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Broadening gene therapy applications requires manufacturable vectors that efficiently transduce target cells in humans and preclinical models. Conventional selections of adeno-associated virus (AAV) capsid libraries are inefficient at searching the vast sequence space for the small fraction of vectors possessing multiple traits essential for clinical translation. Here, we present Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait AAV capsids. By leveraging a capsid library that uniformly samples the manufacturable sequence space, reproducible screening data are generated to train accurate sequence-to-function models. Combining six models, we designed a multi-trait (liver-targeted, manufacturable) capsid library and validated 88% of library variants on all six predetermined criteria. Furthermore, the models, trained only on mouse in vivo and human in vitro Fit4Function data, accurately predicted AAV capsid variant biodistribution in macaque. Top candidates exhibited production yields comparable to AAV9, efficient murine liver transduction, up to 1000-fold greater human hepatocyte transduction, and increased enrichment relative to AAV9 in a screen for liver transduction in macaques. The Fit4Function strategy ultimately makes it possible to predict cross-species traits of peptide-modified AAV capsids and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits. Conventional selections of AAV capsid libraries are inefficient at searching sequence space. Here the authors report 'Fit4Function', a generalizable ML approach for systematically engineering multi-trait AAV capsids, and use this to predict cross-species traits of peptide-modified AAV capsids. [ABSTRACT FROM AUTHOR]

Based on well-known complexity theory conjectures, any polynomial-time kernelization algorithm for the NP-hard Line-Cover problem produces a kernel of size Ω (k 2) , where k is the size of the sought line cover. Motivated by the current research in massive data processing, we study the existence of kernelization algorithms with limited space and time complexity for Line-Cover. We prove that every kernelization algorithm for Line-Cover takes time Ω (n log k + k 2 log k) , and present a randomized kernelization algorithm for Line-Cover that produces a kernel of size bounded by k 2 , and runs in time O (n log k + k 2 (log k log log k) 2) and space O (k 2 log 2 k) . Our techniques are also useful for developing deterministic kernelization algorithms for Line-Cover with limited space and improved running time, and for developing streaming kernelization algorithms for Line-Cover with near-optimal update-time. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Ornithology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Synthetic biology applications require finely tuned gene expression, often mediated by synthetic transcription factors (sTFs) compatible with the human genome and transcriptional regulation mechanisms. While various DNA-binding and activation domains have been developed for different applications, advanced artificially controllable sTFs with improved regulatory capabilities are required for increasingly sophisticated applications. Here, in mammalian cells and mice, we validate the transactivator function and homo-/heterodimerization activity of the plant-derived phytochrome chaperone proteins, FHY1 and FHL. Our results demonstrate that FHY1/FHL form a photosensing transcriptional regulation complex (PTRC) through interaction with the phytochrome, ΔPhyA, that can toggle between active and inactive states through exposure to red or far-red light, respectively. Exploiting this capability, we develop a light-switchable platform that allows for orthogonal, modular, and tunable control of gene transcription, and incorporate it into a PTRC-controlled CRISPRa system (PTRCdcas) to modulate endogenous gene expression. We then integrate the PTRC with small molecule- or blue light-inducible regulatory modules to construct a variety of highly tunable systems that allow rapid and reversible control of transcriptional regulation in vitro and in vivo. Validation and deployment of these plant-derived phytochrome chaperone proteins in a PTRC platform have produced a versatile, powerful tool for advanced research and biomedical engineering applications. Synthetic biology applications require finely tuned gene expression, often mediated by synthetic transcription factors. Here the authors validate two plant-derived proteins, FHY1 and FHL, acting as transactivators in mammalian cells for orthogonal, modular, and tunable control of gene transcription by forming a photosensing transcriptional regulation complex with PhyA. [ABSTRACT FROM AUTHOR]

In this paper, we study the overdetermined problem for the p-Laplacian equation on complete noncompact Riemannian manifolds with nonnegative Ricci curvature. We prove that the regularity results of weak solutions of the p-Laplacian equation and obtain some integral identities. As their applications, we give the proof of the p-Laplacian overdetermined problem and obtain some well known results such as the Heintze-Karcher inequality and the Soap Bubble Theorem. [ABSTRACT FROM AUTHOR]

Optimizing thermoelectric conversion efficiency requires the compromise of electrical and thermal properties of materials, which are hard to simultaneously improve due to the strong coupling of carrier and phonon transport. Herein, a one-pot approach realizing simultaneous second phase and Cu vacancies modulation is proposed, which is effective in synergistically optimizing thermoelectric performance in copper sulfides. Multiple lattice defects, including nanoprecipitates, dislocations, and nanopores are produced by adding a refined ratio of Sn and Se. Phonon transport is significantly suppressed by multiple mechanisms. An ultralow lattice thermal conductivity is therefore obtained. Furthermore, extra Se is added in the copper sulfide for optimizing electrical transport properties by inducing generating Cu vacancies. Ultimately, an excellent figure of merit of ~1.6 at 873 K is realized in the Cu1.992SSe0.016(Cu2SnSe4)0.004 bulk sample. The simple strategy of inducing compositional and structural modulation for improving thermoelectric parameters promotes low-cost high-performance copper sulfides as alternatives in thermoelectric applications. It is hard to simultaneously improve electrical and thermal properties of materials due to the strong coupling of carrier and phonon transport. Here, the authors propose a one-pot modulation strategy for simultaneously adjusting carrier and phonon transport in copper sulfids. [ABSTRACT FROM AUTHOR]

The hemorrhagic progression of a contusion (HPC) after Traumatic brain injury (TBI) is one of the important causes of death in trauma patients. The purpose of this meta-analysis was to evaluate the predictive effect of imaging features of Computed tomography (CT) on HPC after TBI. A comprehensive systematic search was performed using PubMed, EMBASE, and WEB OF SCIENCE databases to identify all relevant literature. A total of 8 studies involving 2543 patients were included in this meta-analysis. Meta-analysis showed that subarachnoid hemorrhage (OR 3.28; 95% CI 2.57–4.20), subdural hemorrhage (OR 4.35; 95% CI 3.29–5.75), epidural hemorrhage (OR 1.47;95% CI 1.15–1.89), contrast extravasation (OR 11.81; 95% CI 4.86–28.71) had a predictive effect on the occurrence of HPC. Skull fracture (OR 1.64; 95% CI 0.84–3.19) showed no statistical significance, and midline displacement > 5 mm (OR 4.66; 95% CI 1.87–11.62) showed high heterogeneity. The results of this meta-analysis showed that some imaging features were effective predictors of HPC after TBI. Well-designed prospective studies are needed to more accurately assess the effective predictors of HPC after TBI. [ABSTRACT FROM AUTHOR]

The existing literature primarily examined the impact of unexpected events on the stock market at a single scale, posing the challenge of a lack of multiscale analysis. This paper investigates the impact of COVID-19 on stock markets (China, the U.S., and Hong Kong) from a multiscale perspective using an improved ensemble empirical mode decomposition (EEMD)-based event analysis method. First, the stock price series is decomposed into several independent intrinsic mode functions (IMFs) and a residue. Second, a novel composition method is proposed to reconstruct the IMFs into three components: high-frequency, low-frequency, and long-term trend. We find that the composition of low-frequency and long-term trend components is dominant, which is used to estimate the strength of COVID-19 impact on the stock markets. In addition, the outbreak of COVID-19 significantly increased the intensity of short-term fluctuations in stock prices. Finally, the high-frequency component is analyzed to capture the volatility spillover effects among the three stock markets by the BEKK(Baba-Engle-Kraft-Kroner)-GARCH model. The results show that before the outbreak, there are two-way volatility spillovers between any two of the three markets. After the outbreak, there is no spillover effect between China and Hong Kong, and Hong Kong has no spillover effect on the U.S. However, volatility in the U.S. market still has a significant spillover effect on the other two markets, implying that a mature market can absorb new information more quickly. [ABSTRACT FROM AUTHOR]

Extracting time domain features of facial motion information to recognize unsafe driving behaviors such as fatigue and distraction is helpful to reduce traffic accidents. However, it is uncertain whether facial motion can recognize unsafe behaviors of workers. And whether it can improve recognition accuracy by introducing frequency domain features needs further research. This paper proposes a recognition method of workers' unsafe behavior based on frequency domain features of facial motion information. Firstly, the facial video of workers is obtained. And Gabor, histogram of oriented gradient (HOG) and local binary patterns (LBP) motion information are extracted. Then frequency domain features of these information are calculated, and finally sent to machine learning classifiers to recognize unsafe behavior. The results show that: (1) Compared with safe behavior, the complexity of facial motions during unsafe behavior is higher, especially in nose and mouth areas. (2) Wavelet entropy frequency domain features of Gabor motion information can better describe the complexity and have higher recognition accuracy (AUC = 0.766); (3) The proposed method can recognize unsafe behaviors of workers and is effective for operation errors (AUC = 0.818). The results can be used as a new idea to recognize unsafe behaviors of workers and provide technical support for on-site safety management. [ABSTRACT FROM AUTHOR]

The molecular landscapes of diffuse large B-cell lymphoma (DLBCL) remained to be comprehensively investigated with an urgent need to identify novel prognostic biomarkers guiding prognostic stratification and disease monitoring. Baseline tumor samples of 148 DLBCL patients were analyzed using targeted next-generation sequencing (NGS) for mutational profiling, whose clinical reports were retrospectively reviewed. In this cohort, the subgroup of old DLBCL patients (age at diagnosis > 60, N = 80) exhibited significantly higher Eastern Cooperative Oncology Group scores and International Prognostic Index than their young counterparts (age at diagnosis ≤ 60, N = 68). As revealed by the NGS results, PIM1 (43.9%), KMT2D (31.8%), MYD88 (29.7%), and CD79B (27.0%) were identified as the most frequently mutated genes. Aberrations of genes of the immune escape pathway were significantly enriched in the young subgroup, while the altered epigenetic regulators were more abundant in the old patients. FAT4 mutation was identified as a positive prognostic biomarker, associated with longer progression-free survival and overall survival in the entire cohort and the old subgroup, using the Cox regression analyses. However, the prognostic function of FAT4 was not reproduced in the young subgroup. We comprehensively analyzed the pathological and molecular characteristics of old and young DLBCL patients and demonstrated the prognostic value of FAT4 mutation, which requires further validation with sizable cohorts in future research. [ABSTRACT FROM AUTHOR]

Cervical cancer (CC) is the fourth most common cancer in women, and circular RNAs (circRNAs) have been shown to regulate CC development. However, the role of circ_0006646 in CC progression is still unclear. The levels of circ_0006646, miR-758-3p, and ribonucleotide reductase regulatory subunit M2 (RRM2) were evaluated by quantitative real-time PCR. Cell proliferation was tested by cell counting kit 8 and 5-ethynyl-2′-deoxyuridine assays. Flow cytometry was used to test cell apoptosis. Migration and invasion were estimated by transwell assay. Western blot assay was performed to examine protein expression. Dual-luciferase reporter assay, RIP assay, and RNA pull down assay were used to analyze the connection between miR-758-3p and circ_0006646 or RRM2. Tumor growth was detected by in vivo experiments. Exosomes were isolated form CC patients and healthy controls. Circ_0006646 expression was elevated in CC cells, and its knockdown suppressed CC cell growth, migration, and invasion. MiR-758-3p was sponged by circ_0006646, and RRM2 was targeted by miR-758-3p. In addition, the effects of circ_0006646 depletion on CC cell progression were overturned by miR-758-3p inhibitor, and either RRM2 overexpression reversed those effects of miR-758-3p overexpression on CC cell progression. Circ_0006646 was highly expressed in the exosomes of CC patients. Circ_0006646 expedited CC cell growth and metastasis by regulating miR-758-3p/RRM2 axis, and exosomal circ_0006646 might be a potential diagnostic indicator of CC. [ABSTRACT FROM AUTHOR]

Purpose: To modify the traditional surgical approach to treat patients diagnosed with congenital lower eyelid entropion using inferior eyelid margin fixation of the orbicularis eyelid muscle. Methods: Ninety-six participants (180 eyes) with congenital lower eyelid entropion diagnosed between January 2019 and April 2021 were included in this study. The patients were divided into Group A (cutaneous orbicularis oculi excision treatment) and Group B (inferior eyelid margin fixation treatment). The efficiency and recurrence rate of treatments were used to compare the two treatments. Results: There was no significant difference in age, sex, and eyes distribution in both groups. And higher efficiency rate was found in Group B (P < 0.05). And Group A had a higher recurrence rate in the follow-up after surgical treatment (P < 0.05). Conclusions: This modified inferior eyelid margin fixation of the orbicularis eyelid muscle treatment is an ideal procedure with a high degree of efficacy and low recurrence rate in patients with congenital lower eyelid entropion. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) and ulcerative colitis (UC) are two intestinal diseases with different pathological changes. Electroacupuncture (EA) at Zusanli (ST36) on both IBS and UC is widely used in clinic practice. But it is unclear whether acupuncture at one acupoint can treat two different intestinal diseases at different layers of intestinal barrier. To address this question, we explored three intestinal barrier lesions in IBS and UC mice with the aid of transcriptome data analysis and studied the efficacy of EA at ST36 on them. The transcriptome data analysis showed that both UC and IBS had disrupted intestinal barrier in various layers. And both UC and IBS had epithelial barrier lesions with reduction of ZO-1, Occludin and Claudin-1, while UC rather than IBS had the destruction of the mucus barrier with less MUC2 expression. As to the vascular barrier, UC showed a higher CD31 level and mesenteric blood flow reduction, while IBS showed a lower PV-1 level. EA at ST36 can significantly improve the above lesions of intestinal barrier of IBS and UC. Our results gave more details about the comprehensive protective effect of EA for UC and IBS. We guess the effect of acupuncture may be a kind of homeostasis regulation. [ABSTRACT FROM AUTHOR]

Copyright of Advances in Atmospheric Sciences is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Patients with chronic hepatitis B (CHB) have a dynamic disease process and risk of end-stage liver disease. It is critical to unambiguously differentiate the stages of the disease and focus on therapy prior to onset of an irreversible clinical endpoint. Methods: We retrospectively analyzed a wide range of CHB patients at different stages. The predictive power of serum complement component 3 (C3) levels for the development of acute-on-chronic liver failure (ACLF) in patients with decompensated cirrhosis was established and validated. Results: The decrease in serum C3 levels paralleled the severity of diseases related to hepatitis B virus. Patients with decompensated cirrhosis who developed ACLF had significantly lower serum C3 levels than others on admission (0.50 vs. 0.80 g/L, P < 0.001). Data analysis also revealed that low serum C3 was a significant risk factor for developing ACLF (hazard ratio = 0.32, P < 0.01). The area under the receiver operating characteristic curve (auROC) for serum C3 levels that predicted the development of ACLF in patients with decompensated cirrhosis was 0.90, which had sensitivity and specificity of 88.2% and 88.7%, respectively. A similar result was observed in the validation set (auROC = 0.86 for predicting development of ACLF in patients with decompensated cirrhosis). Conclusions: Serum C3 levels are valuable in assessing the severity of CHB-related stages. Low C3 levels signifies the development of ACLF in patients with decompensated cirrhosis. Plain Language Summary: Generally, acute-on-chronic liver failure is a rapidly worsening liver failure syndrome. This disease is intractable and with high mortality. Acute decompensation of the liver is defined as the occurrence of complications of liver disease (i.e., ascites, hepatic encephalopathy, gastrointestinal bleeding, and bacterial infection). Clinically, acute decompensation in hepatitis B virus-related cirrhosis (a result of chronic liver injury by virus) often develops into acute-on-chronic liver failure. In addition, the complement component 3 is a serum protein, which participates in the immune response against virus infection and has been reported to be associated with liver failure. We tried to explore the feature of serum complement component 3 to differentiate the stages of the disease and assess its predictive value for acute-on-chronic liver failure. So, we analyzed the complement component 3 data from a broad range of hepatitis B virus-cirrhosis patients. Through analysis, we found that complement component 3 levels are valuable in assessing the severity of chronic hepatitis B-related stages. Low complement component 3 levels can also signify the development of acute-on-chronic liver failure in patients with decompensated cirrhosis. [ABSTRACT FROM AUTHOR]

Let (M , g) be an n-dimensional complete Riemannian manifold with nonnegative Ricci curvature. In this paper, we consider an overdetermined problem of the biharmonic operator on a bounded smooth domain Ω in M. We deduce that the overdetermined problem has a solution only if Ω is isometric to a ball in R n . Our method is based on using a P-function and the maximum principle argument. This result is a generalization of the overdetermined problem for the biharmonic equation in Euclidean space. [ABSTRACT FROM AUTHOR]

The ongoing COVID-19 pandemic has demonstrated that viral diseases represent an enormous public health and economic threat to mankind and that individuals with compromised immune systems are at greater risk of complications and death from viral diseases. The development of broad-spectrum antivirals is an important part of pandemic preparedness. Here, we have engineer a series of designer cells which we term autonomous, intelligent, virus-inducible immune-like (ALICE) cells as sense-and-destroy antiviral system. After developing a destabilized STING-based sensor to detect viruses from seven different genera, we have used a synthetic signal transduction system to link viral detection to the expression of multiple antiviral effector molecules, including antiviral cytokines, a CRISPR-Cas9 module for viral degradation and the secretion of a neutralizing antibody. We perform a proof-of-concept study using multiple iterations of our ALICE system in vitro, followed by in vivo functionality testing in mice. We show that dual output ALICESaCas9+Ab system delivered by an AAV-vector inhibited viral infection in herpetic simplex keratitis (HSK) mouse model. Our work demonstrates that viral detection and antiviral countermeasures can be paired for intelligent sense-and-destroy applications as a flexible and innovative method against virus infection. The development of broad-spectrum antivirals is an important part of pandemic preparedness and response. Here the authors present ALICE, synthetic biology designer immune-like cells that act as a sense-and-destroy antiviral system can detect viruses from seven different genera, mimicking the human innate immune system. [ABSTRACT FROM AUTHOR]

Intra-articular masses are not a rare finding in routine imaging. This is particularly true in patients with underlying joint diseases such as degenerative arthritis. Nevertheless, concomitant presentation is rather uncommon in imaging studies. The authors report an unusual concomitant lipoma arborescens and synovial osteochondromatosis (which has not previously been reported in the literature to the best of the authors' knowledge) in a man in his 60 s with a long-standing history of knee osteoarthritis. In this case presentation, we review the differential diagnosis for noninfectious synovial proliferative disorders presenting as intra-articular masses, their potential association with underlying joint pathology, and discuss the key imaging features and appropriate treatment. [ABSTRACT FROM AUTHOR]

Males and females often exhibit differences in behaviour, life histories, and ecology, many of which are typically reflected in their brains. Neuronal protection and maintenance include complex processes led by the microglia, which also interacts with metabolites such as hormones or immune components. Despite increasing interest in sex-specific brain function in laboratory animals, the significance of sex-specific immune activation in the brain of wild animals along with the variables that could affect it is widely lacking. Here, we use the Kentish plover (Charadrius alexandrinus) to study sex differences in expression of immune genes in the brain of adult males and females, in two wild populations breeding in contrasting habitats: a coastal sea-level population and a high-altitude inland population in China. Our analysis yielded 379 genes associated with immune function. We show a significant male-biased immune gene upregulation. Immune gene expression in the brain did not differ in upregulation between the coastal and inland populations. We discuss the role of dosage compensation in our findings and their evolutionary significance mediated by sex-specific survival and neuronal deterioration. Similar expression profiles in the coastal and inland populations suggest comparable genetic control by the microglia and possible similarities in pathogen pressures between habitats. We call for further studies on gene expression of males and females in wild population to understand the implications of immune function for life-histories and demography in natural systems. [ABSTRACT FROM AUTHOR]

Whether membrane-anchored PD-L1 homodimerizes in living cells is controversial. The biological significance of the homodimer waits to be expeditiously explored. However, characterization of the membrane-anchored full-length PD-L1 homodimer is challenging, and unconventional approaches are needed. By using genetically incorporated crosslinkers, we showed that full length PD-L1 forms homodimers and tetramers in living cells. Importantly, the homodimerized intracellular domains of PD-L1 play critical roles in its complex glycosylation. Further analysis identified three key arginine residues in the intracellular domain of PD-L1 as the regulating unit. In the PD-L1/PD-L1-3RE homodimer, mutations result in a decrease in the membrane abundance and an increase in the Golgi of wild-type PD-L1. Notably, PD-1 binding to abnormally glycosylated PD-L1 on cancer cells was attenuated, and subsequent T-cell induced toxicity increased. Collectively, our study demonstrated that PD-L1 indeed forms homodimers in cells, and the homodimers play important roles in PD-L1 complex glycosylation and T-cell mediated toxicity. Membrane-anchored PD-L1 homodimerizes in cells. N-glycosylation of PD-L1 regulates its homodimerization. The formation of PD-L1 homodimers further regulates their glycan processing, localization to the plasma membrane, and binding to PD-1. [ABSTRACT FROM AUTHOR]

Individuals with South Asian ancestry have a higher risk of heart disease than other groups but have been largely excluded from genetic research. Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort, we conducted genome-wide association studies of coronary artery disease and its key risk factors. Using power-adjusted transferability ratios, we found evidence for transferability for the majority of cardiometabolic loci powered to replicate. The performance of polygenic scores was high for lipids and blood pressure, but lower for BMI and coronary artery disease. Adding a polygenic score for coronary artery disease to clinical risk factors showed significant improvement in reclassification. In Mendelian randomisation using transferable loci as instruments, our findings were consistent with results in European-ancestry individuals. Taken together, trait-specific transferability of trait loci between populations is an important consideration with implications for risk prediction and causal inference. Most genetic studies of disease have been done in European ancestry cohorts, and the relevance to other populations is not guaranteed. Here, the authors use data from 22,000 British South Asian individuals and find that the transferability of polygenic scores was high for lipids and blood pressure, and lower for BMI and coronary artery disease. [ABSTRACT FROM AUTHOR]

Two types of CdS QDs with the capped ligands of thioglycollic acid (TGA) and mercaptopropionic acid (MPA) were successfully prepared by in situ electron beam radiation at room temperature. These morphologies and microstructures of CdS QDs were determined efficiently by FTIR, UV–vis, XRD, DLS, XPS, Inverted-FL, BET, FE-SEM and HR-TEM and so on. In view of CdS QDs were prepared by different methods and each one had its own unique properties, which may lead to different potential toxicity. In this study, the effects of two types of CdS QDs on the cytotoxicity in mouse embryonic osteoblast precursor cells (MC3T3-E1) were evaluated. The cytotoxicity results revealed that the water soluble CdS QDs were toxic and inhibiting activity to MC3T3-E1 cells. Specially, compared with MPA-CdS QDs with longer ligands and larger sizes, TGA-CdS QDs with shorter ligands and smaller sizes were more significantly cytotoxicity on MC3T3-E1 cells. A possible mechanism for the cytotoxicity behavior was established. This work will be beneficial to the design and modification of CdS QDs by electron beam radiation method for probing the cytotoxicity on MC3T3-E1 cells and further benefit to cell imaging and tissue engineering. [ABSTRACT FROM AUTHOR]

Previous genetic and public health research in the Pakistani population has focused on the role of consanguinity in increasing recessive disease risk, but little is known about its recent population history or the effects of endogamy. Here, we investigate fine-scale population structure, history and consanguinity patterns using genotype chip data from 2,200 British Pakistanis. We reveal strong recent population structure driven by the biraderi social stratification system. We find that all subgroups have had low recent effective population sizes (Ne), with some showing a decrease 15‒20 generations ago that has resulted in extensive identity-by-descent sharing and homozygosity, increasing the risk of recessive disorders. Our results from two orthogonal methods (one using machine learning and the other coalescent-based) suggest that the detailed reporting of parental relatedness for mothers in the cohort under-represents the true levels of consanguinity. These results demonstrate the impact of cultural practices on population structure and genomic diversity in Pakistanis, and have important implications for medical genetic studies. Little is known about the recent population history or the effects of endogamy on the Pakistani population. Here the authors examine the impact of the biraderi social stratification system on the population structure of individuals of British Pakistani ancestry in the Born in Bradford cohort. [ABSTRACT FROM AUTHOR]

Researches on the bidirectional communications between the gut microbiota and brain, termed the gut-brain axis, often bring about discoveries and drive the development of medicine and biology for stroke. Following stroke, the gut-brain axis is perturbed significantly on dysbiotic gut microbiome, intestinal dysfunction, enteric nervous system, increased gut permeability, and activated immune cells in the gut, which in turn results in infiltration of pro-inflammatory cells or bacterial toxins into brain tissue through impaired blood–brain barrier (BBB), finally exacerbated brain infarction. Herein, we illuminate the changes in the immune system and highlight the possible mechanisms of the gut microbiota to regulate inflammatory and immune processes in the context of stroke. We conducted a systematic literatures search in PubMed, Web of Science, Embase, and guideline-specific databases until May 2021 using the following key terms: gut microbiota, stroke, immune, and inflammation. [ABSTRACT FROM AUTHOR]

Let N be a normal subgroup of a finite group G, and x an element of N. Objective that | x G | = | G : C G (x) | , so | x G | is called “minimal” when C G (x) is a maximal subgroup of G. In this paper, we characterize the structure of N when | x G | is minimal for every non-G-central element x of N. [ABSTRACT FROM AUTHOR]

Novel biocompatible acrylpimaric acid– and polyoxyethylene-based surfactant was prepared in our laboratory. Moreover, the influence of chain rigidity on the morphological transformation and adsorption behaviors of polyoxyethylene acrylpimaric acid copolymer and marketed polyethylene-polypropylene glycol (F188) surfactants was evaluated. The adsorption behaviors including critical micelle concentration (CMC), morphological change, and adsorption capacity were investigated. Reorientation theory was put forward to depict the adsorption and the morphological transformation for these two kinds of polyoxyethylene-based surfactants at water and air surface. The solvent molar fraction decreased and that of surfactant molecules increased as polyester concentration increased. The amounts of state 1 and state 2 surfactants adsorbing on the surface were calculated. The free energy of adsorption is far less than the energy of micellar formation. The consequences are helpful to illustrate the chain rigidity effect on adsorption behaviors and to expand in the formulation of micelles. [ABSTRACT FROM AUTHOR]

To study the effects of dissolved oxygen concentration on thermal oxidation coking of Chinese RP-3 aviation kerosene, a deoxygenation device and an on-line measurement device are designed and built. The coking amounts at different initial dissolved oxygen concentrations are measured, the morphology and elemental compositional analysis of coking deposits are analyzed by scanning electron microscope and energy disperse spectroscopy. By varying the heating length of the electrically heated tube, the distribution of the dissolved oxygen concentration along the tube is also measured. The experimental results suggest that lower initial dissolved oxygen concentration leads to less thermal oxidation coke. When the initial dissolved oxygen concentration decreases from 70.0 ppm to 22.4 ppm and to near 0 ppm, the total coking amount reduced by 47.6 and 75.4%. But at the oxygen-starved condition, the coke is not completely eliminated, and its surface morphology is obviously different. The dissolved oxygen concentration shows a declining trend along the tube, and it decreases dramatically from 39.3 to 4.5 ppm at the axial position of 40–50 cm. The measuring results along the tube indicate that thermal oxidation coking is affected by both temperature and dissolved oxygen concentration, but the sensitivities are different at different stages. [ABSTRACT FROM AUTHOR]

Thrombotic events are the most frequent causes of death in patients with antiphospholipid syndrome (APS). Previous studies have reported infection to be the most important trigger of thrombosis in APS, with molecular mimicry considered to be a major mechanism. Although timely management of infections has been recommended in patients with high suspicion of infection, anti-infective therapy would not take effect in a short time due to the dilemma in determining the origins of infection, especially in patients undergoing immunosuppressive therapy. Here, we describe a 26-year-old patient with systemic lupus erythematosus with triple antiphospholipid antibody positivity who had a stroke involving her dorsolateral medulla, despite timely anti-infective treatment within the context of skin infection caused by Stenotrophomonas maltophilia. To the best of our knowledge, it is the first report about the association between Stenotrophomonas maltophilia infection and thrombotic complications in APS. Thus, solely focusing on anti-infective therapy by the current recommendation for the management of APS may be insufficient within the context of infection; early initiation of effective anticoagulation should also be suggested until the anti-infective therapy becomes effective, especially in patients with high-risk antiphospholipid antibody profiles, in whom the potential benefit would outweigh the risk of bleeding. [ABSTRACT FROM AUTHOR]

Let G be a p-solvable finite group for some prime p, G p ′ a p ′ -Hall subgroup of G and x a p-regular element of G. Clearly, ⟨ x ⟩ ≤ C G (x) ≤ G . Notice that the structure of G p ′ is easily decided when C G (x) = ⟨ x ⟩ and C G (x) = G for every p-regular element x of G. So, in this paper, we investigate the structure of G p ′ by assuming that C G (x) is maximal in G for every non-central p-regular element x of G. [ABSTRACT FROM AUTHOR]

The solubilities, densities and refractive indices of the ternary KCl + PEG8000 + H2O system were determined at 288.2, 298.2, and 308.2 K. In terms of phase diagrams at 288.2, 298.2, and 308.2 K, they are all made up of three areas, where the homogeneous area (L) contains unsaturated liquid, area (L + S) contains one saturated liquid and one solid (KCl), and area (L + 2S) contains one saturated liquid and two solids (KCl and PEG8000). The results of these experiments showed that with an addition of PEG8000 to the liquid, the solubility of KCl and density of the liquid phase decreased, whereas the refractive index inceased. By comparing the phase diagrams at 288.2, 298.2, and 308.2 K, it is seen that with an increase of temperature, the areas of (L) and (L + S) enlarged, whereas the area of (L + 2S) reduced. The phase diagrams of the ternary systems KCl + PEG1000/4000/6000/8000 + H2O were also compared and showed that with an increase of the molar mass of PEG, the ovedrall phase diagrams did not change although the areas of each part varied in size. Also, a modified Pitzer model was adopted as the equilibrium thermodynamics model to correlate the experimental data. [ABSTRACT FROM AUTHOR]

Although tremendous efforts have been paid on electrocatalysts toward efficient electrochemical hydrogen generation, breakthrough is still highly needed in the design and synthesis of wonderful non-precious-metal electrocatalyst. Herein, a nanovilli Ni2P electrode, which with superaerophobic and superhydropholic can significantly facilitate the mass and electron transfer was constructed via a facial morphology control strategy. Meanwhile, the substitution of sluggish oxygen evolution with urea oxidation, lowering the two-electrode cell voltage to only 1.48 volts to achieve a current density of 10 mAcm−2. Thus, the as-constructed electrode achieves the operation of hydrogen generation by an AA battery. This work sheds new light on the exploration of other high-efficient electrocatalysts for hydrogen generation by using intermittent clean energy. [ABSTRACT FROM AUTHOR]

Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) expressing microRNAs have been highlighted in human diseases. However, the detailed molecular mechanism of hucMSCs-derived exosomal miR-18b-3p on preeclampsia (PE) remains further investigation. We aimed to investigate the effect of exosomes and miR-18b-3p/leptin (LEP) on occurrence of PE. The morphology of the hucMSC and hucMSC-exosomes (Exos) was identified. The exosomes were infected with different lentivirus expressing miR-18b-3p to explore the role of miR-18b-3p in PE. The PE rat model was established by intraperitoneal injection of N-nitro-l-arginine methyl ester. The expression of LEP and miR-18b-3p was tested in PE rat placenta tissues. Also, the effect of exosomes on LEP and miR-18b-3p expression was detected. The systolic blood pressure (SBP), proteinuria, inflammatory factors, the weight of fetal rat and placenta and cell apoptosis in PE rats were detected. Finally, the relationship between miR-18b-3p and LEP was verified using dual-luciferase reporter gene assay and RNA pull-down assay. Exosomes, restoring miR-18b-3p or inhibiting LEP reduced SBP and proteinuria of PE rats as well as increased the weight of fetal rat and placenta, decreased serum levels of inflammatory factors as well as suppressed apoptotic cells of PE rats, exerting a suppressive effect on PE progression. miR-18b-3p was decreased and LEP was increased in placenta tissues of PE rats. LEP was the direct target gene of miR-18b-3p. Upregulation of miR-18b-3p or treatment of the exosomes suppressed LEP expression and reduced PE occurrence, while downregulation of miR-18b-3p had contrary effects. Downregulated LEP reversed the effect of miR-18b-3p reduction on PE rats. HucMSCs-derived exosomal miR-18b-3p targets LEP to participate in the occurrence and development of PE. This study may provide a novel theoretical basis for the mechanism and investigation of PE. [ABSTRACT FROM AUTHOR]

In this work, a Zr702 sheet was subjected to β air cooling and then rolled to 15% reduction at room temperature, with their detailed microstructural characteristics characterized by electron channeling contrast imaging and electron backscatter diffraction techniques. Results show that after the β air cooling, the prior equiaxed grains in the as-received material are completely transformed into Widmanstätten structures featured by coarse plates with typical phase transformation misorientations between them. The subsequent 15% rolling allows both slip and twinning (especially the {10–12} type) to be activated readily, leading to significant grain refinement and the appearance of misorientation angle peaks around 3°–5° and 85°. Analyses on kernel average misorientations reveal that there exist very low residual strains in the β-air-cooled specimen while they are markedly increased after the 15% rolling and preferably distributed near low-angle and twin boundaries. Hardness measurements show that the specimen hardness is evidently decreased from ~ 199 to ~ 170 HV after the β air cooling, which can be attributed to grain coarsening and the scattered orientations associated with the slow β → α transformation. For the 15%-rolled specimen, however, effective grain refinement by twinning and denser low-angle boundaries jointly lead to ~ 35% hardness increment to ~ 228 HV. [ABSTRACT FROM AUTHOR]

Clinical studies reveal changes in blood eosinophil counts and eosinophil cationic proteins that may serve as risk factors for human coronary heart diseases. Here we report an increase of blood or heart eosinophil counts in humans and mice after myocardial infarction (MI), mostly in the infarct region. Genetic or inducible depletion of eosinophils exacerbates cardiac dysfunction, cell death, and fibrosis post-MI, with concurrent acute increase of heart and chronic increase of splenic neutrophils and monocytes. Mechanistic studies reveal roles of eosinophil IL4 and cationic protein mEar1 in blocking H2O2- and hypoxia-induced mouse and human cardiomyocyte death, TGF-β-induced cardiac fibroblast Smad2/3 activation, and TNF-α-induced neutrophil adhesion on the heart endothelial cell monolayer. In vitro-cultured eosinophils from WT mice or recombinant mEar1 protein, but not eosinophils from IL4-deficient mice, effectively correct exacerbated cardiac dysfunctions in eosinophil-deficient ∆dblGATA mice. This study establishes a cardioprotective role of eosinophils in post-MI hearts. Blood eosinophil (EOS) counts may serve as risk factors for human coronary heart diseases. Here the authors show that increased circulating and myocardial EOS after myocardial infarction play a cardioprotective role by reducing cardiomyocyte death, cardiac fibroblast activation and fibrosis, and endothelium activation-mediated inflammatory cell accumulation. [ABSTRACT FROM AUTHOR]

Machine learning (ML) models have been applied to monthly streamflow forecasting in recent decades. In this study, forecasting skills of eight ML models are evaluated based on the Model Parameter Estimation Experiment (MOPEX) dataset. We consider two skill scores, i.e., the Nash–Sutcliffe efficiency (NSE) and the adjusted NSE (ANSE), and the latter is the skill score based on the interannual mean monthly value (MMV) as the reference (benchmark) model. Furthermore, NSE of the MMV model (NSEmmv) is used as a measure of the seasonality of monthly streamflow, as it is the ratio of variance explained by the MMV process. An important result is that forecasting skills of ML models for monthly streamflow are largely controlled by NSEmmv. Moreover, based on comparisons of different ML models, we have found that the selection of models is not a dominating factor impacting the final skill. Three key factors influencing NSE, i.e., NSEmmv, the base flow index (BFI) and the aridity index (AI), are explored in this paper. Specifically, NSEmmv impacts NSE directly and is the predominant factor; BFI influences the memory of the monthly streamflow and therefore influences NSE. The relationship between AI and NSE is much complex and indirect. Firstly, basins with higher AI tend to have lower NSEmmv, and this will lead to lower NSE; secondly, basins with higher AI tend to have lower BFI, which will also lead to lower NSE; thirdly, for a given BFI level, basins with higher AI tend to have higher memory and higher NSE. For ANSE, basins with AI between 1 and 2 show higher ANSE, which corresponds to higher autocorrelation coefficients. [ABSTRACT FROM AUTHOR]

In this paper, we investigate CSS-quasinormality of maximal subgroups of Sylow subgroups of some Fitting subgroup and obtain a sufficient condition about the supersolvablity of finite groups, such that some known results about c-normality and SS-quasinormality are generalized and unified. [ABSTRACT FROM AUTHOR]

MucA and MucB are critical negative modulators of sigma factor AlgU and regulate the mucoid conversion of Pseudomonas aeruginosa. Previous studies have revealed that lipid signals antagonize MucA-MucB binding. Here we report the crystal structure of MucB in complex with the periplasmic domain of MucA and polyethylene glycol (PEG), which unveiled an intermediate state preceding the MucA-MucB dissociation. Based on the biochemical experiments, the aliphatic side chain with a polar group was found to be of primary importance for inducing MucA cleavage. These results provide evidence that the hydrophobic cavity of MucB is a primary site for sensing lipid molecules and illustrates the detailed control of conformational switching within MucA-MucB in response to lipophilic effectors. Tao Li et al. report crystal structure of MucA-MucB complex and identify a cavity region of MucB that binds PEG molecule. They further show that this hydrophobic cavity of MucB is a primary site for sensing lipid molecules and that lipid A stimulates MucB to release MucA for AlgW cleavage, helping to understand the regulation mechanism of alginate biosynthesis. [ABSTRACT FROM AUTHOR]

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4+ T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases. Some immune-mediated diseases may originate in early childhood. The authors mapped eQTLs and response eQTLs to various stimuli in neonatal myeloid cells and T cells, and revealed their potential role in immune-mediated diseases using colocalisation and Mendelian randomisation. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate whether TIPE2 participates in the protective actions of dexmedetomidine (DEX) in a mouse model of sepsis-induced acute lung injury (ALI). We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Control mice were infected with an adeno-associated virus expressing no transgene. Three weeks later, an animal model of caecal ligation-perforation (CLP)-induced sepsis was established. DEX was administered intravenously 30 min after CLP. Twenty-four hours after sepsis, lung injury was assayed by lung histology, the ratio of polymorphonuclear leukocytes (PMNs) to total cells in the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, BALF protein content and the lung wet-to-dry (W/D) weight ratio. Proinflammatory factor levels in the BALF of mice were measured. The protein expression levels in lung tissues were analysed by Western blotting. The results showed that DEX treatment markedly mitigated sepsis-induced lung injury, which was characterized by the deterioration of histopathology, histologic scores, the W/D weight ratio and total protein levels in the BALF. Moreover, DEX markedly attenuated sepsis-induced lung inflammation, as evidenced by the decrease in the number of PMNs in the BALF, lung MPO activity and proinflammatory cytokines in the BALF. In addition, DEX dramatically prevented sepsis-induced pulmonary cell apoptosis in mice, as reflected by decreases in the number of TUNEL-positive cells, the protein expression of cleaved caspase-9 and cleaved caspase 3 and the Bax/Bcl-2 ratio. In addition, evaluation of protein expression showed that DEX blocked sepsis-activated JNK phosphorylation and NF-κB p65 nuclear translocation. Similar results were also observed in the TIPE2 overexpression group. Our study demonstrated that DEX inhibits acute inflammation and apoptosis in a murine model of sepsis-stimulated ALI via the upregulation of TIPE2 and the suppression of the activation of the NF-κB and JNK signalling pathways. [ABSTRACT FROM AUTHOR]

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Purpose: This study aimed to explore the association between low-frequency and rare variants of Wnt signaling genes and postmenopausal osteoporosis (OP) by the next generation sequencing (NGS) technology. Methods: We performed targeted NGS of nine Wnt signaling genes in 400 Chinese postmenopausal women, including 226 cases with decreased bone mineral density (BMD) and 174 controls with normal values. Proxy External Controls Association Test (ProxECAT) and logistic regression analysis were performed by data from internal cases (n = 226) and Genome Aggregation Database (gnomAD) East Asian controls (n = 9435). Results: The genomic region of interest (ROI) of 94 functional low-frequency and rare variants was associated with OP risk (P < 0.05). The LGR6 gene was associated significantly with OP risk and BMD measurements (BMD, T-score and Z-score) (adjusted-P < 0.05) after adjusting for confounders. The allele A of rs199693693 (K82N) in LRP6 and G of novel variant 1: 202287949 (R840G) in LGR6 were associated with higher BMD, T-score, and Z-score (all adjusted-P < 0.05). ProxECAT showed that LGR4 was significantly different between the internal cases and the external controls (all adjusted-P < 0.05). Logistic regression analysis revealed that the allele G of rs765778410 (T645A) (OR = 26.16, 95% CI: 4.36–156.95, adjusted-P value = 0.026) in LGR6 and A of rs61370283 (L987M) (OR = 15.39, 95% CI: 2.98–79.55, adjusted-P value = 0.037) in LRP5 were associated with increased risk of postmenopausal OP. Conclusion: The LGR4 and LGR6 genes and four potential functional rare variants associate with postmenopausal OP risk. These results highlight the significance of rare functional variants in postmenopausal OP genetics and provide new insights into the potential mutations in this field. [ABSTRACT FROM AUTHOR]

Mercury pollution is a global problem and of particular concern in high emissions areas, such as China. We studied the migratory Kentish Plover, Charadrius alexandrinus, which breeds in coastal northern/central China and the inland Qinghai Lake, and the White-faced Plover C. dealbatus, a year-round resident of coastal southern China. We measured total mercury (THg) concentrations in feather and blood samples of breeding females. We expected low levels at the remote Qinghai Lake, but we found instead that feather THg concentrations were highest there (3.89 ± 1.53 [SD] μg/g DW [n = 34]; compared to 1.29 ± 0.61 μg/g of Kentish Plover elsewhere [n = 35] and 2.08 ± 1.45 μg/g for White-faced Plover [n = 56]), a result is consistent over 2 years. When including only coastal populations in the analysis, there were no differences in THg concentrations between the two species, although White-faced Plover had more variation. Feather THg concentrations for the coastal populations are similar to other studies on plovers and sandpipers globally, with most birds under the threshold of adverse effects (3 μg/g, an estimate that itself may be too low). Nevertheless, the Qinghai Kentish Plover population has mean feather concentrations above this threshold, indicating high exposure during the nonbreeding season, and some individuals have extreme values (e.g., a bird with a blood level of 7.63 μg/g DW from Zhanjiang, south China), so further research and monitoring are needed. [ABSTRACT FROM AUTHOR]

Eosinophilic gastrointestinal disorders (EGID) comprise a spectrum of inflammatory diseases that can affect any segment of the gastrointestinal tract. The pathogenesis of these conditions is complex; differentiating between primary and secondary forms of these disorders can be clinically challenging. We report a case of primary EGID in a patient with remote parasite exposure, whose symptoms were initially attributed to irritable bowel syndrome. Endoscopy revealed the rare finding of EGID involving the entire gastrointestinal tract; symptoms improved with an elimination diet. This case raises the possibility of a link between prior parasite exposure and development of EGID, and underscores the necessity of exploring alternative diagnoses in patients with presumed IBS who present with severe symptoms. [ABSTRACT FROM AUTHOR]

Critically short telomeres indicate cellular senescence. Leukocyte telomere length (LTL) is regarded as an aging predictor. Osteoporosis is an age-related disease. The purpose of our study is to examine the association between LTL, and BMD and osteoporosis among an elderly Chinese population. A total of 1017 participants (584 postmenopausal women) with a mean age of 66.4 years were recruited from April 2016 to August 2017. Dual-energy X-ray absorptiometry was used for BMD measurement at skeleton sites of lumbar spine (LS), femoral neck (FN), and total hip (TH). LTL was measured using quantitative real-time polymerase chain reaction. Among women, age significantly modified the effect of LTL on BMD at FN. Additionally, significant age modification was observed for the association between LTL and LS BMD category (indicative of control or osteopenia or osteoporosis), and the number of osteoporotic sites at LS or TH. The corresponding estimates (95% CI) for the relative excess risk due to interaction (RERI) were - 0.07 (- 0.11, - 0.01) and - 0.11 (- 0.16, - 0.03) sequentially in ordinal logistic regression models. The estimated RERIs (95% CI) were - 0.11 (- 0.25, - 0.02) and - 0.23 (- 0.39, - 0.10) in multinomial logistic regression models for LS/FN/TH BMD category, and - 0.20 (- 0.31, - 0.09) and - 0.34 (- 0.49, - 0.21) for FN BMD category. However, similar findings did not show in men. The effect of LTL on BMD and osteoporosis risk is modified by age in elderly women but not in men, suggesting that the predictive role of LTL in bone loss differs by sex. [ABSTRACT FROM AUTHOR]

Objective: Tumour necrosis factor-α-induced protein 8-like 2 (TIPE2) has strong anti-inflammatory properties. However, it is unknown whether increased TIPE2 is protective against lipopolysaccharide (LPS)-induced ALI. In the current study, we aimed to investigate whether increased TIPE2 can exert protective effects in a mouse model of ALI induced by LPS. Methods: We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Three weeks later, ALI was induced by intratracheal injection of LPS into BALB/c mice. Twenty-four hours later, lung bronchoalveolar lavage fluid (BALF) was acquired to analyse cells and protein, arterial blood was collected for arterial blood gas analysis and the determination of pro-inflammatory factor levels, and lung issues were collected for histologic examination, transmission electron microscopy (TEM), TUNEL staining, wet/dry (W/D) weight ratio analysis, myeloperoxidase (MPO) activity analysis and blot analysis of protein expression. Results: We found that TIPE2 overexpression markedly mitigated LPS-induced lung injury, which was evaluated by the deterioration of histopathology, histologic scores, the W/D weight ratio, and total protein expression in the BALF. Moreover, TIPE2 overexpression markedly attenuated lung inflammation, as evidenced by the downregulation of polymorphonuclear neutrophils (PMNs) in the BALF, lung MPO activity, and pro-inflammatory cytokine levels in the serum. Moreover, TIPE2 overexpression not only dramatically prevented LPS-induced pulmonary cell apoptosis in mice but also blocked LPS-activated JNK phosphorylation and NF-κB p65 nuclear translocation. Conclusions: Our study shows that the increased expression of AAV-mediated TIPE2 in the lungs of mice inhibits acute inflammation and apoptosis and suppresses the activation of NF-κB and JNK in a murine model of ALI. [ABSTRACT FROM AUTHOR]