The accumulations of different types of genetic alterations such as nucleotide substitutions, structural rearrangements and viral genome integrations and epigenetic alterations contribute to carcinogenesis. Here, we report correlation between the occurrence of epigenetic features and genetic aberrations by whole-genome bisulfite, whole-genome shotgun, long-read, and virus capture sequencing of 373 liver cancers. Somatic substitutions and rearrangement breakpoints are enriched in tumor-specific hypo-methylated regions with inactive chromatin marks and actively transcribed highly methylated regions in the cancer genome. Individual mutation signatures depend on chromatin status, especially, signatures with a higher transcriptional strand bias occur within active chromatic areas. Hepatitis B virus (HBV) integration sites are frequently detected within inactive chromatin regions in cancer cells, as a consequence of negative selection for integrations in active chromatin regions. Ultra-high structural instability and preserved unmethylation of integrated HBV genomes are observed. We conclude that both precancerous and somatic epigenetic features contribute to the cancer genome architecture.

Forests mitigate climate change by sequestering large amounts of carbon (C). However, forest C storage is not permanent, and large pulses of tree mortality can thwart climate mitigation efforts. Forest pests are increasingly redistributed around the globe. Yet, the potential future impact of invasive alien pests on the forest C cycle remains uncertain. Here we show that large parts of Europe could be invaded by five detrimental alien pests already under current climate. Climate change increases the potential range of alien pests particularly in Northern and Eastern Europe. We estimate the live C at risk from a potential future invasion as 1027 Tg C (10% of the European total), with a C recovery time of 34 years. We show that the impact of introduced pests could be as severe as the current natural disturbance regime in Europe, calling for increased efforts to halt the introduction and spread of invasive alien species.

Many non-histone proteins are lysine methylated and a novel function of this modification is to trigger the proteolysis of methylated proteins. Here, we report that the methylated lysine 142 of DNMT1, a major DNA methyltransferase that preserves epigenetic inheritance of DNA methylation patterns during DNA replication, is demethylated by LSD1. A novel methyl-binding protein, L3MBTL3, binds the K142-methylated DNMT1 and recruits a novel CRL4DCAF5 ubiquitin ligase to degrade DNMT1. Both LSD1 and PHF20L1 act primarily in S phase to prevent DNMT1 degradation by L3MBTL3-CRL4DCAF5. Mouse L3MBTL3/MBT-1 deletion causes accumulation of DNMT1 protein, increased genomic DNA methylation, and late embryonic lethality. DNMT1 contains a consensus methylation motif shared by many non-histone proteins including E2F1, a key transcription factor for S phase. We show that the methylation-dependent E2F1 degradation is also controlled by L3MBTL3-CRL4DCAF5. Our studies elucidate for the first time a novel mechanism by which the stability of many methylated non-histone proteins are regulated.

Arp2/3 complex-mediated actin assembly at cell membranes drives the formation of protrusions or endocytic vesicles. To identify the mechanism by which different membrane deformations can be achieved, we reconstitute the basic membrane deformation modes of inward and outward bending in a confined geometry by encapsulating a minimal set of cytoskeletal proteins into giant unilamellar vesicles. Formation of membrane protrusions is favoured at low capping protein (CP) concentrations, whereas the formation of negatively bent domains is promoted at high CP concentrations. Addition of non-muscle myosin II results in full fission events in the vesicle system. The different deformation modes are rationalized by simulations of the underlying transient nature of the reaction kinetics. The relevance of the regulatory mechanism is supported by CP overexpression in mouse melanoma B16-F1 cells and therefore demonstrates the importance of the quantitative understanding of microscopic kinetic balances to address the diverse functionality of the cytoskeleton.

Consumption of methane by aerobic and anaerobic microbes governs the atmospheric level of this powerful greenhouse gas. Whereas a biochemical understanding of aerobic methanotrophy is well developed, a mechanistic understanding of anaerobic methanotrophy has been prevented by the unavailability of pure cultures. Here we report a biochemical investigation of Methanosarcina acetivorans, a methane-producing species capable of anaerobic methanotrophic growth dependent on reduction of Fe(III). Our findings support a pathway anchored by Fe(III)-dependent mechanisms for energy conservation driving endergonic reactions that are key to methanotrophic growth. The pathway is remarkably similar to pathways hypothesized for uncultured anaerobic methanotrophic archaea. The results contribute to an improved understanding of the methane cycle that is paramount to understanding human interventions influencing Earth's climate. Finally, the pathway enables advanced development and optimization of biotechnologies converting methane to value-added products through metabolic engineering of M. acetivorans.

Endometriosis is a common benign gynecological disease, characterized by growth and proliferation of endometrial glands and stroma outside the uterus. With studies showing metabolic changes in various biofluids of endometriosis women, we have set upon to investigate whether endometrial tissue show differences in their metabolic profiles. 1H NMR analysis was performed on eutopic endometrial tissue of women with endometriosis and controls. Analysis was performed on spectral data and on relative concentrations of metabolites obtained from spectra using multivariate and univariate data analysis. Analysis shows that various energy, ketogenic and glucogenic metabolites have significant altered concentrations in various stages of endometriosis. In addition, altered tissue metabolites in minimal and mild stages of endometriosis were explored in serum of these patients to assess their role in disease diagnosis. For Stage I diagnosis alanine was found to have 90% sensitivity (true positives) and 58% specificity (true negatives). For Stage II diagnosis alanine, leucine, lysine, proline and phenylalanine showed significant altered levels in serum. While sensitivity of these serum metabolites varied between 69.2-100% the specificity values ranged between 58.3-91.7%. Further, a regression model generated with this panel of serum markers showed an improved sensitivity and specificity of 100% and 83%, respectively for Stage II diagnosis.

Hippo signaling pathway is an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis and stem cell self-renewal. TAZ (transcriptional coactivator with the PDZ-binding motif) is a key downstream effector of the mammalian Hippo pathway. Here, using a transgenic mouse model with mammary-gland-specific expression of constitutively active TAZ, we found that TAZ induction in mammary epithelial cells was associated with an increase in mammary glandular size, which probably resulted from adipocyte hypertrophy. Consistent with its known oncogenic potential, we observed tumor formation in TAZ transgenic mice after administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA) and demonstrated that tumorigenesis was reliant on the presence of TAZ. Our findings establish a previously unknown roles of TAZ in regulating both mammary gland morphogenesis as well as carcinogen-induced mammary tumor formation.

The risk of suffering from Alzheimer's disease (AD) is higher in individuals from AD-affected mothers. The purpose of this investigation was to study whether maternal transmission might produce AD-related alterations in progenies of mice that do not have any genotypic alteration. We used cognitively-intact mothers harbouring in heterozygosity the transgene for overexpressing the Swedish double mutant version of the human amyloid precursor protein (hAβPPswe). The phenotype of the offspring with or without the transgene resulting from crossing young Tg2576 females with wild-type males were compared with those of the offspring resulting from crossing wild-type females with Tg2576 males. The hAβPPswe-bearing offspring from Tg2576 mothers showed an aggravated AD-like phenotype. Remarkably, cognitive, immunohistochemical and some biochemical features displayed by Tg2576 heterozygous mice were also found in wild-type animals generated from Tg2576 females. This suggests the existence of a maternal imprinting in the wild-type offspring that confers a greater facility to launch an AD-like neurodegenerative cascade. Such progeny, lacking any mutant amyloid precursor protein, constitutes a novel model to study maternal transmission of AD and, even more important, to discover early risk markers that predispose to the development of AD.

In order to make sense of the objects we encounter in everyday life we largely rely on previous knowledge stored in our semantic memory. Semantic memory is considered dependent on lifelong experience and cultural knowledge. So far, a few studies have investigated the role of expertise on the organization of semantic memory, whereas life-long experience has largely been overlooked. In this study, we investigated this issue using food concepts. In particular, we administered different semantic tasks using food (natural and transformed) and non-food (living and non-living things) as stimuli to participants belonging to three different age cohorts (56-74, 75-91, 100-108), who were also asked to report on the dietary habits held throughout their life. In addition, we investigated to what extent psycholinguistic variables influence the semantic performance of different age cohorts. Results showed that Centenarians recognized natural food better than transformed food, while the other two groups showed the opposite pattern. According to our analyses, experience is responsible for this effect in Centenarians, as their dietary habits seem to suggest. Moreover, significant correlations between picture naming and age of acquisition, familiarity and frequency were observed. This study indicates that lifelong experience can shape conceptual knowledge of food concepts, and that semantic memory is less resilient to aging than initially thought.

The emergence of >300 serovars of Leptospira confounded the use of generalized bacterin, the whole cell lysate, as vaccines to control leptospirosis. Because of substantial genetic and geographic heterogeneity among circulating serovars, one vaccine strain per serovar cannot be efficacious against all the serovars. We have performed heterologous DNA prime-protein boost vaccination challenge studies in hamsters using in vivo expressed, leptospiral recombinase A (RecA) and flagellar hook associated protein (FliD). We prepared the monovalent recombinant protein, plasmid DNA, and DNA prime protein boost adjuvant vaccines. The whole cell bacterin served as a control. Our data show that (i) RecA and FliD have multiple immunogenic B and T-cell epitopes with highly conserved domains among most prevalent pathogenic Leptospira spp., (ii) humoral and cell mediated immune responses were induced remarkably, (iii) provides significant protection against homologous (Autumnalis strain N2) and cross-clade heterologous (Canicola strain PAI-1) challenge infection for the heterologous prime-protein boost (∼91-100%) and, the DNA vaccine (∼75-83%). Recombinant protein vaccine shows only partial protection (∼58-66%), (iv) RecA prime-protein boost vaccine shows sterilizing immunity, with heterologous protection. This RecA/FliD prime-protein boost strategy holds potential for vaccination against animal leptospirosis and for a better control of zoonotic transmission.

Creative insight occurs with an "Aha!" experience when solving a difficult problem. Here, we investigated large-scale networks associated with insight problem solving. We recruited 232 healthy participants aged 21-69 years old. Participants completed a magnetic resonance imaging study (MRI; structural imaging and a 10 min resting-state functional MRI) and an insight test battery (ITB) consisting of written questionnaires (matchstick arithmetic task, remote associates test, and insight problem solving task). To identify the resting-state functional connectivity (RSFC) associated with individual creative insight, we conducted an exploratory voxel-based morphometry (VBM)-constrained RSFC analysis. We identified positive correlations between ITB score and grey matter volume (GMV) in the right insula and middle cingulate cortex/precuneus, and a negative correlation between ITB score and GMV in the left cerebellum crus 1 and right supplementary motor area. We applied seed-based RSFC analysis to whole brain voxels using the seeds obtained from the VBM and identified insight-positive/negative connections, i.e. a positive/negative correlation between the ITB score and individual RSFCs between two brain regions. Insight-specific connections included motor-related regions whereas creative-common connections included a default mode network. Our results indicate that creative insight requires a coupling of multiple networks, such as the default mode, semantic and cerebral-cerebellum networks.

Epstein-Barr virus (EBV)-associated Burkitt's lymphoma is characterised by the deregulation of c-Myc expression and a restricted viral gene expression pattern in which the EBV nuclear antigen-1 (EBNA1) is the only viral protein to be consistently expressed. EBNA1 is required for viral genome propagation and segregation during latency. However, it has been much debated whether the protein plays a role in viral-associated tumourigenesis. We show that the lymphomas which arise in EµEBNA1 transgenic mice are unequivocally linked to EBNA1 expression and that both C-Myc and Mdm2 deregulation are central to this process. Tumour cell survival is supported by IL-2 and there is a skew towards CD8-positive T cells in the tumour environment, while the immune check-point protein PD-L1 is upregulated in the tumours. Additionally, several isoforms of Mdm2 are upregulated in the EµEBNA1 tumours, with increased phosphorylation at ser166, an expression pattern not seen in Eµc-Myc transgenic tumours. Concomitantly, E2F1, Xiap, Mta1, C-Fos and Stat1 are upregulated in the tumours. Using four independent inhibitors of Mdm2 we demonstrate that the EµEBNA1 tumour cells are dependant upon Mdm2 for survival (as they are upon c-Myc) and that Mdm2 inhibition is not accompanied by upregulation of p53, instead cell death is linked to loss of E2F1 expression, providing new insight into the underlying tumourigenic mechanism. This opens a new path to combat EBV-associated disease.

Mothers provide their offspring with symbionts. Maternally transmitted, intracellular symbionts must disperse from mother to offspring with other cytoplasmic elements, like mitochondria. Here, we investigated how the intracellular symbiont Wolbachia interacts with mitochondria during maternal transmission. Mitochondria and Wolbachia may interact antagonistically and compete as each population tries to ensure its own evolutionary success. Alternatively, mitochondria and Wolbachia may cooperate as both benefit from ensuring the fitness of the mother. We characterized the relationship between mitochondria and Wolbachia titers in ovaries of Drosophila melanogaster. We found that mitochondria and Wolbachia titers are positively correlated in common laboratory genotypes of D. melanogaster. We attempted to perturb this covariation through the introduction of Wolbachia variants that colonize at different titers. We also attempted to perturb the covariation through manipulating the female reproductive tract to disrupt maternal transmission. Finally, we also attempted to disrupt the covariation by knocking down gene expression for two loci involved in mitochondrial metabolism: NADH dehydrogenase and a mitochondrial transporter. Overall, we find that mitochondria and Wolbachia titers are commonly positively correlated, but this positive covariation is disrupted at high titers of Wolbachia. Our results suggest that mitochondria and Wolbachia have likely evolved mechanisms to stably coexist, but the competitive dynamics change at high Wolbachia titers. We provide future directions to better understand how their interaction influences the maintenance of the symbiosis.

We tested the hypothesis that genetic variation in ATM and BMI-1 genes can alter the risk of breast cancer through genotyping 6 variants among 524 breast cancer cases and 518 cancer-free controls of Han nationality. This was an observational, hospital-based, case-control association study. Analyses of single variant, linkage, haplotype, interaction and nomogram were performed. Risk was expressed as odds ratio (OR) and 95% confidence interval (CI). All studied variants were in the Hardy-Weinberg equilibrium and were not linked. The mutant allele frequencies of rs1890637, rs3092856 and rs1801516 in ATM gene were significantly higher in cases than in controls (P = .005, <.001 and .001, respectively). Two variants, rs1042059 and rs201024480, in BMI-1 gene were low penetrant, with no detectable significance. After adjustment, rs189037 and rs1801516 were significantly associated with breast cancer under the additive model (OR: 1.37 and 1.52, 95% CI: 1.10-1.71 and 1.14-2.04, P: .005 and .005, respectively). In haplotype analysis, haplotypes A-C-G-G (in order of rs189037, rs3092856, rs1801516 and rs373759) and A-C-A-A in ATM gene were significantly associated with 1.98-fold and 6.04-fold increased risk of breast cancer (95% CI: 1.36-2.90 and 1.65-22.08, respectively). Nomogram analysis estimated that the cumulative proportion of 3 significant variants in ATM gene was about 12.5%. Our findings collectively indicated that ATM gene was a candidate gene in susceptibility to breast cancer in Han Chinese.

Neonatal hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a sexually dimorphic disease. Male infants are not only more vulnerable to ischemic insult; they also suffer more long-term cognitive deficits compared with females with comparable brain damage. The innate immune response plays a fundamental role in mediating acute neonatal HIE injury. However, the mechanism underlying the sex difference in chronic HIE is still elusive. The present study investigated the sex difference in HIE outcomes and inflammatory response in the chronic stage (30 days after HIE). Postnatal day 10 (P10) male and female C57BL/6 pups were subjected to 60-min Rice-Vanucci model (RVM) to induce HIE. Brain atrophy and behavioral deficits were analyzed to measure stroke outcomes at 30 days of HIE. Flow cytometry (FC) was performed to examine central (microglial activation) and peripheral immune responses. Serum levels of cytokines and sex hormones were determined by enzyme-linked immunosorbent assay (ELISA). Neurogenesis was quantified by 5-Bromo-2'-deoxyuridine (BrdU) incorporation with neurons. Results showed males had worse HIE outcomes than females at the endpoint. Female microglia exhibited a more robust anti-inflammatory response that was corresponding to an enhanced expression of CX3C chemokine receptor 1 (CX3CR1) than males. More infiltration of peripheral lymphocytes was seen in male vs. female HIE brains. Cytokine levels of tumor necrosis factor (TNF)-α and interleukin (IL)-10 were more upregulated in males and females respectively than their counterparts. Neurogenesis was more highly induced in females vs. males. No significant difference in circulating hormonal level was found between males and females after HIE. We conclude that a sex dichotomy in pro- and anti-inflammatory response underlies the sex-specific chronic HIE outcomes, and an enhanced neurogenesis in females also contribute to the sex difference.

The replication-deficient orthopoxvirus modified vaccinia virus Ankara (MVA) is a promising vaccine vector against various pathogens and has an excellent safety record. However, pre-existing vector-specific immunity is frequently suggested to be a drawback of MVA-based vaccines. To address this issue, mice were vaccinated with MVA-based influenza vaccines in the presence or absence of orthopoxvirus-specific immunity. Importantly, protective efficacy of an MVA-based influenza vaccine against a homologous challenge was not impaired in the presence of orthopoxvirus-specific pre-existing immunity. Nonetheless, orthopoxvirus-specific pre-existing immunity reduced the induction of antigen-specific antibodies under specific conditions and completely prevented induction of antigen-specific T cell responses by rMVA-based vaccination. Notably, antibodies induced by vaccinia virus vaccination, both in mice and humans, were not capable of neutralizing MVA. Thus, when using rMVA-based vaccines it is important to consider the main correlate of protection induced by the vaccine, the vaccine dose and the orthopoxvirus immune status of vaccine recipients.

The objective of this study was to evaluate the safety and effectiveness of the TearCare® System in adult patients with clinically significant dry eye disease (DED).

Precision medicine is being enabled in high-income countries by the growing availability of health data, increasing knowledge of the genetic determinants of disease and variation in response to treatment (pharmacogenomics), and the decreasing costs of data generation, which promote routine application of genomic technologies in the health sector. However, there is uncertainty about the feasibility of applying precision medicine approaches in low- and middle-income countries, due to the lack of population-specific knowledge, skills, and resources. The Human Heredity and Health in Africa (H3Africa) initiative was established to drive new research into the genetic and environmental basis for human diseases of relevance to Africans as well as to build capacity for genomic research on the continent. Precision medicine requires this capacity, in addition to reference data on local populations, and skills to analyze and interpret genomic data from the bedside. The H3Africa consortium is collectively processing samples and data for over 70,000 participants across the continent, accompanied in most cases by rich clinical information on a variety of non-communicable and infectious diseases. These projects are increasingly providing novel insights into the genetic basis of diseases in indigenous populations, insights that have the potential to drive the development of new diagnostics and treatments. The consortium has also invested significant resources into establishing high-quality biorepositories in Africa, a bioinformatic network, and a strong training program that has developed skills in genomic data analysis and interpretation among bioinformaticians, wet-lab researchers, and health-care professionals. Here, we describe the current perspectives of the H3Africa consortium and how it can contribute to making precision medicine in Africa a reality.

The majority of the reviews and studies on chronic pain in pregnancy have primarily focused on the pharmacological and non-pharmacological treatment options. The purpose of our review was to identify evidence-based clinical research for the evaluation and management of preexisting chronic pain in pregnancy, chronic pain associated with pregnancy, and chronic pain in relation to mode of delivery.

Management of menstruation in contexts of humanitarian emergencies can be challenging. A lack of empirical research about effective interventions which improve menstrual hygiene management (MHM) among female populations in humanitarian emergencies and a lack of clarity about which sectors within a humanitarian response should deliver MHM interventions can both be attributable to the lack of clear guidance on design and delivery of culturally appropriate MHM intervention in settings of humanitarian emergencies. The objective of this review was to collate, summarize, and appraise existing peer-reviewed and gray literature that describes the current scenario of MHM in emergency contexts in order to describe the breadth and depth of current policies, guidelines, empirical research, and humanitarian aid activities addressing populations' menstrual needs. A structured-search strategy was conducted for peer-reviewed and gray literature to identify studies, published reports, guidelines, and policy papers related to menstrual response in emergency humanitarian contexts. Of the 51 articles included in the review, 16 were peer-reviewed papers and 35 were gray literature. Most of the literature agreed that hardware interventions should focus on the supply of adequate material (not only absorbent material but also other supportive material) and adequate sanitation facilities, with access to water and private space for washing, changing, drying, and disposing menstrual materials. Software interventions should focus on education in the usage of materials to manage menstruation hygienically and education about the female body's biological processes. There was clear agreement that the needs of the target population should be assessed before designing any intervention. Although there is insight about which factors should be included in an effective menstrual hygiene intervention, there is insufficient empirical evidence to establish which interventions are most effective in humanitarian emergencies and which sectors should be responsible for the coordination and implementation of such. Increased monitoring and evaluation studies of interventions should be completed and publicly shared, in order to feed evidence-based guidelines in the humanitarian sector.