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Abstract Nanoindentation simulations on a binary metallic glass were performed under various strain rates by using molecular dynamics. The rate-dependent serrated plastic flow was clearly observed, and the spatiotemporal behavior of its underlying irreversible atomic rearrangement was probed. Our findings clearly validate that the serration is a temporally inhomogeneous characteristic of such rearrangements and not directly dependent on the resultant shear-banding spatiality. The unique spatiotemporal distribution of shear banding during nanoindentation is highlighted in terms of the potential energy landscape (PEL) theory.

Spermatogonial stem cells (SSCs) play crucial roles in the preservation of male fertility. However, successful ex vivo expansion of authentic human SSCs remains elusive due to the inadequate understanding of SSC homeostasis regulation. Using rhesus monkeys (Macaca mulatta) as a representative model, we characterized SSCs and progenitor subsets through single-cell RNA sequencing using a cell-specific network approach. We also profiled chromatin status and major histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K27me3 and H3K9me3), and subsequently mapped promoters and active enhancers in TSPAN33+ putative SSCs. Comparing the epigenetic changes between fresh TSPAN33+ cells and cultured TSPAN33+ cells (resembling progenitors), we identified the regulatory elements with higher activity in SSCs, and the potential transcription factors and signaling pathways implicated in SSC regulation. Specifically, TGF-β signaling is activated in monkey putative SSCs. We provided evidence supporting its role in promoting self-renewal of monkey SSCs in culture. Overall, this study outlines the epigenetic landscapes of monkey SSCs and provides clues for optimization of the culture condition for primate SSCs expansion., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Two-coordinate coinage metal complexes have been exploited for various applications. Herein, a new donor-metal-acceptor (D-M-A) complex PZI-Au-TOT, using bulky pyrazine-fused N-heterocyclic carbene (PZI) and trioxytriphenylamine (TOT) ligands, was synthesized. PZI-Au-TOT displays decent thermally activated delayed fluorescence (TADF) with a quantum yield of 93 % in doped film. The crystals of PZI-Au-TOT show simultaneous TADF, polymorphism, and linearly polarized luminescence (LPL). The polymorph-dependent emission properties with widely varied peaks from 560 to 655 nm are attributed to different packing modes in terms of isolated monomers, discrete π-π stacked dimers or dimer PLUS. Two well-defined microcrystals of PZI-Au-TOT exhibit linearly polarized thermally activated delayed fluorescence with a degree of polarization up to 0.64. This work demonstrates that the molecular rotational flexibility of D-M-A type complexes endows an integration of multiple functions into one complex through manipulation of supramolecular aggregation. This type of complexes is expected to serve as a versatile platform for the fabrication of crystal materials for advanced photonic applications., (© 2024 Wiley-VCH GmbH.)

Background: Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics., Methods: We analyzed human lung single-cell RNA sequencing dataset to discern the association of butyrophilin subfamily 3 member A2 (BTN3A2) expression with COVID-19. The BTN3A2 gene edited cell lines and transgenic mice were infected by live SARS-CoV-2 in a biosafety level 3 (BSL-3) laboratory. Immunoprecipitation, flow cytometry, biolayer interferometry and competition ELISA assays were performed in BTN3A2 gene edited cells. We performed quantitative real-time PCR, histological and/or immunohistochemical analyses for tissue samples from mice with or without SARS-CoV-2 infection., Findings: The BTN3A2 mRNA level was correlated with COVID-19 severity. BTN3A2 expression was predominantly identified in epithelial cells, elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same lung cell subtypes. BTN3A2 targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in vivo., Interpretation: These results reveal a key role of BTN3A2 in the fight against COVID-19. Identifying potential monoclonal antibodies which mimic BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19., Funding: This study was supported by the National Natural Science Foundation of China (32070569, U1902215, and 32371017), the CAS "Light of West China" Program, and Yunnan Province (202305AH340006)., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Morphine, a typical opiate, is widely used for controlling pain but can lead to various side effects with long-term use, including addiction, analgesic tolerance, and hyperalgesia. At present, however, the mechanisms underlying the development of morphine analgesic tolerance are not fully understood. This tolerance is influenced by various opioid receptor and kinase protein modifications, such as phosphorylation and ubiquitination. Here, we established a murine morphine tolerance model to investigate whether and how S-nitrosoglutathione reductase (GSNOR) is involved in morphine tolerance. Repeated administration of morphine resulted in the down-regulation of GSNOR, which increased excessive total protein S-nitrosation in the prefrontal cortex. Knockout or chemical inhibition of GSNOR promoted the development of morphine analgesic tolerance and neuron-specific overexpression of GSNOR alleviated morphine analgesic tolerance. Mechanistically, GSNOR deficiency enhanced S-nitrosation of cellular protein kinase alpha (PKCα) at the Cys78 and Cys132 sites, leading to inhibition of PKCα kinase activity, which ultimately promoted the development of morphine analgesic tolerance. Our study highlighted the significant role of GSNOR as a key regulator of PKCα S-nitrosation and its involvement in morphine analgesic tolerance, thus providing a potential therapeutic target for morphine tolerance., Competing Interests: Declaration of competing interest There were no potential conflicts of interest to be disclosed., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The tree shrew ( Tupaia belangeri ) has long been proposed as a suitable alternative to non-human primates (NHPs) in biomedical and laboratory research due to its close evolutionary relationship with primates. In recent years, significant advances have facilitated tree shrew studies, including the determination of the tree shrew genome, genetic manipulation using spermatogonial stem cells, viral vector-mediated gene delivery, and mapping of the tree shrew brain atlas. However, the limited availability of tree shrews globally remains a substantial challenge in the field. Additionally, determining the key questions best answered using tree shrews constitutes another difficulty. Tree shrew models have historically been used to study hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, myopia, and psychosocial stress-induced depression, with more recent studies focusing on developing animal models for infectious and neurodegenerative diseases. Despite these efforts, the impact of tree shrew models has not yet matched that of rodent or NHP models in biomedical research. This review summarizes the prominent advancements in tree shrew research and reflects on the key biological questions addressed using this model. We emphasize that intensive dedication and robust international collaboration are essential for achieving breakthroughs in tree shrew studies. The use of tree shrews as a unique resource is expected to gain considerable attention with the application of advanced techniques and the development of viable animal models, meeting the increasing demands of life science and biomedical research.

Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1β expression levels and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor -/- mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor -/- Nlrp3 -/- double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1β transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

Alzheimer's disease (AD) is the most common chronic progressive neurodegenerative disease in the elderly. It has an increasing prevalence and a growing health burden. One of the limitations in studying AD is the lack of animal models that show features of Alzheimer's pathogenesis. The tree shrew has a much closer genetic affinity to primates than to rodents and has great potential to be used for research into aging and AD. In this study, we aimed to investigate whether tree shrews naturally develop cognitive impairment and major AD-like pathologies with increasing age. Pole-board and novel object recognition tests were used to assess the cognitive performance of adult (about 1 year old) and aged (6 years old or older) tree shrews. The main AD-like pathologies were assessed by Western blotting, immunohistochemical staining, immunofluorescence staining, and Nissl staining. Our results showed that the aged tree shrews developed an impaired cognitive performance compared to the adult tree shrews. Moreover, the aged tree shrews exhibited several age-related phenotypes that are associated with AD, including increased levels of amyloid-β (Aβ) accumulation and phosphorylated tau protein, synaptic and neuronal loss, and reactive gliosis in the cortex and the hippocampal tissues. Our study provides further evidence that the tree shrew is a promising model for the study of aging and AD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although the primate brain contains numerous functionally distinct structures that have experienced diverse genetic changes during the course of evolution and development, these changes remain to be explored in detail. Here we utilize two classic metrics from evolutionary biology, the evolutionary rate index (ERI) and the transcriptome age index (TAI), to investigate the evolutionary alterations that have occurred in each area and developmental stage of the primate brain. We observed a higher evolutionary rate for those genes expressed in the non-cortical areas during primate evolution, particularly in human, with the highest rate of evolution being exhibited at brain developmental stages between late infancy and early childhood. Further, the transcriptome age of the non-cortical areas was lower than that of the cerebral cortex, with the youngest age apparent at brain developmental stages between late infancy and early childhood. Our exploration of the evolutionary patterns manifest in each brain area and developmental stage provides important reference points for further research into primate brain evolution., Competing Interests: Conflict of Interest The authors are unaware of any competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Tree shrews ( Tupaia belangeri chinensis ) share a close relationship to primates and have been widely used in biomedical research. We previously established a spermatogonial stem cell (SSC)-based gene editing platform to generate transgenic tree shrews. However, the influences of long-term expansion on tree shrew SSC spermatogenesis potential remain unclear. Here, we examined the in vivo spermatogenesis potential of tree shrew SSCs cultured across different passages. We found that SSCs lost spermatogenesis ability after long-term expansion (>50 passages), as indicated by the failure to colonize the seminiferous epithelium and generate donor spermatogonia (SPG)-derived spermatocytes or spermatids marking spermatogenesis. RNA sequencing (RNA-seq) analysis of undifferentiated SPGs across different passages revealed significant gene expression changes after sub-culturing primary SPG lines for more than 40 passages on feeder layers. Specifically, DNA damage response and repair genes (e.g., MRE11 , SMC3 , BLM , and GEN1 ) were down-regulated, whereas genes associated with mitochondrial function (e.g., NDUFA9 , NDUFA8 , NDUFA13 , and NDUFB8 ) were up-regulated after expansion. The DNA damage accumulation and mitochondrial dysfunction were experimentally validated in high-passage cells. Supplementation with nicotinamide adenine dinucleotide (NAD + ) precursor nicotinamide riboside (NR) exhibited beneficial effects by reducing DNA damage accumulation and mitochondrial dysfunction in SPG elicited by long-term culture. Our research presents a comprehensive analysis of the genetic and physiological attributes critical for the sustained expansion of undifferentiated SSCs in tree shrews and proposes an effective strategy for extended in vitro maintenance.

Background: Genome-wide association studies have identified dozens of genetic risk loci for Alzheimer's disease (AD), yet the underlying causal variants and biological mechanisms remain elusive, especially for loci with complex linkage disequilibrium and regulation., Methods: To fully untangle the causal signal at a single locus, we performed a functional genomic study of 11p11.2 (the CELF1/SPI1 locus). Genome-wide association study signals at 11p11.2 were integrated with datasets of histone modification, open chromatin, and transcription factor binding to distill potentially functional variants (fVars). Their allelic regulatory activities were confirmed by allele imbalance, reporter assays, and base editing. Expressional quantitative trait loci and chromatin interaction data were incorporated to assign target genes to fVars. The relevance of these genes to AD was assessed by convergent functional genomics using bulk brain and single-cell transcriptomic, epigenomic, and proteomic datasets of patients with AD and control individuals, followed by cellular assays., Results: We found that 24 potential fVars, rather than a single variant, were responsible for the risk of 11p11.2. These fVars modulated transcription factor binding and regulated multiple genes by long-range chromatin interactions. Besides SPI1, convergent evidence indicated that 6 target genes (MTCH2, ACP2, NDUFS3, PSMC3, C1QTNF4, and MADD) of fVars were likely to be involved in AD development. Disruption of each gene led to cellular amyloid-β and phosphorylated tau changes, supporting the existence of multiple likely causal genes at 11p11.2., Conclusions: Multiple variants and genes at 11p11.2 may contribute to AD risk. This finding provides new insights into the mechanistic and therapeutic challenges of AD., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, which has a high heritability of up to 79%. Exploring the genetic basis is essential for understanding the pathogenic mechanisms underlying AD development. Recent genome-wide association studies (GWASs) reported an AD-associated signal in the Cathepsin H (CTSH) gene in European populations. However, the exact functional/causal variant(s), and the genetic regulating mechanism of CTSH in AD remain to be determined. In this study, we carried out a comprehensive study to characterize the role of CTSH variants in the pathogenesis of AD. We identified rs2289702 in CTSH as the most significant functional variant that is associated with a protective effect against AD. The genetic association between rs2289702 and AD was validated in independent cohorts of the Han Chinese population. The CTSH mRNA expression level was significantly increased in AD patients and AD animal models, and the protective allele T of rs2289702 was associated with a decreased expression level of CTSH through the disruption of the binding affinity of transcription factors. Human microglia cells with CTSH knockout showed a significantly increased phagocytosis of Aβ peptides. Our study identified CTSH as being involved in AD genetic susceptibility and uncovered the genetic regulating mechanism of CTSH in pathogenesis of AD., (© 2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Although the continual expansion of the brain during primate evolution accounts for our enhanced cognitive capabilities, the drivers of brain evolution have scarcely been explored in these ancestral nodes. Here, we performed large-scale comparative genomic, transcriptomic, and epigenomic analyses to investigate the evolutionary alterations acquired by brain genes and provide comprehensive listings of innovatory genetic elements along the evolutionary path from ancestral primates to human. The regulatory sequences associated with brain-expressed genes experienced rapid change, particularly in the ancestor of the Simiiformes. Extensive comparisons of single-cell and bulk transcriptomic data between primate and nonprimate brains revealed that these regulatory sequences may drive the high expression of certain genes in primate brains. Employing in utero electroporation into mouse embryonic cortex, we show that the primate-specific brain-biased gene BMP7 was recruited, probably in the ancestor of the Simiiformes, to regulate neuronal proliferation in the primate ventricular zone. Our study provides a comprehensive listing of genes and regulatory changes along the brain evolution lineage of ancestral primates leading to human. These data should be invaluable for future functional studies that will deepen our understanding not only of the genetic basis of human brain evolution but also of inherited disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The Y chromosome usually plays a critical role in determining male sex and comprises sequence classes that have experienced unique evolutionary trajectories. Here we generated 19 new primate sex chromosome assemblies, analysed them with 10 existing assemblies and report rapid evolution of the Y chromosome across primates. The pseudoautosomal boundary has shifted at least six times during primate evolution, leading to the formation of a Simiiformes-specific evolutionary stratum and to the independent start of young strata in Catarrhini and Platyrrhini. Different primate lineages experienced different rates of gene loss and structural and chromatin change on their Y chromosomes. Selection on several Y-linked genes has contributed to the evolution of male developmental traits across the primates. Additionally, lineage-specific expansions of ampliconic regions have further increased the diversification of the structure and gene composition of the Y chromosome. Overall, our comprehensive analysis has broadened our knowledge of the evolution of the primate Y chromosome., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our study reveals that many key genomic innovations occurred in the Simiiformes ancestral node and may have had an impact on the adaptive radiation of the Simiiformes and human evolution.

The cerebellum is essential for motor control and cognitive functioning, engaging in bidirectional communication with the cerebral cortex. The common marmoset, a small non-human primate, offers unique advantages for studying cerebello-cerebral circuits. However, the marmoset cerebellum is not well described in published resources. In this study, we present a comprehensive atlas of the marmoset cerebellum comprising (1) fine-detailed anatomical atlases and surface-analysis tools of the cerebellar cortex based on ultra-high-resolution ex vivo MRI, (2) functional connectivity and gradient patterns of the cerebellar cortex revealed by awake resting-state fMRI, and (3) structural-connectivity mapping of cerebellar nuclei using high-resolution diffusion MRI tractography. The atlas elucidates the anatomical details of the marmoset cerebellum, reveals distinct gradient patterns of intra-cerebellar and cerebello-cerebral functional connectivity, and maps the topological relationship of cerebellar nuclei in cerebello-cerebral circuits. As version 5 of the Marmoset Brain Mapping project, this atlas is publicly available at https://marmosetbrainmapping.org/MBMv5.html., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The acid-base properties of supports have an enormous impact on catalytic reactions to regulate the selectivity and activity of supported catalysts. Herein, a train of Pd-X-UiO-66 (X = NO 2 , NH 2 , and CH 3 ) catalysts with different acidity/alkalinity functional groups and encapsulated Pd(II) species is first developed, whose activities in dimethyl carbonate (DMC) catalysis are then investigated in details. Thereinto, the Pd-NO 2 -UiO-66 catalyst with acidity functionalization exhibits the best catalytic behavior: the DMC selectivity stemmed from methyl nitrite (MN) is up to 68%, the conversion of CO is 73.4%. The obtained experimental results demonstrate that the NO 2 group not only affected the interaction between X-UiO-66 and Pd(II) active sites but also play an indispensable role in the adsorption and activation of MN and CO, which remarkably promote the formation of the COOCH 3 * intermediate and DMC product., (© 2023 Wiley-VCH GmbH.)

Bi 4 Br 4 is a quasi-one-dimensional van der Waals topological insulator with novel electronic properties. Several efforts have been devoted to the understanding of its bulk form, yet it remains a challenge to explore the transport properties in low-dimensional structures due to the difficulty of device fabrication. Here we report for the first time a gate-tunable transport in exfoliated Bi 4 Br 4 nanobelts. Notable two-frequency Shubnikov-de Haas oscillations oscillations are discovered at low temperatures, with the low- and high-frequency parts coming from the three-dimensional bulk state and the two-dimensional surface state, respectively. In addition, ambipolar field effect is realized with a longitudinal resistance peak and a sign reverse in the Hall coefficient. Our successful measurements of quantum oscillations and realization of gate-tunable transport lay a foundation for further investigation of novel topological properties and room-temperature quantum spin Hall states in Bi 4 Br 4 ., (© 2023 IOP Publishing Ltd.)

Ethylene glycol (EG), a useful chemical raw material, has been widely applied in many aspects of modern society. The conventional preparation of ethylene glycol mainly uses the petroleum route at high temperatures and pressure. More and more approaches have been developed to synthesize EG from CO 2 and its derivatives under mild conditions. In this review, the ambient synthesis of EG from thermocatalysis, photocatalysis, and electrocatalysis is highlighted. The coal-to-ethylene glycol technology, one of the typical thermal catalysis routes for EG preparation, is relatively mature. However, it still faces some problems to be solved in industrialization. The recent progress in the development of coal-to-ethylene glycol technology is introduced. The main focus is on how to realize the preparation of EG under mild conditions. The strategies include doping promoters, modification of supports, design of catalysts with special structures, etc. Furthermore, the emerging technological progress of photocatalytic and electrocatalytic ethylene glycol synthesis under ambient conditions is introduced. Compared with the thermal catalytic reaction, the reaction conditions are milder. However, there are still many problems in large-scale production. Finally, we propose future development issues and related prospects for the ambient synthesis of EG using different catalytic routes.

Primate-specific genes (PSGs) tend to be expressed in the brain and testis. This phenomenon is consistent with brain evolution in primates but is seemingly contradictory to the similarity of spermatogenesis among mammals. Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia. SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates. As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes. Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology. Further, RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis. Collectively, our experimental observations in humans and cynomolgus monkey and tree shrew models highlight the crucial role of SSX1 in spermatogenesis. Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy. This study provides important guidance for genetic counseling and clinical diagnosis and, significantly, describes the approaches for elucidating the functions of testis-enriched PSGs in spermatogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most common neurodegenerative disease with high heritability. Growth factors (GFs) might contribute to the development of AD due to their broad effects on neuronal system. We herein aimed to investigate the role of rare and common variants of GFs in genetic susceptibility of AD. We screened 23 GFs in 6324 individuals using targeted sequencing. A rare-variant-based burden test and common-variant-based single-site association analyses were performed to identify AD-associated GF genes and variants. The burden test showed an enrichment of rare missense variants (p = 6.08 × 10 -4 ) in GF gene-set in AD patients. Among the GFs, EGF showed the strongest signal of enrichment, especially for loss-of-function variants (p = 0.0019). A common variant rs4698800 of EGF showed significant associations with AD risk (p = 3.24 × 10 -5 , OR = 1.26). The risk allele of rs4698800 was associated with an increased EGF expression, whereas EGF was indeed upregulated in AD brain. These findings suggested EGF as a novel risk gene for AD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Ganoapplins A and B (1 and 2) with a 6/6/6/5/6-fused pentacyclic skeleton containing an aromatic E ring, were obtained from Ganoderma applanatum. Their structures were established through extensive spectroscopic analyses, quantum chemical calculations, including calculated chemical shifts with DP4 + analysis and electronic circular dichroism (ECD). A plausible biosynthetic pathway for 1 and 2 was proposed. Furthermore, their roles in activating autophagy were investigated and the cellular assays showed that 1 and 2 can inhibit tau pathology by inducing autophagy, suggesting their potential against Alzheimer's disease (AD)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A new ent -abietane diterpenoid, named Euphejolkinolide A ( 1 ), was isolated from the whole plant of Euphorbia peplus L. Its structure, including absolute configurations, was determined by spectroscopic analyses and was corroborated by single-crystal X-ray diffraction analysis. This new compound was assessed for its activity to induce lysosome biogenesis through Lyso-Tracker Red staining, in which compound 1 could significantly induce lysosome biogenesis. In addition, quantitative real-time PCR (qRT-PCR) analysis demonstrated a direct correlation between the observed lysosome biogenesis and the transcriptional activation of the lysosomal genes after treatment with the compound 1 . Moreover, compound 1 promoted autophagic flux by upregulating LC3-II and downregulating SQSTM1 in both human microglia cells and U251 cells, which is required for cellular homeostasis. Further results suggested 1 induced lysosome biogenesis and autophagy which was mediated by TFEB (transcription factor EB). The structure activity relationships (SAR) analysis suggested that the carbony1 at C-7 in 1 might be a key active group. Overall, the current data suggested that 1 could be a potential compound for lysosome disorder therapy by induction of autophagy., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Background: Neuroinflammatory factors, especially chemokines, have been widely reported to be involved in the pathogenesis of Alzheimer's disease (AD). It is unclear how chemokines are altered in AD, and whether dysregulation of chemokines is the cause, or the consequence, of the disease., Methods: We initially screened the transcriptomic profiles of chemokines from publicly available datasets of brain tissues of AD patients and mouse models. Expression alteration of chemokines in the blood from AD patients was also measured to explore whether any chemokine might be used as a potential biomarker for AD. We further analyzed the association between the coding variants of chemokine genes and genetic susceptibility of AD by targeted sequencing of a Han Chinese case-control cohort. Mendelian randomization (MR) was performed to infer the causal association of chemokine dysregulation with AD development., Results: Three chemokine genes (CCL5, CXCL1, and CXCL16) were consistently upregulated in brain tissues from AD patients and the mouse models and were positively correlated with Aβ and tau pathology in AD mice. Peripheral blood mRNA expression of CXCL16 was upregulated in mild cognitive impairment (MCI) and AD patients, indicating the potential of CXCL16 as a biomarker for AD development. None of the coding variants within any chemokine gene conferred a genetic risk to AD. MR analysis confirmed a causal role of CCL5 dysregulation in AD mediated by trans-regulatory variants., Conclusions: In summary, we have provided transcriptomic and genomic evidence supporting an active role of dysregulated CXCL16 and CCL5 during AD development., (© 2023. The Author(s).)

Munronin V (1), isolated from Munronia henryi Harms, is the first example, to the best of our knowledge, of an unprecedented 7/7/6 tricarbocyclic framework featuring an unusual A,B- seco -limonoid ring. The structures of munronin V were established from extensive spectroscopic and electronic circular dichroism (ECD) analyses. The novel A,B- seco with two seven-membered lactones was formed as a result of Baeyer-Villiger oxidation. Compound 1 activated autophagy and inhibited Tau pathology as revealed by flow cytometric analyses, confocal imaging analysis and western blotting, and this effect was mediated by transcription factor EB (TFEB). These findings suggested that 1 might have potential as a compound for combating Alzheimer's disease.

Eleven monoterpenoid indole alkaloids, including three new ones, tabercrassines A-C ( 1 - 3 ), were isolated from the seeds of Tabernaemontana crassa . Tabercrassine A ( 1 ) is an ibogan-ibogan-type bisindole alkaloid which is formed by the polymerization of two classic ibogan-type monomers through a C3 unit aliphatic chain. Their structures were established by extensive analysis of HRESIMS, NMR, and ECD spectra. Cellular assays showed that alkaloids 1 - 3 all reduce A β 42 production and inhibit phospho-tau (Thr217), a new biomarker of Alzheimer's disease [AD] associated with BACE1-, NCSTN-, GSK3β-, and CDK5-mediated pathways, suggesting these alkaloids' potential against AD.

The continuously arising of SARS-CoV-2 variants has been posting a great threat to public health safety globally, from B.1.17 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta) to B.1.1.529 (Omicron). The emerging or re-emerging of the SARS-CoV-2 variants of concern is calling for the constant monitoring of their epidemics, pathogenicity and immune escape. In this study, we aimed to characterize replication and pathogenicity of the Alpha and Delta variant strains isolated from patients infected in Laos. The amino acid mutations within the spike fragment of the isolates were determined via sequencing. The more efficient replication of the Alpha and Delta isolates was documented than the prototyped SARS-CoV-2 in Calu-3 and Caco-2 ​cells, while such features were not observed in Huh-7, Vero E6 and HPA-3 ​cells. We utilized both animal models of human ACE2 (hACE2) transgenic mice and hamsters to evaluate the pathogenesis of the isolates. The Alpha and Delta can replicate well in multiple organs and cause moderate to severe lung pathology in these animals. In conclusion, the spike protein of the isolated Alpha and Delta variant strains was characterized, and the replication and pathogenicity of the strains in the cells and animal models were also evaluated., (Copyright © 2022 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes diverse clinical manifestations and tissue injuries in multiple organs. However, cellular and molecular understanding of SARS-CoV-2 infection-associated pathology and immune defense features in different organs remains incomplete. Here, we profiled approximately 77 000 single-nucleus transcriptomes of the lung, liver, kidney, and cerebral cortex in rhesus macaques ( Macaca mulatta ) infected with SARS-CoV-2 and healthy controls. Integrated analysis of the multi-organ dataset suggested that the liver harbored the strongest global transcriptional alterations. We observed prominent impairment in lung epithelial cells, especially in AT2 and ciliated cells, and evident signs of fibrosis in fibroblasts. These lung injury characteristics are similar to those reported in patients with coronavirus disease 2019 (COVID-19). Furthermore, we found suppressed MHC class I/II molecular activity in the lung, inflammatory response in the liver, and activation of the kynurenine pathway, which induced the development of an immunosuppressive microenvironment. Analysis of the kidney dataset highlighted tropism of tubule cells to SARS-CoV-2, and we found membranous nephropathy (an autoimmune disease) caused by podocyte dysregulation. In addition, we identified the pathological states of astrocytes and oligodendrocytes in the cerebral cortex, providing molecular insights into COVID-19-related neurological implications. Overall, our multi-organ single-nucleus transcriptomic survey of SARS-CoV-2-infected rhesus macaques broadens our understanding of disease features and antiviral immune defects caused by SARS-CoV-2 infection, which may facilitate the development of therapeutic interventions for COVID-19.

Three undescribed monoterpenoid indole alkaloid dimers (kopoffines A-C, which are connected via a methylene unit) and with nine known alkaloids were isolated and identified from the fruits of Kopsia arborea Blume. Their structures, including their absolute configurations, were established by HRESIMS, NMR, single-crystal X-ray diffraction, and ECD analyses. Kopoffines A-C showed significant inhibition against cyclin-dependent kinase 5 (IC 50 : 0.34-2.18 μM). Western blotting analyses showed that kopoffines A-C significantly decreased the protein levels of CDK5 and phospho-CDK5 (Tyr15) (pCDK5) at concentrations of 2.5 and 10 μM. The levels of phospho-Tau (Thr217) (pTau217, a new biomarker of AD), and phospho-Tau (Ser396) (pTau396), which play major roles in the formation of neurofibrillary tangles , were decreased by the kopoffines A-C treatment. Molecular docking studies indicated that kopoffines A-C could form stable interactions with CDK5., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Increasing severe morbidity and mortality by simultaneous or sequential infections with SARS-CoV-2 and influenza A viruses (IAV), especially in the elderly and obese patients, highlight the urgency of developing a combination vaccine against COVID-19 and influenza., Methods: Self-assembling SARS-CoV-2 RBD-trimer and Influenza H1N1 HA1-trimer antigens were constructed, upon the stable fusion core in post-fusion conformation. Immunogenicity of SARS-CoV-2 RBD-trimer vaccine and H1N1 HA1-trimer antigens candidates were evaluated in mice. Protection efficacy of a combination vaccine candidate against SARS-CoV-2 and IAV challenge was identified using the K18-hACE2 mouse model., Findings: Both the resultant RBD-trimer for SARS-CoV-2 and HA1-trimer for H1N1 influenza fully exposed receptor-binding motifs (RBM) or receptor-binding site (RBS). Two-dose RBD-trimer induced significantly higher binding and neutralizing antibody titers, and also a strong Th1/Th2 balanced cellular immune response in mice. Similarly, the HA1-trimer vaccine was confirmed to exhibit potent immunogenicity in mice. A combination vaccine candidate, composed of RBD-trimer and HA1-trimer, afforded high protection efficacy in mouse models against stringent lethal SARS-CoV-2 and homogenous H1N1 influenza co-infection, characterized by 100% survival rate., Interpretation: Our results represent a proof of concept for a combined vaccine candidate based on trimerized receptor binding domain against co-epidemics of COVID-19 and influenza., Funding: This project was funded by the Strategic Priority Research Program of CAS (XDB29040201), the National Natural Science Foundation of China (81830050, 81901680, and 32070569) and China Postdoctoral Science Foundation (2021M703450)., Competing Interests: Declaration of interests R. Shi, Q. Huang, and J. Yan are listed as inventors on pending patent applications for RBD-trimer and HA1-trimer. The other authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Pathogenic mitochondrial DNA (mtDNA) mutations can cause a variety of human diseases. The recent development of genome-editing technologies to manipulate mtDNA, such as mitochondria-targeted DNA nucleases and base editors, offer a promising way for curing mitochondrial diseases caused by mtDNA mutations. The CRISPR-Cas9 system is a widely used tool for genome editing; however, its application in mtDNA editing is still under debate. In this study, we developed a mito-Cas9 system by adding the mitochondria-targeted sequences and 3' untranslated region of nuclear-encoded mitochondrial genes upstream and downstream of the Cas9 gene, respectively. We confirmed that the mito-Cas9 system was transported into mitochondria and enabled knockin of exogenous single-stranded DNA oligonucleotides (ssODNs) into mtDNA based on proteinase and DNase protection assays. Successful knockin of exogenous ssODNs into mtDNA was further validated using polymerase chain reaction-free third-generation sequencing technology. We also demonstrated that RS-1, an agonist of RAD51, significantly increased knockin efficiency of the mito-Cas9 system. Collectively, we provide direct evidence that mtDNA can be edited using the CRISPR-Cas9 system. The mito-Cas9 system could be optimized as a promising approach for the treatment of mitochondrial diseases caused by pathogenic mtDNA mutations, especially those with homoplasmic mtDNA mutations., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

The diversity of Central Asians has been shaped by multiple migrations and cultural diffusion. Although ancient DNA studies have revealed the demographic changes of the Central Asian since the Bronze Age, the contribution of the ancient populations to the modern Central Asian remains opaque. Herein, we performed high-coverage sequencing of 131 whole genomes of Indo-European-speaking Tajik and Turkic-speaking Kyrgyz populations to explore their genomic diversity and admixture history. By integrating the ancient DNA data, we revealed more details of the origins and admixture history of Central Asians. We found that the major ancestry of present-day Tajik populations can be traced back to the admixture of the Bronze Age Bactria-Margiana Archaeological Complex and Andronovo-related populations. Highland Tajik populations further received additional gene flow from the Tarim mummies, an isolated ancient North Eurasian-related population. The West Eurasian ancestry of Kyrgyz is mainly derived from Historical Era populations in Xinjiang of China. Furthermore, the recent admixture signals detected in both Tajik and Kyrgyz are ascribed to the expansions of Eastern Steppe nomadic pastoralists during the Historical Era., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

The S-nitrosoglutathione reductase (GSNOR) is a key denitrosating enzyme that regulates protein S-nitrosation, a process which has been found to be involved in the pathogenesis of Parkinson's disease (PD). However, the physiological function of GSNOR in PD remains unknown. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we found that GSNOR expression was significantly increased and accompanied by autophagy mediated by MPTP-induced cyclin dependent kinase 5 (CDK5), behavioral dyskinesias and dopaminergic neuron loss. Whereas, knockout of GSNOR, or treatment with the GSNOR inhibitor N6022, alleviated MPTP-induced PD-like pathology and neurotoxicity. Mechanistically, deficiency of GSNOR inhibited MPTP-induced CDK5 kinase activity and CDK5-mediated autophagy by increasing S-nitrosation of CDK5 at Cys83. Our study indicated that GSNOR is a key regulator of CDK5 S-nitrosation and is actively involved in CDK5-mediated autophagy induced by MPTP., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Chinese tree shrew ( Tupaia belangeri chinensis ) has the potential to replace the use of non-human primates in biomedical research. To increase the availability of this species, we have undertaken the ambitious task of establishing inbred lines of the Chinese tree shrew; however, we have been hindered by a low survival rate of inbred pups. Here, we report our artificial rearing (AR) of Chinese tree shrew pups using four different milk substitutes: the formula described by Tsang and Collins (milk TC) and three commercially available milk substitutes intended for possums (milk A and milk C) and for guinea pigs (milk B). We compared the effects of these milk substitutes and maternal milk on the daily milk consumption, growth performance, and survival of the pups. We also assessed the life span and reproductive performance of the F 1 individuals given the best milk substitute as compared to the maternally reared (MR) pups. Milk B was found to be appropriate for AR. Pups fed with milk B had a high survival rate at the weaning age compared to those fed with the other milk substitutes. The AR pups fed with milk B had a life span similar to that of MR pups. AR females fed with milk B had an earlier age of the first reproduction, a larger number of litters, and a higher rate of survival of the offspring at the weaning age compared with the MR females. The successful optimization of a milk substitute for AR of Chinese tree shrew pups will undoubtedly facilitate the wide usage of this experimental animal.

Bulk chemicals such as ethylene glycol (EG) can be industrially synthesized from either ethylene or syngas, but the latter undergoes a bottleneck reaction and requires high hydrogen pressures. We show that fullerene (exemplified by C 60 ) can act as an electron buffer for a copper-silica catalyst (Cu/SiO 2 ). Hydrogenation of dimethyl oxalate over a C 60 -Cu/SiO 2 catalyst at ambient pressure and temperatures of 180° to 190°C had an EG yield of up to 98 ± 1%. In a kilogram-scale reaction, no deactivation of the catalyst was seen after 1000 hours. This mild route for the final step toward EG can be combined with the already-industrialized ambient reaction from syngas to the intermediate of dimethyl oxalate.

Background: Genome-wide association studies (GWASs) have identified multiple risk loci for Parkinson's disease (PD). However, identifying the functional (or potential causal) variants in the reported risk loci and elucidating their roles in PD pathogenesis remain major challenges. To identify the potential causal (or functional) variants in the reported PD risk loci and to elucidate their regulatory mechanisms, we report a functional genomics study of PD., Methods: We first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) (from neuronal cells and human brain tissues) data and GWAS-identified single-nucleotide polymorphisms (SNPs) in PD risk loci. We then conducted a series of experiments and analyses to validate the regulatory effects of these (i.e., functional) SNPs, including reporter gene assays, allele-specific expression (ASE), transcription factor (TF) knockdown, CRISPR-Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis., Results: We identified 44 SNPs (from 11 risk loci) affecting the binding of 12 TFs and we validated the regulatory effects of 15 TF binding-disrupting SNPs. In addition, we also identified the potential target genes regulated by these TF binding-disrupting SNPs through eQTL analysis. Finally, we showed that 4 eQTL genes of these TF binding-disrupting SNPs were dysregulated in PD cases compared with controls., Conclusion: Our study systematically reveals the gene regulatory mechanisms of PD risk variants (including widespread disruption of CTCF binding), generates the landscape of potential PD causal variants, and pinpoints promising candidate genes for further functional characterization and drug development., (© 2022. The Author(s).)