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Lymphocytes spanning the entire innate-adaptive spectrum can stably reside in tissues and constitute an integral component of the local defense network against immunological challenges. In tight interactions with the epithelium and endothelium, tissue-resident lymphocytes sense antigens and alarmins elicited by infectious microbes and abiotic stresses at barrier sites and mount effector responses to restore tissue homeostasis. Of note, such a host cell-directed immune defense system has been recently demonstrated to surveil epithelial cell transformation and carcinoma development, as well as cancer cell metastasis at selected distant organs, and thus represents a primordial cancer immune defense module. Here we review how distinct lineages of tissue-resident innate lymphoid cells, innate-like T cells, and adaptive T cells participate in a form of multilayered cancer immunity in murine models and patients, and how their convergent effector programs may be targeted through both shared and private regulatory pathways for cancer immunotherapy.
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Inmunidad Innata , Neoplasias , Humanos , Animales , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos/inmunología , Linfocitos/metabolismo , Microambiente Tumoral/inmunología , Inmunidad Adaptativa , Inmunoterapia/métodosRESUMEN
Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.
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Canales Iónicos Sensibles al Ácido , Isquemia Encefálica , Ácido Glutámico , Animales , Femenino , Humanos , Masculino , Ratones , 2-Amino-5-fosfonovalerato/efectos adversos , 2-Amino-5-fosfonovalerato/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Canales Iónicos Sensibles al Ácido/química , Canales Iónicos Sensibles al Ácido/deficiencia , Canales Iónicos Sensibles al Ácido/efectos de los fármacos , Canales Iónicos Sensibles al Ácido/genética , Canales Iónicos Sensibles al Ácido/metabolismo , Regulación Alostérica/efectos de los fármacos , Sitios de Unión/genética , Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ácido Glutámico/análogos & derivados , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Ácido Glutámico/toxicidad , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Protones , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
The genomes of living lungfishes can inform on the molecular-developmental basis of the Devonian sarcopterygian fish-tetrapod transition. We de novo sequenced the genomes of the African (Protopterus annectens) and South American lungfishes (Lepidosiren paradoxa). The Lepidosiren genome (about 91 Gb, roughly 30 times the human genome) is the largest animal genome sequenced so far and more than twice the size of the Australian (Neoceratodus forsteri)1 and African2 lungfishes owing to enlarged intergenic regions and introns with high repeat content (about 90%). All lungfish genomes continue to expand as some transposable elements (TEs) are still active today. In particular, Lepidosiren's genome grew extremely fast during the past 100 million years (Myr), adding the equivalent of one human genome every 10 Myr. This massive genome expansion seems to be related to a reduction of PIWI-interacting RNAs and C2H2 zinc-finger and Krüppel-associated box (KRAB)-domain protein genes that suppress TE expansions. Although TE abundance facilitates chromosomal rearrangements, lungfish chromosomes still conservatively reflect the ur-tetrapod karyotype. Neoceratodus' limb-like fins still resemble those of their extinct relatives and remained phenotypically static for about 100 Myr. We show that the secondary loss of limb-like appendages in the Lepidosiren-Protopterus ancestor was probably due to loss of sonic hedgehog limb-specific enhancers.
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Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Cilios , Cinesinas , Neuroglía , Animales , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Cinesinas/metabolismo , Cinesinas/genética , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Neuroglía/metabolismo , Cilios/metabolismo , Neuronas/metabolismo , Mutación , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patologíaRESUMEN
Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.
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Inmunidad Innata , Neoplasias , Humanos , Animales , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Células Asesinas Naturales/inmunología , Vigilancia Inmunológica , Microambiente Tumoral/inmunología , Ratones , Linfocitos/inmunología , Activación de Linfocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
The significance of biochemical cues in the tumor immune microenvironment in affecting cancer metastasis is well established, but the role of physical factors in the microenvironment remains largely unexplored. In this article, we investigated how the mechanical interaction between cancer cells and immune cells, mediated by extracellular matrix (ECM), influences immune escape of cancer cells. We focus on the mechanical regulation of macrophages' targeting ability on two distinct types of colorectal carcinoma (CRC) cells with different metastatic potentials. Our results show that macrophages can effectively target CRC cells with low metastatic potential, due to the strong contraction exhibited by the cancer cells on the ECM, and that cancer cells with high metastatic potential demonstrated weakened contractions on the ECM and can thus evade macrophage attack to achieve immune escape. Our findings regarding the intricate mechanical interactions between immune cells and cancer cells can serve as a crucial reference for further exploration of cancer immunotherapy strategies.
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Neoplasias Colorrectales , Matriz Extracelular , Macrófagos , Escape del Tumor , Microambiente Tumoral , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Macrófagos/inmunología , Humanos , Microambiente Tumoral/inmunología , Matriz Extracelular/metabolismo , Matriz Extracelular/inmunología , Línea Celular Tumoral , Metástasis de la Neoplasia , Animales , Ratones , Comunicación Celular/inmunologíaRESUMEN
Aging in an individual refers to the temporal change, mostly decline, in the body's ability to meet physiological demands. Biological age (BA) is a biomarker of chronological aging and can be used to stratify populations to predict certain age-related chronic diseases. BA can be predicted from biomedical features such as brain MRI, retinal, or facial images, but the inherent heterogeneity in the aging process limits the usefulness of BA predicted from individual body systems. In this paper, we developed a multimodal Transformer-based architecture with cross-attention which was able to combine facial, tongue, and retinal images to estimate BA. We trained our model using facial, tongue, and retinal images from 11,223 healthy subjects and demonstrated that using a fusion of the three image modalities achieved the most accurate BA predictions. We validated our approach on a test population of 2,840 individuals with six chronic diseases and obtained significant difference between chronological age and BA (AgeDiff) than that of healthy subjects. We showed that AgeDiff has the potential to be utilized as a standalone biomarker or conjunctively alongside other known factors for risk stratification and progression prediction of chronic diseases. Our results therefore highlight the feasibility of using multimodal images to estimate and interrogate the aging process.
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Envejecimiento , Suministros de Energía Eléctrica , Humanos , Cara , Biomarcadores , Enfermedad CrónicaRESUMEN
Prokaryotic clustered regularly interspaced short palindromic repeat (CRISPR)-Cas systems are highly vulnerable to phage-encoded anti-CRISPR (Acr) factors. How CRISPR-Cas systems protect themselves remains unclear. Here we uncovered a broad-spectrum anti-anti-CRISPR strategy involving a phage-derived toxic protein. Transcription of this toxin is normally repressed by the CRISPR-Cas effector but is activated to halt cell division when the effector is inhibited by any anti-CRISPR proteins or RNAs. We showed that this abortive infection-like effect efficiently expels Acr elements from bacterial population. Furthermore, we exploited this anti-anti-CRISPR mechanism to develop a screening method for specific Acr candidates for a CRISPR-Cas system and successfully identified two distinct Acr proteins that enhance the binding of CRISPR effector to nontarget DNA. Our data highlight the broad-spectrum role of CRISPR-repressed toxins in counteracting various types of Acr factors. We propose that the regulatory function of CRISPR-Cas confers host cells herd immunity against Acr-encoding genetic invaders whether they are CRISPR targeted or not.
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CpG islands near promoters are normally unmethylated despite being surrounded by densely methylated regions. Aberrant hypermethylation of these CpG islands has been associated with the development of various human diseases. Although local genetic elements have been speculated to play a role in protecting promoters from methylation, only a limited number of methylation barriers have been identified. In this study, we conducted an integrated computational and experimental investigation of colorectal cancer methylomes. Our study revealed 610 genes with disrupted methylation barriers. Genomic sequences of these barriers shared a common 41-bp sequence motif (MB-41) that displayed homology to the chicken HS4 methylation barrier. Using the CDKN2A (P16) tumor suppressor gene promoter, we validated the protective function of MB-41 and showed that loss of such protection led to aberrant hypermethylation. Our findings highlight a novel sequence signature of cis-acting methylation barriers in the human genome that safeguard promoters from silencing.
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Neoplasias Colorrectales , Metilación de ADN , Regiones Promotoras Genéticas , Animales , Humanos , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Islas de CpG , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Genoma Humano , Motivos de Nucleótidos , Pollos , Estudio de Asociación del Genoma CompletoRESUMEN
While functional brain imaging studies in humans suggest that chronic cocaine use alters functional connectivity (FC) within and between key large-scale brain networks, including the default mode network (DMN), the salience network (SN), and the central executive network (CEN), cross-sectional studies in humans are challenging to obtain brain FC prior to cocaine use. Such information is critical to reveal the relationship between individual's brain FC and the subsequent development of cocaine dependence and brain changes during abstinence. Here, we performed a longitudinal study examining functional magnetic resonance imaging (fMRI) data in male rats (n = 7), acquired before cocaine self-administration (baseline), on 1â d of abstinence following 10â d of cocaine self-administration, and again after 30â d of experimenter-imposed abstinence. Using repeated-measures analysis of variance (ANOVA) with network-based statistics (NBS), significant connectivity changes were found between anterior insular cortex (AI) of the SN, retrosplenial cortex (RSC) of the DMN, somatosensory cortex, and caudate-putamen (CPu), with AI-RSC FC showing the most robust changes between baseline and 1â d of abstinence. Additionally, the level of escalated cocaine intake is associated with AI-RSC and AI-CPu FC changes between 1â d and 30â d of abstinence; further, the subjects' AI-RSC FC prior to cocaine intake is a significant moderator for the AI-RSC changes during abstinence. These results provide novel insights into the roles of AI-RSC FC before and after cocaine intake and suggest this circuit to be a potential target to modulate large-scale network and associated behavioral changes in cocaine use disorders.
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Trastornos Relacionados con Cocaína , Cocaína , Humanos , Masculino , Animales , Ratas , Giro del Cíngulo , Mapeo Encefálico/métodos , Corteza Insular , Estudios Longitudinales , Estudios Transversales , Encéfalo , Imagen por Resonancia Magnética/métodos , Corteza Cerebral/diagnóstico por imagen , Red NerviosaRESUMEN
Genome-wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual-level genotype data, many existing gene-based association tests have been adapted to require only GWAS summary statistics rather than individual-level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene-based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginal Z scores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.
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Caries Dental , Estudio de Asociación del Genoma Completo , Humanos , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Modelos Genéticos , FenotipoRESUMEN
The Hippo-YAP signaling pathway plays a central role in many biological processes such as regulating cell fate, organ size, and tissue growth, and its key components are spatiotemporally expressed and posttranslationally modified during these processes. Neddylation is a posttranslational modification that involves the covalent attachment of NEDD8 to target proteins by NEDD8-specific E1-E2-E3 enzymes. Whether neddylation is involved in Hippo-YAP signaling remains poorly understood. Here, we provide evidence supporting the critical role of NEDD8 in facilitating the Hippo-YAP signaling pathway by mediating neddylation of the transcriptional coactivator yes-associated protein 1 (YAP1). Overexpression of NEDD8 induces YAP1 neddylation and enhances YAP1 transactivity, but inhibition of neddylation suppresses YAP1 transactivity and attenuates YAP1 nuclear accumulation. Furthermore, inhibition of YAP1 signaling promotes MLN4924-induced ovarian granulosa cells apoptosis and disruption of nedd8 in zebrafish results in downregulation of yap1-activated genes and upregulation of yap1-repressed genes. Further assays show that the xiap ligase promotes nedd8 conjugates to yap1 and that yap1 neddylation. In addition, we identify lysine 159 as a major neddylation site on YAP1. These findings reveal a novel mechanism for neddylation in the regulation of Hippo-YAP signaling.
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The advancement of single-cell sequencing technology has smoothed the ability to do biological studies at the cellular level. Nevertheless, single-cell RNA sequencing (scRNA-seq) data presents several obstacles due to the considerable heterogeneity, sparsity and complexity. Although many machine-learning models have been devised to tackle these difficulties, there is still a need to enhance their efficiency and accuracy. Current deep learning methods often fail to fully exploit the intrinsic interconnections within cells, resulting in unsatisfactory results. Given these obstacles, we propose a unique approach for analyzing scRNA-seq data called scMPN. This methodology integrates multi-layer perceptron and graph neural network, including attention network, to execute gene imputation and cell clustering tasks. In order to evaluate the gene imputation performance of scMPN, several metrics like cosine similarity, median L1 distance and root mean square error are used. These metrics are utilized to compare the efficacy of scMPN with other existing approaches. This research utilizes criteria such as adjusted mutual information, normalized mutual information and integrity score to assess the efficacy of cell clustering across different approaches. The superiority of scMPN over current single-cell data processing techniques in cell clustering and gene imputation investigations is shown by the experimental findings obtained from four datasets with gold-standard cell labels. This observation demonstrates the efficacy of our suggested methodology in using deep learning methodologies to enhance the interpretation of scRNA-seq data.
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Benchmarking , Análisis de Expresión Génica de una Sola Célula , Análisis por Conglomerados , Análisis de Datos , Redes Neurales de la Computación , Análisis de Secuencia de ARN , Perfilación de la Expresión GénicaRESUMEN
ConspectusAfter decades of palladium dominating the realm of transition-metal-catalyzed cross-coupling, recent years have witnessed exciting advances in the development of new nickel-catalyzed cross-coupling reactions to form C(sp3) centers. Nickel possesses distinct properties compared with palladium, such as facile single-electron transfer to C(sp3) electrophiles and rapid C-C reductive elimination from NiIII. These properties, among others, make nickel particularly well-suited for reductive cross-coupling (RCC) in which two electrophiles are coupled and an exogenous reductant is used to turn over the metal catalyst. Ni-catalyzed RCCs use readily available and stable electrophiles as starting materials and exhibit good functional group tolerance, which makes them appealing for applications in the synthesis of complex molecules. Building upon the foundational work in Ni-catalyzed RCCs by the groups of Kumada, Durandetti, Weix, and others, as well as the advancements in Ni-catalyzed enantioselective redox-neutral cross-couplings led by Fu and co-workers, we initiated a program to explore the feasibility of developing highly enantioselective Ni-catalyzed RCCs. Our research has also been driven by a keen interest in unraveling the factors contributing to enantioinduction and electrophile activation as we seek new avenues for advancing our understanding and further developing these reactions.In the first part of this Account, we organize our reported methods on the basis of the identity of the C(sp3) electrophiles, including benzylic chlorides, N-hydroxyphthalimide (NHP) esters, and α-chloro esters and nitriles. We highlight how the selection of specific chiral ligands plays a pivotal role in achieving high cross-selectivity and enantioselectivity. In addition, we show that reduction can be accomplished not only with heterogeneous reductants, such as Mn0, but also with the soluble organic reductant tetrakis(dimethylamino)ethylene (TDAE), as well as electrochemically. The use of homogeneous reductants, such as TDAE, is well suited for studying the mechanism of the transformation. Although this Account primarily focuses on RCCs, we also highlight our work using trifluoroborate (BF3K) salts as radical precursors for enantioselective dual-Ni/photoredox systems.At the end of this Account, we summarize the relevant mechanistic studies of two closely related asymmetric reductive alkenylation reactions developed in our laboratory and provide a context between our work and related mechanistic studies by others. We discuss how the ligand properties influence the rates and mechanisms of electrophile activation and how understanding the mode of C(sp3) radical generation can be used to optimize the yield of an RCC. Our research endeavors to offer insights on the intricate mechanisms at play in asymmetric Ni-catalyzed RCCs with the goal of using the rate of electrophile activation to improve the substrate scope of enantioselective RCCs. We anticipate that the insights we share in this Account can provide guidance for the development of new methods in this field.
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In the adult mammalian brain, new neurons are continuously generated from neural stem cells (NSCs) in the subventricular zone (SVZ)-olfactory bulb (OB) pathway. YAP, a transcriptional co-activator of the Hippo pathway, promotes cell proliferation and inhibits differentiation in embryonic neural progenitors. However, the role of YAP in postnatal NSCs remains unclear. Here, we showed that YAP was present in NSCs of the postnatal mouse SVZ. Forced expression of Yap promoted NSC maintenance and inhibited differentiation, whereas depletion of Yap by RNA interference or conditional knockout led to the decline of NSC maintenance, premature neuronal differentiation, and collapse of neurogenesis. For the molecular mechanism, thyroid hormone receptor-interacting protein 6 (TRIP6) recruited protein phosphatase PP1A to dephosphorylate LATS1/2, therefore inducing YAP nuclear localization and activation. Moreover, TRIP6 promoted NSC maintenance, cell proliferation, and inhibited differentiation through YAP. In addition, YAP regulated the expression of the Sonic Hedgehog (SHH) pathway effector Gli2 and Gli1/2 mediated the effect of YAP on NSC maintenance. Together, our findings demonstrate a novel TRIP6-YAP-SHH axis, which is critical for regulating postnatal neurogenesis in the SVZ-OB pathway.
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Proteínas Hedgehog , Células-Madre Neurales , Animales , Ratones , Neuronas , Neurogénesis , Encéfalo , MamíferosRESUMEN
Despite numerous studies demonstrate that genetics and epigenetics factors play important roles on smoking behavior, our understanding of their functional relevance and coordinated regulation remains largely unknown. Here we present a multiomics study on smoking behavior for Chinese smoker population with the goal of not only identifying smoking-associated functional variants but also deciphering the pathogenesis and mechanism underlying smoking behavior in this under-studied ethnic population. After whole-genome sequencing analysis of 1329 Chinese Han male samples in discovery phase and OpenArray analysis of 3744 samples in replication phase, we discovered that three novel variants located near FOXP1 (rs7635815), and between DGCR6 and PRODH (rs796774020), and in ARVCF (rs148582811) were significantly associated with smoking behavior. Subsequently cis-mQTL and cis-eQTL analysis indicated that these variants correlated significantly with the differential methylation regions (DMRs) or differential expressed genes (DEGs) located in the regions where these variants present. Finally, our in silico multiomics analysis revealed several hub genes, like DRD2, PTPRD, FOXP1, COMT, CTNNAP2, to be synergistic regulated each other in the etiology of smoking.
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BACKGROUND INFORMATION: Microtubules serve as integral components in cellular operations such as cell division, intracellular trafficking, and cellular architecture. Composed of tubulin protein subunits, these hollow tubular structures have been increasingly elucidated through advanced cryo-electron microscopy (Cryo-EM), which has unveiled the presence of microtubule inner proteins (MIPs) within the microtubular lumen. RESULTS: In the present investigation, we employ a synergistic approach incorporating high-pressure freezing, cryo-focused ion beam milling, and Cryo-electron tomography (Cryo-ET) to interrogate the in situ architecture of microtubules in Caenorhabditis elegans larvae. Our Cryo-ET assessments across neuronal cilia and diverse tissue types consistently demonstrate the formation of annular configurations within the microtubular lumen. CONCLUSIONS: In concert with recently characterized MIPs, our in situ observations within a living organism corroborate the hypothesis that intricate luminal assemblages exist within microtubule scaffolds. These findings necessitate further exploration into the molecular constituents and functional ramifications of these internal microtubular configurations in both cellular physiology and pathophysiology.
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Litchi (Litchi chinensis Sonn.) is a valuable subtropical fruit tree with high-quality fruit. However, its economic benefits and sustainable development are restrained by a number of challenges. One major challenge is the lack of extremely early and late maturing high-quality varieties due to limited availability of varieties suitable for commercial cultivation and outdated breeding methods, resulting in an imbalanced supply and low price of litchi. Flowering time is a crucial genetic factor influencing the maturation period of litchi. Our previous research has highlighted the pivotal role of the LcFT1 gene in regulating the flowering time of litchi and identified a gene associated with LcFT1 (named as LcSOC1) based on RNA-Seq and weight gene co-expression network (WGCNA) analysis. This study further investigated the function of LcSOC1. Subcellular localization analysis revealed that LcSOC1 is primarily localized in the nucleus, where it acts as a transcription factor. LcSOC1 overexpression in Nicotiana tabacum and Arabidopsis thaliana resulted in significant early flowering. Furthermore, LcSOC1 was found to be expressed in various tissues, with the highest expression in mature leaves. Analysis of spatial and temporal expression patterns of LcSOC1 in litchi varieties with different flowering time under low temperature treatment and across an annual cycle demonstrated that LcSOC1 is responsive to low temperature induction. Interestingly, early maturing varieties exhibited higher sensitivity to low temperature, with significantly premature induction of LcSOC1 expression relative to late maturing varieties. Activation of LcSOC1 triggered the transition of litchi into the flowering phase. These findings demonstrate that LcSOC1 plays a pivotal role in regulating the flowering process and determining the flowering time in litchi. Overall, this study provides theoretical guidance and important target genes for molecular breeding to regulate litchi production period.
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Litchi , Litchi/genética , Litchi/metabolismo , Frutas/genética , Fitomejoramiento , Hojas de la Planta/genética , Frío , Regulación de la Expresión Génica de las PlantasRESUMEN
Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.
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Many organisms in nature thrive in intricate habitats through their unique bio-adhesive surfaces, facilitating tasks such as capturing prey and reproduction. It's important to note that the remarkable adhesion properties found in these natural biological surfaces primarily arise from their distinct micro- and nanostructures and/or chemical compositions. To create artificial surfaces with superior adhesion capabilities, researchers delve deeper into the underlying mechanisms of these captivating adhesion phenomena to draw inspiration. This article provides a systematic overview of various biological surfaces with different adhesion mechanisms, focusing on surface micro- and nanostructures and/or chemistry, offering design principles for their artificial counterparts. Here, the basic interactions and adhesion models of natural biological surfaces are introduced first. This will be followed by an exploration of research advancements in natural and artificial adhesive surfaces including both dry adhesive surfaces and wet/underwater adhesive surfaces, along with relevant adhesion characterization techniques. Special attention is paid to stimulus-responsive smart artificial adhesive surfaces with tunable adhesive properties. The goal is to spotlight recent advancements, identify common themes, and explore fundamental distinctions to pinpoint the present challenges and prospects in this field.