays significantly increased plant biomass, Cd accumulation and bioconcentration. Phenolic concentrations showed significantly positive correlations with Cd accumulation in roots (R 2 = 0.793, 0.807 and 0.739) and leaves (R 2 = 0.707, 721 and 0.866). Similarly, proline was significantly positively correlated with Cd accumulation in roots (R 2 = 0.668, 0.694 and 0.673) and leaves (R 2 = 0.831, 0.964 and 0.930). Foliar application was found to be the most effective way to deliver Mo in terms of increase in plant growth, Cd accumulation and production of phenolics and proline

Author Correction: The landscape of viral associations in human cancers

Correction to: Nature Genetics https://doi.org/10.1038/s41588-019-0558-9, published online 05 February 2020

Author Correction: Comprehensive molecular characterization of mitochondrial genomes in human cancers

Correction to: Nature Genetics, published online 05 February 2020. In the published version of this paper, the members of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium were listed in the Supplementary Information; however, these members should have been included in the main paper. The original Article has been corrected to include the members and affiliations of the PCAWG Consortium in the main paper; the corrections have been made to the HTML version of the Article but not the PDF version. Additional corrections to affiliations have been made to the PDF and HTML versions of the original Article for consistency of information between the PCAWG list and the main paper

Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma.

Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease.To classify PDAC according to distinct mutational processes, and explore their clinical significance.We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens.Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies.The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens.Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe