Direct oral anticoagulants' (DOAC) pharmacokinetics are affected by obesity. Their efficacy and safety in obesity (BMI≥30 kg/m2) and morbid obesity (BMI≥40 kg/m2) are still unclear in the treatment of venous thromboembolism (VTE).

Tuberculosis (TB) and coronavirus disease 2019 (COVID-19) are currently the two main causes of death among infectious diseases. There is an increasing number of studies trying to elucidate the interactions between Mycobacterium tuberculosis and SARS-CoV-2. Some of the first case reports point to a worsening of respiratory symptoms in co-infected TB/COVID-19 individuals. However, data from the cohort studies has shown some conflicting results. This study proposes to conduct a systematic review on the current literature on TB/COVID-19 co-infection cohorts, evaluating clinical and epidemiological data, focusing on its implications to the immune system. From an immunological perspective, the TB/COVID-19 co-infection has the potential to converge in a "perfect storm". The disorders induced by each pathogen to the immunomodulation tend to induce an unbalanced inflammatory response, which can promote the progression and worsening of both diseases. Understanding the nature of the interactions between M. tuberculosis and SARS-CoV-2 will be crucial for the development of therapeutic strategies against co-infection.

Brain metastasis (BM) is the primary first failure pattern in patients with curatively resected locally advanced non-small cell lung cancer (LA-NSCLC). It is not yet possible to accurately predict the occurrence of BM. The purpose of the research is to develop and validate a prediction model of BM-free survival based on radiomics characterising the primary lesions combined with clinical characteristics in patients with curatively resected LA-NSCLC.

Previously, we reported a [99mTc(ǀ)]+ labeled d-glucoamine derivative (99mTc-CN5DG) and evaluated it as a tumor imaging agent in mice bearing A549 tumor xenografts. In this paper, 99mTc-CN5DG was further studied in U87 MG (human glioma cells), HCT-116 (human colon cancer cells), PANC-1 (human pancreatic cancer cells) and TE-1 (human esophageal cancer cells) tumor xenografts models to verify its potential application for imaging of different kinds of tumors. The biodistribution data showed that 99mTc-CN5DG had a similar biodistribution pattern in four tumor models at 2 h post-injection with high accumulation in tumors and kidneys. The tumor/muscle ratios (from 4.08 ± 0.42 to 9.63 ± 3.53) and tumor/blood ratios (from 17.18 ± 7.40 to 53.17 ± 16.16) of 99mTc-CN5DG in four tumor models were high. All four kinds of tumors could be clearly seen on their corresponding SPECT/CT images. Pharmacokinetic study in healthy CD-1 mice demonstrated that 99mTc-CN5DG cleared fast from blood (2 min, 12.97 ± 0.88%ID/g; 60 min, 0.33 ± 0.06%ID/g) and the blood distribution, elimination half-life was 5.81 min and 21.16 min, respectively. No abnormality was observed through the abnormal toxicity study. All of the above results demonstrated that 99mTc-CN5DG could be a broad-spectrum SPECT probe for tumor imaging and its further clinical application is warranted.

The processing of facial emotion is an important social skill that develops throughout infancy and early childhood. Here we investigate the neural underpinnings of the ability to process facial emotion across changes in facial identity in cross-sectional groups of 5- and 7-month-old infants. We simultaneously measured neural metabolic, behavioral, and autonomic responses to happy, fearful, and angry faces of different female models using functional near-infrared spectroscopy (fNIRS), eye-tracking, and heart rate measures. We observed significant neural activation to these facial emotions in a distributed set of frontal and temporal brain regions, and longer looking to the mouth region of angry faces compared to happy and fearful faces. No differences in looking behavior or neural activations were observed between 5- and 7-month-olds, although several exploratory, age-independent associations between neural activations and looking behavior were noted. Overall, these findings suggest more developmental stability than previously thought in responses to emotional facial expressions of varying identities between 5- and 7-months of age.

Isoprenoids, also known as terpenes or terpenoids, represent a large family of natural products composed of five-carbon isopentenyl diphosphate or its isomer dimethylallyl diphosphate as the building blocks. Isoprenoids are structurally and functionally diverse and include dolichols, steroid hormones, carotenoids, retinoids, aromatic metabolites, the isoprenoid side-chain of ubiquinone, and isoprenoid attached signaling proteins. Productions of isoprenoids are catalyzed by a group of enzymes known as prenyltransferases, such as farnesyltransferases, geranylgeranyltransferases, terpenoid cyclase, squalene synthase, aromatic prenyltransferase, and cis- and trans-prenyltransferases. Because these enzymes are key in cellular processes and metabolic pathways, they are expected to be potential targets in new drug discovery. In this review, six distinct subsets of characterized prenyltransferases are structurally and mechanistically classified, including (1) head-to-tail prenyl synthase, (2) head-to-head prenyl synthase, (3) head-to-middle prenyl synthase, (4) terpenoid cyclase, (5) aromatic prenyltransferase, and (6) protein prenylation. Inhibitors of those enzymes for potential therapies against several diseases are discussed. Lastly, recent results on the structures of integral membrane enzyme, undecaprenyl pyrophosphate phosphatase, are also discussed.

Neuroimaging research has identified a network of brain regions that are more active when we daydream compared to when we are engaged in a task. This network has been named the default mode network. Furthermore, differences in the default mode network are the most consistent findings in neuroimaging research in autism. Recent studies suggest that the default mode network is composed of subnetworks that are tied to different functions, namely memory and understanding others' minds. In this study, we investigated if default mode network differences in autism are related to specific subnetworks of the default mode network and if these differences change across childhood and adolescence. Our results suggest that the subnetworks of the default mode network are less differentiated in autism in middle childhood compared to neurotypicals. By late adolescence, the default mode network subnetwork organisation was similar in the autistic and neurotypical groups. These findings provide a foundation for future studies to investigate if this developmental pattern relates to improvements in the integration of memory and social understanding as autistic children grow up.

The appropriate regulation of thylakoid lipid synthesis is essential for the function of chloroplasts. In plant cells, membrane lipids synthesized in the ER are utilized as a precursor for the synthesis of chloroplast glycolipids. This pathway is thought to be mediated by the transport of glycerolipids synthesized in the ER into chloroplasts. However, we have little knowledge about the proteins involved in the lipid transfer between these organelles in plant cells. Here we show a protein, STAR2, containing the START (Steroidogenic acute regulatory protein-related lipid transfer) domain known to function as a lipid transporter, is involved in the incorporation of ER-derived fatty acids into chloroplast glycolipids in Marchantia polymorpha. We found that STAR2 localizes on the chloroplast envelope membrane as a punctuate structure and is required for the increase of C20 fatty acids, which are synthesized in the ER, in chloroplast glycolipids in response to phosphate deprivation. Our results indicate that STAR2 of M. polymorpha is likely to be involved in the lipid transfer from ER to chloroplast, presumably as a lipid transporter.

Most women with epithelial ovarian cancer (EOC) are diagnosed after the disease has metastasized and survival in this group remains poor. Circulating proteins associated with the risk of developing EOC have the potential to serve as biomarkers for early detection and diagnosis. We integrated large-scale genomic and proteomic data to identify novel plasma proteins associated with EOC risk.

Obesity, a global health problem nowadays, is a state of low-grade chronic inflammation of adipose tissue (AT) associated with increased adipocyte growth and proliferation and immune cell polarization towards an inflammatory phenotype within the stromal vascular fraction (SVF). Pro-inflammatory cells in the AT produce mediators of inflammation (IL-1β, TNF, macrophage migration inhibitory factor - MIF), thereby surpassing the anti-inflammatory response mediated by IL-10 and TGF-β, cytokines produced by regulatory T (Treg) cells. In this study we demonstrate that the absence of the pro-inflammatory cytokine MIF led to obesity and inflammation in the visceral AT (VAT) in 6 months old MIF-/- mice. Besides the increment of pro-inflammatory AT macrophages and the enhanced production of TNF and IL-1β, VAT of MIF-/- mice contained increased numbers of Treg cells. In situ proliferation of Treg cells did not differ between MIF-/- and wild type mice, but Treg cells isolated from the VAT of MIF-deficient mice, and not from the cervical lymph nodes, exhibited lower expression and production of IL-10 and TGF-β. Additionally, SVF cells had significantly lower levels of STAT3 and IL-33, altogether indicating that VAT Treg cells in MIF-/- mice, albeit abundantly present, are not fully functional. These results indicate that MIF is a new regulator of VAT Treg cell function, necessary for their immunosuppressive activities.

High-protein diets and total diet replacements are becoming increasingly popular for weight loss; however, further research is needed to elucidate their impact on the mechanisms involved in weight regulation.

Ustilago maydis is the causal agent of maize smut disease. During the colonization process, the fungus secretes effector proteins that suppress immune responses and redirect the host metabolism in favor of the pathogen. As effectors play a critical role during plant colonization, their identification and functional characterization are essential to understanding biotrophy and disease. Using biochemical, molecular, and transcriptomic techniques, we performed a functional characterization of the U. maydis effector Jasmonate/Ethylene signaling inducer 1 (Jsi1). Jsi1 interacts with several members of the plant corepressor family Topless/Topless related (TPL/TPR). Jsi1 expression in Zea mays and Arabidopsis thaliana leads to transcriptional induction of the ethylene response factor (ERF) branch of the jasmonate/ethylene (JA/ET) signaling pathway. In A. thaliana, activation of the ERF branch leads to biotrophic susceptibility. Jsi1 likely activates the ERF branch via an EAR (ET-responsive element binding-factor-associated amphiphilic repression) motif, which resembles EAR motifs from plant ERF transcription factors, that interacts with TPL/TPR proteins. EAR-motif-containing effector candidates were identified from different fungal species, including Magnaporthe oryzae, Sporisorium scitamineum, and Sporisorium reilianum. Interaction between plant TPL proteins and these effector candidates from biotrophic and hemibiotrophic fungi indicates the convergent evolution of effectors modulating the TPL/TPR corepressor hub.

COVID-19 is caused by a novel virus with an unknown aetiology. People across the globe are dealing with not only a health crisis but also an 'infodemic', a term coined by the World Health Organization to refer to the avalanche of contradictory information that is arousing widespread confusion and anxiety. This study aimed to examine the prevalence of anxiety and sleep disturbance at the early stage of the pandemic, and unveil the information coping process underlying differential susceptibility to COVID-19 infection anxiety and sleep disturbance. The participants were 1,270 adults (47% men, Mage  = 42.82) from the UK and US who completed initial (Time 1) and follow-up (Time 2) surveys from 16 to 22 March and 18 to 24 May 2020, respectively. The prevalence of probable clinically relevant anxiety was 61% and 45% at the first and second time points, and more than half of the participants in this anxiety group also reported mild to severe sleep disturbance. Moreover, 41% of the participants perceived themselves as not having enough COVID-19-related information and reported higher levels of COVID-19 infection anxiety and sleep disturbance over time than those who perceived themselves as having enough of such information. Moderated mediation analysis identified two groups who were more vulnerable to both psychological problems: high blunters who sought COVID-19-related information online more frequently and high monitors who sought such information offline less frequently. These findings highlight the importance of a good match between information coping style and strategy deployment in dealing with an infodemic surrounding a novel disease.

Working memory (WM) problems are frequently present in people with multiple sclerosis (MS). Even though hippocampal damage has been repeatedly shown to play an important role, the underlying neurophysiological mechanisms remain unclear. This study aimed to investigate the neurophysiological underpinnings of WM impairment in MS using magnetoencephalography (MEG) data from a visual-verbal 2-back task. We analysed MEG recordings of 79 MS patients and 38 healthy subjects through event-related fields and theta (4-8 Hz) and alpha (8-13 Hz) oscillatory processes. Data was source reconstructed and parcellated based on previous findings in the healthy subject sample. MS patients showed a smaller maximum theta power increase in the right hippocampus between 0 and 400 ms than healthy subjects (p = .014). This theta power increase value correlated negatively with reaction time on the task in MS (r = -.32, p = .029). Evidence was provided that this relationship could not be explained by a 'common cause' confounding relationship with MS-related neuronal damage. This study provides the first neurophysiological evidence of the influence of hippocampal dysfunction on WM performance in MS.

Whole Slide Imaging (WSI) is an alternative method to light microscopy (LM). However, few studies have compared the diagnostic agreement between WSI and LM, especially to grade oral epithelial dysplasia (OED). The purpose of this study was to evaluate the variability in grading OED by the World Health Organization grading system, using WSI and conventional LM, and to investigate whether the access to clinical information, and psychologic or physical states of the pathologists could interfere with the diagnosis.

The diagnosis of renal cell carcinoma (RCC) is often made late since there is no early symptom, which thus results in dismal patient prognosis. As a result, new biomarkers are urgently needed and efforts should be made to identify their functions in predicting RCC prognosis. microRNAs (miRNAs) are a class of small noncoding RNAs that are about 20-22 nucleotides in length, and they have been demonstrated to function as prognostic markers in numerous tumors. This study aimed to assess the role of miR-30b-5p in predicting the prognosis of RCC postoperatively. In this study, RNA was extracted from 284 formalin-fixed and paraffin-embedded kidney cancer tissue samples. After cDNA synthesis, real-time quantitative PCR (RT-qPCR) was adopted for detecting the relative miR-30b-5p level. Then, the Kaplan-Meier method, Cox regression analysis, and the receiver operating characteristic curve analysis were applied in analyzing the miR-30b-5p effect on the prognosis for patients. Our findings indicated that, following adjustment for age, gender, tumor stage, and tumor size, patients with low miR-30b-5p expression had remarkably longer overall survival. Thus, the miR-30b-5p level might be related to RCC prognosis.

Since the discovery of admixture between modern humans and Neandertals, multiple studies investigated the effect of Neandertal-derived DNA on human disease and nondisease phenotypes. These studies have linked Neandertal ancestry to skin- and hair-related phenotypes, immunity, neurological, and behavioral traits. However, these inferences have so far been limited to cohorts with participants of European ancestry. Here, I analyze summary statistics from 40 disease GWAS (genome-wide association study) cohorts of ∼212,000 individuals provided by the Biobank Japan Project for phenotypic effects of Neandertal DNA. I show that Neandertal DNA is associated with autoimmune diseases, prostate cancer and type 2 diabetes. Many of these disease associations are linked to population-specific Neandertal DNA, highlighting the importance of studying a wider range of ancestries to characterize the phenotypic legacy of Neandertals in people today.

Meiotic recombination is a critical process that ensures proper segregation of chromosome homologs through DNA double-strand break repair mechanisms. Rates of recombination are highly variable among various taxa, within species, and within genomes with far-reaching evolutionary and genomic consequences. The genetic basis of recombination rate variation is therefore crucial in the study of evolutionary biology but remains poorly understood. In this study, we took advantage of a set of experimental temperature-evolved populations of Drosophila melanogaster with heritable differences in recombination rates depending on the temperature regime in which they evolved. We performed whole-genome sequencing and identified several chromosomal regions that appear to be divergent depending on temperature regime. In addition, we identify a set of single-nucleotide polymorphisms and associated genes with significant differences in allele frequency when the different temperature populations are compared. Further refinement of these gene candidates emphasizing those expressed in the ovary and associated with DNA binding reveals numerous potential candidate genes such as Hr38, EcR, and mamo responsible for observed differences in recombination rates in these experimental evolution lines thus providing insight into the genetic basis of recombination rate variation.

Individuals with type 2 diabetes have an increased risk of endothelial dysfunction and cardiovascular disease. Plasma aldosterone could contribute by reactive oxygen species-dependent mechanisms by inducing a shift in the balance between a vasoconstrictor and vasodilator response to aldosterone.

Genomic variation in the model plant Arabidopsis thaliana has been extensively used to understand evolutionary processes in natural populations, mainly focusing on single-nucleotide polymorphisms. Conversely, structural variation has been largely ignored in spite of its potential to dramatically affect phenotype. Here, we identify 155,440 indels and structural variants ranging in size from 1 bp to 10 kb, including presence/absence variants (PAVs), inversions, and tandem duplications in 1,301 A. thaliana natural accessions from Morocco, Madeira, Europe, Asia, and North America. We show evidence for strong purifying selection on PAVs in genes, in particular for housekeeping genes and homeobox genes, and we find that PAVs are concentrated in defense-related genes (R-genes, secondary metabolites) and F-box genes. This implies the presence of a "core" genome underlying basic cellular processes and a "flexible" genome that includes genes that may be important in spatially or temporally varying selection. Further, we find an excess of intermediate frequency PAVs in defense response genes in nearly all populations studied, consistent with a history of balancing selection on this class of genes. Finally, we find that PAVs in genes involved in the cold requirement for flowering (vernalization) and drought response are strongly associated with temperature at the sites of origin.