Transcatheter edge-to-edge repair (TEER) of mitral regurgitation is less invasive than surgery but has greater 5-year mortality and reintervention risks, and leads to smaller improvements in physical functioning. The study objective was to quantify patient preferences for risk-benefit trade-offs associated with TEER and surgery.

Increased serum cortisol (COR) concentrations may induce glucocorticoid resistance by down-regulation of glucocorticoid receptor (GCR), resulting in decreased chemotherapy efficacy in dogs with lymphoma.

We investigated indirect genetic effects (IGEs), also known as genetic nurture, in education with a novel approach that uses phased data to include parent-offspring pairs in the transmitted/nontransmitted study design. This method increases the power to detect IGEs, enhances the generalizability of the findings, and allows for the study of effects by parent-of-origin. We validated and applied this method in a family-based subsample of adolescents and adults from the Lifelines Cohort Study in the Netherlands (N = 6147), using the latest genome-wide association study data on educational attainment to construct polygenic scores (PGS). Our results indicated that IGEs play a role in education outcomes in the Netherlands: we found significant associations of the nontransmitted PGS with secondary school level in youth between 13 and 24 years old as well as with education attainment and years of education in adults over 25 years old (β = 0.14, 0.17 and 0.26, respectively), with tentative evidence for larger maternal IGEs. In conclusion, we replicated previous findings and showed that including parent-offspring pairs in addition to trios in the transmitted/nontransmitted design can benefit future studies of parental IGEs in a wide range of outcomes.

Exosomes derived from cancer are regarded as significant mediators of cancer-host crosstalk. Hypoxia, on the other hand, is one of the essential characteristics of solid tumors. This research set out to discover how circulating exosomes from hypoxic esophageal squamous cell carcinoma (ESCC) contribute to the formation of metastatic niches and distant metastasis. First, we noticed that human umbilical vein endothelial cells (HUVECs) had their tight connections disrupted and the expression of proteins involved in angiogenesis boosted by ESCC hypoxic exosomes. Hypoxia significantly induced Circ-ZNF609 expression in exosomes from ESCC, which was then internalized by HUVECs, as determined by circular RNA screening. High Circ-ZNF609 expression in HUVECs facilitated angiogenesis and vascular permeability, thereby promoting pre-metastatic niche formation, and enhancing distant metastasis in vitro and in vivo. Exosomal Circ-ZNF609 activated vascular endothelial growth factor A (VEGFA) mechanistically by sponging miR-150-5p. Exosomal Circ-ZNF609 also interacted with HuR and inhibited HuR binding to ZO-1, Claudin-1, and Occludin mRNAs, thereby reducing their translation. Collectively, our findings identified an essential function for exosomal Circ-ZNF609 from ESCC cells, suggesting the potential therapeutic value of exosomes for ESCC patients.

The pathogenesis of psoriasis, a chronic inflammatory autoimmune skin disease with a high global prevalence, remains unclear. We performed a high-resolution single-cell RNA sequencing analysis of 94,759 cells from 13 samples, including those from psoriasis model mice and wild-type mice. We presented a single-cell atlas of the skin of imiquimod-induced mice with psoriasis and WT mice, especially the heterogeneity of keratinocytes and fibroblasts. More interestingly, we discovered that special keratinocyte subtypes and fibroblast subtypes could interact with each other through epithelial-mesenchymal transition and validated the results with drug verification. Moreover, we conducted a tentative exploration of the potential pathways involved and revealed that the IL-17 signalling pathway may be the most relevant pathway. Collectively, we revealed the full-cycle landscape of key cells associated with psoriasis and provided a more comprehensive understanding of the pathogenesis of psoriasis.

Astronomical forcing of Earth's climate is embedded in the rhythms of stratigraphic records, most famously as short-period (104-105 year) Milankovitch cycles. Astronomical grand cycles with periods of millions of years also modulate climate variability but have been detected in relatively few proxy records. Here, we apply spectral analysis to a dataset of Cenozoic deep-sea hiatuses to reveal a ~2.4 Myr eccentricity signal, disrupted by episodes of major tectonic forcing. We propose that maxima in the hiatus cycles correspond to orbitally-forced intensification of deep-water circulation and erosive bottom current activity, linked to eccentricity maxima and peaks in insolation and seasonality. A prominent episode of cyclicity disturbance coincides with the Paleocene-Eocene Thermal Maximum (PETM) at ~56 Myr ago, and correlates with a chaotic orbital transition in the Solar System evident in several astronomical solutions. This hints at a potential intriguing coupling between the PETM and Solar System chaos.

Voice disorders resulting from various pathological vocal fold conditions or postoperative recovery of laryngeal cancer surgeries, are common causes of dysphonia. Here, we present a self-powered wearable sensing-actuation system based on soft magnetoelasticity that enables assisted speaking without relying on the vocal folds. It holds a lightweighted mass of approximately 7.2 g, skin-alike modulus of 7.83 × 105 Pa, stability against skin perspiration, and a maximum stretchability of 164%. The wearable sensing component can effectively capture extrinsic laryngeal muscle movement and convert them into high-fidelity and analyzable electrical signals, which can be translated into speech signals with the assistance of machine learning algorithms with an accuracy of 94.68%. Then, with the wearable actuation component, the speech could be expressed as voice signals while circumventing vocal fold vibration. We expect this approach could facilitate the restoration of normal voice function and significantly enhance the quality of life for patients with dysfunctional vocal folds.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and the development of non-alcoholic steatohepatitis (NASH) might cause irreversible hepatic damage. Hyperlipidemia (HLP) is the leading risk factor for NAFLD. This study aims to illuminate the causative contributor and potential mechanism of Kallistatin (KAL) mediating HLP to NAFLD. 221 healthy control and 253 HLP subjects, 62 healthy control and 44 NAFLD subjects were enrolled. The plasma KAL was significantly elevated in HLP subjects, especially in hypertriglyceridemia (HTG) subjects, and positively correlated with liver injury. Further, KAL levels of NAFLD patients were significantly up-regulated. KAL transgenic mice induced hepatic steatosis, inflammation, and fibrosis with time and accelerated inflammation development in high-fat diet (HFD) mice. In contrast, KAL knockout ameliorated steatosis and inflammation in high-fructose diet (HFruD) and methionine and choline-deficient (MCD) diet-induced NAFLD rats. Mechanistically, KAL induced hepatic steatosis and NASH by down-regulating adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) by LRP6/Gɑs/PKA/GSK3β pathway through down-regulating peroxisome proliferator-activated receptor γ (PPARγ) and up-regulating kruppel-like factor four (KLF4), respectively. CGI-58 is bound to NF-κB p65 in the cytoplasm, and diminishing CGI-58 facilitated p65 nuclear translocation and TNFα induction. Meanwhile, hepatic CGI-58-overexpress reverses NASH in KAL transgenic mice. Further, free fatty acids up-regulated KAL against thyroid hormone in hepatocytes. Moreover, Fenofibrate, one triglyceride-lowering drug, could reverse hepatic steatosis by down-regulating KAL. These results demonstrate that elevated KAL plays a crucial role in the development of HLP to NAFLD and may be served as a potential preventive and therapeutic target.

While onion cultivars, irrigation and soil and crop management have been given much attention in Brazil to boost onion yields, nutrient management at field scale is still challenging due to large dosage uncertainty. Our objective was to develop an accurate feature-based fertilization model for onion crops. We assembled climatic, edaphic, and managerial features as well as tissue tests into a database of 1182 observations from multi-environment fertilizer trials conducted during 13 years in southern Brazil. The complexity of onion cropping systems was captured by machine learning (ML) methods. The RReliefF ranking algorithm showed that the split-N dosage and soil tests for micronutrients and S were the most relevant features to predict bulb yield. The decision-tree random forest and extreme gradient boosting models were accurate to predict bulb yield from the relevant predictors (R2 > 90%). As shown by the gain ratio, foliar nutrient standards for nutritionally balanced and high-yielding specimens producing > 50 Mg bulb ha-1 set apart by the ML classification models differed among cultivars. Cultivar × environment interactions support documenting local nutrient diagnosis. The split-N dosage was the most relevant controllable feature to run future universality tests set to assess models' ability to generalize to growers' fields.

Gefitinib is one of the most extensively utilized epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for treating advanced lung adenocarcinoma (LUAD) patients harboring EGFR mutation. However, the emergence of drug resistance significantly compromised the clinical efficacy of EGFR-TKIs. Gaining further insights into the molecular mechanisms underlying gefitinib resistance holds promise for developing novel strategies to overcome the resistance and improve the prognosis in LUAD patients. Here, we identified that the inhibitory efficacy of gefitinib on EGFR-mutated LUAD cells was partially dependent on the induction of ferroptosis, and ferroptosis protection resulted in gefitinib resistance. Among the ferroptosis suppressors, aldo-keto reductase family 1 member C1 (AKR1C1) exhibited significant upregulation in gefitinib-resistant strains of LUAD cells and predicted poor progression-free survival (PFS) and overall survival (OS) of LUAD patients who received first-generation EGFR-TKI treatment. Knockdown of AKR1C1 partially reversed drug resistance by re-sensitizing the LUAD cells to gefitinib-mediated ferroptosis. The decreased expression of miR-338-3p contributed to the aberrant upregulation of AKR1C1 in gefitinib-resistant LUAD cells. Furthermore, upregulated long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1_1 (NEAT1_1) sponged miR-338-3p to neutralize its suppression on AKR1C1. Dual-luciferase reporter assay and miRNA rescue experiment confirmed the NEAT1_1/miR-338-3p/AKR1C1 axis in EGFR-mutated LUAD cells. Gain- and loss-of-function assays demonstrated that the NEAT1_1/miR-338-3p/AKR1C1 axis promoted gefitinib resistance, proliferation, migration, and invasion in LUAD cells. This study reveals the effects of NEAT1_1/miR-338-3p/AKR1C1 axis-mediated ferroptosis defence in gefitinib resistance in LUAD. Thus, targeting NEAT1_1/miR-338-3p/AKR1C1 axis might be a novel strategy for overcoming gefitinib resistance in LUAD harboring EGFR mutation.

Small bowel vascular malformation disease (SBVM) commonly causes obscure gastrointestinal bleeding (OGIB). However, the pathogenetic mechanism and the role of lncRNAs in SBVM remain largely unknown. Here, we found that hypoxia and low-glucose environments co-augment angiogenesis and existed in SBVM. Mechanistically, hypoxia and low-glucose environments supported angiogenesis via activation of hypoxia and glucose deprivation-induced lncRNA (HGDILnc1) transcription by increasing binding of the NeuroD1 transcription factor to the HGDILnc1 promoter. Raised HGDILnc1 acted as a suppressor of α-Enolase 1 (ENO1) small ubiquitin-like modifier modification (SUMOylation)-triggered ubiquitination, and an activator of transcription of Aldolase C (ALDOC) via upregulation of Histone H2B lysine 16 acetylation (H2BK16ac) level in the promoter of ALDOC, and consequently promoting glycolysis and angiogenesis. Moreover, HGDILnc1 was clinically positively correlated with Neurogenic differentiation 1 (NeuroD1), ENO1, and ALDOC in SBVM tissues, and could function as a biomarker for SBVM diagnosis and therapy. These findings suggest that hypoxia and low-glucose environments were present in SBVM tissues, and co-augmented angiogenesis. Hypoxia and low-glucose environments co-induced HGDILnc1, which is higher expressed in SBVM tissue compared with normal tissue, could promoted glycolysis and angiogenesis.

The reorientation of Earth through rotation of its solid shell relative to its spin axis is known as True polar wander (TPW). It is well-documented at present, but the occurrence of TPW in the geologic past remains controversial. This is especially so for Late Jurassic TPW, where the veracity and dynamics of a particularly large shift remain debated. Here, we report three palaeomagnetic poles at 153, 147, and 141 million years (Myr) ago from the North China craton that document an ~ 12° southward shift in palaeolatitude from 155-147 Myr ago (~1.5° Myr-1), immediately followed by an ~ 10° northward displacement between 147-141 Myr ago (~1.6° Myr-1). Our data support a large round-trip TPW oscillation in the past 200 Myr and we suggest that the shifting back-and-forth of the continents may contribute to the biota evolution in East Asia and the global Jurassic-Cretaceous extinction and endemism.

Geospatial methods, such as GIS and remote sensing, map radon levels, pinpoint high-risk areas and connect geological traits to radon presence. These findings direct health planning, focusing tests, mitigation, and policies where radon levels are high. Overall, geospatial analyses offer vital insights, shaping interventions and policies to reduce health risks from radon exposure. There is a formidable threat to human well-being posed by the naturally occurring carcinogenic radon (222Rn) gas due to high solubility in water. Under the current scenario, it is crucial to assess the extent of 222Rn pollution in our drinking water sources across various regions and thoroughly investigate the potential health hazards it poses. In this regard, the present study was conducted to investigate the concentration of 222Rn in groundwater samples collected from handpumps and wells and to estimate health risks associated with the consumption of 222Rn-contaminated water. For this purpose, groundwater samples (n = 30) were collected from handpumps, and wells located in the Mulazai area, District Peshawar. The RAD7 radon detector was used as per international standards to assess the concentration of 222Rn in the collected water samples. The results unveiled that the levels of 222Rn in the collected samples exceeded the acceptable thresholds set by the US Environmental Protection Agency (US-EPA) of 11.1 Bq L-1. Nevertheless, it was determined that the average annual dose was below the recommended limit of 0.1 mSv per year, as advised by both the European Union Council and the World Health Organization. In order to avoid the harmful effects of such excessive 222Rn concentrations on human health, proper ventilation and storage of water in storage reservoirs for a long time before use is recommended to lower the 222Rn concentration.

Bacteriophages constitute an invaluable biological reservoir for biotechnology and medicine. The ability to exploit such vast resources is hampered by the lack of methods to rapidly engineer, assemble, package genomes, and select phages. Cell-free transcription-translation (TXTL) offers experimental settings to address such a limitation. Here, we describe PHage Engineering by In vitro Gene Expression and Selection (PHEIGES) using T7 phage genome and Escherichia coli TXTL. Phage genomes are assembled in vitro from PCR-amplified fragments and directly expressed in batch TXTL reactions to produce up to 1011 PFU/ml engineered phages within one day. We further demonstrate a significant genotype-phenotype linkage of phage assembly in bulk TXTL. This enables rapid selection of phages with altered rough lipopolysaccharides specificity from phage genomes incorporating tail fiber mutant libraries. We establish the scalability of PHEIGES by one pot assembly of such mutants with fluorescent gene integration and 10% length-reduced genome.

Understanding the molecular and cellular processes involved in lung epithelial regeneration may fuel the development of therapeutic approaches for lung diseases. We combine mouse models allowing diphtheria toxin-mediated damage of specific epithelial cell types and parallel GFP-labeling of functionally dividing cells with single-cell transcriptomics to characterize the regeneration of the distal lung. We uncover cell types, including Krt13+ basal and Krt15+ club cells, detect an intermediate cell state between basal and goblet cells, reveal goblet cells as actively dividing progenitor cells, and provide evidence that adventitial fibroblasts act as supporting cells in epithelial regeneration. We also show that diphtheria toxin-expressing cells can persist in the lung, express specific inflammatory factors, and transcriptionally resemble a previously undescribed population in the lungs of COVID-19 patients. Our study provides a comprehensive single-cell atlas of the distal lung that characterizes early transcriptional and cellular responses to concise epithelial injury, encompassing proliferation, differentiation, and cell-to-cell interactions.

The gamma-band auditory steady-state response (ASSR), primarily generated from the auditory cortex, has received substantial attention as a potential brain marker indicating the pathophysiology of schizophrenia. Previous studies have shown reduced gamma-band ASSR in patients with schizophrenia and demonstrated correlations with impaired neurocognition and psychosocial functioning. Recent studies in clinical and healthy populations have suggested that the neural substrates of reduced gamma-band ASSR may be distributed throughout the cortices surrounding the auditory cortex, especially in the right hemisphere. This study aimed to investigate associations between the gamma-band ASSR and white matter alterations in the bundles broadly connecting the right frontal, parietal and occipital cortices to clarify the networks underlying reduced gamma-band ASSR in patients with schizophrenia. We measured the 40 Hz ASSR using electroencephalography and diffusion tensor imaging in 42 patients with schizophrenia and 22 healthy comparison subjects. The results showed that the gamma-band ASSR was positively correlated with fractional anisotropy (an index of white matter integrity) in the regions connecting the right frontal, parietal and occipital cortices in healthy subjects (β = 0.41, corrected p = 0.075, uncorrected p = 0.038) but not in patients with schizophrenia (β = 0.17, corrected p = 0.46, uncorrected p = 0.23). These findings support our hypothesis that the generation of gamma-band ASSR is supported by white matter bundles that broadly connect the cortices and that these relationships may be disrupted in schizophrenia. Our study may help characterize and interpret reduced gamma-band ASSR as a useful brain marker of schizophrenia.

Schistosomiasis is a major Neglected Tropical Disease, caused by the infection with blood flukes in the genus Schistosoma. To complete the life cycle, the parasite undergoes asexual and sexual reproduction within an intermediate snail host and a definitive mammalian host, respectively. The intra-molluscan phase provides a critical amplification step that ensures a successful transmission. However, the cellular and molecular mechanisms underlying the development of the intra-molluscan stages remain poorly understood. Here, single cell suspensions from S. mansoni mother sporocysts were produced and sequenced using the droplet-based 10X Genomics Chromium platform. Six cell clusters comprising two tegument, muscle, neuron, parenchyma and stem/germinal cell clusters were identified and validated by in situ hybridisation. Gene Ontology term analysis predicted key biological processes for each of the clusters, including three stem/germinal sub-clusters. Furthermore, putative transcription factors predicted for stem/germinal and tegument clusters may play key roles during parasite development and interaction with the intermediate host.

Mobile Health (mHealth) has the potential to be transformative in the management of chronic conditions. Machine learning can leverage self-reported data collected with apps to predict periods of increased health risk, alert users, and signpost interventions. Despite this, mHealth must balance the treatment burden of frequent self-reporting and predictive performance and safety. Here we report how user engagement with a widely used and clinically validated mHealth app, myCOPD (designed for the self-management of Chronic Obstructive Pulmonary Disease), directly impacts the performance of a machine learning model predicting an acute worsening of condition (i.e., exacerbations). We classify how users typically engage with myCOPD, finding that 60.3% of users engage frequently, however, less frequent users can show transitional engagement (18.4%), becoming more engaged immediately ( < 21 days) before exacerbating. Machine learning performed better for users who engaged the most, however, this performance decrease can be mostly offset for less frequent users who engage more near exacerbation. We conduct interviews and focus groups with myCOPD users, highlighting digital diaries and disease acuity as key factors for engagement. Users of mHealth can feel overburdened when self-reporting data necessary for predictive modelling and confidence of recognising exacerbations is a significant barrier to accurate self-reported data. We demonstrate that users of mHealth should be encouraged to engage when they notice changes to their condition (rather than clinically defined symptoms) to achieve data that is still predictive for machine learning, while reducing the likelihood of disengagement through desensitisation.

Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.

Neutrophils are one of the first responders to infection and are a key component of the innate immune system through their ability to phagocytose and kill invading pathogens, secrete antimicrobial molecules and produce extracellular traps. Neutrophils are produced in the bone marrow, circulate within the blood and upon immune challenge migrate to the site of infection. We wanted to understand whether this transition shapes the mouse neutrophil protein landscape, how the mouse neutrophil proteome is impacted by systemic infection and perform a comparative analysis of human and mouse neutrophils. Using quantitative mass spectrometry we reveal tissue-specific, infection-induced and species-specific neutrophil protein signatures. We show a high degree of proteomic conservation between mouse bone marrow, blood and peritoneal neutrophils, but also identify key differences in the molecules that these cells express for sensing and responding to their environment. Systemic infection triggers a change in the bone marrow neutrophil population with considerable impact on the core machinery for protein synthesis and DNA replication along with environmental sensors. We also reveal profound differences in mouse and human blood neutrophils, particularly their granule contents. Our proteomics data provides a valuable resource for understanding neutrophil function and phenotypes across species and model systems.