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Elderly patients with coronavirus disease 2019 (COVID-19) who have comorbidities, frailty or profound disabilities experience poor outcomes. We analyzed the clinical characteristics of elderly patients from Wuhan who had COVID-19 during the early stages of the pandemic.To identify factors affecting the early mortality of elderly patients with COVID-19.The records of 234 patients who were 65-years-old or more and were hospitalized in Wuhan Huoshenshan Hospital from February 4 to March 4, 2020 were reviewed. All patients had confirmed COVID-19 and the final date of follow-up was April 4, 2020.There were 163 cases of mild disease (69.66%), 39 cases of severe disease (16.67%) and 32 cases of critical disease (13.68%). Twenty-nine patients died within 1 mo (12.40%), all of whom had critical disease. Surviving patients and deceased patients had no significant differences in age or chronic diseases. Overall, the most common symptoms were fever (65.4%), dry cough (57.3%), fatigue (47.4%) and shortness of breath (41%). The deceased patients had higher levels of multiple disease markers (C-reactive protein, D-dimer, lactate dehydrogenase, alanine amino transferase, aspartate aminotransferase, creatinine kinase and creatinine kinase-MB) and higher incidences of lymphocytopenia and hypoproteinemia.This single-center study of elderly patients from Wuhan, China who were hospitalized with COVID-19 indicated that age and chronic diseases were not associated with mortality. Hypertension, diabetes and cardiovascular disease were the most common comorbidities and the most common symptoms were fever, dry cough, fatigue and shortness of breath. Lymphocytopenia, increased levels of D-dimer and other markers indicative of damage to the heart, kidneys or liver were associated with an increased risk of death.

Miro1, a mitochondrial Rho GTPase1, is a kind of mitochondrial outer membrane protein involved in the regulation of mitochondrial anterograde transport and its subcellular distribution. Mitochondria influence reproductive processes of mammals in some aspects. Mitochondria are important for oocyte maturation, fertilization and embryonic development. The purpose of this study was to evaluate whether Miro1 regulates mouse oocyte maturation by altering mitochondrial homeostasis. We showed that Miro1 was expressed in mouse oocyte at different maturation stages. Miro1 mainly distributed in the cytoplasm and around the spindle during oocyte maturation. Small interference RNA-mediated Miro1 depletion caused significantly abnormal distribution of mitochondria and endoplasmic reticulum as well as mitochondrial dysfunction, resulting in severely impaired germinal vesicle breakdown (GVBD) of mouse oocytes. For those oocytes which went through GVBD in the Miro1-depleted group, part of them were inhibited in meiotic prophase I stage with abnormal chromosome arrangement and scattered spindle length. Our results suggest that Miro1 is essential for maintaining the maturation potential of mouse oocyte.

info:eu-repo/semantics/publishedVersion

Objective Diabetic cardiomyopathy (DCM) constitutes a primary cause of mortality in diabetic patients. Histone deacetylase (HDAC) inhibition can alleviate diabetes-associated myocardial injury. This study investigated the mechanism of HDAC1 on myocardial fibrosis (MF) in DCM. Methods A murine model of DCM was established by a high-fat diet and streptozotocin injection. The bodyweight, blood glucose, serum insulin, and cardiac function of mice were analyzed. Lentivirus-packaged sh-HDAC1 was injected into DCM mice and high glucose (HG)-induced cardiac fibroblasts (CFs). The pathological structure of the myocardium and the level of myocardial fibrosis were observed by histological staining. HDAC1 expression in mouse myocardial tissues and CFs was determined. Collagen I, collagen III, alpha-smooth muscle actin (α-SMA), and vimentin levels in CFs were detected, and CF proliferation was tested. HDAC activity and histone acetylation levels in tissues and cells were measured. Bone morphogenetic protein-7 (BMP-7) expression in myocardial tissues and CFs was determined. Functional rescue experiments were conducted to confirm the effects of histone acetylation and BMP-7 on myocardial fibrosis. Results DCM mice showed decreased bodyweight, elevated blood glucose and serum insulin, and cardiac dysfunction. Elevated HDAC1 and reduced BMP-7 expressions were detected in DCM mice and HG-induced CFs. HDAC1 repressed BMP-7 transcription through deacetylation. HDAC1 silencing alleviated MF, reduced CF proliferation and decreased collagen I, -III, α-SMA, and vimentin levels. However, reducing histone acetylation level or BMP-7 downregulation reversed the effects of HDAC1 silencing on CF fibrosis. Conclusion HDAC1 repressed BMP-7 transcription by enhancing histone deacetylation, thereby promoting MF and aggravating DCM.

Deep learning models have achieved high performance across different domains, such as medical decision-making, autonomous vehicles, decision support systems, among many others. However, despite this success, the inner mechanisms of these models are opaque because their internal representations are too complex for a human to understand. This opacity makes it hard to understand the how or the why of the predictions of deep learning models. There has been a growing interest in model-agnostic methods that make deep learning models more transparent and explainable to humans. Some researchers recently argued that for a machine to achieve human-level explainability, this machine needs to provide human causally understandable explanations, also known as causability. A specific class of algorithms that have the potential to provide causability are counterfactuals. This paper presents an in-depth systematic review of the diverse existing literature on counterfactuals and causability for explainable artificial intelligence (AI). We performed a Latent Dirichlet topic modeling analysis (LDA) under a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework to find the most relevant literature articles. This analysis yielded a novel taxonomy that considers the grounding theories of the surveyed algorithms, together with their underlying properties and applications to real-world data. Our research suggests that current model-agnostic counterfactual algorithms for explainable AI are not grounded on a causal theoretical formalism and, consequently, cannot promote causability to a human decision-maker. Furthermore, our findings suggest that the explanations derived from popular algorithms in the literature provide spurious correlations rather than cause/effects relationships, leading to sub-optimal, erroneous, or even biased explanations. Thus, this paper also advances the literature with new directions and challenges on promoting causability in model-agnostic approaches for explainable AI.

The ternary PtNiCo catalyst grafted by sulfonic group on reduced graphene oxide (RGO–SO3H) was prepared by a simple solvothermal method. The sheets of nanostructure were stacked in the shape of near-sphere by field-emission scanning electron microscope (FESEM). X-ray diffraction, X-ray photoelectron spectroscopy and Raman spectroscopy were carried out to explore the phase structure, element analysis and carbon hybridization, respectively. The ternary PtNiCo alloys were evenly distributed on the supports of RGO–SO3H with size ranging from tens of nanometer in thickness and hundreds of nanometer in length. The electrocatalysis of PtNiCo/RGO–SO3H was superior to that of PtNiCo/RGO and PtNiCo/GO catalyst for ORR. The stability of PtNiCo/RGO–SO3H catalysts was characterized by the electrochemical surface area (ECSA) with 35% loss of the hydrogen adsorption/desorption after repeating 5000 cycles. The –SO3H groups grafted on RGO were in favor of ORR and anchoring site for PtNiCo nanoparticles. The high lattice contraction will support the retention of Ni and Co to enhance the catalyst activity in the ternary PtNiCo alloy. The synergistic effect of –SO3H groups and alloying elements can improve the catalytic efficiency and stability of PtNiCo/RGO–SO3H in the potential application of proton exchange membrane fuel cells.

Batch processing is used in many production and service processes and can help achieve efficiencies of scale; however, it can also increase inventories and introduce process delays. Before organizations can develop good understanding about the effects of batch processing on process performance, they should be able to identify potential batch-processing behavior in business processes. However, in many cases such behavior may not be known; for example, batch processing may be occasionally performed during certain time frames, by specific employees, and/or for particular customers. This article presents a novel approach for the identification of batching behavior from process execution data recorded in event logs. The approach can discover different types of batch-processing behaviors and allows users to configure batch-processing characteristics they are interested in. The approach is implemented and evaluated through experiments with synthetic event logs and case studies with real-life event logs. The evaluation demonstrates that the approach can identify various batch-processing behaviors in the context of business processes.

Nondipping heart rate (HR), defined as a night/day HR ratio0.90, has been associated with increased mortality in epidemiologic studies. However, its prognostic value in stage 5 chronic kidney disease (CKD5) patients and the effects of parathyroidectomy (PTX) on nondipping HR remain unknown.This case-control study of 162 healthy controls and 502 CKD5 patients was performed between 2011 and 2018, in which CKD5 patients were further divided into non-PTX (n = 186) and severe secondary hyperparathyroidism (SHPT) with PTX (n = 316) subgroups. Each participant underwent 24-hour Holter monitoring for HR ratio. Mortality was followed up in CKD5 patients (median time: 46.0 months).The HR ratio in CKD5 patients was higher than in controls (0.92 ± 0.08 vs 0.81 ± 0.08, P.001), associated with a 44% increase in mortality risk per 0.1 increment (hazard ratio, 1.44; 95% CI: 1.02-2.03; P =.04), and was positively related to serum intact parathyroid hormone levels (P.001). PTX reversed nondipping HR in SHPT patients (n = 50, median time: 6.3 months, P.001). Survival probabilities for PTX (n = 294) were better than non-PTX (n = 47) (hazard ratio, 0.31; 95% CI: 0.14-0.67; P.01) in SHPT patients (serum intact parathyroid hormone500.0 pg/mL).CKD5 patients displayed a nondipping HR pattern, which is a prognostic marker of all-cause mortality. PTX for SHPT patients was associated with a reversal in nondipping HR ratio, which may mediate a better outcome.

Heart space-occupying lesions are a disease that occurs frequently in clinical setting, and therefore, it is important to diagnose and treat this type of pathologies properly. Angiographic echocardiography and transesophageal sonogram are widely used for clinical diagnosis. Their application provides a guarantee for the diagnosis of cardiac space-occupying lesions. In this paper, the application of cardiac contrast echocardiography and transesophageal echocardiography in cardiac space-occupying lesions was studied. Prediction of cardiac lesions can accurately determine the nature of cardiac occupancies and provide a basis for clinical diagnosis and management judgments. The results of pathological analysis and experimental comparison showed that myocardial contrast echocardiography can accurately distinguish tumor and thrombus and make contribution to patients taking appropriate medical measures. At the same time, it can compare conventional transthoracic echocardiography and transesophageal echocardiography. The results showed that TEE could clearly show the cardiac lesions. The experimental data of 76.9% confirmed cases showed that the diagnostic accuracy is greatly improved. TEE can also clearly show small thrombus that TTE cannot, in which 2DTEE can clearly show the boundary between the space-occupying and surrounding tissues, and whether there is a clear boundary between the space-occupying and surrounding tissues is an important distinguishing point of benign and malignant tumors. In addition, the TEE probe can also be used for large angle imaging and multiangle rotation, so as to determine the tumor boundary and the spatial position relationship between the tumor and the surrounding tissue. All in all, myocardial contrast echocardiography and transesophageal echocardiography have better clinical application effect on cardiac space-occupying lesions.

A novel porous iron phosphide loading on nitrogen-doped carbon fiber/carbon paper (p-FeP/NCF/CP) as highly effective self-supporting catalysts for the hydrogen evolution reaction is synthesized by a three-step approach.

A facile three-step approach for tubular CoP preparation and its catalytic activity for HER and OER are reported. The CoP microtubes show superior HER performance in a wide pH range with low overpotentials of 91, 101 and 113 mV at 10 mA cm−2 in 0.5 M H2SO4, 1 M KOH and 1 M PBS, respectively. Additionally, it also depicts superior OER performance with an overpotential of 300 mV at 10 mA cm−2, which is lower than reported precious metal oxides. The improved electrocatalytic performance of tubular CoP is likely attributed to the porous tube-like structural features, which not only afford rich exposed active sites, but also accelerate the charge or mass transfer efficiency, and thus efficiently promote the HER performance. The synthesis of tubular CoP confirms the importance of morphology features and provides a new insight to rationally design and synthesize highly effective non-noble metal phosphide-based pH-universal electrocatalysts for HER.

FeP/Ni2P/CP catalyst exhibits superior electrocatalytic activities for HER and long-term durability.

As the most abundant organelles in oocytes, mitochondria play an important role in maintaining oocyte quality. Here, we report that March5, encoding a mitochondrial ubiquitin ligase that promotes mitochondrial elongation, plays a critical role in mouse oocyte meiotic maturation via regulating mitochondrial function. The subcellular localization of MARCH5 was similar to the mitochondrial distribution during mouse oocyte meiotic progression. Knockdown of March5 caused decreased ratios of the first polar body extrusion. March5-siRNA injection resulted in oocyte mitochondrial dysfunctions, manifested by increased reactive oxygen species, decreased ATP content as well as decreased mitochondrial membrane potential, leading to reduced ability of spindle formation and an increased ratio of kinetochore–microtubule detachment. Further study showed that the continuous activation of the spindle assembly checkpoint and the failure of Cyclin B1 degradation caused MI arrest and first polar body (PB1) extrusion failure in March5 knockdown oocytes. Taken together, our results demonstrated that March5 plays an essential role in mouse oocyte meiotic maturation, possibly via regulation of mitochondrial function and/or ubiquitination of microtubule dynamics- or cell cycle-regulating proteins.

Prenatal imaging phenotypes and genotypes were analyzed in 13 cases prenatally diagnosed with Joubert syndrome (JS), all of which underwent magnetic resonance imaging (MRI), ultrasound, and genetic testing. Prenatal MRI diagnosed 10 cases as JS with a typical molar tooth sign (MTS), while prenatal ultrasound diagnosed or suspiciously diagnosed 11 cases as JS with typical or mild MTS in 10 cases. Mutations in JS-related genes and other prenatal JS imaging phenotypes were identified in 10 cases, including OFD1 in two cases [cerebellar vermis (CV) absence, posterior fossa dilation, ventriculomegaly, polydactyly, malformations of cortical development (MCD), and persistent left superior vena cava], TMEM67 in two cases (CV absence, polydactyly, hyperechoic kidneys or polycystic kidneys, posterior fossa dilation, and ventriculomegaly), CC2D2A in two cases (CV absence, polydactyly, MCD, agenesis of the corpus callosum, encephalocele and hydrocephalus, ventriculomegaly, and posterior fossa dilation), RPGRIP1L in one case (CV absence), TCTN3 in one case (CV absence, polydactyly, MCD, and posterior fossa dilation), CEP290 in one case (CV absence and polycystic kidney), and NPHP1 in one case (CV absence). The prenatal diagnosis of JS presents a number of challenges, including the variants of unknown significance, the lack of functional assessment in prenatal imaging, unclear phenotype–genotype relationships in prenatal evaluation, and the incorrect identification of the JS hallmark, the MTS, in prenatal imaging, especially on ultrasound. Although combined MRI, ultrasound, and exome sequencing could help improve the prenatal diagnosis of JS, there still exist significant challenges.

Maternal ageing is one of the major causes of reduced ovarian reserve and low oocyte quality in elderly women. Decreased oocyte quality is the main cause of age-related infertility. Mitochondria are multifunctional energy stations that determine the oocyte quality. The mitochondria in aged oocytes display functional impairments with mtDNA damage, which leads to reduced competence and developmental potential of oocytes. To improve oocyte quality, mitochondrial supplementation is carried out as a potential therapeutic approach. However, the selection of suitable cells as the source of mitochondria remains controversial. We cultivated endometrial mesenchymal stem cells (EnMSCs) from aged mice and extracted mitochondria from EnMSCs. To improve the quality of oocytes, GV oocytes were supplemented with mitochondria via microinjection. And MII oocytes from aged mice were fertilized by intracytoplasmic sperm injection (ICSI), combining EnMSCs' mitochondrial microinjection. In this study, we found that the mitochondria derived from EnMSCs could significantly improve the quality of aged oocytes. Supplementation with EnMSC mitochondria significantly increased the blastocyst ratio of MII oocytes from aged mice after ICSI. We also found that the birth rate of mitochondria-injected ageing oocytes was significantly increased after embryo transplantation. Our study demonstrates that supplementation with EnMSC-derived mitochondria can improve the quality of oocytes and promote embryo development in ageing mice, which might provide a prospective strategy for clinical treatment.

Business Process Management Systems ( BPMSs ) provide automated support for the execution of business processes in modern organisations. With the emergence of cloud computing, BPMS deployment considerations are shifting from traditional on-premise models to the Software-as-a-Service ( SaaS ) paradigm, aiming at delivering Business Process Automation as a Service. However, scaling up a traditional BPMS to cope with simultaneous demand from multiple organisations in the cloud is challenging, since its underlying system architecture has been designed to serve a single organisation with a single process engine. Moreover, the complexity in addressing both the dynamic execution environment and the elasticity requirements of users impose further challenges to deploying a traditional BPMS in the cloud. A typical SaaS often deploys multiple instances of its core applications and distributes workload to these application instances via load balancing. But, for stateful and often long-running process instances, standard stateless load balancing strategies are inadequate. In this article, we propose a conceptual design of BPMS capable of addressing dynamically varying demands of end users in the cloud, and present a prototypical implementation using an open source traditional BPMS platform. Both the design and system realisation offer focused strategies on achieving scalability and demonstrates the system capabilities for supporting both upscaling, to address large volumes of user demand or workload, and downscaling, to release underutilised computing resources, in a cloud environment.

Previous studies reported that microRNA-1298 was abnormally expressed in the myocardium of rat hearts after hypoxia/normoxia injury. This study aims to investigate the function and specific mechanism of miR-1298 in myocardial ischemia/reperfusion (IR) injury. Neonatal rat cardiomyocytes (NRCMs) were isolated from neonatal rat hearts and subjected to oxygen/glucose deprivation/reperfusion (OGD/R) to induce I/R injury. The rat model with I/R injury was induced by ligating the proximal left anterior descending artery (LAD). MiR-1298 expression was detected by qRT-PCR. The levels of PP2A, Bcl-2, Bax, and AMPK signaling members (p-AMPK, p-GSK3β) was detected by Western blot. Cell apoptosis was evaluated by TUNEL staining assay and flow cytometry. The infarct size of rat hearts was assessed by TTC staining assay. Premature and mature MiR-1298 were significantly downregulated while PP2A was significantly upregulated during I/R injury both in vitro and in vivo. The prediction of Starbase suggested that PP2A was a potential target of miR-1298. MiR-1298 overexpression significantly reduced cardiomyocyte apoptosis in vitro, and its protective effect was obviously attenuated by PP2A overexpression. Luciferase reporter assay showed that miR-1298 targeted PP2A directly. In addition, miR-1298 overexpression significantly reduced infarct size and cardiomyocyte apoptosis in the hearts of rats received with I/R injury in vivo. Moreover, miR-1298 overexpression significantly elevated the levels of Bcl-2 and AMPK signaling members (p-AMPK, p-GSK3β) while decreased Bax level, and these effects were partially reversed by PP2A overexpression. MiR-1298 participated in myocardial I/R injury by targeting the PP2A/AMPK/GSK3β signaling pathway, suggesting that miR-1298 might be a potential therapeutic target for myocardial I/R injury.

The anaphase promoting complex/cyclosome (APC/C) and its cofactors CDH1 and CDC20 regulate the accumulation/degradation of CCNB1 during mouse oocyte meiotic maturation. Generally, the CCNB1 degradation mediated by APC/C

This study aims to understand the effects that role-diverse online communities have on informal carers, particularly in providing support. Australian Facebook communities used to support those involved in the National Disability Insurance Scheme (NDIS) were explored. Social network analysis of an NDIS-centred community was conducted, based on 909 publicly visible interactions that occurred in May-June and August-September 2019. Two managers of informal NDIS communities were interviewed, the transcripts of which were analysed using NVivo. Results from the two analyses suggest that both an individual carer's attributes and the collective attributes of the network defined the capability of the network to support the carer, often depending on the experiences and expertise of those offering support. Support was unconstrained by role, though differing goals and expectations often impeded collaboration between roles. The outcomes of support provision were shown to affect not only individuals but also the collective network. However, while effective, community spaces currently lack organisational backing and resources available to informal communities are constrained. Findings drawn from this study, which we believe are applicable to a broader, international context, are three-fold. Firstly, it is recommended that informal support communities clearly define purpose and create multiple channels to ensure that all participants can meet their needs. Secondly, the benefits of participation to organisations should be further explored. Finally, the use of social network analysis as a method in this study has provided significant insights into the communication patterns and activities of the community under study. Future use of SNA in similar studies may provide further insight into the effectiveness and interactions of community-based support methods.

A Cyber-Physical-Social System (CPSS), as an extension of cyber-physical system (CPS), has received considerable attention in recent years both in academia and industry. Compared to CPS, CPSS has great advantages on efficiency, adaption and robustness due to the existence of self-organizing social system. One of the difficulties in the design of CPSS is anchored in the lack of a control mechanism to achieve self-organizing capability while the system is evolving. To address this problem, we propose a design framework for evolving CPSS based on the force field, which is composed of inner force and task force field. In addition to the framework, we present several performance evaluation indicators to quantify the self-organizing capability of the system, including consumption, emergence, and scalability. We test the performance of the framework using a disaster-relief example, which involves the computational control algorithm (cyber system), robot (physical system), and self-organizing swarm (social system). The result shows that based on our framework, the system can automatically evolve from disorder to order, adapt to the changeable environment and successfully finish the task in a very efficient manner.

In mammals, oocytes are arrested at G2/prophase for a long time, which is called germinal vesicle (GV) arrest. After puberty, fully-grown oocytes are stimulated by a gonadotropin surge to resume meiosis as indicated by GV breakdown (GVBD). CCNB1 is accumulated to a threshold level to trigger the activation of maturation promoting factor (MPF), inducing the G2/M transition. It is generally recognized that the anaphase-promoting complex/cyclosome (APC/C) and its cofactor CDH1 (also known as FZR1) regulates the accumulation/degradation of CCNB1. Here, by using small interfering RNA (siRNA) and messenger RNA (mRNA) microinjection, immunofluorescence and confocal microscopy, immunoprecipitation, time-lapse live imaging, and immunoblotting analysis, we showed that Septin 4 regulates the G2/M transition by regulating the accumulation of CCNB1 via APC/CCDC20 . Depletion of Septin 4 caused GV arrest by reducing CCNB1 accumulation. Unexpectedly, the expression level of CDC20 was higher in Septin 4 siRNA-injected oocytes than in control oocytes, but there was no significant change in the expression level of CDH1. Importantly, the reduced GVBD after Septin 4 depletion could be rescued not only by over-expressing CCNB1 but also could be partially rescued by depleting CDC20. Taken together, our results demonstrate that Septin 4 may play a critical role in meiotic G2/M transition by indirect regulation of CCNB1 stabilization in mouse oocytes.

BackgroundAmelioration of depression in patients with post-stroke depression (PSD) remains challenging.ObjectiveThe primary vision was to explore the effect of transcranial magnetic stimulation (TMS) in combination with citalopram on patients with PSD.MethodsOne hundred eligible patients who were diagnosed with PSD were recruited and randomly assigned to the control group (n = 50) or the TMS group (n = 50). The controls were given citalopram (10 mg/d for consecutive 8 weeks), while, in addition to citalopram, patients in the TMS group were also given TMS at 5 Hz once a workday for 8 weeks. The primary outcome was patient depression status as reflected by 17-item Hamilton Rating Scale for Depression (HAMD-17) score, and the secondary outcome was patient neuropsychological score determined by Mini-Mental State Examination (MMSE) and Wisconsin Card Sorting Test (WCST).ResultsPatients treated with TMS in combination with citalopram had a drastic decrease in HAMD-17 score during treatment. Bigger changes in HAMD-17 score between baseline and 2 weeks as well as between baseline and 8 weeks in the TMS group were observed (P < 0.01). Patients in both groups had increased MMSE scores after treatment. Data of WCST revealed patients with TMS treatment completed more categories (P < 0.01) and had a lower RPP in comparison to patients in the control group (P < 0.0001). Additionally, TMS in combination with citalopram strikingly improved patients' MMSE scores when compared with those taking citalopram alone. Last, there was no striking difference in side effects between the two groups (P > 0.05).ConclusionOur study found TMS in combination with citalopram is conducive to improving depression status and neuropsychological function, which holds great promise for treating PSD.

AZD1208, a pan-inhibitor that can effectively inhibit PIM kinase, is used for the treatment of advanced solid tumors and malignant lymphomas. Numerous studies have proved its curative effects while its potential cellular toxicity on reproduction was still little known. In this study, we investigated the toxic effects of AZD1208 on mouse oocytes. The results showed that AZD1208 treatment did not affect meiotic resumption, but postponed oocyte maturation as indicated by delayed first polar body extrusion. Further mechanistic study showed that AZD1208 treatment delayed spindle assembly. In addition, we found that oocytes treated with AZD1208 showed mitochondrial dysfunction. Abnormal mitochondrial clusters with decreased mitochondrial membrane potential were observed in oocytes during incubation in vitro. Moreover, increased oxidative stress was observed by testing the level of reactive oxygen species. In summary, our results suggest that AZD1208 treatment influences oocyte meiotic progression by causing mitochondrial dysfunctions and subsequent delayed spindle assembly.

During oocyte growth, various epigenetic modifications are gradually established, accompanied by accumulation of large amounts of mRNAs and proteins. However, little is known about the relationship between epigenetic modifications and meiotic progression. Here, by using

Mammalian early embryo cells have complex DNA repair mechanisms to maintain genomic integrity, and homologous recombination (HR) plays the main role in response to double-strand DNA breaks (DSBs) in these cells. Polo-like kinase 1 (PLK1) participates in the HR process and its overexpression has been shown to occur in a variety of human cancers. Nevertheless, the regulatory mechanism of PLK1 remains poorly understood, especially during the S and G2 phase. Here, we show that protein phosphatase 4 catalytic subunit (PPP4C) deletion causes severe female subfertility due to accumulation of DNA damage in oocytes and early embryos. PPP4C dephosphorylated PLK1 at the S137 site, negatively regulating its activity in the DSB response in early embryonic cells. Depletion of PPP4C induced sustained activity of PLK1 when cells exhibited DNA lesions that inhibited CHK2 and upregulated the activation of CDK1, resulting in inefficient loading of the essential HR factor RAD51. On the other hand, when inhibiting PLK1 in the S phase, DNA end resection was restricted. These results demonstrate that PPP4C orchestrates the switch between high-PLK1 and low-PLK1 periods, which couple the checkpoint to HR.

Recently, theory of collective intelligence (CI) evolution is proposed as a meta algorithm toward artificial general intelligence. But the only implementation of the CI algorithm of the theory is the Monte Carlo tree search (MCTS) used by AlphaZero. Since ant colony optimization (ACO) is an extensively used CI algorithm, it is useful to implement CI evolution using ACO. A genetic version of ACO is adapted to satisfy the CI evolution theory by two methods. One method is realized by using a policy network, namely policy network guided ACO (P-ACO). The other method is realized by using a policy network and a value network, namely policy and value network guided ACO (PV-ACO). Both methods of ACO evolution algorithm are applied to Tic-Tac-Toe and Four in a Row, where traditional ACO played poorly compared to the tree search algorithm, e.g., MCTS. Computational experiments are done to compare both methods with pure ACO and MCTS. As a result, the intelligence level of ACO evolution algorithm quickly exceeds pure ACO and MCTS. In this article, the performance of ACO evolution algorithm is analyzed and the feasibility of applying the CI evolution theory to a specific application is verified.

Parathyroid hormone-related protein (PTHrP), the main cause of humoral hypercalcemia in malignancies, promotes cell proliferation and delays terminal cell maturation during embryonic development. Our previous study reported that PTHrP plays important roles in blastocyst formation, pluripotency gene expression, and histone acetylation during mouse preimplantation embryonic development. In this study, we further investigated the mechanism of preimplantation embryonic development regulated by PTHrP. Our results showed that Pthrp depletion decreased both the developmental rate of embryos at the cleavage stage and the cell number of morula-stage embryos. Pthrp-depleted embryos had significantly decreased levels of cyclin D1, phospho (p)-AKT (Thr308) and E2F1. However, Pthrp depletion did not cause significant changes in CDK4, β-catenin or RUNX2 expression. In addition, our results indicated that Pthrp depletion promoted HDAC4 translocation from the cytoplasm to the nucleus in cleavage-stage embryos by stimulating the activity of protein phosphatase 2A (PP2A), which resulted in dephosphorylation of HDAC4. Taken together, these results suggest that PTHrP regulates cleavage division progression and blastocyst formation through the AKT/cyclin D1 pathway and that PTHrP modulates histone acetylation patterns through nuclear translocation of HDAC4 via PP2A-dependent HDAC4 dephosphorylation during preimplantation embryonic development in mice.

The rapid activity degradation of layered double hydroxides (LDHs) is caused by the mismatch of surface component and construction. Herein, MXene quantum dot (MQD) rivets are used to adjust the surface composition and structure of Ni–Co LDH to boost electrochemical activity and stability. The cap of MQD rivets would enrich a large number of unpaired electrons, thereby enhancing the adsorption of electrolyte ions. The surface functional groups of MQDs as rivet shafts can produce a strong interface coupling with LDH to keep stability. The coupling effect should also promote the charge transfer between LDH and MQDs and activate LDH surface adsorption. The effect can be described using the electron location function mapping, charge distribution and X-ray photoelectron spectroscopy. Ni–Co LDH@MQDs exhibits high energy storage activity (87 mA h g−1 at 1 A g−1) and durable stability (98.6% retention after 10 000 cycles) in a two-electrode device. This work opens up a new path for the realization of high-efficiency and long-term stable electrochemically active materials through the interface coupling between MQDs and LDH.

Carbon materials, like carbon fiber, carbon nanotubes and graphene, were widely used as promising reinforcements to strengthen aluminum matrix composites (AMCs). The dispersion of reinforcement in matrix and interface wettability between matrix and reinforcing phase have been key factors affecting AMCs properties. In this study, electroless copper-coated carbon fibers reinforced aluminum (Cu-Cf/Al) composites were prepared by spark plasma sintering processing followed by heat treatment. Microstructure and mechanical properties were investigated. Microstructure observation indicated that fibers distributed uniformly in the composites containing up to 9 wt% copper-coated carbon fibers (Cu-Cf). In addition, an interfacial layer of 50 nm thickness was formed between the fiber and Al matrix due to mutual diffusion of Cu and Al atoms. Vickers hardness, tensile strength and bending strength of 9 wt% Cu-Cf/Al composite increased from 40 to 93 HV, 59 to 190 MPa and 110 to 326 MPa, respectively, compared to Al matrix. The improved mechanical properties are ascribed to the synergistic effect of dispersion, precipitation and solution strengthening. However, the elongation of composite decreased as compared to that of Al matrix. Moreover, Cu-Cf/Al composite exhibits superior corrosion resistance over uncoated carbon fiber/Al composite but less than Al matrix.

Atherosclerosis (AS) is a cardiovascular disease caused by multiple factors, leading to high mortality and morbidity in aged people. Some long noncoding RNAs have been reported to be associated with AS progression. However, the roles of OIP5-AS1 in AS development are still little known. In this study, the levels of OIP5-AS1 and miR-26a-5p in oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs) were determined by quantitative real-time polymerase chain reaction. Cell proliferation and apoptosis were evaluated by Cell Counting Kit-8 assay and flow cytometric analysis, respectively. The protein levels of proliferating cell nuclear antigen, B-cell lymphoma-2, cleaved caspase 3, inflammatory cytokines (IL-6 and IL-1β), protein kinase B (AKT), p-AKT, p65, p-p65, IκBα, and p-IκBα were detected by Western blot analysis. The targeting relationship between OIP5-AS1 and miR-26a-5p was verified by dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA pull-down assay. As a result, the expression of OIP5-AS1 was upregulated and miR-26a-5p was downregulated in ox-LDL-treated HUVECs. MiR-26a-5p was identified as a direct target of OIP5-AS1. OIP5-AS1 knockdown reversed the inhibitory effect on cell proliferation and the promotional effects on apoptosis and inflammation induced by ox-LDL treatment in HUVECs. Interestingly, the effects caused by OIP5-AS1 knockdown were further attenuated by miR-26a-5p inhibition. Furthermore, OIP5-AS1 knockdown blocked the AKT/NF-κB pathway by regulating miR-26a-5p expression. In conclusion, OIP5-AS1 knockdown promoted cell proliferation and suppressed apoptosis and inflammatory response in ox-LDL-treated HUVECs by targeting miR-26a-5p through blocking the AKT/NF-κB pathway, indicating a promising strategy for AS treatment.

Alternative splicing expands the transcriptome and proteome complexity and plays essential roles in tissue development and human diseases. However, how alternative splicing regulates spermatogenesis remains largely unknown. Here, using germ cell-specific knockout mouse model, we demonstrated that the splicing factor Srsf10 is essential for spermatogenesis and male fertility. Depletion of Srsf10 in germ cells had little effect on the formation of SSCs but impeded the expansion of progenitor spermatogonia, leading to the failure of spermatogonia differentiation and meiosis initiation. This was further evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Furthermore, the expression of genes involved in cell cycle was abnormal in all subtypes of spermatogonia identified in single-cell RNA-seq data. Notably, using isolated spermatogonia, we found that Srsf10 depletion disturbed the alternative splicing of hundreds of genes, which were preferentially associated with cell cycle, mitotic cell cycle checkpoint and germ cell development, including Dazl, Kit, Ret, Sycp1, Nasp and Bora. These data suggest that SRSF10 is critical for the expansion of progenitor spermatogonia by regulating alternative splicing, expanding our understanding of the mechanism underlying spermatogenesis.

Alternative splicing expands the transcriptome and proteome complexity and plays essential roles in tissue development and human diseases. However, how alternative splicing regulates spermatogenesis remains largely unknown. Here, using a germ cell-specific knockout mouse model, we demonstrated that the splicing factor Srsf10 is essential for spermatogenesis and male fertility. In the absence of SRSF10, spermatogonial stem cells can be formed, but the expansion of Promyelocytic Leukemia Zinc Finger (PLZF)-positive undifferentiated progenitors was impaired, followed by the failure of spermatogonia differentiation (marked by KIT expression) and meiosis initiation. This was further evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Notably, SRSF10 directly binds thousands of genes in isolated THY+ spermatogonia, and Srsf10 depletion disturbed the alternative splicing of genes that are preferentially associated with germ cell development, cell cycle, and chromosome segregation, including Nasp, Bclaf1, Rif1, Dazl, Kit, Ret, and Sycp1. These data suggest that SRSF10 is critical for the expansion of undifferentiated progenitors by regulating alternative splicing, expanding our understanding of the mechanism underlying spermatogenesis.

Precise regulation of chromosome separation through spindle assembly checkpoint (SAC) during oocyte meiosis is critical for mammalian reproduction. The kinetochore plays an important role in the regulation of SAC through sensing microtubule tension imbalance or missing microtubule connections. Here, we report that kinetochore scaffold 1 (KNL1, also known as CASC5), an outer kinetochore protein, plays a critical role in the SAC function of mouse oocytes. KNL1 localized at kinetochores from GVBD to the MII stage, and microinjection of KNL1-siRNA caused accelerated metaphase-anaphase transition and premature first meiosis completion, producing aneuploid eggs. The SAC was prematurely silenced in the presence of unstable kinetochore-microtubule attachments and misaligned chromosomes in KNL1-depleted oocytes. Additionally, KNL1 and MPS1 had a synergistic effect on the activation and maintenance of SAC. Taken together, our results suggest that KNL1, as a kinetochore platform protein, stabilizes SAC to ensure timely anaphase entry and accurate chromosome segregation during oocyte meiotic maturation.

Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity.

Serum uric acid level has been found to be associated with cerebrovascular diseases. However, whether serum uric acid level is a risk factor for arterial stiffness in the hypertension population is unclear. This study was designed to determine the relationship between serum uric acid level and arterial stiffness in the hypertension population. A total of 10450 participants were evaluated for the risk of arterial stiffness. Brachial-ankle pulse wave velocity (baPWV) was assessed, and high baPWV was determined as the highest quartile of baPWV values in a sex-specific manner. We evaluated the association between serum uric acid level and baPWV through multivariate-adjusted linear and logistic regression analyses. There was a significant difference on high baPWV between patients with quartiles of serum uric acid level in females and males (p

Oocyte meiotic maturation failure and unfaithful chromosome segregation are major causes for female infertility. Here, we showed that CENP-W, a relatively novel member of the kinetochore protein family, was expressed in mouse oocytes from the germinal vesicle (GV) to metaphase II (MII) stages. Confocal microscopy revealed that CENP-W was localized in the germinal vesicle in the GV stage, and then became concentrated on kinetochores during oocyte maturation. Knockdown of CENP-W by specific siRNA injection in vitro caused kinetochore-microtubule detachment, resulting in severely defective spindles and misaligned chromosomes, leading to metaphase I arrest and failure of first polar body (PB1) extrusion. Correspondingly, spindle assembly checkpoint (SAC) activation was observed in CENP-W knockdown oocytes even after 10h of culture. Our results suggest that CENP-W acts as a kinetochore protein, which takes part in kinetochore-microtubule attachment, thus mediating the progression of oocyte meiotic maturation.

Mammalian cyclin A1 is prominently expressed in testis and essential for meiosis in the male mouse, however, it shows weak expression in ovary, especially during oocyte maturation. To understand why cyclin A1 behaves in this way in the oocyte, we investigated the effect of cyclin A1 overexpression on mouse oocyte meiotic maturation. Our results revealed that cyclin A1 overexpression triggered meiotic resumption even in the presence of germinal vesicle breakdown inhibitor, milrinone. Nevertheless, the cyclin A1-overexpressed oocytes failed to extrude the first polar body but were completely arrested at metaphase I. Consequently, cyclin A1 overexpression destroyed the spindle morphology and chromosome alignment by inducing premature separation of chromosomes and sister chromatids. Therefore, cyclin A1 overexpression will prevent oocyte maturation although it can promote meiotic resumption. All these results show that decreased expression of cyclin A1 in oocytes may have an evolutional significance to keep long-lasting prophase arrest and orderly chromosome separation during oocyte meiotic maturation.

OTSSP167 is an anti-tumor drug significantly inhibiting tumor growth in xenotransplantation studies using mouse breast, lung, prostate, and pancreatic cancer cell lines. Its phase I clinical trial has been completed, indicating its great potential for future treatment of solid tumors. However, its drug-related adverse effects on reproductive systems have not yet been reported. In this study, we evaluated the effects of OTSSP167 on reproduction of female mice by determining oocyte quality and follicular development. We selected four-week-old female ICR mice for a 21-day intraperitoneal injection of OTSSP167 at a dose of 5 mg/kg/d. We found that OTSSP167 could block the meiotic process of oocytes, leading to a decrease in oocyte maturation and ovulated oocyte numbers, as well as a decrease in the quality of oocytes. The results showed that OTSSP167 treatment caused disordered spindle assembly, decreased mitochondria membrane potential, and increased accumulation of reactive oxygen species in oocytes. Further investigation showed that OTSSP167 induced DNA double-strand breaks, as indicated by increased levels of γH2AX in oocytes of primordial follicles and granulosa cells of growing follicles, which induced follicular atresia and decreased the numbers of follicles at various growing stages. Our study suggests that OTSSP167 treatment may have serious effects on the ovary and consequences for female cancer patients, providing strong evidence for the necessity of protecting female fertility in clinical OTSSP167 trials.