Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.

Population structure and adaptability analysis of Schizothorax o'connori based on whole-genome resequencing.

BACKGROUND: Schizothorax o'connori is an endemic fish distributed in the upper and lower reaches of the Yarlung Zangbo River in China. It has experienced a fourth round of whole gene replication events and is a good model for exploring the genetic differentiation and environmental adaptability of fish in the Qinghai-Tibet Plateau. The uplift of the Qinghai-Tibet Plateau has led to changes in the river system, thereby affecting gene exchange and population differentiation between fish populations. With the release of fish whole genome data, whole genome resequencing has been widely used in genetic evolutionary analysis and screening of selected genes in fish, which can better elucidate the genetic basis and molecular environmental adaptation mechanisms of fish. Therefore, our purpose of this study was to understand the population structure and adaptive characteristics of S. o'connori using the whole-genome resequencing method. RESULTS: The results showed that 23,602,746 SNPs were identified from seven populations, mostly distributed on chromosomes 2 and 23. There was no significant genetic differentiation between the populations, and the genetic diversity was relatively low. However, the Zangga population could be separated from the Bomi, Linzhi, and Milin populations in the cluster analysis. Based on historical dynamics analysis of the population, the size of the ancestral population of S. o'connori was affected by the late accelerated uplift of the Qinghai Tibet Plateau and the Fourth Glacial Age. The selected sites were mostly enriched in pathways related to DNA repair and energy metabolism. CONCLUSION: Overall, the whole-genome resequencing analysis provides valuable insights into the population structure and adaptive characteristics of S. o'connori. There was no obvious genetic differentiation at the genome level between the S. o'connori populations upstream and downstream of the Yarlung Zangbo River. The current distribution pattern and genetic diversity are influenced by the late accelerated uplift of the Qinghai Tibet Plateau and the Fourth Ice Age. The selected sites of S. o'connori are enriched in the energy metabolism and DNA repair pathways to adapt to the low temperature and strong ultraviolet radiation environment at high altitude.

Electrical-Driven Directed-Evolution of Copper Nanowires Catalysts for Efficient Nitrate Reduction to Ammonia.

The electrocatalytic conversion of nitrate (NO3 -) to NH3 (NO3RR) at ambient conditions offers a promising alternative to the Haber-Bosch process. The pivotal factors in optimizing the proficient conversion of NO3 - into NH3 include enhancing the adsorption capabilities of the intermediates on the catalyst surface and expediting the hydrogenation steps. Herein, the Cu/Cu2O/Pi NWs catalyst is designed based on the directed-evolution strategy to achieve an efficient reduction of NO3‾. Benefiting from the synergistic effect of the OV-enriched Cu2O phase developed during the directed-evolution process and the pristine Cu phase, the catalyst exhibits improved adsorption performance for diverse NO3RR intermediates. Additionally, the phosphate group anchored on the catalyst's surface during the directed-evolution process facilitates water electrolysis, thereby generating Hads on the catalyst surface and promoting the hydrogenation step of NO3RR. As a result, the Cu/Cu2O/Pi NWs catalyst shows an excellent FE for NH3 (96.6%) and super-high NH3 yield rate of 1.2 mol h-1 gcat. -1 in 1 m KOH and 0.1 m KNO3 solution at -0.5 V versus RHE. Moreover, the catalyst's stability is enhanced by the stabilizing influence of the phosphate group on the Cu2O phase. This work highlights the promise of a directed-evolution approach in designing catalysts for NO3RR.

Ensemble Prototype Network For Weakly Supervised Temporal Action Localization.

Weakly supervised temporal action localization (TAL) aims to localize the action instances in untrimmed videos using only video-level action labels. Without snippet-level labels, this task should be hard to distinguish all snippets with accurate action/background categories. The main difficulties are the large variations brought by the unconstraint background snippets and multiple subactions in action snippets. The existing prototype model focuses on describing snippets by covering them with clusters (defined as prototypes). In this work, we argue that the clustered prototype covering snippets with simple variations still suffers from the misclassification of the snippets with large variations. We propose an ensemble prototype network (EPNet), which ensembles prototypes learned with consensus-aware clustering. The network stacks a consensus prototype learning (CPL) module and an ensemble snippet weight learning (ESWL) module as one stage and extends one stage to multiple stages in an ensemble learning way. The CPL module learns the consensus matrix by estimating the similarity of clustering labels between two successive clustering generations. The consensus matrix optimizes the clustering to learn consensus prototypes, which can predict the snippets with consensus labels. The ESWL module estimates the weights of the misclassified snippets using the snippet-level loss. The weights update the posterior probabilities of the snippets in the clustering to learn prototypes in the next stage. We use multiple stages to learn multiple prototypes, which can cover the snippets with large variations for accurate snippet classification. Extensive experiments show that our method achieves the state-of-the-art weakly supervised TAL methods on two benchmark datasets, that is, THUMOS'14, ActivityNet v1.2, and ActivityNet v1.3 datasets.

F-free etching and ingenious construction of hydrogel layer-prepared MXene membranes for oily wastewater separation.

A strategy for the preparation of hydrogel layer MXene membranes by an F-free method was proposed. It maintained high permeance (2686.1 L m-2 h-1 bar-1) and separation efficiency (99.99%) even after 300 min of emulsion separation. The membrane resisted harsh chemical and microbiological environments and efficiently treated actual oily wastewater.

Exploring HIV-1 transmission features among older individuals in developed eastern China.

The number of newly reported HIV-1 infections among older individuals (aged ≥50 years) has increased rapidly in Hangzhou, a central city in the Yangtze River Delta region of China. To provide a scientific basis for prevention and intervention strategies targeted at older individuals in Hangzhou, an epidemiological survey combined with molecular transmission network analysis was conducted. A total of 2899 individuals with newly confirmed HIV-1 infections, including 635 older individuals and 2264 younger individuals (aged <50 years), were enrolled in this study. Among older individuals, heterosexual contact was the predominant mode of HIV-1 transmission. Additionally, it was observed that older individuals with lower levels of education exhibited a higher susceptibility to HIV-1 infection. The analysis of transmission network which was inferred using HIV-TRACE algorithm revealed that the newly diagnosed HIV-1 infections among older individuals in Hangzhou exhibited a pattern of scattered transmission, with key clusters primarily located in non-main urban areas. The predominant mode of transmission in these areas was non-marital and non-commercial or non-marital and commercial heterosexual transmission. Notably, the study highlighted a significant proportion of older individuals (73.3%, 11/15) within B subtype. Multivariate logistic regression analysis further revealed that the subtype B was a significant factor associated with older individuals having ≥3 node degrees in the network, occurring 5.55 times more frequent than subtype CRF07_BC (95% CI = 1.17-26.22, p = 0.031). Furthermore, the lower CD4 levels observed among older individuals underscored the challenge of late diagnosis in Hangzhou. Taken together, it is imperative to test and intervene for high-risk older individuals. To tackle this issue effectively, it is essential to enhance the detection of the B subtype and implement targeted interventions in key clusters within non-main urban areas. Additionally, proactive measures should be implemented to address the challenge of late diagnosis in Hangzhou by promoting widespread testing among the older individuals, particularly in priority areas.

Microscopy aided detection of the self-intercalation mechanism and in situ electronic properties in chromium selenide.

Two-dimensional (2D) chromium-based self-intercalated materials Cr1+nX2 (0 ≤ n ≤ 1, X = S, Se, Te) have attracted much attention because of their tunable magnetism with good environmental stability. Intriguingly, the magnetic and electrical properties of the materials can be effectively tuned by altering the coverage and spatial arrangement of the intercalated Cr (ic-Cr) within the van der Waals gap, contributing to different stoichiometries. Several different Cr1+nX2 systems have been widely investigated recently; however, those with the same stoichiometric ratio (such as Cr1.25Te2) were reported to exhibit disparate magnetic properties, which still lacks explanation. Therefore, a systematic in situ study of the mechanisms with microscopy techniques is in high demand to look into the origin of these discrepancies. Herein, 2D self-intercalated Cr1+nSe2 nanoflakes were synthesized as a platform to conduct the characterization. Combining scanning transmission electron microscopy (STEM) and scanning tunneling microscopy (STM), we studied in depth the microscopic structure and local electronic properties of the Cr1+nSe2 nanoflakes. The self-intercalation mechanism of ic-Cr and local stoichiometric-ratio variation in a Cr1+nSe2 ultrathin nanoflake is clearly detected at the nanometer scale. Scanning tunneling spectroscopy (STS) measurements indicate that Cr1.5Se2/Cr2Se2 and Cr1.25Se2 exhibit conductive and semiconductive behaviors, respectively. The STM tip manipulation method is further applied to manipulate the microstructure of Cr1+nSe2, which successfully produces clean zigzag-type boundaries. Our systematic microscopy study paves the way for the in-depth study of the magnetic mechanism of 2D self-intercalated magnets at the nano/micro scale and the development of new magnetic and spintronic devices.

Phosphorothioate-modified G-quadruplex as a signal-on dual-mode reporter for CRISPR/Cas12a-based portable detection of environmental pollutants.

BACKGROUND: Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a-powered biosensor with a G-quadruplex (G4) reporter offer the benefits of simplicity and sensitivity, making them extensively utilized in detection applications. However, these biosensors used for monitoring pollutants in environmental water samples may face the problem of high background signal and easy interference due to the "signal-off" output. It is obvious that a biosensor based on the CRISPR/Cas12a system and G4 with a "signal on" output mode needs to be designed for detecting environmental pollutants. RESULTS: By using phosphorothioate-modified G4 as a reporter and catalytic hairpin assembly (CHA) integrated with Cas12a as an amplification strategy, a "signal-on" colorimetric/photothermal biosensor (psG4-CHA/Cas) for portable detection of environmental pollutants was developed. With the help of functional nucleotides, the target pollutant (kanamycin or Pb2+) triggers a CHA reaction to produce numerous double-strand DNA, which can activate Cas12a's trans-cleavage activity. The active Cas12a cleaves locked DNA to release caged psG-rich sequences. Upon binding hemin, the psG-rich sequence forms a psG4/hemin complex, facilitating the oxidation of the colorless 3,3',5,5'-tetramethylbenzidine (TMB) into the blue photothermal agent (oxTMB). The smartphone was employed for portable colorimetric detection of kanamycin and Pb2+. The detection limits were found to be 100 pM for kanamycin and 50 pM for Pb2+. Detection of kanamycin and Pb2+ was also carried out using a portable thermometer with a detection limit of 10 pM for kanamycin and 8 pM for Pb2+. SIGNIFICANCE: Sensitive, selective, simple and robust detection of kanamycin and Pb2+ in environmental water samples is achieved with the psG4-CHA/Cas system. This system not only provides a new perspective on the development of efficient CRISPR/Cas12a-based "signal-on" designs, but also has a promising application for safeguarding human health and environmental monitoring.

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with low tau pathology and slowdown of cognitive decline despite the causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the molecular effects enabling E3S/S mutation to confer protection remain unclear. Here, we replaced mouse Apoe with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly mitigated tau load and protected against tau-induced synaptic loss, myelin loss, and spatial learning. Additionally, the R136S mutation reduced microglial interferon response to tau pathology both in vivo and in vitro, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates the protective effects of R136S against tauopathy.

Screening, identification, and characterization of molds for brewing rice wine: Scale-up production in a bioreactor.

Rice wine, well known for its unique flavor, rich nutritional value, and health benefits, has potential for extensive market development. Rhizopus and Aspergillus are among several microorganisms used in rice wine brewing and are crucial for determining rice wine quality. The strains were isolated via Rose Bengal and starch as a combined separation medium, followed by oenological property and sensory evaluation screening. The strain exhibiting the best performance can be screened using the traditional rice wine Qu. The strains YM-8, YM-10, and YM-16, which exhibited strong saccharification and fermentation performance along with good flavor and taste, were obtained from traditional rice wine Qu. Based on ITS genetic sequence analysis, the YM-8, YM-10, and YM-16 strains were identified as Rhizopus microsporus, Rhizopus arrhizus, and Aspergillus oryzae. The optimum growth temperature of each of the three strains was 30°C, 32°C, and 30°C, and the optimum initial pH was 6.0, 6.5, and 6.5, respectively. The activities of α-amylase, glucoamylase, and protease of YM-16 were highest at 220.23±1.88, 1,269.04±30.32, and 175.16±1.81 U/g, respectively. The amino acid content of rice wine fermented in a 20-L bioreactor with the three mold strains was higher than that of the control group, except for arginine, which was significantly lower than that of the control group. The total amino acid content and the total content of each type of amino acid were ranked as YM-16 > YM-8 > YM-10 > control group, and the amino acid content varied greatly among the strains. The control group had a higher content, whereas YM-8 and YM-16 had lower contents of volatile aroma components than the control group and had the basic flavor substances needed for rice wine, which is conducive to the formation of rice wine aroma. This selected strain, YM-16, has strong saccharification and fermentation ability, is a rich enzyme system, and improves the flavor of rice wine, thereby demonstrating its suitability as a production strain for brewing.

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

The strongest risk factors for Alzheimer's disease (AD) include the χ4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H ( R47H ) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

Mental health status and coping strategies of Chinese university students during the COVID-19 pandemic: A rapid review.

Since the coronavirus (COVID-19) outbreak in December 2019, students have been under unparalleled psychological stress worldwide. As part of its prevention and control strategies, the Chinese Ministry of Education proposed online teaching activities for universities. For the first time, teaching and learning shifted completely online, significantly impacting university students used to classroom learning. This research addresses the knowledge gap about the mental health and coping strategies employed by Chinese university students during the COVID-19 pandemic. Electronic databases (PsycINFO, Scopus, Medline, Cochranes and CNKI) were searched systematically from 2019 to 2023, as part of this literature review. From the 349 articles found, 25 met the inclusion criteria for analysis. Thematic analysis was used to identify six sub-themes, organized under two main themes: Mental health issues of Chinese university students and their coping mechanisms. Heightened stress, anxiety, and depression appeared in Chinese university students during the pandemic, which may have been compounded by their isolation and the disruptions to their studies. Although the impact of COVID-19 on Chinese university students is waning, this study emphasizes the potential long-lasting impact on their mental health, which requires further investigation, particularly regarding gender differences. Moreover, positive and negative coping strategies were found in this review. Strategies for seeking social and family support and participating in sports activities had significant alleviating effects, while negative coping strategies such as alcohol-use and smoking did not. This rapid review informs the development of policies and interventions to enhance the mental health of university students during crisis events. The findings serve to inform health policymakers, university psychologists, and educators in improving the well-being of this student population.