Massively parallel in vivo Perturb-seq reveals cell-type-specific transcriptional networks in cortical development.

Leveraging AAVs' versatile tropism and labeling capacity, we expanded the scale of in vivo CRISPR screening with single-cell transcriptomic phenotyping across embryonic to adult brains and peripheral nervous systems. Through extensive tests of 86 vectors across AAV serotypes combined with a transposon system, we substantially amplified labeling efficacy and accelerated in vivo gene delivery from weeks to days. Our proof-of-principle in utero screen identified the pleiotropic effects of Foxg1, highlighting its tight regulation of distinct networks essential for cell fate specification of Layer 6 corticothalamic neurons. Notably, our platform can label >6% of cerebral cells, surpassing the current state-of-the-art efficacy at <0.1% by lentivirus, to achieve analysis of over 30,000 cells in one experiment and enable massively parallel in vivo Perturb-seq. Compatible with various phenotypic measurements (single-cell or spatial multi-omics), it presents a flexible approach to interrogate gene function across cell types in vivo, translating gene variants to their causal function.

SUMOylation is enriched in the nuclear matrix and required for chromosome segregation.

As an important posttranslational modification, SUMOylation plays critical roles in almost all biological processes. Although it has been well-documented that SUMOylated proteins are mainly localized in the nucleus and have roles in chromatin-related processes, we showed recently that the SUMOylation machinery is actually enriched in the nuclear matrix rather than chromatin. Here, we provide compelling biochemical, cellular imaging and proteomic evidence that SUMOylated proteins are highly enriched in the nuclear matrix. We demonstrated that inactivation of SUMOylation by inhibiting SUMO-activating E1 enzyme or KO of SUMO-conjugating E2 enzyme UBC9 have only mild effect on nuclear matrix composition, indicating that SUMOylation is neither required for nuclear matrix formation nor for targeting proteins to nuclear matrix. Further characterization of UBC9 KO cells revealed that loss of SUMOylation did not result in significant DNA damage, but led to mitotic arrest and chromosome missegregation. Altogether, our study demonstrates that SUMOylated proteins are selectively enriched in the nuclear matrix and suggests a role of nuclear matrix in mediating SUMOylation and its regulated biological processes.

Cisplatin-based combination therapies: Their efficacy with a focus on ginsenosides co-administration.

Cisplatin, a frequently prescribed chemotherapeutic agent, serves as a clinically therapeutic strategy for a broad range of malignancies. Its primary mode of action centers around interference with DNA replication and RNA transcription, thereby inducing apoptosis in cancer cells. Nevertheless, the clinical utility of cisplatin is constrained by its severe adverse effects and the burgeoning problem of drug resistance. Ginsenosides, potent bioactive constituents derived from ginseng, possess an array of biological activities. Recent scientific investigations underscore the substantial amplification of cisplatin's anticancer potency and the mitigation of its harmful side effects when administered concomitantly with ginsenosides. This review aims to explore the underlying mechanisms at play in this combination therapy. Initially, we provide a concise introduction to the cisplatin. Then, we pivot towards illuminating how ginsenosides bolster the anticancer efficacy of cisplatin and counteract cisplatin resistance, culminating in enhanced therapeutic outcomes. Furthermore, we provide an extensive discussion on the reduction of cisplatin-induced toxicity in the kidneys, liver, gastrointestinal tract, nervous system, and ear, accompanied by immune-fortification with ginsenosides. The existing clinical combined use of cisplatin and ginsenosides is also discussed. We propose several recommendations to propel additional research into the mechanisms governing the synergistic use of ginsenosides and cisplatin, thereby furnishing invaluable insights and fostering advancement in combined modality therapy.

Investigation of the lattice thermal transport properties of Janus XClO (X = Cr, Ir) monolayers by first-principles calculations.

In the context of the global energy crisis, the development of high-performance heat transport devices within nano scales has become increasingly important. Theoretical discovery and evaluation of novel structures with high performance in thermal conductivity by affordable calculations could provide significant instructions for experimental studies focusing on thermoelectric device development. For 2-dimensional (2D) functional materials, their heat transport efficiency is correlated with their electronic properties and structural features. In this study, we computationally investigated the heat transport within Janus XClO (X = Cr, Ir); its structural and electronic properties were well solved by first-principles calculations. Furthermore, to evaluate thermodynamics stability and applicability, ab initio molecular dynamics (AIMD) simulations are conducted. Through a benchmarking study upon these XClO monolayers with different compositions, we noticed that their heat transport efficiency is associated with the percentage of doped magnetic atoms. The theoretical insights provided by this study are highly instructive for future experimental studies focusing on thermal device development.

Preparation of core-shell structure Ag@TiO2 plasma photocatalysts and reduction of Cr(VI): Size dependent and LSPR effect.

The poor light absorption and low carrier separation efficiency of Titanium dioxide (TiO2) limit its further application. The introduction of plasma metal Ag have the potential to solve these drawbacks owing to its plasma resonance effect. Thus core-shell structure Ag@TiO2 plasma photocatalysts was prepared by using facile reduction method in this work. More specifically, Ag@TiO2 composite catalysts with different Ag loading amounts were prepared in the presence of surfactant PVP. Ag@TiO2 demonstrates excellent light absorption performance and photoelectric separation efficiency compared with pure TiO2. As a result, it displays excellent performance of Cr(VI) reduction under visible light. The optimal composite catalysts Ag@TiO2-5P achieves exceptional visible-light-driven photocatalytic Cr(VI) reduction efficiency of 0.01416 min-1 that is 2.29 times greater than pure TiO2. To investigate the role of PVP, we also synthesized Ag@TiO2-5 without PVP. The experimental results show that although Ag@TiO2-5 Cr(VI) reduction performance is superior to pure TiO2, it significantly decreases compared with Ag@TiO2-5P. The results of TEM and optoelectronic testing show that agglomeration of Ag particles leads to a decrease in the photoelectric separation efficiency of Ag@TiO2-5. The smaller Ag particles provide more active sites and demonstrating a stronger overall local surface plasmon resonance (LSPR) effect. DMPO spin-trapping ESR spectra testing indicates that ∙O2- and ∙OH are the main reactive species. This research provides a potential strategy to prepare Ag-based plasma photocatalysts for environment protection.

A Chinese verb semantic feature dataset (CVFD).

Language is an advanced cognitive function of humans, and verbs play a crucial role in language. To understand how the human brain represents verbs, it is critical to analyze what knowledge humans have about verbs. Thus, several verb feature datasets have been developed in different languages such as English, Spanish, and German. However, there is still a lack of a dataset of Chinese verbs. In this study, we developed a semantic feature dataset of 1140 Chinese Mandarin verbs (CVFD) with 11 dimensions including verb familiarity, agentive subject, patient, action effector, perceptual modality, instrumentality, emotional valence, action imageability, action complexity, action intensity, and the usage scenario of action. We calculated the semantic features of each verb and the correlation between dimensions. We also compared the difference between action, mental, and other verbs and gave some examples about how to use CVFD to classify verbs according to different dimensions. Finally, we discussed the potential applications of CVFD in the fields of neuroscience, psycholinguistics, cultural differences, and artificial intelligence. All the data can be found at https://osf.io/pv29z/ .

Functional characterization and structural basis of a reversible glycosyltransferase involves in plant chemical defence.

Plants experience numerous biotic stresses throughout their lifespan, such as pathogens and pests, which can substantially affect crop production. In response, plants have evolved various metabolites that help them withstand these stresses. Here, we show that two specialized metabolites in the herbaceous perennial Belamcanda chinensis, tectorigenin and its glycoside tectoridin, have diverse defensive effects against phytopathogenic microorganisms and antifeeding effects against insect pest. We further functionally characterized a 7-O-uridine diphosphate glycosyltransferase Bc7OUGT, which catalyses a novel reversible glycosylation of tectorigenin and tectoridin. To elucidate the catalytic mechanisms of Bc7OUGT, we solved its crystal structure in complex with UDP and UDP/tectorigenin respectively. Structural analysis revealed the Bc7OUGT possesses a narrow but novel substrate-binding pocket made up by plentiful aromatic residues. Further structure-guided mutagenesis of these residues increased both glycosylation and deglycosylation activities. The catalytic reversibility of Bc7OUGT was also successfully applied in an one-pot aglycon exchange reaction. Our findings demonstrated the promising biopesticide activity of tectorigenin and its glycosides, and the characterization and mechanistic study of Bc7OUGT could facilitate the design of novel reversible UGTs to produce valuable glycosides with health benefits for both plants and humans.

Heat transport properties of novel carbon monolayer (net-Y): a comparative study with graphene.

With the rapid development of material preparation and quantum computation technologies, the discovery of superior electronic devices in the nanoscale has been widely facilitated. For materials for application in thermoelectric and thermal conductivity devices, their overall performance can be demonstrated by their inner heat transport efficiency. Thus, fundamental elucidation of the heat transport mechanism within low-dimensional materials with physical insight, is of great significance for novel electric device development. In addition, theoretical clarification can also help with the efficient control of the developed thermal devices, and furthermore, provide strategies to improve the efficiency of heat conversion. In this study, we focus on a novel carbon monolayer (net-Y) that is composed of sp2 hybridized C atoms, we systematically assess its practical applicability in electronic device design by conducting first-principles calculations. Furthermore, to obtain in-depth understanding of the factors that determine its heat transport efficiency, its mechanical and phonon spectrum related properties were also investigated. Through a comparative study with graphene, the heat transport mechanism of net-Y was successfully summarized; the methodology and theoretical findings presented in this study could provide an instructive reference for future experimental work.

HBO1 is a versatile histone acyltransferase critical for promoter histone acylations.

Recent studies demonstrate that histones are subjected to a series of short-chain fatty acid modifications that is known as histone acylations. However, the enzymes responsible for histone acylations in vivo are not well characterized. Here, we report that HBO1 is a versatile histone acyltransferase that catalyzes not only histone acetylation but also propionylation, butyrylation and crotonylation both in vivo and in vitro and does so in a JADE or BRPF family scaffold protein-dependent manner. We show that the minimal HBO1/BRPF2 complex can accommodate acetyl-CoA, propionyl-CoA, butyryl-CoA and crotonyl-CoA. Comparison of CBP and HBO1 reveals that they catalyze histone acylations at overlapping as well as distinct sites, with HBO1 being the key enzyme for H3K14 acylations. Genome-wide chromatin immunoprecipitation assay demonstrates that HBO1 is highly enriched at and contributes to bulk histone acylations on the transcriptional start sites of active transcribed genes. HBO1 promoter intensity highly correlates with the level of promoter histone acylation, but has no significant correlation with level of transcription. We also show that HBO1 is associated with a subset of DNA replication origins. Collectively our study establishes HBO1 as a versatile histone acyltransferase that links histone acylations to promoter acylations and selection of DNA replication origins.

Neural correlates underlying preference changes induced by food Go/No-Go training.

Consistently not responding to appetitive foods during food go/no-go training could change individuals' food choices and sometimes even body weight, however, fewer studies have explored the neural pathways underlying the effects of food go/no-go training. In this study, we scanned eighty-six female participants using functional magnetic resonance imaging and investigated the neural bases of preference changes in a binary food choice task following action (e.g., go) or inaction (e.g., no-go) toward distinct foods within a food go/no-go training paradigm. In line with prior behavioral work, we found that participants' food preferences changed as a function of food go/no-go training, with participants choosing more "go" over "no-go" foods for consumption following training. At a neural level, preference changes were inversely associated with frontoparietal and salience network activity when choosing go (vs. no-go) foods. Additionally, task-related functional connectivities from the inferior parietal lobule to the pre-supplementary motor cortex, dorsolateral prefrontal cortex, and dorsal anterior cingulate cortex were related to these preference changes. Together, current work supports that food go/no-go training reliably changes people's preferences. More importantly, our findings suggest that a neural pathway centered on areas traditionally associated with selective attention may interface with prefrontal regions to guide preference changes induced by food go/no-go training, though future studies using other tasks (e.g., passive viewing tasks) are still needed to test this potential neural mechanism.

Linking nuclear matrix-localized PIAS1 to chromatin SUMOylation via direct binding of histones H3 and H2A.Z.

As a conserved posttranslational modification, SUMOylation has been shown to play important roles in chromatin-related biological processes including transcription. However, how the SUMOylation machinery associates with chromatin is not clear. Here, we present evidence that multiple SUMOylation machinery components, including SUMO E1 proteins SAE1 and SAE2 and the PIAS (protein inhibitor of activated STAT) family SUMO E3 ligases, are primarily associated with the nuclear matrix rather than with chromatin. We show using nuclease digestion that all PIAS family proteins maintain nuclear matrix association in the absence of chromatin. Of importance, we identify multiple histones including H3 and H2A.Z as directly interacting with PIAS1 and demonstrate that this interaction requires the PIAS1 SAP (SAF-A/B, Acinus, and PIAS) domain. We demonstrate that PIAS1 promotes SUMOylation of histones H3 and H2B in both a SAP domain- and an E3 ligase activity-dependent manner. Furthermore, we show that PIAS1 binds to heat shock-induced genes and represses their expression and that this function also requires the SAP domain. Altogether, our study reveals for the first time the nuclear matrix as the compartment most enriched in SUMO E1 and PIAS family E3 ligases. Our finding that PIAS1 interacts directly with histone proteins also suggests a molecular mechanism as to how nuclear matrix-associated PIAS1 is able to regulate transcription and other chromatin-related processes.

An acetylation-enhanced interaction between transcription factor Sox2 and the steroid receptor coactivators facilitates Sox2 transcriptional activity and function.

SRY-box 2 (Sox2) is a transcription factor with critical roles in maintaining embryonic stem (ES) cell and adult stem cell functions and in tumorigenesis. However, how Sox2 exerts its transcriptional function remains unclear. Here, we used an in vitro protein-protein interaction assay to discover transcriptional regulators for ES cell core transcription factors (Oct4, Sox2, Klf4, and c-Myc) and identified members of the steroid receptor coactivators (SRCs) as Sox2-specific interacting proteins. The SRC family coactivators have broad roles in transcriptional regulation, but it is unknown whether they also serve as Sox2 coactivators. We demonstrated that these proteins facilitate Sox2 transcriptional activity and act synergistically with p300. Furthermore, we uncovered an acetylation-enhanced interaction between Sox2 and SRC-2/3, but not SRC-1, demonstrating it is Sox2 acetylation that promotes the interaction. We identified putative Sox2 acetylation sites required for acetylation-enhanced interaction between Sox2 and SRC-3 and demonstrated that acetylation on these sites contributes to Sox2 transcriptional activity and recruitment of SRC-3. We showed that activation domains 1 and 2 of SRC-3 both display a preferential binding to acetylated Sox2. Finally, functional analyses in mouse ES cells demonstrated that knockdown of SRC-2/3 but not SRC-1 in mouse ES cells significantly downregulates the transcriptional activities of various Sox2 target genes and impairs ES cell stemness. Taken together, we identify specific SRC family proteins as novel Sox2 coactivators and uncover the role of Sox2 acetylation in promoting coactivator recruitment and Sox2 transcriptional function.

The Hippocampal-Ventral Medial Prefrontal Cortex Neurocircuitry Involvement in the Association of Daily Life Stress With Acute Perceived Stress and Cortisol Responses.

OBJECTIVE: Daily life stressors include everyday irritants, hassles, and inconveniences, such as problems in traffic and unexpected work deadlines. A growing body of research has suggested higher daily stress is associated with blunted cortisol response to acute psychosocial stressors. However, so far, the neural mechanism underlying this association has not been elucidated. The current study aimed to examine the role of stress neurocircuitry between the hippocampus and the ventral medial prefrontal cortex in this relationship. METHODS: To this end, as an index of daily stress in 44 young healthy individuals (23 females; mean [standard deviation] age = 19.07 [1.11] years), the total stressful rating score of daily life stress events that occurred in a 24-hour period was quantified. Individuals were then administered a modified version of the Montreal Imaging Stress Task while undergoing functional magnetic resonance imaging scans, and their saliva samples were collected for assessment of the stress hormone cortisol. RESULTS: Results revealed that a higher level of daily stress was associated with lower salivary cortisol secretion (r = -0.39, p = .008) and lower activation of the left hippocampus (tpeak = -5.51) in response to the Montreal Imaging Stress Task. Furthermore, a higher level of daily stress was associated with stronger functional connectivity between the left hippocampus and the ventral medial prefrontal cortex/subgenual anterior cingulate cortex (tpeak = 4.91, R2= 0.365). CONCLUSIONS: Taken together, the current study suggested a possible neurocircuitry of the hippocampus and ventral medial prefrontal cortex in the relationship between daily life stress and acute psychosocial stress.

Hypoxia-inducible factor-dependent induction of myeloid-derived netrin-1 attenuates natural killer cell infiltration during endotoxin-induced lung injury.

Sepsis and sepsis-associated lung inflammation significantly contribute to the morbidity and mortality of critical illness. Here, we examined the hypothesis that neuronal guidance proteins could orchestrate inflammatory events during endotoxin-induced lung injury. Through a targeted array, we identified netrin-1 as the top upregulated neuronal guidance protein in macrophages treated with lipopolysaccharide (LPS). Furthermore, we found that netrin-1 is highly enriched in infiltrating myeloid cells, particularly in macrophages during LPS-induced lung injury. Transcriptional studies implicate hypoxia-inducible factor HIF-1α in the transcriptional induction of netrin-1 during LPS treatment. Subsequently, the deletion of netrin-1 in the myeloid compartment (Ntn1loxp/loxp LysM Cre) resulted in exaggerated mortality and lung inflammation. Surprisingly, further studies revealed enhanced natural killer cells (NK cells) infiltration in Ntn1loxp/loxp LysM Cre mice, and neutralization of NK cell chemoattractant chemokine (C-C motif) ligand 2 (CCL2) reversed the exaggerated lung inflammation. Together, these studies provide functional insight into myeloid cell-derived netrin-1 in controlling lung inflammation through the modulation of CCL2-dependent infiltration of NK cells.

Lower thermal conductivity of body centered cubic carbon (C14): a comparative study with diamond.

In recent years, the material preparation technology has ushered into a stage of rapid development, increasingly more carbon materials are found to display superior properties, making them suitable for designing nano-scale devices. Within the applications of electronic devices, a considerable amount of consumed energy has to be converted into heat; thus the efficiency of heat transport inside these devices can largely determine their overall performance. Decent elucidations of the heat transport mechanisms within low-dimensional materials will be helpful to achieve thermal management control of the related devices and furthermore, to improve their conversion efficiency. It is well understood that the heat transport within these kinds of materials is largely associated with their structural features. In this study, we focused on a novel material, body centered cubic carbon (C14), which is composed of sp3 hybridized carbon atoms. Such a novel material displays superior electronic properties; however, its thermal properties remain to be investigated. In order to systematically evaluate the practical applicability of this novel material, first-principles calculations were employed to systematically solve its structure; furthermore, its thermal conductivity, phonon dispersion spectrum, phonon properties, Grüneisen parameters, scattering phase space and mechanical properties were all described in detail. We found that C14 performs well in heat transport; and via systematical comparison with another allotrope, diamond, its transport mechanism was further summarized. We hope the physical insights provided by this study could serve as theoretical support for nano-scale device design.

A methylation-phosphorylation switch determines Sox2 stability and function in ESC maintenance or differentiation.

Sox2 is a key factor for maintaining embryonic stem cell (ESS) pluripotency, but little is known about its posttranslational regulation. Here we present evidence that the precise level of Sox2 proteins in ESCs is regulated by a balanced methylation and phosphorylation switch. Set7 monomethylates Sox2 at K119, which inhibits Sox2 transcriptional activity and induces Sox2 ubiquitination and degradation. The E3 ligase WWP2 specifically interacts with K119-methylated Sox2 through its HECT domain to promote Sox2 ubiquitination. In contrast, AKT1 phosphorylates Sox2 at T118 and stabilizes Sox2 by antagonizing K119me by Set7 and vice versa. In mouse ESCs, AKT1 activity toward Sox2 is greater than that of Set7, leading to Sox2 stabilization and ESC maintenance. In early development, increased Set7 expression correlates with Sox2 downregulation and appropriate differentiation. Our study highlights the importance of a Sox2 methylation-phosphorylation switch in determining ESC fate.

A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association.

LSH, a SNF2 family DNA helicase, is a key regulator of DNA methylation in mammals. How LSH facilitates DNA methylation is not well defined. While previous studies with mouse embryonic stem cells (mESc) and fibroblasts (MEFs) derived from Lsh knockout mice have revealed a role of Lsh in de novo DNA methylation by Dnmt3a/3b, here we report that LSH contributes to DNA methylation in various cell lines primarily by promoting DNA methylation by DNMT1. We show that loss of LSH has a much bigger effect in DNA methylation than loss of DNMT3A and DNMT3B. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association and UHRF1-catalyzed histone H3 ubiquitination in an ATPase activity-dependent manner, which in turn promotes DNMT1 recruitment to replication fork and DNA methylation. Notably, UHRF1 also enhances LSH association with the replication fork. Thus, our study identifies LSH as an essential factor for DNA methylation by DNMT1 and provides novel insight into how a feed-forward loop between LSH and UHRF1 facilitates DNMT1-mediated maintenance of DNA methylation in chromatin.

Neural processing of personal, relational, and collective self-worth reflected individual differences of self-esteem.

INTRODUCTION: Self-esteem stems from an individual's attributes (PSE), relationships with important others (RSE), and collective membership (CSE). Our study aimed to identify neurological indicators in the processing of personal, relational, and collective self-worth, and to investigate whether these neural indicators could reflect individual differences of self-esteem. METHODS: Fifty students underwent the evaluation of personal, relational, and collective self-worth using a self-referential paradigm while brain activities were recorded using functional-magnetic-resonance-imaging. Meanwhile, their PSE, RSE, and CSE were measured through questionnaires. RESULTS: Conjunction analysis found self-worth processing recruited the precuneus, posterior cingulate cortex, and posterior insula. Multivariate pattern analysis showed compared to relational and collective self-worth, personal self-worth processing was distinguished by cortical-midline-structures and affective-related regions, including caudate and putamen, and that these neural patterns could reflect individual differences of PSE. Compared to personal self-worth, relational self-worth was distinguished by the neural activity of temporoparietal-junction, and this neural pattern reflected individual differences of RSE. Compared to relational self-worth, collective self-worth was distinguished by neural activity of the anterior insula, and this neural pattern reflected individual differences of CSE. DISCUSSION: These results suggested the neurological indicators of self-worth can be recognized as an alternative way to reflect individual differences of self-esteem.

SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1.

Faithful inheritance of DNA methylation across cell division requires DNMT1 and its accessory factor UHRF1. However, how this axis is regulated to ensure DNA methylation homeostasis remains poorly understood. Here we show that SET8, a cell-cycle-regulated protein methyltransferase, controls protein stability of both UHRF1 and DNMT1 through methylation-mediated, ubiquitin-dependent degradation and consequently prevents excessive DNA methylation. SET8 methylates UHRF1 at lysine 385 and this modification leads to ubiquitination and degradation of UHRF1. In contrast, LSD1 stabilizes both UHRF1 and DNMT1 by demethylation. Importantly, SET8 and LSD1 oppositely regulate global DNA methylation and do so most likely through regulating the level of UHRF1 than DNMT1. Finally, we show that UHRF1 downregulation in G2/M by SET8 has a role in suppressing DNMT1-mediated methylation on post-replicated DNA. Altogether, our study reveals a novel role of SET8 in promoting DNA methylation homeostasis and identifies UHRF1 as the hub for tuning DNA methylation through dynamic protein methylation.

Collective self-esteem and perceived stress among the non-infected general public in China during the 2019 coronavirus pandemic: A multiple mediation model.

This study aimed to investigate the multiple mediating effects of perceived social support and anxiety between collective self-esteem and perceived stress during the 2019 coronavirus disease (COVID-19) pandemic. From February 18 to 25, 2020, 1921 participants aged 18-68 were recruited to complete the questionnaire online. The results showed that collective self-esteem reduced the perceived stress by increasing perceived social support and decreasing anxiety, and their chain mediation path. Our findings identified the important factors in reducing perceived stress and their relationship, which can be used to develop interventions to improve the mental health of the general public during the COVID-19 pandemic.