Search

Longitudinal observational data on patients can be used to investigate causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for estimating such effects by controlling for the time-dependent confounding that typically occurs. The most commonly used is marginal structural models (MSM) estimated using inverse probability of treatment weights (IPTW) (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, and involves creating a sequence of "trials" from new time origins and comparing treatment initiators and non-initiators. Individuals are censored when they deviate from their treatment assignment at the start of each "trial" (initiator or noninitiator), which is accounted for using inverse probability of censoring weights. The analysis uses data combined across trials. We show that the sequential trials approach can estimate the parameters of a particular MSM. The causal estimand that we focus on is the marginal risk difference between the sustained treatment strategies of "always treat" vs "never treat." We compare how the sequential trials approach and MSM-IPTW estimate this estimand, and discuss their assumptions and how data are used differently. The performance of the two approaches is compared in a simulation study. The sequential trials approach, which tends to involve less extreme weights than MSM-IPTW, results in greater efficiency for estimating the marginal risk difference at most follow-up times, but this can, in certain scenarios, be reversed at later time points and relies on modelling assumptions. We apply the methods to longitudinal observational data from the UK Cystic Fibrosis Registry to estimate the effect of dornase alfa on survival.

In the central nervous system (CNS), insulin-like growth factor 1 (IGF-1) regulates myelination by oligodendrocyte (ODC) precursor cells and shows anti-apoptotic properties in neuronal cells in different in vitro and in vivo systems. Previous work also suggests that IGF-1 protects ODCs from cell death and enhances remyelination in models of toxin-induced and autoimmune demyelination. However, since evidence remains controversial, the therapeutic potential of IGF-1 in demyelinating CNS conditions is unclear. To finally shed light on the function of IGF1-signaling for ODCs, we deleted insulin-like growth factor 1 receptor (IGF1R) specifically in mature ODCs of the mouse. We found that ODC survival and myelin status were unaffected by the absence of IGF1R until 15 months of age, indicating that IGF-1 signaling does not play a major role in post-mitotic ODCs during homeostasis. Notably, the absence of IGF1R did neither affect ODC survival nor myelin status upon cuprizone intoxication or induction of experimental autoimmune encephalomyelitis (EAE), models for toxic and autoimmune demyelination, respectively. Surprisingly, however, the absence of IGF1R from ODCs protected against clinical neuroinflammation in the EAE model. Together, our data indicate that IGF-1 signaling is not required for the function and survival of mature ODCs in steady-state and disease.

BackgroundEpidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties.ObjectiveWe used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors.MethodsWe used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses.ResultsWe confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31).ConclusionsWe show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

AzoChignolin is a photoswitchable variant of the mini-protein Chignolin with an azobenzene (AMPP) replacing the central loop. AzoChignolin is unfolded with AMPP in the trans-isomer. Transition to the cis-isomer causes β-hairpin folding similar to Chignolin. The AzoChignolin system is excellently suited for comprehensive analysis of folding nucleation kinetics. Utilizing multiple long-time MD simulations of AzoChignolin and Chignolin in MeOH and water, we estimated Markov models to examine folding kinetics of both peptides. We show that while AzoChignolin mimics Chignolin's structure well, the folding kinetics are quite different. Not only folding times but also intermediate states differ, particularly Chignolin is able to fold in MeOH into an α-helical intermediate which is impossible to form in AzoChignolin. The Markov models demonstrate that AzoChignolin's kinetics are generally faster, specifically when comparing the two main microfolding processes of hydrophobic collapse and turn formation. Photoswitchable loops are used frequently to understand the kinetics of elementary protein folding nucleation. However, our results indicate that intermediates and folding kinetics may differ between natural loops and photoswitchable variants.

1. Variation in genome size spans multiple orders of magnitude among animals. Despite the longstanding debate regarding the adaptive value or costs of genomic complexity, genome size has been proposed to influence extinction risk under the rapidly changing environments of the Anthropocene.2. The main hypothesis suggests that genome enlargement increases the accumulation of deleterious mutations while reducing rates of organismal growth and development. These combined effects of larger genome size are predicted to trigger population declines that can lead to extinction, especially under rapidly changing environments that disrupt demographic resilience.3. Comparative evidence from terrestrial plants and across vertebrates has provided mixed support for this hypothesis. However, large-scale comparative studies based on explicit phylogenetic approaches remain lacking. Using a global-scale amphibian dataset and two recognised proxies of extinction risk (International Union for Conservation of Nature IUCN conservation categories and population trends), we test the prediction that genomes are larger (as estimated by C-value) in species facing extinction risk. We combine these analyses with life-history traits widely known to be implicated with extinctions (body size, fecundity), along with a range of environmental factors.4. Our phylogenetic analyses consistently failed to identify an effect of genome size on either of the two proxies for extinction risk. The only consistent predictor of extinction risk observed across models performed for amphibians combined and for orders separately was decreasing geographical range size. We also identified a role for larger body size, decreasing range of environmental temperature (for anurans) and increasing levels of UV-B radiation (for salamanders) as drivers of increasing threat.5. Our study provides no support for the prediction that species with larger genomes suffer heightened risk of extinction. We discuss some fundamental limitations underlying the genome size-extinction hypothesis, and suggest that it is not a promising avenue to elucidate the causes of biodiversity declines in the Anthropocene.

Plants have evolved diverse secondary metabolites to counteract biotic stress. Volatile organic compounds (VOCs) are released upon herbivore attack or pathogen infection. Recent studies suggest that VOCs can act as signalling molecules in plant defence and induce resistance in distant organs and neighbouring plants. However, knowledge is lacking on the function of VOCs in biotrophic fungal infection on cereal plants. We analysed VOCs emitted by 13 ± 1-day-old barley plants (Hordeum vulgare L.) after mechanical wounding using passive absorbers and TD-GC/MS. We investigated the effect of pure VOC and complex VOC mixtures released from wounded plants on the barley-powdery mildew interaction by pre-exposure in a dynamic headspace connected to a powdery mildew susceptibility assay. Untargeted metabolomics and lipidomics were applied to investigate metabolic changes in sender and receiver barley plants. Green leaf volatiles (GLVs) dominated the volatile profile of wounded barley plants, with (Z)-3-hexenyl acetate (Z3HAC) as the most abundant compound. Barley volatiles emitted after mechanical wounding enhanced resistance in receiver plants towards fungal infection. We found volatile-mediated modifications of the plant-pathogen interaction in a concentration-dependent manner. Pre-exposure with physiologically relevant concentrations of Z3HAC resulted in induced resistance, suggesting that this GLV is a key player in barley anti-pathogen defence. The complex VOC mixture released from wounded barley and Z3HAC induced e.g. accumulation of chlorophyll, linolenic acid and linolenate-conjugated lipids, as well as defence-related secondary metabolites, such as hordatines in receiving plants. Barley VOCs hence induce a complex physiological response and disease resistance in receiver plants.

There is a growing body of work suggesting that social class stereotypes are amplified when people perceive higher levels of economic inequality—that is, the wealthy are perceived as more competent and assertive and the poor as more incompetent and unassertive. The present study tested this prediction in 32 societies and also examines the role of wealth-based categorization in explaining this relationship. We found that people who perceived higher economic inequality were indeed more likely to consider wealth as a meaningful basis for categorization. Unexpectedly, however, higher levels of perceived inequality were associated with perceiving the wealthy as less competent and assertive and the poor as more competent and assertive. Unpacking this further, exploratory analyses showed that the observed tendency to stereotype the wealthy negatively only emerged in societies with lower social mobility and democracy and higher corruption. This points to the importance of understanding how socio-structural features that co-occur with economic inequality may shape perceptions of the wealthy and the poor. © 2022 The Authors. European Journal of Social Psychology published by John Wiley & Sons Ltd. WOS:000880016700001 2-s2.0-85141616689 Social Sciences Citation Index Q2 Article Uluslararası işbirliği ile yapılan - EVET 2022 YÖK - 2022-23 Kasım

The heat shock protein 70 kDa (Hsp70) chaperone system serves as a critical component of protein quality control across a wide range of prokaryotic and eukaryotic organisms. Divergent evolution and specialization to particular organelles have produced numerous Hsp70 variants which share similarities in structure and general function, but differ substantially in regulatory aspects, including conformational dynamics and activity modulation by cochaperones. The human Hsp70 variant BiP (also known as GRP78 or HSPA5) is of therapeutic interest in the context of cancer, neurodegenerative diseases, and viral infection, including for treatment of the pandemic virus SARS-CoV-2. Due to the complex conformational rearrangements and high sequential variance within the Hsp70 protein family, it is in many cases poorly understood which amino acid mutations are responsible for biochemical differences between protein variants. In this study, we predicted residues associated with conformational regulation of human BiP and Escherichia coli DnaK. Based on protein structure networks obtained from molecular dynamics simulations, we analyzed the shared information between interaction timelines to highlight residue positions with strong conformational coupling to their environment. Our predictions, which focus on the binding processes of the chaperone's substrate and cochaperones, indicate residues filling potential signaling roles specific to either DnaK or BiP. By combining predictions of individual residues into conformationally coupled chains connecting ligand binding sites, we predict a BiP specific secondary signaling pathway associated with substrate binding. Our study sheds light on mechanistic differences in signaling and regulation between Hsp70 variants, which provide insights relevant to therapeutic applications of these proteins.

To assess the effect of respiratory motion and cardiac driven pulsation in renal DWI and to examine asymmetrical velocity-compensated diffusion encoding waveforms for robust ADC mapping in the kidneys.The standard monopolar Stejskal-Tanner pulsed gradient spin echo (pgse) and the asymmetric bipolar velocity-compensated (asym-vc) diffusion encoding waveforms were used for coronal renal DWI at 3T. The robustness of the ADC quantification in the kidneys was tested with the aforementioned waveforms in respiratory-triggered and breath-held cardiac-triggered scans at different trigger delays in 10 healthy subjects.The pgse waveform showed higher ADC values in the right kidney at short trigger delays in comparison to longer trigger delays in the respiratory triggered scans when the diffusion gradient was applied in the feet-head (FH) direction. The coefficient of variation over all respiratory trigger delays, averaged over all subjects was 0.15 for the pgse waveform in the right kidney when diffusion was measured in the FH direction; the corresponding coefficient of variation for the asym-vc waveform was 0.06. The effect of cardiac driven pulsation was found to be small in comparison to the effect of respiratory motion.Short trigger delays in respiratory-triggered scans can cause higher ADC values in comparison to longer trigger delays in renal DWI, especially in the right kidney when diffusion is measured in the FH direction. The asym-vc waveform can reduce ADC variation due to respiratory motion in respiratory-triggered scans at the cost of reduced SNR compared to the pgse waveform.

Recent advances in terrestrial laser scanning (TLS) technology have enabled the automatic capture of three‐dimensional vegetation structure at high resolution, but the scalability of using these data for large‐scale forest monitoring is limited by reliance on intensive manual data processing, including the use of stem maps generated in the field to determine tree species. New methods from data science have the capacity to automate this identification process, reducing the hurdles towards automated inventories with TLS. In particular, contemporary developments in point cloud processing methods, alongside large increases in the computing power of consumer‐level graphics processing units, provide new opportunities. Here, we apply a deep learning‐based approach, based on joint classification from multiple viewpoints for each stem, to automatically classify tree species directly from laser scanning data obtained in structurally complex Mediterranean forests. We also explore the use of data augmentation techniques to maximise performance for a fixed number of manually labelled stems. Our method does not require expensive pre‐processing such as leaf‐wood separation or quantitative reconstructions. Using modern network architectures and data augmentation techniques, and without extensive pre‐processing, we are able to achieve high overall and per‐species accuracy that is comparable or higher than in existing work while using data from a water‐limited ecosystem complicated by structural convergence and multi‐stem trees. Our findings demonstrate the power of deep learning to remove a major TLS data processing obstacle—individual species identification—and to minimise the bottleneck created by manual data labelling requirements in the use of TLS for standard forest monitoring.

To help health economic modelers respond to demands for greater use of complex systems models in public health. To propose identifiable features of such models and support researchers to plan public health modeling projects using these models. A working group of experts in complex systems modeling and economic evaluation was brought together to develop and jointly write guidance for the use of complex systems models for health economic analysis. The content of workshops was informed by a scoping review. A public health complex systems model for economic evaluation is defined as a quantitative, dynamic, non-linear model that incorporates feedback and interactions among model elements, in order to capture emergent outcomes and estimate health, economic and potentially other consequences to inform public policies. The guidance covers: when complex systems modeling is needed; principles for designing a complex systems model; and how to choose an appropriate modeling technique. This paper provides a definition to identify and characterize complex systems models for economic evaluations and proposes guidance on key aspects of the process for health economics analysis. This document will support the development of complex systems models, with impact on public health systems policy and decision making.

Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off-target effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta on cardiovascular structure and function, and underlying molecular mechanism using the chicken embryo, an established model system to isolate effects of therapy on the developing heart and vasculature, independent of effects on the mother or placenta. Fertilized eggs were treated with Dex (0.1 mg kg-1 ), Beta (0.1 mg kg-1 ), or water vehicle (Control) on embryonic day 14 (E14, term = 21 days). At E19, biometry, cardiovascular function, stereological, and molecular analyses were determined. Both glucocorticoids promoted growth restriction, with Beta being more severe. Beta compared with Dex induced greater cardiac diastolic dysfunction and also impaired systolic function. While Dex triggered cardiomyocyte hypertrophy, Beta promoted a decrease in cardiomyocyte number. Molecular changes of Dex on the developing heart included oxidative stress, activation of p38, and cleaved caspase 3. In contrast, impaired GR downregulation, activation of p53, p16, and MKK3 coupled with CDK2 transcriptional repression linked the effects of Beta on cardiomyocyte senescence. Beta but not Dex impaired NO-dependent relaxation of peripheral resistance arteries. Beta diminished contractile responses to potassium and phenylephrine, but Dex enhanced peripheral constrictor reactivity to endothelin-1. We conclude that Dex and Beta have direct differential detrimental effects on the developing cardiovascular system.

In this contribution, a simple method for the screening of photocatalytic activity of catalyst materials is presented. The method is based on two steps: the immobilization of the photocatalyst and the subsequent testing of their photocatalytic activity, using the gas evolution at the solid‐liquid interface. Up to four catalysts can be tested under the same conditions. The observed gas evolution for selected photocatalysts is consistent with trends reported in the literature from conventional photocatalytic reactors.

It remains unknown whether the global small vessel disease (SVD) burden predicts post-stroke outcomes.In a prospective multicenter study of 666 ischemic and hemorrhagic stroke patients, we quantified magnetic resonance imaging (MRI)-based SVD markers (lacunes, white matter hyperintensities, microbleeds, perivascular spaces) and explored associations with 6- and 12-month cognitive (battery of 15 neuropsychological tests) and functional (modified Rankin scale) outcomes.A global SVD score (range 0-4) was associated with cognitive impairment; worse performance in executive function, attention, language, and visuospatial ability; and worse functional outcome across a 12-month follow-up. Although the global SVD score did not improve prediction, individual SVD markers, assessed across their severity range, improved the calibration, discrimination, and reclassification of predictive models including demographic, clinical, and other imaging factors.SVD presence and severity are associated with worse cognitive and functional outcomes 12 months after stroke. Assessing SVD severity may aid prognostication for stroke patients.In a multi-center cohort, we explored associations of small vessel disease (SVD) burden with stroke outcomes. SVD burden associates with post-stroke cognitive and functional outcomes. A currently used score of SVD burden does not improve the prediction of poor outcomes. Assessing the severity of SVD lesions adds predictive value beyond known predictors. To add predictive value in assessing SVD in stroke patients, SVD burden scores should integrate lesion severity.

Tropical forests are a major component of the global carbon cycle and home to two‐thirds of terrestrial species. Upper‐canopy trees store the majority of forest carbon and can be vulnerable to drought events and storms. Monitoring their growth and mortality is essential to understanding forest resilience to climate change, but in the context of forest carbon storage, large trees are underrepresented in traditional field surveys, so estimates are poorly constrained. Aerial photographs provide spectral and textural information to discriminate between tree crowns in diverse, complex tropical canopies, potentially opening the door to landscape monitoring of large trees. Here we describe a new deep convolutional neural network method, Detectree2, which builds on the Mask R‐CNN computer vision framework to recognize the irregular edges of individual tree crowns from airborne RGB imagery. We trained and evaluated this model with 3797 manually delineated tree crowns at three sites in Malaysian Borneo and one site in French Guiana. As an example application, we combined the delineations with repeat lidar surveys (taken between 3 and 6 years apart) of the four sites to estimate the growth and mortality of upper‐canopy trees. Detectree2 delineated 65 000 upper‐canopy trees across 14 km2 of aerial images. The skill of the automatic method in delineating unseen test trees was good (F1 score = 0.64) and for the tallest category of trees was excellent (F1 score = 0.74). As predicted from previous field studies, we found that growth rate declined with tree height and tall trees had higher mortality rates than intermediate‐size trees. Our approach demonstrates that deep learning methods can automatically segment trees in widely accessible RGB imagery. This tool (provided as an open‐source Python package) has many potential applications in forest ecology and conservation, from estimating carbon stocks to monitoring forest phenology and restoration. Python package available to install at https://github.com/PatBall1/Detectree2.

With this study, we present the development of a transportable x‐ray emission spectrometer (XES) that was realized in a net time of 20 h, in order to verify the presence of Platinum (Pt) in gold Celtic coins belonging to 3rd–1st century BCE. Prior to the XES study, measurements using Scanning Electron Microscopy coupled with Energy Dispersive Spectroscopy (SEM‐EDS) revealed that the coins were made of highly concentrated gold (Au) alloy with trace amounts of bismuth (Bi) and, in one case, osmium (Os) and iridium (Ir). Os and Ir together with Pt and other components belong to the Platinum Group Elements (PGE). They form inclusions in ancient gold alloys and their presence is significant in provenance studies since they indicate the use of alluvial gold. Detection of platinum trace elements in a golden matrix is not possible using energy dispersive x‐ray emission techniques (SEM‐EDS, ED‐XRF, or PIXE) because of the limited energy resolution of the Si detectors. A way to overcome this problem is by using a high‐resolution wavelength dispersive x‐ray emission technique. For this purpose, we built a crystal spectrometer in Von‐Hamos geometry. In the framework of this study three samples/coins have been measured, and the presence of Pt was verified in one of them. The limitations of our spectrometer are critically evaluated and ways to optimize the performance of the spectrometer are discussed.

The benefit of pollinators to crop production is normally calculated using “pollinator dependence ratios,” which reflect the proportion of yield lost (here reported as a value between 0 and 1) in the absence of pollinators; these ratios are quantified experimentally using pollinator exclusion experiments. Pollinator dependence ratio estimates can vary considerably for a single crop, creating large, frequently overlooked, uncertainty in economic valuations of pollinators. The source of this variation is usually unclear. We experimentally measured the pollinator dependence ratio of two UK commercial cultivars of raspberry Rubus idaeus L., using a range of yield metrics—fruit set, marketable fruit set, fruit weight, and marketable fruit weight—over 3 years (2019–2021), to quantify the effects of yield metric, interannual variation, and cultivar on pollinator dependence ratio estimates. We found a difference in the pollinator dependence ratio for fruit set of 0.71 between 2019 and 2020, showing the importance of carrying out exclusion studies over multiple years. Averaged over multiple years and two cultivars, the dependence ratio was 0.68 measured using marketable fruit set and 0.64 using marketable fruit weight. Imposing a quality threshold (size and shape) below which fruits would not be of commercial value (marketable fruit set/weight) dramatically increased both the pollinator dependence ratio and subsequent economic valuations of pollination service derived from it. Our study shows that, for raspberry, estimates of the pollinator dependence ratio, and therefore, the economic value of insect pollinators, are highly sensitive to the choice of yield metric and can change between years and cultivars. Many economic decisions about pollinator management, at farm, regional and national scales rely on estimates of pollinator dependence. We, therefore, recommend that for estimating pollinator dependence ratios, pollinator exclusion studies are conducted over three or more years and use yield metrics that incorporate quality criteria linked to actual market values and commercial thresholds.

Extracellular vesicles (EVs) are secreted nanostructures that play various roles in critical cancer processes. They operate as an intercellular communication system, transferring complex sets of biomolecules from cell to cell. The concentration of EVs is difficult to decipher, and there is an unmet technological need for improved (faster, simpler, and gentler) approaches to isolate EVs from complex matrices. Herein, an acoustofluidic concentration of extracellular vesicles (ACEV) is presented, based on a thin‐film printed circuit board with interdigital electrodes mounted on a piezoelectric substrate. An angle of 120° is identified between the electrodes and the reference flat of the piezoelectric substrate for simultaneous generation of Rayleigh and shear horizontal waves. The dual waves create a complex acoustic field in a droplet, resulting in effective concentration of nanoparticles and EVs. The ACEV is able to concentrate 20 nm nanospheres within 105 s and four EV dilutions derived from the human prostate cancer (Du145) cell line in approximately 30 s. Cryo‐electron microscopy confirmed the preservation of EV integrity. The ACEV device holds great potential to revolutionize investigations of EVs. Its faster, simpler, and gentler approach to EV isolation and concentration can save time and effort in phenotypic and functional studies of EVs.

The naked mole-rat (NMR, Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that mature ADAM10 is expressed in NMR primary skin fibroblasts (NPSF), and that ionomycin increases cell surface ADAM10 localization. However, we observed an absence of ADAM10 mediated CD44 cleavage, as well as shedding of exogenous and overexpressed betacellulin in NPSF, whereas in mouse primary skin fibroblasts ionomycin induced ADAM10-dependent cleavage of both CD44 and betacellulin. Overexpressing a hyperactive form of the Ca2+ -dependent phospholipid scramblase ANO6 in NPSF increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted cell migration in NPSF in an ADAM10-dependent manner. These findings suggest that dysregulation of ADAM10 shedding activity is due to a deficient PS externalization in NMR., This work was funded by the Dunhill Medical Trust (RPGF2002\188)

Marine heatwaves caused by global warming are progressively degrading coral reefs worldwide via the process of coral bleaching – the expulsion of photosynthetic endosymbionts. However, coral bleaching is not spatially homogeneous, but varies across environmental gradients in association with local conditions and taxonomic composition. Emerging evidence suggests that mangrove habitats are recurrent ‘'microenvironments' for reef corals, providing key biogeochemical services believed to influence their resilience, and housing co‐tolerant coral taxa. This close association between coral reefs and mangroves has led to the hypothesis that the extent of coral bleaching is reduced by the proximity of reef building corals to mangroves. Here, we present the first global‐scale test addressing this hypothesis. Using Bayesian generalised linear mixed effect modelling, we show that coral bleaching tends to increase under higher thermal stress when corals are further away from mangroves. When comparing conditional effects, corals furthest away from mangroves also show the highest levels of bleaching, suggesting a phenomenon of reduced bleaching for corals residing closer to mangroves under thermal stress. The drivers of this pattern may be numerous, but most likely include the presence of co‐tolerant coral species which are known to be associated with mangroves. Future research should focus on disentangling the mechanisms underlying these coral bleaching patterns in association with mangroves, specifically focusing on in‐situ environmental and taxonomic data collection. These endeavours will most likely require high‐resolution analyses of coral reefs at more local‐scales. Ultimately, our findings add to the ever‐growing importance of mangroves for near‐shore coral reef environments, and suggest a potentially important benefit for coral reefs associated with mangroves in the Anthropocene.

Funder: Gates Cambridge Trust; Id: http://dx.doi.org/10.13039/501100005370, Funder: Linnean Society of London; Id: http://dx.doi.org/10.13039/501100001264, Funder: Marsden Fund; Id: http://dx.doi.org/10.13039/501100009193, Funder: Newnham College, University of Cambridge; Id: http://dx.doi.org/10.13039/501100000663, Funder: Society of Systematic Biologists; Id: http://dx.doi.org/10.13039/100006069, Funder: Swedish Research Council; Id: http://dx.doi.org/10.13039/501100004359, Aim: How mountains accumulate species diversity remains poorly understood, particularly the relative role of in situ cladogenesis compared with colonization from lower elevations. Here, we estimated the contributions of in situ cladogenesis and colonization in generating biodiversity of a large mountain plant radiation and determined the importance of niche adaptation and divergence in these processes. We expected cladogenesis would accompany novel habitats formed by mountain uplift, but colonization would become more important with time as dispersal opportunities accrue. Location: New Zealand, Southern Alps. Taxon: Veronica sect. Hebe (Plantaginaceae). Methods: We estimated the most complete time‐calibrated phylogeny to date for Veronica sect. Hebe to quantify rates of in situ cladogenesis and colonization of mountain habitat based on historical biogeographical models. We used environmental niche modelling to quantify species' climate niches and estimate niche disparity and divergence over time. Results: In situ cladogenesis generated more species in the mountains than colonization from lowlands. Whereas cladogenesis slowed over time, colonization increased, especially in the alpine zone. Both adaptive ecological speciation along climate niche axes and non‐adaptive, vicariant speciation contributed to cladogenesis. However, climate niche disparity through time became saturated, suggesting competition for niche space was important. Colonization brought more divergent species into mountain niches. Main Conclusions: We suggest mountain diversity accumulates through three main stages: high cladogenesis after initial colonization, decreasing cladogenesis with increasing competition and increasing colonization after niches saturate, likely promoted by niche divergence. Combining lineage and mountain uplift trajectories, these stages provide a conceptual model to understand how diversity accumulates elsewhere. Assuming these deep‐time findings apply to anthropogenic conditions, alpine specialists could struggle to outcompete colonizers facilitated by climate change, especially from generalist clades. Considering novel competitive interactions alongside niche traits and biogeographical processes will be crucial for predicting the fate of alpine biodiversity in a changing world.

When the brain is in a pathological state, the content of lipid droplets (LDs), the lipid storage organelles, is increased, particularly in glial cells, but rarely in neurons. The biology and mechanisms leading to LD accumulation in astrocytes, glial cells with key homeostatic functions, are poorly understood. We imaged fluorescently labeled LDs by microscopy in isolated and brain tissue rat astrocytes and in glia‐like cells in Drosophila brain to determine the (sub)cellular localization, mobility, and content of LDs under various stress conditions characteristic for brain pathologies. LDs exhibited confined mobility proximal to mitochondria and endoplasmic reticulum that was attenuated by metabolic stress and by increased intracellular Ca2+, likely to enhance the LD–organelle interaction imaged by electron microscopy. When de novo biogenesis of LDs was attenuated by inhibition of DGAT1 and DGAT2 enzymes, the astrocyte cell number was reduced by ~40%, suggesting that in astrocytes LD turnover is important for cell survival and/or proliferative cycle. Exposure to noradrenaline, a brain stress response system neuromodulator, and metabolic and hypoxic stress strongly facilitated LD accumulation in astrocytes. The observed response of stressed astrocytes may be viewed as a support for energy provision, but also to be neuroprotective against the stress‐induced lipotoxicity., Main points Astroglial lipid droplets are dynamic organelles with confined mobility.Lipid droplet turnover is important for astrocyte survival/proliferation.Stressed astrocytes accumulate lipid droplets likely to provide energy and reduce lipotoxicity.

Age-related hearing loss (ARHL, formerly presbycusis) is due to a variety of lifetime damages to the auditory system and is characterized by bilateral sensorineural hearing loss, impaired speech understanding in noise and central sound processing deficits. Despite its commonness, the pathogenesis has not been completely clarified yet; especially the existence of an independent central ARHL component still remains controversial. We present the results of a cross-sectional topodiagnostic test battery study which aimed at separating aging- and hearing loss-related effects on all parts of the auditory system by current test procedures. Three groups of 30 participants each underwent extensive topodiagnostic test procedures (otoscopy, tympanometry, questionnaires, pure-tone audiometry, DPOAE threshold measurements, auditory brainstem response, central auditory discrimination tests, and speech-in-noise test). By comparing the results of the normally hearing young (18-26 years) and healthy control group, the normally hearing elderly group (60-80 years) and the hearing-impaired elderly group (60-80 years), we deduced aging and hearing loss-related effects on auditory performance. All measurements indicated a significant deterioration of auditory performance in the elderly, partly associated with aging and partly with age-related hearing loss. Our study thereby contributes to a multifocal concept of ARHL. All parts of the auditory system are impaired by aging, age-related hearing loss, or a combination of both. Further evidence for an independent central ARHL component, not attributable to peripheral hearing loss, is provided by the results of the central auditory discrimination test.

Funder: Fondation Ernst et Lucie Schmidheiny; Id: http://dx.doi.org/10.13039/501100007636, Funder: International Association for Plant Taxonomy; Id: http://dx.doi.org/10.13039/501100020652, Funder: International Palm Society, Funder: Swiss Systematics Society, Aim: Central America is largely covered by hyperdiverse, yet poorly understood, rain forests. Understorey palms are diverse components of these forests, but little is known about their historical assembly. It is not clear when palms in Central America reached present diversity levels and whether most species arrived from neighbouring regions or evolved locally. We addressed these questions using the most species‐rich American palm clades indicative of rain forests. We reconstructed and compared their phylogenomic and biogeographical history with the diversification of 54 other plant lineages, to gain a better understanding of the processes that shaped the assembly of Central American rain forests. Location: Central America. Time period: Cretaceous to present. Major taxa studied: Arecaceae: Arecoideae: Bactridinae, Chamaedoreeae, Geonomateae. Methods: We sampled 218 species through fieldwork and living collections. We sequenced their genomic DNA using target sequence‐capture procedures. Using 12 calibration points, we reconstructed dated phylogenies under three approaches (multispecies coalescent, maximum likelihood and Bayesian inference), conducted biogeographical analyses (dispersal–extinction–cladogenesis) and estimated phylogenetic diversity metrics. Results: Dated phylogenies revealed intense diversification in Central America from 12 Ma. Local diversification events were four times more frequent than dispersal events, and we found strong phylogenetic clustering in relationship to Central America. Main conclusions: Our results suggest that most understorey palm species that characterize the Central American rain forests today evolved locally after repeated dispersal events, mostly from South America. Understorey palms in Central American rain forests diversified primarily after closure of the Central American Seaway at c. 13 Ma, suggesting that the Great American Biotic Interchange was a major trigger for plant diversification in Central American rain forests. This recent diversification contrasts with the much earlier existence of rain forest palms in neighbouring South America since c. 58 Ma. We found similar timings of diversification in 54 other seed plant lineages, suggesting an unexpectedly recent assembly of the hyperdiverse Central American flora.

BACKGROUND: As Parkinson's disease (PD) progresses, response to oral medications decreases and motor complications appear. Timely intervention has been demonstrated as effective in reducing symptoms. However, current instruments for the identification of these patients are often complicated and inadequate. It has been suggested that anti‐PD intensified therapy (IT) can serve as a proxy for increased burden of disease. OBJECTIVE: To explore whether IT aligns with events reflecting advanced PD (APD) burden. METHODS: This was a retrospective analysis of PD beneficiaries in the second‐largest healthcare provider in Israel. Patients with PD diagnosed between January 2000 and June 2018 and treated with levodopa (l‐dopa) ≥5 times/day and/or ≥1000 mg l‐dopa equivalent daily dose were defined as the IT cohort (n = 2037). Treated patients with PD not fulfilling this criterion were defined as the nonintensified therapy (NIT) cohort (n = 3402). Point prevalence and 5‐ and 10‐year cumulative incidence of IT were assessed. Baseline demographic and comorbidities, 1‐year healthcare resource use, health costs, and time to clinical events were assessed and compared between cohorts. RESULTS: IT was associated with significantly (P

Summary: Stored topsoil acts as a microbial inoculant for ecological restoration of land after disturbance, but the altered circumstances frequently create unfavourable conditions for microbial survival. Nitrogen cycling is a critical indicator for ecological success and this study aimed to investigate the cornerstone taxa driving the process. Previous in silico studies investigating stored topsoil discovered persistent archaeal taxa with the potential for re‐establishing ecological activity. Ammonia oxidization is the limiting step in nitrification and as such, ammonia‐oxidizing archaea (AOA) can be considered one of the gatekeepers for the re‐establishment of the nitrogen cycle in disturbed soils. Semi‐arid soil samples were enriched with ammonium sulfate to promote the selective enrichment of ammonia oxidizers for targeted genomic recovery, and to investigate the microbial response of the microcosm to nitrogen input. Ammonia addition produced an increase in AOA population, particularly within the genus Candidatus Nitrosotalea, from which metagenome‐assembled genomes (MAGs) were successfully recovered. The Ca. Nitrosotalea archaeon candidates' ability to survive in extreme conditions and rapidly respond to ammonia input makes it a potential bioprospecting target for application in ecological restoration of semi‐arid soils and the recovered MAGs provide a metabolic blueprint for developing potential strategies towards isolation of these acclimated candidates.

Aim: Rising ocean temperatures are widely recognized as the dominant driver behind the rapid degradation of coral reefs via the process of coral bleaching (the expulsion of photosynthetic endosymbionts, which reveals the coral skeleton). However, bleaching of hard corals is often assumed to be further aggravated by the effect of local‐scale stressors from anthropogenic activity, accelerating coral reef decline where these stressors are stronger. Despite the importance of this hypothesis, the interaction between climate change and local stressors for driving coral bleaching has only been investigated in a handful of studies, with no large scale (regional or global) test conducted thus far. We investigate the impact of human population density (HPD) – a proxy for local stressors – in both protected and non‐protected marine regions, and their interaction under heat stress as drivers of coral bleaching. Location: Global. Time period: 2002–2018. Major taxa studied: Scleractinia corals. Methods: Using 9,170 coral reef surveys worldwide, we performed Bayesian modelling to assess the probability of coral bleaching in response to local‐scale stressors in interaction with global warming. Results: Local HPD does not exacerbate coral bleaching, either independently or under thermal stress from climate change. Rather, the relationship between HPD and temperature stress appears weakly antagonistic for coral bleaching, contradicting the expectation that HPD increases sensitivity of corals to bleaching under thermal stress. Main conclusions: Local HPD does not interact with global warming for degrading coral reefs. However, regional variation in bleaching patterns exists. Consequently, bleaching will continue to occur on most coral reefs globally regardless of local HPD. Thus, it is likely that even isolated, well‐protected, coral reefs will continue to decline because of climate warming‐induced bleaching. Therefore, tackling the source of global warming remains the most effective way to mitigate coral reef decline via coral bleaching.

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression. We investigated whether variants in BET genes are associated with survival outcomes for lung cancer. To do this, the associations between 77 variants in BET family genes and survival outcomes were analyzed in 773 non‐small‐cell lung cancer (NSCLC) patients who underwent surgery (349 and 424 patients in the discovery and validation cohorts, respectively). We found that six variants were significantly associated with overall survival (OS) in the discovery cohort, and one variant (rs2506711C>T) was replicated in the validation cohort. BRD3 rs2506711C>T is located in the repressed area and has a strong linkage disequilibrium with rs2427964C>T in the promoter region. BRD3 rs2427964C>T was significantly associated with worse OS in the discovery cohort, validation cohort, and combined analysis. In a luciferase assay, promoter activity in the BRD3 rs2427964 T allele was significantly higher than that in the BRD3 rs2427964 C allele, which selectively bound with the transcriptional repressor SIN3A. Knockdown of BRD3 with BRD3‐specific siRNA decreased the proliferation and migration of lung cancer cells while also increasing the rate of apoptosis. These results suggest that BRD3 rs2427964C>T increases BRD3 expression through increased promoter activity, which is associated with poor prognosis for lung cancer., In this study, we investigated the association of BET gene variants with survival of patients with non‐small‐cell lung cancer (NSCLC). We observed that the rs2427964C>T SNP in the BRD3 promoter region was associated with poorer survival outcome. BRD3 promoter activity was higher in rs2427964_T than in rs2427964_C, which selectively bound with the transcriptional repressor SIN3A. Additionally, BRD3 silencing decreased the proliferation and migration of NSCLC cells. Our data suggest that elevated BRD3 expression regulated by rs2427964C>T leads to reduced overall survival in patients with NSCLC.

Cancer‐associated fibroblasts (CAF) are the most abundant stromal cells in tumor and exert a pro‐tumoral effect in cancer progression. Numerous evidence shows long non‐coding RNA (lncRNA) abnormally regulates gene expression in various cancers. However, little is known about the role of lncRNA in the interaction between CAF and cancer cells. Here, we first identify an uncharacterized lncRNA, LOC100506114, which is significantly upregulated in CAF and is involved in the functional transformation of normal fibroblasts (NF) and CAF. Expression of LOC100506114 enhances the expression of fibroblast activation protein alpha and α‐smooth muscle actin in NF and promotes malignant characteristics of NF and CAF in vivo and in vitro. The profile of gene co‐expression analysis shows that growth differentiation factor 10 (GDF10) is positively correlated with the expression of LOC100506114. CAF promote stromal fibroblast activation and the proliferation and migration of tumor cells by secreting GDF10. Our data demonstrate that lncRNA plays a critical role in the interplay of stromal fibroblasts and tumor cells in oral squamous cell carcinoma., Abnormal expression of lncRNA LOC100506114 in oral squamous cell carcinoma (OSCC) induced normal fibroblasts (NF) to transform into CAF by upregulating growth differentiation factor 10 (GDF10) expression and secretion. The interaction of GDF10 with the transcription factor RUNX family transcription factor 2 further enhanced the growth and migration of OSCC tumor cells by activating the TGFβRI/Smad3/ERK pathway. Our results demonstrate that lncRNA play an important role in the functional transformation of human NF into CAF and promote OSCC tumorigenesis.

MreC is a scaffold protein required for cell shape determination through interactions with proteins related to cell wall synthesis. Here, we determined the crystal structure of the major periplasmic part of MreC from Escherichia coli at 2.1 Å resolution. The periplasmic part of MreC contains a coiled‐coil domain and two six‐stranded barrel domains. The coiled‐coil domain is essential for dimer formation, and the two monomers are prone to relative motion that is related to the small interface of β‐barrel domains. In addition, MreC forms an antiparallel filament‐like structure along the coiled‐coil direction, which is different from the helical array structure in Pseudomonas aeruginosa. Our structure deepens our understanding of polymer formation of MreC., As a scaffolding protein, MreC is required to interact with proteins associated with cell wall synthesis to determine the cell shape. The crystal structure of MreC shows that the peripheral portion of MreC contains a coiled‐coil and two six‐stranded barrel‐like structural domains. In the resolved crystal structure, MreC exists as a dimer, further forms a tetramer, and eventually forms an antiparallel filamentous structure along the direction of the coiled coil. Our structure provides new structural insights and deepens the understanding of the polymer formation of MreC.

Long noncoding RNAs (lncRNAs) have a profound effect on biological processes in various malignancies. However, few studies have investigated their functions and specific mechanisms in endometrial cancer. In this study, we focused on the role and mechanism of lncRNA‐ZXF1 in endometrial cancer. Bioinformatics and in vitro and in vivo experiments were used to explore the expression and function of lncRNA‐ZXF1. We found that lncRNA‐ZXF1 altered the migration and invasion of endometrioid endometrial cancer (EEC) cells. Furthermore, our results suggest that lncRNA‐ZXF1 regulates EEC cell proliferation. This regulation may be achieved by the lncRNA‐ZXF1‐mediated alteration in the expression of P21 through two mechanisms. One is that lncRNA‐ZXF1 functions as a molecular sponge of miR‐378a‐3p to regulate PCDHA3 expression and then modulate the expression of P21. The other is that lncRNA‐ZXF1 inhibits CDC20‐mediated degradation of ubiquitination by directly binding to P21. To the best of our knowledge, this study is the first to explore lncRNA‐ZXF1 functioning as a tumor‐suppressing lncRNA in EEC. LncRNA‐ZXF1 may become therapeutic, diagnostic, and prognostic indicator in the future., In this study, we found that lncRNA‐ZXF1 may act as a tumor suppressor gene to regulate the proliferation and invasion of endometrioid endometrial cancer (EEC). LncRNA‐ZXF1 potentially alters P21 expression in EEC through two mechanisms: by regulating P21 protein expression through the miR‐378a‐3p/PCDHA3 axis and by directly binding to P21 to prevent its CDC20‐mediated ubiquitin degradation.

Resveratrol is a polyphenol with antiaging and anticancer effects. Most previous studies used a single analysis to determine the key functions of resveratrol in inhibiting cancer progression. However, most of the signal transmission pathways in biological processes are multilevel. We used bioinformatics to elucidate the mechanism of resveratrol inhibition of breast cancer development. The mRNA expression profile of GSE25412 from the National Center for Biotechnology Information (NCBI) and the microRNA (miRNA) expression profile of PubMed identifier (PMID) 26890143 were integrated. De novo motifs were used to obtain predicted transcription factor (TF) motifs for differentially expressed genes. The regulatory effect of resveratrol on key nodes in the comprehensive analysis results was verified. The TF–miRNA–mRNA interaction network based on the STITCH and miRDB databases showed that resveratrol exerted a dual inhibitory effect by activating inhibitory TFs to block the cell cycle and inhibit miRNAs from upregulating apoptosis. However, these two processes did not work completely independently. TP53 is the dominant hub gene associated with the cell cycle and apoptosis throughout the TF–miRNA network. Kaplan–Meier plotter analysis found that resveratrol‐induced expression changes in key RNAs, such as E2F2, JUN, FOS, BRCA1, CDK1, CDKN1A, TNF, and hsa‐miR‐34a‐5p, significantly improved the prognosis of breast cancer patients, which was further verified using real‐time quantitative PCR (qPCR) and western blotting. This study constructed a TF–miRNA regulatory network with TP53 and E2F as the main central genes to elucidate the molecular mechanism of resveratrol in the treatment of breast cancer., Resveratrol is a polyphenol with anti‐aging and anti‐cancer effects, which can significantly inhibit cell proliferation in MCF‐7 cells. Here, we found that resveratrol induces cell cycle arrest and promotes apoptosis by regulating transcription factors and microRNA networks. In addition, TP53 and E2F2 are hub proteins in the regulation network.

The transcription factor, hypoxia‐inducible factor‐1α (HIF‐1α), has previously been shown to upregulate the expression of hypoxia‐related genes, including erythropoietin (EPO). However, the role of hypoxia‐inducible factor‐1α in morphogenesis during salivary gland development is unclear. We investigated the function of HIF‐1α in submandibular gland (SMG) organ cultures obtained from embryonic day 13.5 embryos from ICR female mice. Expression of HIF‐1α, glucose transporter 1, and vascular endothelial growth factor was induced under hypoxia (5% O2). We further showed that BAY 87‐2243‐mediated inhibition of HIF‐1α suppressed salivary gland development. Under severe hypoxia (1% O2), HIF‐1α did not promote salivary gland development; this was due to suppression of cell proliferation and inhibition of the cell cycle and not because of autophagy and apoptosis. Additionally, using the inhibitor U0126, we verified that the ERK1/2 pathway is upstream of HIF‐1α. Overall, we found that the HIF‐1α signaling pathway plays a critical role in salivary gland development in ex vivo SMG organ cultures., The role of the HIF‐1α signaling pathway in salivary gland development is currently unknown. Through the use of inhibitors, including U0126 and BAY87‐2243, we demonstrated that the HIF‐1α signaling pathway, including phosphorylated ERK and HIF‐1α signaling pathway‐related proteins (VEGF and GLUT1), plays a critical role in salivary gland development in ex vivo organ culture.

Voltage‐gated proton channels (HV1) are expressed in eukaryotes, including basal hexapods and polyneopteran insects. However, currently, there is little known about HV1 channels in insects. A characteristic aspartate (Asp) that functions as the proton selectivity filter (SF) and the RxWRxxR voltage‐sensor motif are conserved structural elements in HV1 channels. By analysing Transcriptome Shotgun Assembly (TSA) databases, we found 33 polyneopteran species meeting these structural requirements. Unexpectedly, an unusual natural variation Asp to glutamate (Glu) at SF was found in Phasmatodea and Mantophasmatodea. Additionally, we analysed the expression and function of HV1 in the phasmatodean stick insect Extatosoma tiaratum (Et). EtHV1 is strongly expressed in nervous tissue and shows pronounced inward proton conduction. This is the first study of a natural occurring Glu within the SF of a functional HV1 and might be instrumental in uncovering the physiological function of HV1 in insects., We report the discovery of voltage‐gated proton channels (HV1) in polyneopteran insects. We found a novel, naturally occurring glutamate in the selectivity filter of HV1. We further characterized the HV1 of the phasmatodean Extatosoma tiaratum, EtHV1. This study provides the first step in the discovery of the physiological function of HV1 channels in insects and its relationship with their evolution.

Wilms tumour (WT), an embryonal kidney cancer, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of foetal kidney with two WT cell lines, filtering our results to remove common cancer‐associated epigenetic changes and to enrich for genes involved in early kidney development. This identified four hypermethylated genes, of which ESRP2 (epithelial splicing regulatory protein 2) was the most promising for further study. ESRP2 was commonly repressed by DNA methylation in WT, and this occurred early in WT development (in nephrogenic rests). ESRP2 expression was reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was overexpressed in WT cell lines, it inhibited cellular proliferation in vitro, and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA‐seq of the ESRP2‐expressing WT cell lines identified several novel splicing targets. We propose a model in which epigenetic inactivation of ESRP2 disrupts the mesenchymal to epithelial transition in early kidney development to generate WT., ESRP2 regulates alternative splicing events that are critical for the mesenchymal to epithelial transition (MET) that occurs during kidney development. We show that in Wilms tumour, ESRP2 is commonly inactivated by DNA methylation at an early stage of carcinogenesis. We propose that epigenetic inactivation of ESRP2 disrupts the regulation of alternative splicing during MET. Disrupted MET leads in turn to persistence of undifferentiated foetal kidney cells that may progress to a tumour.

Tongue squamous cell carcinoma (TSCC) is one of the deadliest cancers of the head and neck, but the role of the ferroptosis pathway in its development is still unknown. In this study we explored the pathogenetic mechanisms associated with ferroptosis in TSCC. We identified differentially expressed genes (DEGs) of TSCC patients and used gene ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) to annotate, visualize, and integrate these DEGs. Receiver operating characteristic curve (ROC) analysis was performed, and the STRING database was used to construct a protein–protein interaction network to evaluate the predictive value of ferroptosis‐related DEGs. A total of 219 DEGs were identified and GO, KEGG, and GSEA showed that extracellular matrix (ECM)‐receptor interaction and interleukin (IL)‐17 signaling pathways were substantially upregulated in TSCC. Univariate Cox analysis revealed that high expression of CA9, TNFAIP3, and NRAS were predictive of a worse outcome. We then constructed a prognostic model that predicted survival in the validation cohort at 1 year and 32 months. Finally, 60 cases of tongue carcinoma and normal tissues were collected, and immunohistochemistry was used to detect the expression of CA9. We found that CA9 was strongly expressed in tongue carcinoma tissues and absent in adjacent tissues. Overall, we found that ferroptosis‐related genes may affect TSCC prognosis through the ECM‐receptor interaction and IL‐17 signaling pathways. Additionally, immunohistochemistry confirmed that CA9 was highly expressed in tongue carcinoma tissues, and a model based on ferroptosis‐related genes showed a good ability to predict overall survival in TSCC., Here we identified differentially expressed genes (DEGs) in tongue squamous cell carcinoma (TSCC) patients and intersected them with ferroptosis‐related genes. Ferroptosis‐related genes may affect TSCC prognosis through the ECM‐receptor interaction and IL‐17 signaling pathways. We constructed a prognostic model based on a subset of the ferroptosis‐related genes and confirmed that one of these genes, CA9, is highly expressed in tongue carcinoma tissues.

Exercise is known to create a transient, but potent increase in skeletal muscle expression of potentially anti‐inflammatory myokine interleukin‐6 (IL‐6). This effect may be clinically important in managing chronic inflammatory states. It has previously been proposed that lactic acidosis following exercise promotes this IL‐6 up‐regulation, but the mechanism of this acidosis effect is unknown. Rat skeletal muscle cell line L6‐G8C5 has been used previously to model metabolic effects of acidosis, sensing low pH through the resulting inhibition of amino acid transporter SNAT2(SLC38A2). Use of ionophore ionomycin to model the rise in intracellular Ca2+ concentration occurring in contracting muscle strongly up‐regulates IL‐6 mRNA in L6‐G8C5 myotubes. This study used this model to test the hypothesis that low extracellular pH (7.1) enhances ionomycin‐induced IL‐6 mRNA up‐regulation by inhibiting SNAT2. Incubation of L6‐G8C5 myotubes for 6 h with 0.5 µM ionomycin at control pH (7.4) resulted in a 15‐fold increase in IL‐6 mRNA which was further enhanced (1.74‐fold) at pH 7.1. In contrast low pH had no significant effect on IL‐6 mRNA without ionomycin, nor on the IL‐6 mRNA increase that was induced by cyclic stretch. Even though pH 7.1 halved the transport activity of SNAT2, alternative methods of SNAT2 inhibition (JNK inhibitor SP600125; SNAT2 antagonist MeAIB; or SNAT2 silencing with siRNA) did not mimic the enhancing effect of low pH on IL‐6 mRNA. On the contrary, JNK inhibition blunted the effect of pH 7.1 with ionomycin, but had no effect at pH 7.4. It is concluded that low pH promotes Ca2+/ionomycin–induced up‐regulation of IL‐6 mRNA through a novel SNAT2‐independent JNK‐dependent pH‐sensing pathway not previously described in this skeletal muscle model.

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin‐based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5‐aza deoxy‐cytosine (5‐aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5‐aza‐resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin‐resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5‐aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5‐aza and 5‐aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5‐aza‐resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin‐resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5‐aza‐resistant cells, the exact opposite changes seen in cisplatin‐resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5‐aza resistance and cisplatin sensitization, and mediated genome‐wide repression of polycomb target gene expression. Finally, genome‐wide analysis revealed that 5‐aza‐resistant, cisplatin‐resistant, and DNMT3B‐knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5‐aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs., Alternative therapies are needed for testicular germ cell tumors (TGCTs) refractory to cisplatin. Recent preclinical and clinical studies suggest that cisplatin refractory TGCTs are distinctly sensitive to hypomethylating agents. The current study suggests a reciprocal relationship between cisplatin and hypomethylation agent sensitivity in TGCTs involving DNMT3B and the polycomb pathway that could lead to biomarkers for future clinical trials.

Numerous reports of neuropsychiatric symptoms highlighted the pathologic potential of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its relationship the onset and/or exacerbation of mental disease. However, coronavirus disease 2019 (COVID‐19) treatments, themselves, must be considered as potential catalysts for new‐onset neuropsychiatric symptoms in COVID‐19 patients. To date, immediate and long‐term neuropsychiatric complications following SARS‐CoV‐2 infection are currently unknown. Here we report on five patients with SARS‐CoV‐2 infection with possible associated neuropsychiatric involvement, following them clinically until resolution of their symptoms. We will also discuss the contributory roles of chloroquine and dexamethasone in these neuropsychiatric presentations., Highlights SARS‐CoV‐2 Infection and COVID‐19 treatments have a potential catalytic role on neuropsychiatric complications.Cytokine storm and exacerbated cytotoxicity could be implicated in COVID‐19 related neuropsychiatric symptoms.The use of corticosteroids must be considered balancing risk/benefit to the patient.

Cisplatin (DDP)‐based chemotherapy is a preferred treatment for a broad spectrum of cancers, but the precise mechanisms of its hepatotoxicity are not yet clear. Recently, the role of voltage‐dependent anion channel protein 1 (VDAC1) in mitochondrial activity and cell apoptosis has attracted much attention. Our aim was to investigate the effects of mitochondrial outer membrane protein VDAC1 oligomerization in DDP‐induced hepatocyte apoptosis. L‐02 hepatocytes were divided into 4 groups: (a) control group, (b) 4,4'diisothiocyanate‐2,2'‐disulfonic acid (DIDS; 40 μm) group, (c) DDP (5 μm) group, and (d) DDP and DIDS combination group. Cell apoptosis was tested by Annexin V/FITC assay, protein expression of caspase‐3, γH2AX and NDUFB6 were observed by western blot assay, reactive oxygen species (ROS), and mitochondrial superoxide anion radical (O2 •−) were detected by DCFH‐DA and MitoSOX probe, and DNA damage was assessed by comet assay. Moreover, the activity of mitochondrial respiratory chain complex I was determined by the colorimetry method. Compared with the control group, apoptosis rate and activated cleaved‐caspase‐3 protein, ROS and O2 •− generation, DNA damage marker comet tail length, and γH2AX protein level increased in the DDP treatment group (P, This study found that DDP might convert VDAC1 monomers to VDAC1 oligomers, which promoted ROS and mtDNA fragments to be released from the mitochondria to the cytoplasm through VDAC1 channel, resulting in the expansion of mitochondrial oxidative stress and DNA damage. DIDS, an inhibitor of VDAC1 oligomerization, can alleviate DDP‐induced mitochondrial oxidative stress, DNA damage, and cell apoptosis in L‐02 hepatocytes.

Objectives: SlowMo therapy is a pioneering blended digital therapy for paranoia, augmenting face‐to‐face therapy with an interactive ‘webapp’ and a mobile app. A recent large‐scale trial demonstrated small–moderate effects on paranoia alongside improvements in self‐esteem, worry, well‐being and quality of life. This paper provides a comprehensive account of therapy personalisation within this targeted approach. Design: Case examples illustrate therapy delivery and descriptive data are presented on personalised thought content. Method: Thought content was extracted from the webapp (n = 140 participants) and coded using newly devised categories: Worries: (1) Persecutory, (2) Negative social evaluation, (3) Negative self‐concept, (4) Loss/life stresses, (5) Sensory‐perceptual experiences and (6) Health anxieties. Safer thoughts: (1) Safer alternative (specific alternatives to worries), (2) Second‐wave (generalised) coping, (3) Positive self‐concept, (4) Positive activities and (5) Third‐wave (mindfulness‐based) coping. Data on therapy fidelity are also presented. Results: Worries: ‘Persecutory’ (92.9% of people) and ‘Negative social evaluation’ (74.3%) were most common. ‘General worries/ life stresses’ (31.4%) and ‘Negative self‐concept’ (22.1%) were present in a significant minority; ‘Health anxieties’ (10%) and ‘Sensory‐perceptual’ (10%) were less common. Safer thoughts: ‘Second‐wave (general) coping’ (85%), ‘Safer alternatives’ (76.4%), ‘Positive self‐concept’ (65.7%) and ‘Positive activities’ (64.3%) were common with ‘Third‐wave’ (mindfulness) coping observed for 30%. Fidelity: Only three therapy withdrawals were therapy related. Session adherence was excellent (mean = 15.2/16; SD = 0.9). Behavioural work was conducted with 71% of people (119/168). Conclusion: SlowMo therapy delivers a targeted yet personalised approach. Potential mechanisms of action extend beyond reasoning. Implications for cognitive models of paranoia and causal interventionist approaches are discussed.

Ulcerative colitis is a common inflammatory bowel disease with a complex genetic and immune etiology. Immune infiltration plays a vital role in the development of ulcerative colitis. To explore potential biomarkers for ulcerative colitis and analyze characteristics of immune cell infiltration, we used bioinformatic analyses, including machine learning algorithms, cell type deconvolution methods, and pathway enrichment methods. In this study, we identified 216 differentially expressed mRNAs (DEMs), of which 153 were upregulated, and 63 were downregulated genes. DEMs were mainly enriched in infiltrating neutrophils and regulation of leukocyte migration. Moreover, eight candidate biomarkers, DPP10, MST1L, DPP10‐AS1, CEP55, ACSL1, MGP, OLFM4, and SGK1, were identified. Of these candidate biomarkers, MST1L, OLFM4, and DPP10 were then validated in the GSE48958 dataset and were predicted to be strongly correlated with infiltrating immune cells of ulcerative colitis. The underlying mechanism of these key genes in the development of colitis was also predicted by gene set variation analysis. To further validate these biomarkers' expression in ulcerative colitis, we determined mRNA levels of SGK1, CEP55, ACSL1, OLFM4, and DPP10 in lipopolysaccharides (LPS)‐stimulated Raw264.7 cells by quantitative reverse transcription‐polymerase chain reaction. We also examined SGK1, CEP55, ACSL1, OLFM4, DPP10, and MGP expression in the colon tissues of dextran sodium sulfate‐induced colitis mice. Consistent with the predicted computational results, the mRNA levels of these candidate genes were markedly changed in LPS‐stimulated Raw264.7 cells and inflamed colon tissues. Hence, our findings indicated that these critical genes may act as diagnostic biomarkers for ulcerative colitis and that differential immune infiltration cells may help illustrate the progression of ulcerative colitis., In this study, we identified eight critical genes closely related to ulcerative colitis by machine learning algorithms and validated them in GSE48958 and quantitative reverse transcription‐polymerase chain reaction in in vitro bioassays. For these genes, we also analyzed their characteristics of immune cell infiltration and their downstream signaling pathways. Hence, our findings indicated that these genes may act as diagnostic biomarkers for ulcerative colitis.

Aims To explore the practice effect of establishing an integrated treatment process by stroke emergency nurses in general hospitals for acute ischaemic stroke (AIS). Design Compared the time spent in each link before and after the establishment of AIS integrated treatment. Methods Since March 2016, we set up a team of emergency stroke nurses (ESN), trained and assessed the knowledge of emergency stroke, and set up a post of ESN. Results The median time of admission‐judgement, admission‐establishment of venous access, admission‐cranial CT examination and admission‐intravenous thrombolytic therapy was statistically significantly shortened after the implementation of the integrated treatment process of AIS coordinated by stroke emergency nurses (p

Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non‐small‐cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted‐capture high‐throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early‐stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative‐intent tumor resection (median follow‐up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1–2 weeks postsurgery, and during follow‐up. Deep next‐generation sequencing using unique molecular identifiers was performed to identify and quantify tumor‐specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL−1, respectively). Four patients (19%) remained ctDNA‐positive at 1–2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA‐negative patients (33%) after surgery experienced relapse during follow‐up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression‐free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early‐stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse., ctDNA profiling in plasma revealed higher levels and detection rates of ctDNA during tumor resection as compared to pretreatment time points in patients with early‐stage or locally advanced NSCLC. Moreover, patients testing positive for ctDNA immediately after tumor resection had worse clinical outcomes than patients with undetectable ctDNA. Our research highlights the role of ctDNA assessment for guiding treatment in patients with respectable NSCLC.