Predicting protein synergistic effect in Arabidopsis using epigenome profiling.

Histone modifications can regulate transcription epigenetically by marking specific genomic loci, which can be mapped using chromatin immunoprecipitation sequencing (ChIP-seq). Here we present QHistone, a predictive database of 1534 ChIP-seqs from 27 histone modifications in Arabidopsis, offering three key functionalities. Firstly, QHistone employs machine learning to predict the epigenomic profile of a query protein, characterized by its most associated histone modifications, and uses these modifications to infer the protein's role in transcriptional regulation. Secondly, it predicts synergistic regulatory activities between two proteins by comparing their profiles. Lastly, it detects previously unexplored co-regulating protein pairs by screening all known proteins. QHistone accurately identifies histone modifications associated with specific known proteins, and allows users to computationally validate their results using gene expression data from various plant tissues. These functions demonstrate an useful approach to utilizing epigenome data for gene regulation analysis, making QHistone a valuable resource for the scientific community ( https://qhistone.paoyang.ipmb.sinica.edu.tw ).

Characteristics and Prevalence of Vancomycin-variable Enterococcus faecium bacteremia in southern Taiwan.

BACKGROUND: Vancomycin-variable enterococci (VVE) are vanA-carrying Enterococcus faecium that are phenotypically susceptible to vancomycin and can only be detected using molecular methods, leading to the possibility of treatment failure and posing threats to infection control. This study aimed to determine the prevalence of VVE and its associated clinical risk factors. METHODS: This retrospective study was conducted in two hospitals in southern Taiwan. Patients with phenotypically vancomycin-susceptible E. faecium bacteremia were enrolled between 2017 and 2021. VVEs were defined as isolates harboring the vanA gene that were phenotypically susceptible to vancomycin. Vancomycin-susceptible E. faecium (VSE) isolates were phenotypically susceptible to vancomycin and lacked vanA or vanB genes. RESULTS: Of the 142 enrolled patients, 121 (85.2%) had VSE and 21 (14.8%) had VVE. Resistance rates to penicillin, tetracycline, and fosfomycin were higher in VVE isolates. Malignancy (adjusted odds ratio [aOR] = 4.87; 95% confidence interval [CI] 1.54-15.41, p = 0.007) and central venous catheter usage (aOR = 4.69; 95% CI 1.49-14.78, p = 0.008) were the independent risk factors associated with VVE bacteremia. Being male (aOR = 0.12, CI 0.03-0.44, p = 0.002) was less likely to be associated with VVE bacteremia. Although VVE was not associated with 30-day mortality (38.1% [VVE] vs. 35.5% [VSE], p = 0.822), one case of subsequent vancomycin-resistant enterococci infection in the VVE group with vancomycin treatment (4.8%, 1/21) was identified, which led to subsequent mortality. CONCLUSIONS: The prevalence of VVE was high among E. faecium isolates with vancomycin-susceptible phenotypes in southern Taiwan. Although the current study revealed that VVE bacteremia was not associated with poor clinical outcome, further multicenter surveillance survey is recommended to evaluate the possible impact of VVE on public health in Taiwan.

Surveillance of pathogenic yeasts in hospital environments in Taiwan in 2020.

BACKGROUND: A predominate azole-resistant Candida tropicalis clade 4 genotype causing candidemia has been detected in not only Taiwan but also China, Singapore, and Australia. It can also be detected on fruit surfaces. In addition to determining distribution and drug susceptibilities of pathogenic yeasts in environments of intensive care units of 25 hospitals in Taiwan, we would also like to investigate whether the azole-resistant C. tropicalis exists in Taiwan's hospital environment. METHODS: The swabs of hospital environments were collected from August to November in 2020 and were cultured for yeasts. The yeasts were identified by rDNA sequence and the antifungal susceptibilities of those isolates were determined by the broth microdilution method. RESULTS: The average yeast-culture rate of hospitals was 9.4% (217/2299). Sinks had the highest yeast-positive culture rate (32.7%), followed by bedside tables (28.9%), floors (26.0%), water-dispenser buttons (23.8%), and TV controller/touch panels (19.0%). Of 262 identified isolates, Candida parapsilosis was the most common species, accounting for 22.1%, followed by Filobasidium uniguttulatum (18.3%), Candida albicans (9.5%), C. tropicalis (8.0%), Candida glabrata (Nakaseomyces glabratus) (6.9%), and 30 other species (35.1%). Of the 21 C. tropicalis isolates from 11 units in 9 hospitals, 15 diploid sequence types (DSTs) were identified. The two DST506 fluconazole-resistant ones belonged to clade 4. CONCLUSION: We detected not only various pathogenic yeast species but also the predominant clade 4 genotype of azole-resistant C. tropicalis. Our findings highlight and re-emphasize the importance of regular cleaning and disinfection practices.

A high-fidelity lithium-ion battery emulator for electric vehicle application.

Lithium-ion (Li-ion) battery has played a key role for the development of electric vehicle (EV) at present, while the Li-ion batteries in the market come from different manufactures. Verifying the performance of the battery management system (BMS) for various battery chemistries is a complex undertaking. This paper proposes a high-fidelity Li-ion battery emulator for EV applications. The emulator utilizes a battery model parameterized by a series of performance tests and a special-designed hardware platform. A three-order battery equivalent circuit model (ECM) is selected to provide the voltage and current reference signal in the processor. Subsequently, the hardware generates the high voltage and current signal in accordance with the reference. To ensure the high accuracy of the battery ECM, a 37 Ah nickel manganese cobalt (NMC) battery was selected for testing under both charge and discharge conditions, as well as across a temperature range of - 30℃ to 45℃. The battery emulator is verified on charge and discharge mode for both accuracy and dynamic performance validations.

Unacclimated activated sludge improved nitrate reduction and N2 selectivity in iron filling/biochar systems.

Iron (Fe)-based denitrification is a proven technology for removing nitrate from water, yet challenges such as limited pH preference range and low N2 selectivity (reduction of nitrate to N2) persist. Adding biochar (BC) can improve the pH preference range but not N2 selectivity. This study aimed to improve nitrate reduction and N2 selectivity in iron filling/biochar (Fe/BC) systems with a simplified approach by coupling unacclimated microbes (M) in the system. Factors such as initial pH, Fe/BC ratio, and Fe/BC dosage on nitrate removal efficiency and N2 selectivity were evaluated. Results show that the introduction of microbes significantly enhanced nitrate removal and N2 selectivity, achieving 100 % nitrate removal and 79 % N2 selectivity. The Fe/BC/M system exhibited efficient nitrate reduction at pH of 2-10. Moreover, the Fe/BC/M system demonstrated an improved electrochemical active surface area (ECSA), lower electron transfer resistance and lower corrosion potential, leading to enhanced nitrate reduction. The high i0 value in Fe/BC/M system means more Hads could be generated, thus improving the N2 selectivity. This study provides valuable insights into a novel approach for effective nitrate removal, offering a potential solution to the environmental challenges posed by excessive nitrate in wastewater, surface water and ground water.

Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.

Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to mitochondria post-translationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome on the surface of the mitochondria in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membrane. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.

Sex Differences in the Expression of Cardiac Remodeling and Inflammatory Cytokines in Patients with Obstructive Sleep Apnea and Atrial Fibrillation.

Although there is a link between obstructive sleep apnea (OSA) and atrial fibrillation (AF) and numerous investigations have examined the mechanism of AF development in OSA patients, which includes cardiac remodeling, inflammation, and gap junction-related conduction disorder, there is limited information regarding the differences between the sexes. This study analyzes the impact of sex differences on the expression of cardiac remodeling, inflammatory cytokines, and gap junctions in patients with OSA and AF. A total of 154 individuals diagnosed with sleep-related breathing disorders (SRBDs) were enrolled in the study and underwent polysomnography and echocardiography. Significant OSA was defined as an apnea-hypopnea index (AHI) of ≥15 per hour. Exosomes were purified from the plasma of all SRBD patients and incubated in HL-1 cells to investigate their effects on inflammatory cytokines and GJA1 expression. The differences in cardiac remodeling and expression of these biomarkers in both sexes were analyzed. Of the 154 enrolled patients, 110 patients were male and 44 patients were female. The LA sizes and E/e' ratios of male OSA patients with concomitant AF were greater than those of control participants and those without AF (all p < 0.05). Meanwhile, female OSA patients with AF had a lower left ventricular ejection fraction than those OSA patients without AF and control subjects (p < 0.05). Regarding the expression of inflammatory cytokines and GJA1, the mRNA expression levels of GJA1 were lower and those of IL-1ß were higher in those male OSA patients with AF than in those male OSA patients without AF and control subjects (p < 0.05). By contrast, mRNA expression levels of HIF-1α were higher in those female OSA patients with and without AF than in control subjects (p < 0.05). In conclusion, our study revealed sex-specific differences in the risk factors and biomarkers associated with AF development in patients with OSA.

First-year outcomes of very low birth weight preterm singleton infants with hypoxemic respiratory failure treated with milrinone and inhaled nitric oxide (iNO) compared to iNO alone: A nationwide retrospective study.

BACKGROUND: Inhaled nitric oxide (iNO) has a beneficial effect on hypoxemic respiratory failure. The increased use of concurrent iNO and milrinone was observed. We aimed to report the trends of iNO use in the past 15 years in Taiwan and compare the first-year outcomes of combining iNO and milrinone to the iNO alone in very low birth weight preterm (VLBWP) infants under mechanical ventilation. METHODS: This nationwide cohort study enrolled preterm singleton infants with birth weight <1500g treated with iNO from 2004 to 2019. Infants were divided into two groups, with a combination of intravenous milrinone (Group 2, n = 166) and without milrinone (Group 1, n = 591). After propensity score matching (PSM), each group's sample size is 124. The primary outcomes were all-cause mortality and the respiratory condition, including ventilator use and duration. The secondary outcomes were preterm morbidities within one year after birth. RESULTS: After PSM, more infants in Group 2 needed inotropes. The mortality rate was significantly higher in Group 2 than in Group 1 from one month after birth till 1 year of age (55.1% vs. 13.5%) with the adjusted hazard ratio of 4.25 (95%CI = 2.42-7.47, p <0.001). For infants who died before 36 weeks of postmenstrual age (PMA), Group 2 had longer hospital stays compared to Group 1. For infants who survived after 36 weeks PMA, the incidence of moderate and severe bronchopulmonary dysplasia (BPD) was significantly higher in Group 2 than in Group 1. For infants who survived until one year of age, the incidence of pneumonia was significantly higher in Group 2 (28.30%) compared to Group 1 (12.62%) (p = 0.0153). CONCLUSION: Combined treatment of iNO and milrinone is increasingly applied in VLBWP infants in Taiwan. This retrospective study did not support the benefits of combining iNO and milrinone on one-year survival and BPD prevention. A future prospective study is warranted.

Classification Prediction of Alzheimer's Disease and Vascular Dementia Using Physiological Data and ECD SPECT Images.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common forms of dementia. However, their neuropsychological and pathological features often overlap, making it difficult to distinguish between AD and VaD. In addition to clinical consultation and laboratory examinations, clinical dementia diagnosis in Taiwan will also include Tc-99m-ECD SPECT imaging examination. Through machine learning and deep learning technology, we explored the feasibility of using the above clinical practice data to distinguish AD and VaD. We used the physiological data (33 features) and Tc-99m-ECD SPECT images of 112 AD patients and 85 VaD patients in the Taiwanese Nuclear Medicine Brain Image Database to train the classification model. The results, after filtering by the number of SVM RFE 5-fold features, show that the average accuracy of physiological data in distinguishing AD/VaD is 81.22% and the AUC is 0.836; the average accuracy of training images using the Inception V3 model is 85% and the AUC is 0.95. Finally, Grad-CAM heatmap was used to visualize the areas of concern of the model and compared with the SPM analysis method to further understand the differences. This research method can quickly use machine learning and deep learning models to automatically extract image features based on a small amount of general clinical data to objectively distinguish AD and VaD.

Comparative analyses of the Smith-Magenis syndrome protein RAI1 in mice and common marmoset monkeys.

Retinoic acid-induced 1 (RAI1) encodes a transcriptional regulator critical for brain development and function. RAI1 haploinsufficiency in humans causes a syndromic autism spectrum disorder known as Smith-Magenis syndrome (SMS). The neuroanatomical distribution of RAI1 has not been quantitatively analyzed during the development of the prefrontal cortex, a brain region critical for cognitive function and social behaviors and commonly implicated in autism spectrum disorders, including SMS. Here, we performed comparative analyses to uncover the evolutionarily convergent and divergent expression profiles of RAI1 in major cell types during prefrontal cortex maturation in common marmoset monkeys (Callithrix jacchus) and mice (Mus musculus). We found that while RAI1 in both species is enriched in neurons, the percentage of excitatory neurons that express RAI1 is higher in newborn mice than in newborn marmosets. By contrast, RAI1 shows similar neural distribution in adult marmosets and adult mice. In marmosets, RAI1 is expressed in several primate-specific cell types, including intralaminar astrocytes and MEIS2-expressing prefrontal GABAergic neurons. At the molecular level, we discovered that RAI1 forms a protein complex with transcription factor 20 (TCF20), PHD finger protein 14 (PHF14), and high mobility group 20A (HMG20A) in the marmoset brain. In vitro assays in human cells revealed that TCF20 regulates RAI1 protein abundance. This work demonstrates that RAI1 expression and protein interactions are largely conserved but with some unique expression in primate-specific cells. The results also suggest that altered RAI1 abundance could contribute to disease features in disorders caused by TCF20 dosage imbalance.

Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1.

PD-1 is a co-inhibitory receptor expressed by CD8+ T cells which limits their cytotoxicity. PD-L1 expression on cancer cells contributes to immune evasion by cancers, thus, understanding the mechanisms that regulate PD-L1 protein levels in cancers is important. Here we identify tumor-cell-expressed otubain-2 (OTUB2) as a negative regulator of antitumor immunity, acting through the PD-1/PD-L1 axis in various human cancers. Mechanistically, OTUB2 directly interacts with PD-L1 to disrupt the ubiquitination and degradation of PD-L1 in the endoplasmic reticulum. Genetic deletion of OTUB2 markedly decreases the expression of PD-L1 proteins on the tumor cell surface, resulting in increased tumor cell sensitivity to CD8+ T-cell-mediated cytotoxicity. To underscore relevance in human patients, we observe a significant correlation between OTUB2 expression and PD-L1 abundance in human non-small cell lung cancer. An inhibitor of OTUB2, interfering with its deubiquitinase activity without disrupting the OTUB2-PD-L1 interaction, successfully reduces PD-L1 expression in tumor cells and suppressed tumor growth. Together, these results reveal the roles of OTUB2 in PD-L1 regulation and tumor evasion and lays down the proof of principle for OTUB2 targeting as therapeutic strategy for cancer treatment.

Transcriptomic Analysis Reveals Candidate Genes in Response to Sorghum Mosaic Virus and Salicylic Acid in Sugarcane.

Sorghum mosaic virus (SrMV) is one of the most prevalent viruses deteriorating sugarcane production. Salicylic acid (SA) plays an essential role in the defense mechanism of plants and its exogenous application has been observed to induce the resistance against biotic and abiotic stressors. In this study, we set out to investigate the mechanism by which sorghum mosaic virus (SrMV) infected sugarcane responds to SA treatment in two sugarcane cultivars, i.e., ROC22 and Xuezhe. Notably, significantly low viral populations were observed at different time points (except for 28 d in ROC22) in response to post-SA application in both cultivars as compared to control based on qPCR data. Furthermore, the lowest number of population size in Xuezhe (20 copies/µL) and ROC22 (95 copies/µL) was observed in response to 1 mM exogenous SA application. A total of 2999 DEGs were identified, of which 731 and 2268 DEGs were up- and down-regulated, respectively. Moreover, a total of 806 DEGs were annotated to GO enrichment categories: 348 biological processes, 280 molecular functions, and 178 cellular components. GO functional categorization revealed that DEGs were mainly enriched in metabolic processes, extracellular regions, and glucosyltransferase activity, while KEGG annotation revealed that DEGs were mainly concentrated in phenylpropanoid biosynthesis and plant-pathogen interaction suggesting the involvement of these pathways in SA-induced disease resistance of sugarcane in response to SrMV infection. The RNA-seq dataset and qRT-PCR assay showed that the transcript levels of PR1a, PR1b, PR1c, NPR1a, NPR1b, PAL, ICS, and ABA were significantly up-regulated in response to SA treatment under SrMV infection, indicating their positive involvement in stress endorsement. Overall, this research characterized sugarcane transcriptome during SrMV infection and shed light on further interaction of plant-pathogen under exogenous application of SA treatment.

Clinical validation of a saliva-based matrix metalloproteinase-1 rapid strip test for detection of oral cavity cancer.

BACKGROUND: We previously identified matrix metalloproteinase-1 (MMP-1) as one of the most promising salivary biomarkers for oral squamous cell carcinoma (OSCC) and developed a sensitive ELISA for MMP-1 with good performance in detection of OSCC using a cohort of 1160 saliva samples. METHODS: A time-saving rapid strip test (RST) for MMP-1 was developed in this study and its diagnostic performance compared with ELISA using saliva samples from a new cohort of 603 subjects (171 healthy controls, 236 patients with oral potentially malignant disorders, and 196 OSCC patients). RESULTS: Salivary MMP-1 levels measured using RST and ELISA were highly comparable and both assays could effectively distinguish between OSCC and non-cancerous groups. Similar to ELISA, receiver operating characteristic curve analysis of the MMP-1 RST was effective in identifying patients with OSCC at different oral cavity sites and stages. CONCLUSIONS: Salivary MMP-1 can be sensitively detected using both RST and ELISA methods. Our newly developed point-of-care MMP-1 RST is a promising in vitro diagnostic device (IVD) that may serve as a novel auxiliary tool in the routine clinical detection and monitoring of OSCC.

Comparison between a novel salivary marker and several clinical prognosticators in oral cavity cancer.

Objectives: This study aimed to investigate the association between salivary matrix metalloproteinase-1 (MMP-1) and clinicopathological parameters of oral cavity squamous cell carcinoma (OSCC) and compare the prognostic efficacy of salivary MMP-1 and other established circulating markers for OSCC. Methods: Saliva specimens from 479 OSCC subjects were examined using an enzyme-linked immunosorbent assay. The area under the curve (AUC) values of salivary MMP-1 and other markers were calculated, and survival analyses were conducted using Kaplan-Meier and multivariate regression methods. Results: Salivary MMP-1 showed good discrimination in predicting overall survival, with an AUC of 0.638, which was significantly higher than that of albumin (0.530, p = .021) and Charlson comorbidity index (0.568, p = .048) and comparable with neutrophil-to-lymphocyte ratio (0.620, p = .987), platelet-to-lymphocyte ratio (0.575, p = .125), and squamous cell carcinoma antigen (0.609, p = .605). Elevated levels of salivary MMP-1 were significantly associated with higher pT classification, pN classification, overall pathological stage, positive extranodal extension, tumor differentiation, positive lymphovascular invasion, positive perineural invasion, and tumor depth (p all <.05). Multivariate analyses indicated that a higher level of salivary MMP-1 (≥2060.0 pg/mL) was an independent predictive factor of poorer overall survival (adjusted hazard ratio: 1.421 [95% confidential interval: 1.014-1.989], p = .041). Conclusion: The study found that the salivary MMP-1 level was significantly associated with many adverse clinicopathological parameters of OSCC. In OSCC, it was found to have superior efficacy in predicting prognosis and was an independent prognostic factor of post-treatment outcome. Level of evidence: 3.

Estimating genome-wide DNA methylation heterogeneity with methylation patterns.

BACKGROUND: In a heterogeneous population of cells, individual cells can behave differently and respond variably to the environment. This cellular diversity can be assessed by measuring DNA methylation patterns. The loci with variable methylation patterns are informative of cellular heterogeneity and may serve as biomarkers of diseases and developmental progression. Cell-to-cell methylation heterogeneity can be evaluated through single-cell methylomes or computational techniques for pooled cells. However, the feasibility and performance of these approaches to precisely estimate methylation heterogeneity require further assessment. RESULTS: Here, we proposed model-based methods adopted from a mathematical framework originally from biodiversity, to estimate genome-wide DNA methylation heterogeneity. We evaluated the performance of our models and the existing methods with feature comparison, and tested on both synthetic datasets and real data. Overall, our methods have demonstrated advantages over others because of their better correlation with the actual heterogeneity. We also demonstrated that methylation heterogeneity offers an additional layer of biological information distinct from the conventional methylation level. In the case studies, we showed that distinct profiles of methylation heterogeneity in CG and non-CG methylation can predict the regulatory roles between genomic elements in Arabidopsis. This opens up a new direction for plant epigenomics. Finally, we demonstrated that our score might be able to identify loci in human cancer samples as putative biomarkers for early cancer detection. CONCLUSIONS: We adopted the mathematical framework from biodiversity into three model-based methods for analyzing genome-wide DNA methylation heterogeneity to monitor cellular heterogeneity. Our methods, namely MeH, have been implemented, evaluated with existing methods, and are open to the research community.

Long non-coding RNA FKSG29 regulates oxidative stress and endothelial dysfunction in obstructive sleep apnea.

Altered expressions of pro-/anti-oxidant genes are known to regulate the pathophysiology of obstructive sleep apnea (OSA).We aim to explore the role of a novel long non-coding (lnc) RNA FKSG29 in the development of intermittent hypoxia with re-oxygenation (IHR)-induced endothelial dysfunction in OSA. Gene expression levels of key pro-/anti-oxidant genes, vasoactive genes, and the FKSG29 were measured in peripheral blood mononuclear cells from 12 subjects with primary snoring (PS) and 36 OSA patients. Human monocytic THP-1 cells and human umbilical vein endothelial cells (HUVEC) were used for gene knockout and double luciferase under IHR exposure. Gene expression levels of the FKSG29 lncRNA, NOX2, NOX5, and VEGFA genes were increased in OSA patients versus PS subjects, while SOD2 and VEGFB gene expressions were decreased. Subgroup analysis showed that gene expression of the miR-23a-3p, an endogenous competitive microRNA of the FKSG29, was decreased in sleep-disordered breathing patients with hypertension versus those without hypertension. In vitro IHR experiments showed that knock-down of the FKSG29 reversed IHR-induced ROS overt production, early apoptosis, up-regulations of the HIF1A/HIF2A/NOX2/NOX4/NOX5/VEGFA/VEGFB genes, and down-regulations of the VEGFB/SOD2 genes, while the protective effects of FKSG29 knock-down were abolished by miR-23a-3p knock-down. Dual-luciferase reporter assays confirmed that FKSG29 was a sponge of miR-23a-3p, which regulated IL6R directly. Immunofluorescence stain further demonstrated that FKSGH29 knock-down decreased IHR-induced uptake of oxidized low density lipoprotein and reversed IHR-induced IL6R/STAT3/GATA6/ICAM1/VCAM1 up-regulations. The findings indicate that the combined RNA interference may be a novel therapy for OSA-related endothelial dysfunction via regulating pro-/anti-oxidant imbalance or targeting miR-23a-IL6R-ICAM1/VCAM1 signaling.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Health perception and restorative experience in the therapeutic landscape of urban wetland parks during the COVID-19 pandemic.

Introduction: The effects of restoration and inspiration in the therapeutic landscape of natural environments on visitors during the COVID-19 pandemic have been well-documented. However, less attention has been paid to the heterogeneity of visitor perceptions of health and the potential impacts of experiences in wetland parks with green and blue spaces on visitors' overall perceived health. In this study, we investigate the impact of the restorative landscapes of wetland parks on visitors' health perceptions in the context of the COVID-19 pandemic. Methods: In our survey, 582 respondents participated in an online questionnaire. We analyzed the respondents' health perceptions in terms of latent class analysis, used multinomial logistic regression to determine the factors influencing the potential categorization of health perceptions, and used structural equation modeling to validate the relationships between health perceptions of different groups and landscape perceptions of wetland parks, restorative experiences, and personality optimistic tendencies. Results: The results identified three latent classes of health perceptions. Gender, marital status, education, occupation, income, distance, frequency of activities, and intensity of activities were significant predictors of potential classes of perceived health impacts among wetland park visitors. Discussion: This study revealed the nature and strength of the relationships between health perception and landscape perception, restorative experience, and dispositional optimism tendencies in wetland parks. These findings can be targeted not only to improve visitor health recovery but also to provide effective references and recommendations for wetland park design, planning, and management practices during and after an epidemic.

MoS2 as an Effective Cu Diffusion Barrier with a Back-End Compatible Process.

This study demonstrates molybdenum disulfide (MoS2) as a superior candidate as a diffusion barrier and liner. This research explores a newly developed process to show how effectively MoS2 can be applied. First, a new approach is developed to prepare molybdenum disulfide (MoS2) by microwave plasma-enhanced sulfurization (MW-PES). MW-PES can rapidly and directly grow on the target substrate at low temperatures, which is compatible with the back-end-of-line (BEOL) technology. Second, the performance of MW-PES MoS2 as a diffusion barrier and liner is reported in the subsequent section. Through time-dependent dielectric breakdown (TDDB) measurements, MoS2 is shown to have a barrier property better than that of the current material, Ta, with the same thickness. According to the model fitting, the lifetime of the device is about 45.2 times the lifetime under normal operating conditions. Furthermore, MoS2 shows its superior thermal stability in maintaining the barrier properties. MoS2 is proven to be an excellent interface as a liner as it can provide sufficient adhesion and wettability to further effectively reduce the surface scattering of copper (Cu) and significantly lower the circuit resistance.