Science China Life Sciences最新文献

Salivary proteins serve multifaceted roles in maintaining oral health and hold significant potential for diagnosing and monitoring diseases due to the non-invasive nature of saliva sampling. However, the clinical utility of current saliva biomarker studies is limited by the lack of reference intervals (RIs) to correctly interpret the testing result. Here, we developed a rapid and robust saliva proteome profiling workflow, obtaining coverage of >1,200 proteins from a 50-µL unstimulated salivary flow with 30 min gradients. With the workflow, we investigated protein variation in a cohort of 1,743 healthy individuals. The significant differences in non-linear saliva proteomes among age groups resulted in the establishment of age-related RIs covering 1,123 salivary protein variations. We then utilized a cohort of 30 epilepsy patients as a case study to illustrate the practical application of RIs in identifying disease-enriched outlier proteins, elucidating their cellular origins, determining disease diagnosis, and visualizing outlier proteins in each epilepsy patient. Our study showed the classification model based on the RI achieved PR-AUC of 0.815 (95%CI: 0.813-0.826). Additionally, we validated these results in an independent test set. Furthermore, the epilepsy cohort could be further stratified into 2 major subtypes, with one subtype characterized by disrupted metabolic proteins and containing mostly Focal Cortical Dysplasia (FCD) type III epilepsy patients. Overall, our study provided a proof-of-principle workflow for the use of salivary proteome for health monitoring, epilepsy diagnosis and subtyping.

Hematopoiesis is a finely tuned process that generates all blood cell types through self-renewal and differentiation, which is crucial for maintaining homeostasis. Acute infections can prompt a hematopoietic response known as emergency myelopoiesis. In this study, using a Candida albicans (C. albicans) infection model, we demonstrated for the first time that disruption of Fhl2 led to increased fungal burden, heightened inflammatory response and reduced survival rates. Impaired myeloid hematopoiesis and immune cell production were evident, as proved by the decreased numbers of hematopoietic stem and progenitor cells (HSPCs) and granulocytes in the bone marrow of Fhl2-deficient mice. In conclusion, FHL2 regulated emergency myelopoiesis in response to C. albicans, affecting the host's defense against pathogens.

To elucidate the process of adaptation, particularly the traits subject to natural selection and the molecular mechanisms underlying their natural variation, is one of the primary objectives of evolutionary biology. The uplifted landscape offers an excellent framework for understanding how organisms adapt to dramatic climatic gradients. To investigate the genetic basis of plant adaptation to the extremely high altitude, we first compared the genomic and phenotypic variations of two closely related Arabidopsis thaliana accessions from high altitude (Xizang, also known as "Tibet") and low altitude (Yunnan), respectively. The Xizang population represents a relict group characterized by a small effective population size. Notably, the Xizang genome has more transposable elements (TEs) and more gene loss-of-function (LoF) mutations. Differentially expressed genes were enriched in biological processes of cellular response to oxygen-containing compound, regulation of defense response, and response to light intensity. Intriguingly, the phenotypic selection analysis revealed that silique density was under natural selection. Furthermore, we genetically mapped and validated that the LoF mutation of GA20ox1, the homologous gene of green revolution in rice, resulted in a higher silique density in Xizang Arabidopsis. Given that GA20ox1 is linked to Arabidopsis adaptation to the Alps Mountains, its parallel evolution plays an important role in the adaptation to Alpine habitats. Overall, our results highlight that identifying adaptive traits and elucidating the molecular mechanisms underlying natural variation of these traits is crucial for unraveling the mystery of adaptive evolution and has significant implications for crop breeding.

The innovation of CRISPR/Cas gene editing technology has developed rapidly in recent years. It is widely used in the fields of disease animal model construction, biological breeding, disease diagnosis and screening, gene therapy, cell localization, cell lineage tracking, synthetic biology, information storage, etc. However, developing idealized editors in various fields is still a goal for future development. This article focuses on the development and innovation of non-DSB editors BE and PE in the platform-based CRISPR system. It first explains the application of ideas for improvement such as "substitution", "combination", "adaptation", and "adjustment" in BE and PE development and then catalogues the ingenious inversions and leaps of thought reflected in the innovations made to CRISPR technology. It will then elaborate on the efforts currently being made to develop small editors to solve the problem of AAV overload and summarize the current application status of editors for in vivo gene modification using AAV as a delivery system. Finally, it summarizes the inspiration brought by CRISPR/Cas innovation and assesses future prospects for development of an idealized editor.

Plant diversity significantly impacts ecosystem processes and functions, yet its influence on the community assembly of leaf fungi remains poorly understood. In this study, we investigated leaf epiphytic and endophytic fungal communities in a Chinese subtropical tree species richness experiment, ranging from 1 to 16 species, using amplicon sequencing to target the internal transcribed spacer 1 region of the rDNA. We found that the community assembly of epiphytic and endophytic fungi was predominantly governed by stochastic processes, with a higher contribution of dispersal limitation on epiphytic than on endophytic fungal communities but a higher contribution of selection on endophytic than on epiphytic fungal communities. The plant-epiphytic fungus interaction network was more complex (e.g., more highly connected and strongly nested but less specialized and modularized) than the plant-endophytic fungus interaction network. Additionally, tree species richness was positively correlated with the network complexity and diversity of epiphytic (α-, β- and γ-diversity) and endophytic (β- and γ-diversity) fungi, but was not associated with the contribution of the stochastic and deterministic processes on the community assembly of epiphytic and endophytic fungi. This study highlights that tree species diversity enhances the diversity and network complexity, rather than alters the ecological processes in community assembly of leaf-associated fungi.

Asthenoteratozoospermia is a common cause of male infertility. To further define the genetic causes underlying asthenoteratozoospermia, we performed whole-exome sequencing in a cohort of Han Chinese men with asthenoteratozoospermia. Homozygous deleterious variants of MYCBPAP were first identified in two unrelated Chinese cases. Replication analyses in a French cohort revealed an additional asthenoter-atozoospermia-affected case harboring a homozygous nonsense variant in MYCBPAP. All of the identified MYCBPAP variants were absent or extremely rare in the public human genome databases. Further functional assays indicated remarkably reduced abundance of MYCBPAP in the spermatozoa from MYCBPAP-associated cases. Subsequently, we generated a Mycbpap knockout (Mycbpap^-/-) mouse model, which also exhibited male infertility with reduced sperm motility and abnormal morphologies in sperm heads and flagella. Further investigations demonstrated that Mycbpap^-/- male mice presented disrupted acrosome biogenesis and abnormally elongated manchette during spermiogenesis. Intriguingly, proteomic analyses indicated that the proteins related to spermatogenesis, acrosomal and flagellar functions were significantly down-regulated in the testes from Mycbpap^-/- male mice. Endogenous immunoprecipitation combined with mass spectrometry revealed interactions of MYCBPAP with a ribosome elimination related protein ARMC3 and central apparatus proteins including CFAP65 and CFAP70. Furthermore, MYCBPAP-associated male infertility in humans and mice could be partially overcome by using intracytoplasmic sperm injections. Collectively, these findings illustrate the essential role of MYCBPAP in normal spermatogenesis and homozygous deleterious variants in MYCBPAP can be considered as a genetic diagnostic indicator for infertile men with asthenoteratozoospermia. Our study will provide effective guidance for genetic counseling, clinical diagnosis and assisted reproduction treatments of MYCBPAP-associated male infertility.

The minichromosome maintenance complex (MCM) DNA helicase is an important replicative factor during DNA replication. The proper chromatin loading of MCM is a key step to ensure replication initiation during S phase. Because replication initiation is regulated by multiple biological cues, additional changes to MCM may provide better understanding towards this event. Here, we report that histidine methyltransferase SETD3 promotes DNA replication in a manner dependent on enzymatic activity. Nascent-strand sequencing (NS-seq) shows that SETD3 regulates replication initiation, as depletion of SETD3 attenuates early replication origins firing. Biochemical studies reveal that SETD3 binds MCM mainly during S phase, which is required for the CDT1-mediated chromatin loading of MCM. This MCM loading relies on histidine-459 methylation (H459me) on MCM7 which is catalyzed by SETD3. Impairment of H459 methylation attenuates DNA synthesis and chromatin loading of MCM. Furthermore, we show that CDK2 phosphorylates SETD3 at Serine-21 during the G1/S phase, which is required for DNA replication and cell cycle progression. These findings demonstrate a novel mechanism by which SETD3 methylates MCM to regulate replication initiation.