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We investigate the influence of three- and four-phonon scattering, perturbative anharmonic phonon renormalization, and off-diagonal terms of coherent phonons on the thermal conductivity of CsPbBr3 phase change perovskite, by using advanced implementations and first-principles simulations. Our study spans a wide temperature range covering the entire structural spectrum. Notably, we demonstrate that the interactions between acoustic and optical phonons result in contrasting trends of phonon frequency shifts for the high-lying optical phonons in orthorhombic and cubic CsPbBr3 as temperature varies. Our findings highlight the significance of wave-like tunneling of coherent phonons in ultralow and glass-like thermal conductivity in halide perovskites., 9 pages, 4 figures

Shift-workers show an increased incidence of type 2 diabetes mellitus (T2DM). A possible mechanism is the disruption of the circadian timing of glucose homeostasis. Skeletal muscle mitochondrial function is modulated by the molecular clock. We used time-restricted feeding (TRF) during the inactive phase to investigate how mistimed feeding affects muscle mitochondrial metabolism. Rats on an ad libitum (AL) diet were compared to those that could eat only during the light (inactive) or dark (active) phase. Mitochondrial respiration, metabolic gene expressions, and metabolite concentrations were determined in the soleus muscle. Rats on AL feeding or dark-fed TRF showed a clear daily rhythm in muscle mitochondrial respiration. This rhythm in mitochondrial oxidative phosphorylation capacity was abolished in light-fed TRF animals and overall 24h respiration was lower. The expression of several genes involved in mitochondrial biogenesis and the fission/fusion machinery was altered in light-fed animals. Metabolomics analysis indicated that light-fed animals had lost rhythmic levels of α-ketoglutarate and citric acid. Contrastingly, lipidomics showed that light-fed animals abundantly gained rhythmicity in levels of triglycerides. Furthermore, while the RER shifted entirely with the food intake in the light-fed animals, many measured metabolic parameters (e.g., activity and mitochondrial respiration) did not strictly align with the shifted timing of food intake, resulting in a mismatch between expected metabolic supply/demand (as dictated by the circadian timing system and light/dark-cycle) and the actual metabolic supply/demand (as dictated by the timing of food intake). These data suggest that shift-work impairs mitochondrial metabolism and causes metabolic inflexibility, which can predispose to T2DM.

The t(11;14) (q13;q32) translocation resulting in overexpression of cyclin D1 is the major oncogenic mechanism in mantle cell lymphoma (MCL). Most MCLs can be diagnosed based on morphological features, cyclin D1 expression, and IGH/CCND1 rearrangement. However, in some atypical cases where conventional FISH studies fail to detect IGH/CCND1 rearrangement or immunohistochemistry for cyclin D1 is negative, the diagnosis of the disease can be difficult. Hence, next-generation sequencing (NGS) may allow the identification of molecular alterations and assist in the diagnosis of atypical MCL. In this study, we reported a case of a patient diagnosed as asymptomatic MCL who presented with lymphadenopathy during the initial assessment. A lymph node biopsy was performed and the results revealed a high Ki67 index. However, initial diagnosis of aggressive MCL was difficult since the IGH/CCND1 rearrangement result was negative. Ultimately, by the aid of NGS we identified a rare CCND3 rearrangement in the patient, which lead to overexpression of cyclin D3, thereby facilitating the diagnosis of MCL.

We propose a first-principles model of minimum lattice thermal conductivity ($\kappa_{\rm L}^{\rm min}$) based on a unified theoretical treatment of thermal transport in crystals and glasses. We apply this model to thousands of inorganic compounds and discover a universal behavior of $\kappa_{\rm L}^{\rm min}$ in crystals in the high-temperature limit: the isotropically averaged $\kappa_{\rm L}^{\rm min}$ is independent of structural complexity and bounded within a range from $\sim$0.1 to $\sim$2.6 W/[m$\cdot$K], in striking contrast to the conventional phonon gas model which predicts no lower bound. We unveil the underlying physics by showing that for a given parent compound $\kappa_{\rm L}^{\rm min}$ is bounded from below by a value that is approximately insensitive to disorder, but the relative importance of different heat transport channels (phonon gas versus diffuson) depends strongly on the degree of disorder. Moreover, we propose that the diffuson-dominated $\kappa_{\rm L}^{\rm min}$ in complex and disordered compounds might be effectively approximated by the phonon gas model for an ordered compound by averaging out disorder and applying phonon unfolding. With these insights, we further bridge the knowledge gap between our model and the well-known Cahill-Watson-Pohl (CWP) model, rationalizing the successes and limitations of the CWP model in the absence of heat transfer mediated by diffusons. Finally, we construct graph network and random forest machine learning models to extend our predictions to all compounds within the Inorganic Crystal Structure Database (ICSD), which were validated against thermoelectric materials possessing experimentally measured ultralow $\kappa_{\rm L}$. Our work offers a unified understanding of $\kappa_{\rm L}^{\rm min}$, which can guide the rational engineering of materials to achieve $\kappa_{\rm L}^{\rm min}$.

Objective Few studies have explored the clinical features in children infected with SARS-CoV-2 and other common respiratory viruses, including respiratory syncytial virus (RSV), influenza virus (IV), and adenovirus (ADV). Herein, we reported the clinical characteristics and cytokine profiling in children with COVID-19 or other acute respiratory tract infections (ARTI). Methods We enrolled 20 hospitalized children confirmed as COVID-19 positive, 58 patients with ARTI, and 20 age and sex-matched healthy children. The clinical information and blood test results were collected. A total of 27 cytokines and chemokines were measured and analyzed. Results The median age in the COVID-19 positive group was 14.5 years, which was higher than that of the ARTI groups. Around one-third of patients in the COVID-19 group experienced moderate fever, with a peak temperature of 38.27 ℃. None of the patients displayed wheezing or dyspnea. In addition, patients in the COVID-19 group had lower white blood cells, platelet counts as well as a neutrophil-lymphocyte ratio. Lower serum concentrations of 14 out of 27 cytokines were observed in the COVID-19 group than in healthy individuals. Seven cytokines (IL-1Ra, IL-1β, IL-9, IL-10, TNF-α, MIP-1α, and VEGF) changed serum concentration in COVID-19 compared with other ARTI groups. Conclusion Patients with COVID-19 were older and showed milder symptoms and a favorable prognosis than ARTI caused by RSV, IV, and ADV. There was a low grade or constrained innate immune reaction in children with mild COVID-19. This article is protected by copyright. All rights reserved.

Objective To investigate the associations between imaging markers of cerebral small vessel disease (CSVD) and global cognition and cognitive domains in the community elderly people. Methods From August 2016 to October 2019, 933 healthy community elderly subjects were enrolled from three districts in Shanghai. We used MRI to assess imaging markers of CSVD, including lacunar infarct (LACI), white matter hyperintensity (WMH), cerebral microbleeds (CMBs), enlarged perivascular space (EPVS) and total CSVD score. These subjects underwent Montreal Cognitive Assessment (MoCA) to assess global cognition, Auditory Verbal Learning Test (AVLT) to assess memory function, Trial Making Test (TMT) to assess executive function, Stick Test (ST) to assess visuospatial function, adapted Common Objects Sorting Test (COST) to assess language function. We performed Spearman rank correlation and partial correlation analyses to investigate the association between imaging markers and cognition, and multiple linear regression analysis to validate the relationships. Results A total of 863 subjects underwent head MRI and cognitive assessment. In Spearman rank correlation analysis, LACI (rs=⁃0.076, P=0.025) and periventricular WMH (rs=⁃0.070, P=0.044) was correlated with MoCA. LACI (rs=⁃0.086, P=0.022), basal ganglia EPVS (rs=⁃0.078, P=0.038) and total CSVD score (rs=⁃0.090, P=0.023) were correlated with AVLT. LACI was correlated with TMT (rs=0.099, P=0.004). Periventricular WMH (rs=⁃0.113, P=0.029) and strictly lobar CMB (rs=⁃0.107, P=0.041) were correlated with ST. Centrum semiovale EPVS was correlated with COST (rs=⁃0.150, P=0.004). In partial correlation analysis, LACI was associated with TMT (r=0.072, P=0.038). Deep WMH was associated with ST (r=0.105, P=0.047). Periventricular WMH (r=⁃0.111, P=0.001), CMBs (r=⁃0.088, P=0.015) and total CSVD score (r=⁃0.087, P=0.015) were associated with MoCA. In multiple linear regression analysis, after adjusting sex, age, education, hypertension, diabetes mellitus, hyperlipidemia and smoking history factors, periventricular WMH (βstandardized=⁃0.088, PFDR=0.020) and CMBs at any position (βstandardized=⁃0.078, PFDR=0.040) were independently correlated with MoCA. Conclusions In the elderly community population in China, CSVD may already have an impact on cognition. Periventricular WMH and CMBs are early imaging markers for CSVD⁃related global cognitive impairment.

The nature of dark matter is one of the most important open questions in modern physics. The search for dark matter is challenging since, besides gravitational interaction, it feebly interacts with ordinary matter. Mechanical sensors are one of the leading candidates for dark matter searches in the low frequency region. Here, we propose entanglement-enhanced optomechanical sensing systems to assist the search for DM with mechanical sensing devices. To assess the performance of our setup, we adopt the integrated sensitivity, which is particularly suitable for broadband sensing as it precisely quantifies the bandwidth-sensitivity tradeoff of the system. We then show that, by coherently operating the optomechanical sensor array and utilizing continuous-variable multi-partite entanglement between the optical fields, the array of sensors has a scaling advantage over independent sensors (i.e., $\sqrt{M}\rightarrow M$, where $M$ is the number of sensors) as well as a performance boost due to entanglement. Such an advantage is robust to imhomogeneities of the mechanical sensors and is achievable with off-the-shelf experimental components., 5+14 pages, 3+5 figures

This protocol describes a scoping review that will integrate current information about the implementation and effectiveness of China's national program of Community-Based Management and Treatment Services for Psychosis -- the largest such program in the world.

This is a scoping review which aims to systematically map current knowledge generated by economic evaluations on screening for perinatal depression.

As a probabilistic modeling technique, the flow-based model has demonstrated remarkable potential in the field of lossless compression \cite{idf,idf++,lbb,ivpf,iflow},. Compared with other deep generative models (eg. Autoregressive, VAEs) \cite{bitswap,hilloc,pixelcnn++,pixelsnail} that explicitly model the data distribution probabilities, flow-based models perform better due to their excellent probability density estimation and satisfactory inference speed. In flow-based models, multi-scale architecture provides a shortcut from the shallow layer to the output layer, which significantly reduces the computational complexity and avoid performance degradation when adding more layers. This is essential for constructing an advanced flow-based learnable bijective mapping. Furthermore, the lightweight requirement of the model design in practical compression tasks suggests that flows with multi-scale architecture achieve the best trade-off between coding complexity and compression efficiency.

OBJECTIVE: To explore the factors influencing physicians' intentions to use Traditional Chinese Medicine (TCM) to treat coronavirus disease 2019 (COVID-19). METHODS: A cross-sectional, self-report online survey was conducted from March 16, 2020, to April 2, 2020, in China. Participants were recruited through convenience and snowball sampling. Data were collected by using a self-designed questionnaire based on the Theory of Planned Behavior. Structural equation modeling was used for data analysis. RESULTS: A total of 494 physicians were enrolled in this study. Overall, the model explained 75.4% and 75.5% of the total variance in intention and attitude, respectively. Specifically, attitudes (β = 0.467, P < 0.001), past behavior (β = 0.384, P < 0.05), subjective norms (SN) (β = 0.177, P < 0.001), and perceived behavioral control (PBC) (β = 0.133, P < 0.05) significantly affected physicians' intention to use TCM. Cognition (β = 0.606, P < 0.001) and PBC (β = 0.569, P < 0.01) significantly influenced physicians' attitudes toward using TCM. SN (β = 0.064, P = 0.263) was not a factor affecting attitude. CONCLUSION: Physicians’ intention to use TCM was significantly associated with attitude, past behavior, PBC, and SN. The findings may not only be useful for understanding the influencing factors and paths of physicians’ intention to use TCM to treat COVID-19 but also provide a reference for health authorities and policymakers to promote physicians to utilize TCM.

Aims: The effects of exogenously applied salicylic acid (SA) on gas exchange characteristics, photosynthetic pigments and chloroplast ultrastructure were investigated in gerbera at their reproductive stage under salt-stressed conditions. Methodology: A pot experiment was conducted under glasshouse conditions at the Zhejiang University, Hangzhou, China, (30° N/120° E) between February 2008 and March 2009.Plants, pretreated with foliar applications of 0, 0.5, and 1.0 mmoldm-3 SA at the onset of flower initiation were irrigated with 100 mmoldm-3NaCl(aq) for two weeks, starting after three days from the SA pretreatment. Control did not receive either NaCl or SA.Photosynthetic rate, gas exchange, photosynthetic pigments content and chloroplast ultrastructure were investigated against treatments. All data were subjected to analysis of variance (ANOVA) and Generalized Linear Model (GLM) using SAS statistical software. Pearson’s correlation test was carried out to study the relationships among the parameters. The means were compared using Duncan’s multiple range test (DMRT). For all the tests, P< .05 was considered statistically significant. Results: Salt stress adversely affected the gas exchange characteristics, photosynthetic pigment contents and chloroplast ultrastructure. SA application significantly increased the net photosynthesis, stomatal conductivity, intra-cellular CO2 content and transpiration rate but decreased the stomatal limitation, compared to those of untreated salt-stressed plants. Further, the enhanced photosynthetic pigment contents and notably undamaged chloroplast ultrastructure were evident of the ameliorative effects of SA on photosynthetic system under salt stress. Of the two concentrations tested, 0.5 mmoldm-3 SA concentration seemed to have greater effect throughout the experiment showing no significant variation from control in some attributes (chlorophyll contents and chloroplast ultrastructure). Conclusion: Responses of plants pretreated with SA spraying and significant correlation among them plausibly suggest SA-induced enhancement of photosynthetic system as another target for conferring salt tolerance in crop plants.

High thermotolerance is an important property of Saccharomyces cerevisiae for stable and efficient bioethanol production, especially for large-scale bioethanol production with weak heat transfer and the simultaneous saccharification and fermentation (SSF) of lignocellulosic biomass at high temperatures (above 40 °C). Despite extensive studies involving metabolic engineering and chemical mutagenesis, the improvement of thermotolerance in S. cerevisiae under harsh thermal stress (42–45 °C) has been limited. A highly thermotolerant strain, S. cerevisiae Z100, by a 91 days’ laboratory adaptive evolution in wheat straw hydrolysate was applied for cellulosic ethanol fermentation. The results showed that the cell survival ratio of S. cerevisiae Z100 at 50 °C improved by 1.2 times that of the parental strain. The improved thermotolerance of S. cerevisiae Z100 at 50 °C was found to contribute significantly to enhanced cellulosic ethanol fermentability. The ethanol production of S. cerevisiae Z100 increased by 35%, 127%, and 64% when using wheat straw as feedstock after being maintained at 50 °C for 12 h, 24 h, and 48 h, respectively. Transcriptome analyses suggested that the enhanced trehalose and glycogen synthesis, as well as carbon metabolism, potentially contributed to the improved thermotolerance and the ethanol fermentability of S. cerevisiae Z100. This study provides evidence that adaptive evolution is an effective method for increasing the thermotolerance of the S. cerevisiae strain for stable and efficient cellulosic ethanol production.

Zhang, Ji-hui, Chen, Jin-lin, Xu, Wei-bin, Xia, Yi-ping, Zhu, Hao-yue, Wang, Jing-hao, Li, Yao-lan, Wang, Guo-cai, Zhang, Yu-bo, Chen, Neng-hua (2023): Undescribed phloroglucinol derivatives with antiviral activities from Dryopteris atrata (Wall. Ex Kunze) Ching. Phytochemistry (113585) 208: 113585, DOI: 10.1016/j.phytochem.2023.113585, URL: http://dx.doi.org/10.1016/j.phytochem.2023.113585

The ubiquitous RNA-binding protein HuR (ELAVL1) promotes telomerase activity by associating with the telomerase noncoding RNA TERC. However, the role of the neural-specific members HuB, HuC, and HuD (ELAVL2–4) in telomerase activity is unknown. Here, we report that HuB and HuD, but not HuC, repress telomerase activity in human neuroblastoma cells. By associating with AU-rich sequences in TERC, HuB and HuD repressed the assembly of the TERT–TERC core complex. Furthermore, HuB and HuD competed with HuR for binding to TERC and antagonized the function of HuR that was previously shown to enhance telomerase activity to promote cell growth. Our findings reveal a novel mechanism controlling telomerase activity in human neuroblastoma cells that involves a competition between HuR and the related, neural-specific proteins HuB and HuD.

Background: In peripheral tissues, the lipid droplet (LD) organelle links lipid metabolism, inflammation, and insulin resistance. Little is known about the brain LDs. Objectives: We hypothesized that hypothalamic LDs would be altered in metabolic diseases. Methods: We used immunofluorescence labeling of the specific LD protein, PLIN2, as the approach to visualize and quantify LDs. Results: LDs were abundant in the hypothalamic third ventricle wall layer with similar heterogeneous distributions between control mice and humans. The LD content was enhanced by high-fat diet (HFD) in both wild-type and in low-density lipoprotein receptor deficient (Ldlr –/– HFD) mice. Strikingly, we observed a lower LD amount in type 2 diabetes mellitus (T2DM) patients when compared with non-T2DM patients. Conclusions: LDs accumulate in the normal hypothalamus, with similar distributions in human and mouse. Moreover, metabolic diseases differently modify LD content in mouse and human. Our results suggest that hypothalamic LD accumulation is an important target to the study of metabolism.

Adipogenesis and osteoblastogenesis (adipo-osteoblastogenesis) are closely related processes involving with the phosphorylation of numerous cytoplasmic proteins and key transcription factors. Despite the recognition of the importance of protein phosphorylation in adipo-osteoblastocyte biology, relatively little is known about the specific kinases for adipo-osteoblastogenesis. Here, we constructed the comprehensive gene transcriptional landscapes of kinases at 3, 5, and 7 days during adipo-osteoblastogenesis from human bone marrow mesenchymal stem cells (hMSCs). We identified forty-four and eight significant DEGs (differentially expressed genes) separately for adipo-osteoblastogenesis. Five significant DEGs, namely CAMK2A, NEK10, PAK3, PRKG2, and PTK2B, were simultaneously shared by adipo-osteoblastogenic anecdotes. Using a lentivirus system, we confirmed that PTK2B (non-receptor protein tyrosine kinase 2 beta) simultaneously inhibited adipo-osteoblastogenesis through RNAi assays, and PRKG2 (protein kinase cGMP-dependent 2) facilitated adipogenesis and weakened osteoblastogenesis. The only certainty was that the identified candidate significant DEGs encoding kinases responsible for protein phosphorylation, especially PTK2B and PRKG2, were the potential molecular switches of cell fate determination for hMSCs. This study would provide novel study targets for hMSC differentiation and potential clues for the therapy of the adipo-osteoblastogenic balance-derived disorders.

Variants in the gene encoding ankyrin repeat and SOCS box–containing 4 ( ASB4 ) are linked to human obesity. Here, we characterized the pathways underlying the metabolic functions of ASB4. Hypothalamic Asb4 expression was suppressed by fasting in wild-type mice but not in mice deficient in AgRP , which encodes Agouti-related protein (AgRP), an appetite-stimulating hormone, suggesting that ASB4 is a negative target of AgRP. Many ASB4 neurons in the brain were adjacent to AgRP terminals, and feeding induced by AgRP neuronal activation was disrupted in Asb4 -deficient mice. Acute knockdown of Asb4 in the brain caused marked hyperphagia due to increased meal size, and Asb4 deficiency led to increased meal size and food intake at the onset of refeeding, when very large meals were consumed. Asb4 -deficient mice were resistant to the meal-terminating effects of exogenously administered calcitonin and showed decreased neuronal expression of Calcr , which encodes the calcitonin receptor. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus in mice are involved in glucose homeostasis, and Asb4 deficiency specifically in POMC neurons resulted in glucose intolerance that was independent of obesity. Furthermore, individuals with type 2 diabetes showed reduced ASB4 abundance in the infundibular nuclei, the human equivalent of the arcuate nucleus. Together, our results indicate that ASB4 acts in the brain to improve glucose homeostasis and to induce satiety after substantial meals, particularly those after food deprivation.

Supramolecular coordination complexes (SCCs) have emerged as anticancer agents. Tracking the movement of these metallic anticancer agents plays an important role in the field of biomedicines. Herein, we describe a method for tracking the movement of a rhomboidal Pt(II) metallacycle agent using the quantum dots encapsidation in vitro self-assembly system of viral proteins. When incubated with living Vero cells, self-assembly of hybrid viral nanoparticles were employed for simultaneous cell imaging and visual transmission of the Pt(II) metallacycle agent. Considering these results, we believe that the multifunctional biomaterials consisting of a supramolecular coordination complex and quantum dots provide a new alternative for probing of the delivery of Pt(II) metallacycle drugs.

Lipid transport and ATP synthesis are critical for the progression of non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms are largely unknown. Here, we report that the RNA-binding protein HuR (ELAVL1) forms complexes with NAFLD-relevant transcripts. It associates with intron 24 of Apob pre-mRNA, with the 3′UTR of Uqcrb, and with the 5′UTR of Ndufb6 mRNA, thereby regulating the splicing of Apob mRNA and the translation of UQCRB and NDUFB6. Hepatocyte-specific HuR knockout reduces the expression of APOB, UQCRB, and NDUFB6 in mice, reducing liver lipid transport and ATP synthesis, and aggravating high-fat diet (HFD)-induced NAFLD. Adenovirus-mediated re-expression of HuR in hepatocytes rescues the effect of HuR knockout in HFD-induced NAFLD. Our findings highlight a critical role of HuR in regulating lipid transport and ATP synthesis., Human antigen R (HuR) is a RNA binding protein involved in the regulation of many cellular functions. Here the authors show that, hepatocyte specific deletion of HuR exacerbates high-fat diet-induced NAFLD in mice by regulating transcripts involved in lipid transport and ATP synthesis.

The surface charge of nanocarriers inevitably affects drug delivery efficiency; however, the cancer cell specificity, anti-inflammatory effects, and charge-reversal points remain to be further addressed in biomedical applications. The aim of this study was to comprehensively assess the cancer cell specificity of DOX-loaded mesoporous silica-chitosan oligosaccharide-carboxymethyl chitosan nanoparticles (DOX@MSNs-COS-CMC) in MCF-7 and HeLa cells, inhibit the production of inflammatory cytokines, and improve the drug accumulation in the tumor site. Intracellular results reveal that the retention time prolonged to 48 h in both HeLa and MCF-7 cells at pH 7.4. However, DOX@MSNs-COS-CMC exhibited a cell type-dependent cytotoxicity and enhanced intracellular uptake in HeLa cells at pH 6.5, due to the clathrin-mediated endocytosis and macropinocytosis in HeLa cells in comparison with the vesicular transport in MCF-7 cells. Moreover, Pearson's correlation coefficient value significantly decreased to 0.25 after 8 h, prompting endosomal escape and drug delivery into the HeLa nucleus. After the treatment of MSNs-COS-CMC at 200 μg/mL, the inflammatory cytokines IL-6 and TNF-α level decreased by 70% and 80%, respectively. Tumor inhibition of DOX@MSNs-COS-CMC was 0.4 times higher than free DOX, alleviating cardiotoxicity and inflammation in the HeLa xenograft tumor model. Charge-reversible DOX@MSNs-COS-CMC could be a possible candidate for clinical therapy of cervical carcinoma.

Kinases modulate the various physiological activities of microbial fermenting strains including the conversion of lignocellulose-derived phenolic aldehydes (4-hydroxyaldehyde, vanillin, and syringaldehyde). Here, we comprehensively investigated the gene transcriptional profiling of the kinases under the stress of phenolic aldehydes for ethanologenic Zymomonas mobilis using DNA microarray. Among 47 kinase genes, three genes of ZMO0003 (adenylylsulfate kinase), ZMO1162 (histidine kinase), and ZMO1391 (diacylglycerol kinase), were differentially expressed against 4-hydroxybenzaldehyde and vanillin, in which the overexpression of ZMO1162 promoted the phenolic aldehydes conversion and ethanol fermentability. The perturbance originated from plasmid-based expression of ZMO1162 gene contributed to a unique expression profiling of genome-encoding genes under all three phenolic aldehydes stress. Differentially expressed ribosome genes were predicted as one of the main contributors to phenolic aldehydes conversion and thus finally enhanced ethanol fermentability for Z. mobilis ZM4. The results provided an insight into the kinases on regulation of phenolic aldehydes conversion and ethanol fermentability for Z. mobilis ZM4, as well as the target object for rational design of robust biorefinery strains.

In osteoporosis field, it had been clinically well established a given relationship between bone formation and lipid accumulation. Although numerous molecules had been well documented for adipogenesis and osteoblastogenesis (adipo-osteoblastogenesis), the reciprocal transcriptional regulation still remains to be explored.Here, we tried to identify the common candidate genes of adipocyte/osteoblastocyte differentiation at 3, 5, and 7 days using human mesenchymal stem cells (hMSCs) via RNA-Seq technique. By using RNA interference (RNAi), we further confirmed the function of candidate genes during adipo-osteoblastogenesis through Oil Red/Alizarin Red/alkaline phosphatase (ALPL) staining and qRT-PCR (quantitative real-time PCR).The identified 275 significantly differentially expressed genes (DEGs), especially with the down-regulated genes most prevalent and PI3K-AKT signaling pathway mostly enriched, were simultaneously shared by both differentiation events. Using lentiviral system, we further confirmed that ANKRD1 (ankyrin repeat domain 1) promoted adipogenesis and inhibited osteoblastogenesis via RNA interference (RNAi), and IGF1 (insulin like growth factor 1) simultaneously facilitated adipo-osteoblastogenesis on the base of gene expression of biomarkers and cellular phenotype property.This study would provide the potential molecular switches to control the adipocyte/osteoblastocyte balance or hMSCs fate choices and clues to screen the study and therapy targets of metabolic bone disease osteoporosis.

Hui Li,&ast; Wen-Ying Zhou,&ast; Yi-Yuan Xia,&ast; Jun-Xia Zhang Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jun-Xia Zhang, Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, 210006, People’s Republic of China, Tel +86 15366155682, Email zhangjunshia@njmu.edu.cnAbstract: Vascular endothelial cells (ECs), derived from the mesoderm, form a single layer of squamous cells that covers the inner surface of blood vessels. In addition to being regulated by chemical signals from the extracellular matrix (ECM) and blood, ECs are directly confronted to complex hemodynamic environment. These physical inputs are translated into biochemical signals, dictating multiple aspects of cell behaviour and destination, including growth, differentiation, migration, adhesion, death and survival. Mechanosensors are initial responders to changes in mechanical environments, and the overwhelming majority of them are located on the plasma membrane. Physical forces affect plasma membrane fluidity and change of protein complexes on plasma membrane, accompanied by altering intercellular connections, cell-ECM adhesion, deformation of the cytoskeleton, and consequently, transcriptional responses in shaping specific phenotypes. Among the diverse forces exerted on ECs, shear stress (SS), defined as tangential friction force exerted by blood flow, has been extensively studied, from mechanosensing to mechanotransduction, as well as corresponding phenotypes. However, the precise mechanosensors and signalling pathways that determine atheroprone and atheroprotective phenotypes of arteries remain unclear. Moreover, it is worth to mention that some established mechanosensors of atheroprotective SS, endothelial glycocalyx, for example, might be dismantled by atheroprone SS. Therefore, we provide an overview of the current knowledge on mechanosensors in ECs for SS signals. We emphasize how these ECs coordinate or differentially participate in phenotype regulation induced by atheroprone and atheroprotective SS.Keywords: shear stress, endothelial cells, mechanosensors, mechanotransduction

Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.

Microglia are the major innate immune cells in the brain and are essential for maintaining homeostasis in a neuronal microenvironment. Currently, a genetic tool to modify microglial gene expression in specific brain regions is not available. In this report, we introduce a tailor-designed method that uses lipid and polymer hybridized nanoparticles (LPNPs) for the local delivery of small interfering RNAs (siRNAs), allowing the silencing of specific microglial genes in the hypothalamus. Our physical characterization proved that this LPNP-siRNA was uniform and stable. We demonstrated that, due to their natural phagocytic behavior, microglial cells are the dominant cell type taking up these LPNPs in the hypothalamus of rats. We then tested the silencing efficiency of LPNPs carrying a cluster of differentiation molecule 11b (CD11b) or Toll-like receptor 4 (TLR4) siRNA using different in vivo and in vitro approaches. In cultured microglial cells treated with LPNP-CD11b siRNA or LPNP-TLR4 siRNA, we found a silencing efficiency at protein expression levels of 65 or 77%, respectively. In line with this finding, immunohistochemistry and western blotting results from in vivo experiments showed that LPNP-CD11b siRNA significantly inhibited microglial CD11b protein expression in the hypothalamus. Furthermore, following lipopolysaccharide (LPS) stimulation of cultured microglial cells, gene expression of the TLR4 downstream signaling component myeloid differentiation factor 88 and its associated cytokines was significantly inhibited in LPNP-TLR4 siRNA-treated microglial cells compared with cells treated with LPNP-scrambled siRNA. Finally, after LPNP-TLR4 siRNA injection into the rat hypothalamus, we observed a significant reduction in microglial activation in response to LPS compared with the control rats injected with LPNP-scrambled siRNA. Our results indicate that LPNP-siRNA is a promising tool to manipulate microglial activity locally in the brain and may serve as a prophylactic approach to prevent microglial dysfunction-associated diseases.

Antimicrobial use (AMU) is the major driver of antimicrobial resistance (AMR) among bacteria in dairy herds. There have been numerous studies on AMU and AMR in dairy cows; however, studies on AMU and AMR in dairy calves are limited. A comprehensive overview of the current state of knowledge of AMU and AMR among pathogens in dairy calves is important for the development of scientifically supported and applicable measures to curb antimicrobial use and the increasing risk of AMR. Therefore, we performed a systematic review of research on AMU and AMR in dairy calves. A total of 75 publications were included, of which 19 studies reported AMU data for dairy calves and 68 described AMR profiles of the four most prevalent bacteria that are associated with calf diarrhea and calf pneumonia. Large variation in AMU was found among herds across different regions. There seems to be a positive association between exposure to antimicrobials and occurrence of resistance. Most AMU was accounted for by treatment of diseases, while a small proportion of AMU was prophylactic. AMU was more common in treating calf diarrhea than in treating pneumonia, and the resistance rates in bacteria associated with diarrhea were higher than those in pathogens related to pneumonia. Organic farms used significantly fewer antimicrobials to treat calf disease; however, the antimicrobial resistance rates of bacteria associated with calf diarrhea and pneumonia on both types of farms were comparable. Feeding waste or pasteurized milk was associated with a higher risk of AMR in pathogens. Altogether, this review summarizes AMU and AMR data for dairy calves and suggests areas for future research, providing evidence for the design of antimicrobial use stewardship programs in dairy calf farming.

Additional file 1: Table S1. Expression vectors used for functional assays in this study. Table S2. Fatty alcohol oxidase and alcohol dehydrogenase gene sequences. Table S3. Primers used in this study. Figure S1. Experimental workflow of the heterologous expression in a) yeast and b) plant.

Supplemental material, sj-docx-1-dhj-10.1177_20552076221089789 for Associations among eHealth literacy, social support, individual resilience, and emotional status in primary care providers during the outbreak of the SARS-CoV-2 Delta variant by Richard Huan Xu, Lu-shao-bo Shi, Yi Xia and Dong Wang in Digital Health

Hydrogen fuel cell can not only generate electricity efficiently, but also provide a large amount of thermal energy by recovering the waste heat of the fuel cell stack. This study proposed a PEMFC-based distributed energy systems (PEMFC-DES) containing of input energy, PEMFC-based combined cooling, heating and power (PEMFC-CCHP) system and building loads. The performances of energy, environment, economics of the proposed system are investigated through life cycle assessment (LCA) under different hydrogen-electricity contribution rates (RH ), hydrogen production methods and hydrogen gas prices. The results show that the hydrogen production method has a greater impact on primary energy consumption and greenhouse gas emissions. At RH = 1.0, the greenhouse gas emission of coal-to-hydrogen is 2.1 times higher than that of the baseline system. The life cycle primary energy consumption and greenhouse gas emissions of the wind-to-hydrogen are the smallest at RH = 1, which are 85.14% and 87.64% lower than that of the baseline system respectively. Additionally, when the hydrogen price is lower than 20 CNY/kg, the total life cycle cost is lower than that of the baseline system.

C40H28N4O10Co, monoclinic, C2/c (no. 15), a = 29.686(3) Å, b = 6.2315(4) Å, c = 21.0994(15) Å, β = 114.727(8)°, V = 3545.3(5) Å3, Z = 4, Rgt(F) = 0.0386, wRref(F2) = 0.0897, T = 293(2) K.

International audience; Abstract Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.

Intrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their physiological ubiquity and their prevalence in various diseases, including cancer. NUPR1 is an IDP that localizes throughout the whole cell, and is involved in the development and progression of several tumors. We have previously repurposed trifluoperazine (TFP) as a drug targeting NUPR1 and, by using a ligand-based approach, designed the drug ZZW-115 starting from the TFP scaffold. Such derivative compound hinders the development of pancreatic ductal adenocarcinoma (PDAC) in mice, by hampering nuclear translocation of NUPR1. Aiming to further improve the activity of ZZW-115, here we have used an indirect drug design approach to modify its chemical features, by changing the substituent attached to the piperazine ring. As a result, we have synthesized a series of compounds based on the same chemical scaffold. Isothermal titration calorimetry (ITC) showed that, with the exception of the compound preserving the same chemical moiety at the end of the alkyl chain as ZZW-115, an increase of the length by a single methylene group (i.e., ethyl to propyl) significantly decreased the affinity towards NUPR1 measured in vitro, whereas maintaining the same length of the alkyl chain and adding heterocycles favored the binding affinity. However, small improvements of the compound affinity towards NUPR1, as measured by ITC, did not result in a corresponding improvement in their inhibitory properties and in cellulo functions, as proved by measuring three different biological effects: hindrance of the nuclear translocation of the protein, sensitization of cells against DNA damage mediated by NUPR1, and prevention of cancer cell growth. Our findings suggest that a delicate compromise between favoring ligand affinity and controlling protein function may be required to successfully design drugs against NUPR1, and likely other IDPs., This work was supported by Spanish Ministry of Economy and Competitiveness and European ERDF Funds (MCIU/AEI/FEDER, EU) [RTI2018-097991-B-I00 to J.L.N.]; La Ligue Contre le Cancer, INCa, Canceropole PACA and INSERM to JLI; Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III, and European Union (ERDF/ESF, 'Investing in your future') (PI18/00349 to O.A.); Diputacion General de Aragon ('Protein Targets and Bioactive Compounds Group' E45_20R to A.V.-C., 'Digestive Pathology Group' B25_20R to O.A.); Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd) (O.A. and A.V.-C.); CAI YUANPEI Scholarship (201906050187) to Y.X.; and Jeunes Talents France-Chine Program (JTFC) to Y.X. P.S.-C. was supported by Fondation de France; and W.L. by China Scholarship Council.

Semiconductors with very low lattice thermal conductivities are highly desired for applications relevant to thermal energy conversion and management, such as thermoelectrics and thermal barrier coatings. Although the crystal structure and chemical bonding are known to play vital roles in shaping heat transfer behavior, material design approaches of lowering lattice thermal conductivity using chemical bonding principles are uncommon. In this work, we present an effective strategy of weakening interatomic interactions and therefore suppressing lattice thermal conductivity based on chemical bonding principles and develop a high-efficiency approach of discovering low $\kappa_{\rm L}$ materials by screening the local coordination environments of crystalline compounds. The followed first-principles calculations uncover 30 hitherto unexplored compounds with (ultra)low lattice thermal conductivities from thirteen prototype crystal structures contained in the inorganic crystal structure database. Furthermore, we demonstrate an approach of rationally designing high-performance thermoelectrics by additionally incorporating cations with stereochemically active lone-pair electrons. Our results not only provide fundamental insights into the physical origin of the low lattice thermal conductivity in a large family of copper-based compounds but also offer an efficient approach to discovery and design materials with targeted thermal transport properties., Comment: 14 pages, 9 figures

Objectives: Effective treatments for intracerebral hemorrhage (ICH) are limited until now. Ferroptosis, a novel form of iron-dependent cell death, is implicated in neurodegeneration diseases. Here, we attempted to investigate the impact of exosomes from miR-19b-3p-modified adipose-derived stem cells (ADSCs) on ferroptosis in ICH.Methods: Collagenase was used to induce a mouse model of ICH and hemin was used to induce ferroptosis in cultured neurons. Exosomes were isolated from mimic NC- or miR-19b-3p mimic-transfected ADSCs (ADSCs-MNC-Exos or ADSCs-19bM-Exos, respectively) and then administered to ICH mice or hemin-treated neurons. ICH damage was evaluated by assessing the neurological function of ICH mice and cell viability of neurons. Ferroptosis was evaluated in mouse brains or cultured neurons. The interaction between miR-19b-3p and iron regulatory protein 2 (IRP2) 3′-UTR was analyzed by performing luciferase reporter assay.Results: Ferroptosis occurred in ICH mice, which also exhibited decreased miR-19b-3p and increased IRP2 expression. IRP2 was a direct target of miR-19b-3p, and IRP2 expression was repressed by ADSCs-19bM-Exos. Importantly, ADSCs-19bM-Exos effectively attenuated hemin-induced cell injury and ferroptosis. Moreover, ADSCs-19bM-Exos administration significantly improved neurologic function and inhibited ferroptosis in ICH mice.Conclusion: Exosomes from miR-19b-3p-modified ADSCs inhibit ferroptosis in ICH mice.

Dysfunctional regulation of energy homeostasis results in increased bodyweight and obesity, eventually leading to type 2 diabetes mellitus. The infundibular nucleus (IFN) of the hypothalamus is the main regulator of energy homeostasis. The peptidergic neurons and glia cells of the IFN receive metabolic cues concerning energy state of the body from the circulation. The IFN can monitor hormones like insulin and leptin and nutrients like glucose and fatty acids. All these metabolic cues are integrated into an output signal regulating energy homeostasis through the release of neuropeptides. These neuropeptides are released in several inter- and extrahypothalamic brain regions involved in regulation of energy homeostasis. This review will give an overview of the peripheral signals involved in the regulation of energy homeostasis, the peptidergic neurons and glial cells of the IFN, and will highlight the main intra-hypothalamic projection sites of the IFN.

Phenolic aldehydes from lignocellulose pretreatment harshly inhibit the viability and metabolism of ethanol fermenting strains. Direct conversion of phenolic aldehydes is usually incomplete due to their low water solubility and recalcitrance to bioconversion. Here we consolidated phenolic aldehydes bioconversion and ethanol fermentation in a typical ethanologenic bacterium Zymomonas mobilis by constructing an intracellular oxidative pathway. The gene PP_2680 encoding NAD+-dependent aldehyde dehydrogenase from Pseudomonas putida KT2440 was expressed in Z. mobilis ZM4. The expression significantly improved both aldehyde inhibitor conversion and ethanol fermentability in corn stover hydrolysate. The purified PP_2680 aldehyde dehydrogenase showed strong in vitro oxidative capacity on phenolic aldehydes and its in vivo expression significantly up-regulated the key genes in the ED pathway and the oxidative phosphorylation. This study provided an important concept of simultaneous biodetoxification and fermentation in ethanologenic strains for the improvement of ethanol fermentability.

Metabolism homeostasis plays an important role in progenitor-cell differentiation to adipocytes, but less is known about the whole transcriptional profiling of cellular metabolism during adipogenesis. We got the first insight into the whole transcriptional profiling of cellular metabolism during adipogenesis from human mesenchymal stem cells (hMSCs) by the RNA-Seq technique. There were 1,998, 2,629, 3,112, and 3,054 differentially expressed genes (DEGs) at Days 7, 14, 21, and 28, respectively, during adipogenesis. The most enriched phosphatidylinositol 3' kinase-serine/threonine kinase (PI3K-Akt) signaling pathway stimulated and directly regulated cellular metabolism by priming glucose aerobic glycolysis, arginine and proline metabolism, glutathione metabolism, and arachidonic acid metabolism during adipogenesis, targeting the potential key genes, such as fatty acid synthase (FABP4), phosphoenolpyruvate carboxykinase 1 (PKC1), stearoyl-CoA desaturase (SCD), and solute carrier family 2 member 1 of Gluts (SLC2A1). And it confirmed PCK1 as the key player for cellular metabolism by small interfering RNA. A comprehensive understanding of cellular metabolism and its regulatory axis of the signaling pathway during adipogenesis would reveal new study and therapy targets for fat metabolism disorders.

Adipogenesis, the developmental process of progenitor-cell differentiating into adipocytes, leads to fat metabolic disorders. Alternative splicing (AS), a ubiquitous regulatory mechanism of gene expression, allows the generation of more than one unique messenger RNA (mRNA) species from a single gene. Till now, alternative splicing events during adipogenesis from human mesenchymal stem cells (hMSCs) are not yet fully elucidated. We performed RNA-Seq coupled with bioinformatics analysis to identify the differentially expressed AS genes and events during adipogenesis from hMSCs. A global survey separately identified 1262, 1181, 1167, and 1227 ASE involved in the most common types of AS including cassette exon, alt3, and alt5, especially with cassette exon the most prevalent, at 7, 14, 21, and 28 days during adipogenesis. Interestingly, 122 differentially expressed ASE referred to 118 genes, and the three genes including ACTN1 (alt3 and cassette), LRP1 (alt3 and alt5), and LTBP4 (cassette, cassette_multi, and unknown), appeared in multiple AS types of ASE during adipogenesis. Except for all the identified ASE of LRP1 occurred in the extracellular topological domain, alt3 (84) in transmembrane domain significantly differentially expressed was the potential key event during adipogenesis. Overall, we have, for the first time, conducted the global transcriptional profiling during adipogenesis of hMSCs to identify differentially expressed ASE and ASE-related genes. This finding would provide extensive ASE as the regulator of adipogenesis and the potential targets for future molecular research into adipogenesis-related metabolic disorders.

A novel geological hazard assessment model was developed by integrating an analytic hierarchy process (AHP) and a projection pursuit model (PPM) in this study. Remote sensing (RS) and geographic in...

Background Fast, complete, and ultimate removal of inhibitory compounds derived from lignocellulose pretreatment is the prerequisite for efficient production of cellulosic ethanol and biochemicals. Biodetoxification is the most promising method for inhibitor removal by its unique advantages. The biodetoxification mechanisms of a unique diploid fungus responsible for highly efficient biodetoxification in solid-state culture was extensively investigated in the aspects of cellular structure, genome sequencing, transcriptome analysis, and practical biodetoxification. Results The inborn heterozygous diploid structure of A. resinae ZN1 uniquely contributed to the enhancement of inhibitor tolerance and conversion. The co-expression of gene pairs contributed to the enhancement of the degradation of lignocellulose-derived model inhibitors. The ultimate inhibitors degradation pathways and sugar conservation were elucidated by microbial degradation experimentation as well as the genomic and transcriptomic sequencing analysis. Conclusions The finding of the heterozygous diploid structure in A. resinae ZN1 on biodetoxification took the first insight into the global overview of biodetoxification mechanism of lignocellulose-derived inhibitors. This study provided a unique and practical biodetoxification biocatalyst of inhibitor compounds for lignocellulose biorefinery processing, as well as the synthetic biology tools on biodetoxification of biorefinery fermenting strains.

Controllable synthesis of monodisperse nanocrystals is still a great challenge. In this study, the control strategy of alcohol medium was developed to conveniently synthesize monodisperse anatase-TiO2 nanocrystals with controllable size and shape by sol-gel method combined with solvothermal treatment. The effects of the amount of stearic acid and water, and molecular structure of alcohol on the size, the shape and the dispersity of TiO2 nanocrystals were explored. The optimum synthesis conditions were achieved. Monodisperse TiO2 nanoparticles and nanorods were obtained by using linear and branched alcohols, respectively. The size of nanoparticles decreased from 12 to 5 nm with increasing carbon number of linear alcohol. The aspect ratio of nanorods was adjusted from 1 to 5 by selecting alcohols with different locations of branched methyl group. The as-prepared monodisperse TiO2 nanocrystals could be readily dispersed in some commonly-used solvents to form transparent nanodispersions. Furthermore, a possible formation mechanism was also investigated.