LIN28B induced PCAT5 promotes endometrial cancer progression and glycolysis via IGF2BP3 deubiquitination.

Endometrial cancer (EC) cells exhibit abnormal glucose metabolism, characterized by increased aerobic glycolysis and decreased oxidative phosphorylation. Targeting cellular glucose metabolism in these cells could be an effective therapeutic approach for EC. This study aimed to assess the roles of LIN28B, PCAT5, and IGF2BP3 in the glucose metabolism, proliferation, migration, and invasion of EC cells. LIN28B highly expressed in EC, binds and stabilizes PCAT5. PCAT5, overexpressed in EC, and its 1485-2288nt region can bind to the KH1-2 domain of IGF2BP3 to prevent MKRN2 from binding to the K294 ubiquitination site of IGF2BP3, thus stabilizing IGF2BP3. Finally, IGF2BP3 promotes the aerobic glycolysis, proliferation, migration and invasion of EC cells by stabilizing the key enzymes of glucose metabolism HK2 and PKM2. Taken together, our data reveal that the LIN28B/PCAT5/IGF2BP3 axis is critical for glucose reprogramming and malignant biological behavior in EC cells. Therefore, targeting this axis may contribute to the development of a novel therapeutic strategy for EC metabolism.

Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson's disease through Mfn2-cGAS signaling.

BACKGROUND: Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson's disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. METHODS: Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. RESULTS: We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. CONCLUSIONS: This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

An oligo peptide transporter family member, OsOPT7, mediates xylem unloading of Fe for its preferential distribution in rice.

Iron (Fe) needs to be delivered to different organs and tissues of above-ground parts for playing its multiple physiological functions once it is taken up by the roots. However, the mechanisms underlying Fe distribution are poorly understood. We functionally characterized OsOPT7, a member of oligo peptide transporter family in terms of expression patterns, localization, transport activity and phenotypic analysis of knockdown lines. OsOPT7 was highly expressed in the nodes, especially in the uppermost node I, and its expression was upregulated by Fe-deficiency. OsOPT7 transports ferrous iron into the cells coupled with proton. Immunostaining revealed that OsOPT7 is mainly localized in the xylem parenchyma cells of the enlarged vascular bundles in the nodes and vascular tissues in the leaves. Knockdown of OsOPT7 did not affect the Fe uptake, but altered Fe distribution; less Fe was distributed to the new leaf, upper nodes and developing panicle, but more Fe was distributed to the old leaves. Furthermore, knockdown of OsOPT7 also resulted in less Fe distribution to the leaf sheath, but more Fe to the leaf blade. Taken together, OsOPT7 is involved in the xylem unloading of Fe for both long-distance distribution to the developing organs and local distribution within the leaf in rice.

Focal atrial tachycardias originating from the aorta-mitral continuty: Anatomic and electrophysiological characteristics.

BACKGROUND: The aorta-mitral annulus conjunction (AMC) is uncommon site of origin of focal atrial tachycardias (AT). Hence, the electrophysiological and ablation target characteristics are poorly described. OBJECTIVE: To describe the characteristics of AMC AT in detail. METHODS: The study enrolled 650 patients with AT, 21 (3.2%) of whom had AT originating from AMC. A comprehensive evaluation, including electrocardiography, electrophysiologic study, CT scan, and intracardiac echocardiography (ICE) was performed. RESULTS: The majority (90.5%) of ATs occurred spontaneously. The average age of this group was 48.9±21.6 years, with 12 females (57.1%). Seventeen patients had a typical biphasic P wave with a prominent positive component. The earliest activation site in the right atrium was near the His bundle with average activation -10.3±6.0 ms preceding the P wave. The successful ablation targets were distributed as follows: 1 case at 9 o'clock, 6 cases at 10 o'clock, 7 cases at 11 o'clock, 6 cases at 12 o'clock, and 1 case in the left coronary cusp (LCC). The local AMC potential differed from the commonly perceived annular potential, and was characterized by a large A and a small V (A/V ratio >1). The angle of encroachment on the LA anterior wall, compressed by the LCC, was significantly smaller in the AMC-AT group compared to the control group, which may have contributed to the arrhythmia substrate (141.7°±11.5° vs. 155.2°±13.9°, p = 0.026). CONCLUSION: A new strategy for mapping AMC ATs has been introduced. The ablation target should have an A/V ratio greater than 1.

Mechanical characteristics analysis of high dimensional vibration isolation systems based on high-static-low-dynamic stiffness technology.

Large floating raft vibration isolation systems (FRVISs) based on high-static-low-dynamic stiffness (HSLDS) technology offer excellent low frequency vibration isolation performance with broad application prospects. However, the design process for these complex high-dimensional coupled nonlinear systems remains poorly developed, particularly when applied for ocean-going vessels that experience rolling and pitching motions. The present work addresses this issue by establishing a six-degree-of-freedom HSLDS vibration isolation model for FRVISs composed of eight isolators, and the model is applied to fully analyze the swing stability and multidimensional vibration isolation performance of these systems. The influence of nonlinearity on the mechanical properties of the vibration isolators is analyzed more clearly by assuming that each vibration isolator realizes nonlinear HSLDS characteristics in the z direction and linear characteristics in the x and y directions. The results demonstrate that the swing displacement responses of the system are greatly reduced under weak nonlinearity, which reflects the high static stiffness and high static stability characteristics of an HSLDS system. The multidimensional vibration isolation performance of the system is evaluated according to the impacts of nonlinearity, the installation height Hz of the isolators, and the relative position Dr of the two middle isolators. The results of analysis demonstrate that applying a value of Hz = 0 produces the best vibration isolation performance overall under strong nonlinearity by avoiding unnecessary secondary peaks in the force transmission rate under harmonic mechanical excitation and ensuring a maximum high-frequency vibration isolation effect. However, applying a weak nonlinearity is better than a strong nonlinearity if Hz is not zero. In contrast, Dr has little effect on the vibration isolation effect of the raft in the x, y, and z directions. Therefore, an equidistant installation with Dr = 0.5 would be considered ideal from the standpoint of installation stability.

scGHOST: identifying single-cell 3D genome subcompartments.

Single-cell Hi-C (scHi-C) technologies allow for probing of genome-wide cell-to-cell variability in three-dimensional (3D) genome organization from individual cells. Computational methods have been developed to reveal single-cell 3D genome features based on scHi-C, including A/B compartments, topologically associating domains and chromatin loops. However, no method exists for annotating single-cell subcompartments, which is important for understanding chromosome spatial localization in single cells. Here we present scGHOST, a single-cell subcompartment annotation method using graph embedding with constrained random walk sampling. Applications of scGHOST to scHi-C data and contact maps derived from single-cell 3D genome imaging demonstrate reliable identification of single-cell subcompartments, offering insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from complex tissues, scGHOST identifies cell-type-specific or allele-specific subcompartments linked to gene transcription across various cell types and developmental stages, suggesting functional implications of single-cell subcompartments. scGHOST is an effective method for annotating single-cell 3D genome subcompartments in a broad range of biological contexts.

Bottom-Up Construction of Rhombic Lamellar CoNi-MOFs for the Electrochemical Sensing of H2S.

Lamellar metal-organic frameworks (MOFs) have attracted significant attention in the field of electrochemical sensing due to their abundant open active sites and specific electron conductivity. Herein, by employing a bottom-up synthesis strategy, rhombic lamellar heterometallic CoNi-MOFs with varying thicknesses are constructed. This is achieved by using 4-methylpyridine as a capping agent based on the (4,6)-linked Co2(azpy)2(bptc) (azpy = 4,4'-azopyridine, bptc = 3,3',5,5'-biphenyltetracarboxylic acid) structure with a fsc topology and by introducing Ni species simultaneously. To mitigate sulfur deposition on electrodes, the triple pulse amperometry (TPA) method is employed. Among the synthesized lamellar CoNi-MOFs, lamellar CoNi-MOF-3 with the minimum thickness exhibits an optimal electrochemical sensing performance toward hydrogen sulfide, with a sensitivity of 119.3 µA·mM-1·cm-2 in the linear range of 2-2000 µM. This study pioneers a new approach to the controlled construction and electrochemical activity modification of lamellar MOF materials.

Origin and dispersal history of Hepatitis B virus in Eastern Eurasia.

Hepatitis B virus is a globally distributed pathogen and the history of HBV infection in humans predates 10000 years. However, long-term evolutionary history of HBV in Eastern Eurasia remains elusive. We present 34 ancient HBV genomes dating between approximately 5000 to 400 years ago sourced from 17 sites across Eastern Eurasia. Ten sequences have full coverage, and only two sequences have less than 50% coverage. Our results suggest a potential origin of genotypes B and D in Eastern Asia. We observed a higher level of HBV diversity within Eastern Eurasia compared to Western Eurasia between 5000 and 3000 years ago, characterized by the presence of five different genotypes (A, B, C, D, WENBA), underscoring the significance of human migrations and interactions in the spread of HBV. Our results suggest the possibility of a transition from non-recombinant subgenotypes (B1, B5) to recombinant subgenotypes (B2 - B4). This suggests a shift in epidemiological dynamics within Eastern Eurasia over time. Here, our study elucidates the regional origins of prevalent genotypes and shifts in viral subgenotypes over centuries.

A facile and smart strategy to enhance bone regeneration with efficient vitamin D3 delivery through sterosome technology.

The spontaneous healing of critical-sized bone defects is often limited, posing an increased risk of complications and suboptimal outcomes. Osteogenesis, a complex process central to bone formation, relies significantly on the pivotal role of osteoblasts. Despite the well-established osteogenic properties of vitamin D3 (VD3), its lipophilic nature confines administration to oral or muscle injection routes. Therefore, a strategic therapeutic approach involves designing a multifunctional carrier to enhance efficacy, potentially incorporating it into the delivery system. Here, we introduce an innovative sterosome-based delivery system, utilizing palmitic acid (PA) and VD3, aimed at promoting osteogenic differentiation and facilitating post-defect bone regeneration. The delivery system exhibited robust physical characteristics, including excellent stability, loading efficiency, sustained drug release and high cellular uptake efficiency. Furthermore, comprehensive investigations demonstrated outstanding biocompatibility and osteogenic potential in both 2D and 3D in vitro settings. A critical-sized calvarial defect model in mice recapitulated the notable osteogenic effects of the sterosomes in vivo. Collectively, our research proposes a clinically applicable strategy for bone healing, leveraging PA/VD3 sterosomes as an efficient carrier to deliver VD3 and enhance bone regenerative effects.

Stable Interstrand Cross-Links Generated from the Repair of 1,N6-Ethenoadenine in DNA by α-Ketoglutarate/Fe(II)-Dependent Dioxygenase ALKBH2.

DNA cross-links severely challenge replication and transcription in cells, promoting senescence and cell death. In this paper, we report a novel type of DNA interstrand cross-link (ICL) produced as a side product during the attempted repair of 1,N6-ethenoadenine (εA) by human α-ketoglutarate/Fe(II)-dependent enzyme ALKBH2. This stable/nonreversible ICL was characterized by denaturing polyacrylamide gel electrophoresis analysis and quantified by high-resolution LC-MS in well-matched and mismatched DNA duplexes, yielding 5.7% as the highest level for cross-link formation. The binary lesion is proposed to be generated through covalent bond formation between the epoxide intermediate of εA repair and the exocyclic N6-amino group of adenine or the N4-amino group of cytosine residues in the complementary strand under physiological conditions. The cross-links occur in diverse sequence contexts, and molecular dynamics simulations rationalize the context specificity of cross-link formation. In addition, the cross-link generated from attempted εA repair was detected in cells by highly sensitive LC-MS techniques, giving biological relevance to the cross-link adducts. Overall, a combination of biochemical, computational, and mass spectrometric methods was used to discover and characterize this new type of stable cross-link both in vitro and in human cells, thereby uniquely demonstrating the existence of a potentially harmful ICL during DNA repair by human ALKBH2.

Guiding function of positron emission tomography-computed tomography examination in the diagnosis and treatment of ocular adnexal mucosa associated lymphoid tissue lymphoma.

AIM: To explore the role of positron emission tomography-computed tomography (PET-CT) examination in the diagnosis and treatment of ocular adnexal mucosa associated lymphoid tissue lymphoma (OAML). METHODS: The general clinical data, postoperative PET-CT results, treatment regimens, and the prognosis of 21 histopathologically confirmed OAML patients between October 2017 and September 2021 were collected. Among the 21 patients, five patients underwent surgical treatment alone, 13 patients underwent surgical treatment combined with radiotherapy, and three patients underwent surgical treatment combined with chemotherapy. RESULTS: The follow-up period ranged from 8 to 79mo, with four cases of recurrence and no deaths. Through PET-CT examination, two patients exhibited both local ocular metabolic elevation and systemic metastasis, and one of these patients had cervical lymph node metastasis, while the other had submandibular and parotid gland metastasis. Nine patients showed only local ocular metabolic elevation, while 10 patients had no abnormal metabolic activity locally. CONCLUSION: PET-CT examination plays a crucial role in detecting residual lesions and recurrence following tumor resection, aiding in precise disease staging, and facilitating the development of personalized treatment plans, ultimately improving patient prognosis.

Development of an SI-traceable N-terminal pro-B-type natriuretic peptide certified reference material using structure-based impurity-corrected isotope dilution mass spectrometry approaches.

N-Terminal pro-B-type natriuretic peptide (NT-proBNP) is a pivotal biomarker for the diagnosis and prognosis of heart failure (HF). However, no SI-traceable certified reference material (CRM) or reference measurement procedure (RMP) is available for this biomarker, and so clinical testing results obtained in different laboratories cannot be traced to a higher-order standard, leading to incomparable measurements. Protein hydrolysis and protein cleavage isotope dilution mass spectrometry (AAA-IDMS and PepA-IDMS) were used to develop a CRM. Structurally related impurities were identified by high-resolution mass spectrometry. The quantitative AAA-IDMS results were corrected according to the amino acid compositions of the impurities. Using PepA-IDMS, two peptides from the proteolyzed product were confirmed as signature peptides. To obtain traceable and accurate results, the signature peptides were quantified using impurity-corrected AAA-IDMS. The candidate NT-proBNP solution was denatured and enzymatically digested using the Glu-C endoproteinase. The released signature peptides were measured using an isotopic dilution approach. The homogeneity and stability of the candidate CRM were characterized, and their uncertainties were combined with the value assignment process. The developed CRM can be considered a unique SI-traceable NT-proBNP reference material and is expected to be used as a primary calibrator for matrix NT-proBNP CRM development.

IGSF8 is an innate immune checkpoint and cancer immunotherapy target.

Antigen presentation defects in tumors are prevalent mechanisms of adaptive immune evasion and resistance to cancer immunotherapy, whereas how tumors evade innate immunity is less clear. Using CRISPR screens, we discovered that IGSF8 expressed on tumors suppresses NK cell function by interacting with human KIR3DL2 and mouse Klra9 receptors on NK cells. IGSF8 is normally expressed in neuronal tissues and is not required for cell survival in vitro or in vivo. It is overexpressed and associated with low antigen presentation, low immune infiltration, and worse clinical outcomes in many tumors. An antibody that blocks IGSF8-NK receptor interaction enhances NK cell killing of malignant cells in vitro and upregulates antigen presentation, NK cell-mediated cytotoxicity, and T cell signaling in vivo. In syngeneic tumor models, anti-IGSF8 alone, or in combination with anti-PD1, inhibits tumor growth. Our results indicate that IGSF8 is an innate immune checkpoint that could be exploited as a therapeutic target.

Research progress on the microbiota in bladder cancer tumors.

The microbiota, also referred to as the microbial community, is a crucial component of the human microenvironment. It is located predominantly in various organs, including the intestines, skin, oral cavity, respiratory tract, and reproductive tract. The microbiota maintains a symbiotic relationship with the human body, influencing physiological and pathological functions to a significant degree. There is increasing evidence linking the microbial flora to human cancers. In contrast to the traditional belief that the urethra and urine of normal individuals are sterile, recent advancements in high-throughput sequencing technology and bacterial cultivation methods have led to the discovery of specific microbial communities in the urethras of healthy individuals. Given the prevalence of bladder cancer (BCa) as a common malignancy of the urinary system, researchers have shifted their focus to exploring the connection between disease development and the unique microbial community within tumors. This shift has led to a deeper investigation into the role of microbiota in the onset, progression, metastasis, prognosis, and potential for early detection of BCa. This article reviews the existing research on the microbiota within BCa tumors and summarizes the findings regarding the roles of different microbes in various aspects of this disease.

Serum cell division cycle 42 reflects the development and progression of diabetic nephropathy in patients with diabetes mellitus.

Cell division cycle 42 (CDC42) regulates podocyte apoptosis to take part in the development and progression of diabetic nephropathy (DN), but currently the clinical evidence is limited. The aim of the present study was to investigate the capability of serum CDC42 expression level to estimate the development and progression of DN in patients with diabetes mellitus (DM). Patients with type 2 DM (n=306) were enrolled and divided into normoalbuminuria (n=185), microalbuminuria (n=72) and macroalbuminuria (n=49) groups based on the urinary albumin-to-creatinine ratio. Serum CDC42 was measured in all subjects using enzyme-linked immunosorbent assay. The median (interquartile range) CDC42 in patients with DM was 0.461 (0.314-0.690) ng/ml (range, 0.087-1.728 ng/ml). CDC42 was positively associated with the estimated glomerular filtration rate (P<0.001), but negatively correlated with body mass index, systolic blood pressure, hemoglobin A1c, serum creatine, serum uric acid and C reactive protein (all P<0.050). CDC42 levels were lowest in the macroalbuminuria group, followed by the microalbuminuria group, and were highest in the normoalbuminuria group (P<0.001). CDC42 indicated that it was a favorable estimator for the presence of albuminuria [area under the curve (AUC), 0.792; 95% confidence interval (CI), 0.736-0.848] and macroalbuminuria (AUC, 0.845; 95% CI, 0.775-0.915). By analyses in four different multivariate logistic regression models, increased CDC42 was independently associated with the presence of microalbuminuria (all P<0.001), macroalbuminuria (most P<0.001) and microalbuminuria + macroalbuminuria (all P<0.001). Serum CDC42 level negatively correlated with microalbuminuria and macroalbuminuria in patients with DM, suggesting its ability for estimating the development and progression of DN.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022.

BACKGROUND: Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS: A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS: RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS: Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

Integration of hepatitis B virus into patients' sperm genome and its clinical risks.

BACKGROUND: Like the coronavirus disease 2019, the hepatitis B virus is also wreaking havoc worldwide, which has infected over 2 billion people globally. Using an experimental animal model, our previous research observed that the hepatitis B virus genes integrated into human spermatozoa can replicate and express after being transmitted to embryos. However, as of now, this phenomenon has not been confirmed in clinical data from patients. OBJECTIVES: To explore the integration of the hepatitis B virus into patients' sperm genome and its potential clinical risks. MATERIALS AND METHODS: Forty-eight patients with chronic hepatitis B virus infection were categorized into two groups: Test Group-1 comprised 23 patients without integration of hepatitis B virus DNA within the sperm genome. Test Group-2 comprised 25 patients with integration of hepatitis B virus DNA within the sperm genome. Forty-eight healthy male donors were included as control. The standard semen parameter analysis, real-time polymerase chain reaction, quantitative real-time polymerase chain reaction, sperm chromatin structure assay, fluorescence in situ hybridization, and immunofluorescence assays were utilized. RESULTS: The difference in the median copy number of hepatitis B virus DNA per mL of sera between Test Group-1 and Group-2 was not statistically significant. In Test Group-2, the integration rate of hepatitis B virus DNA was 0.109%, which showed a significant correlation with the median copy number of hepatitis B virus DNA in motile spermatozoa (1.18 × 103 /mL). Abnormal semen parameters were found in almost all these 25 patients. The integrated hepatitis B virus S, C, X, and P genes were detected to be introduced into sperm-derived embryos through fertilization and retained their function in replication, transcription, and translation. CONCLUSION: Our findings suggest that hepatitis B virus infection can lead to sperm quality deterioration and reduced fertilization capacity. Furthermore, viral integration causes instability in the sperm genome, increasing the potential risk of termination, miscarriage, and stillbirth. This study identified an unconventional mode of hepatitis B virus transmission through genes rather than virions. The presence of viral sequences in the embryonic genome poses a risk of liver inflammation and cancer.

A Simple Cost-Effective Method to Fabricate Single Nanochannels by Embedding Electrospun Polyethylene Oxide Nanofibers.

Solid state nanochannels provide significant practical advantages in many fields due to their interesting properties, such as controllable shape and size, robustness, ion selectivity. But their complex preparation processes severely limit their application. In this study, a simple cost-effective method to fabricate single nanochannel by embedding a single polyethylene oxide (PEO) nanofiber is presented. Firstly, PEO nanofibers are prepared by electrospinning, and then a single PEO nanofiber are precisely transferred to the target sample using a micromanipulation platform. Then, PDMS is used for embedding, and finally, the PEO nanofiber is dissolved to obtain a single nanochannel. Unlike other methods of preparing nanochannels by embedding nanofibers, this method can prepare single nanochannel. The diameter of nanochannel can be as fine as 100 nm, and the length can reach several micrometers. The power generation between two potassium chloride solutions with various combinations of concentrations was investigated using the nanochannel. This low-cost flexible nanochannel can also be used in various applications, including DNA sequencing and biomimetic ion channel.

Association of sleep traits with male fertility: a two-sample Mendelian randomization study.

Background: Previous observational studies have investigated the association between sleep-related traits and male fertility; however, conclusive evidence of a causal connection is lacking. This study aimed to explore the causal relationship between sleep and male fertility using Mendelian randomisation. Methods: Eight sleep-related traits (chronotype, sleep duration, insomnia, snoring, dozing, daytime nap, oversleeping, and undersleeping) and three descriptors representing male fertility (male infertility, abnormal sperm, and bioavailable testosterone levels) were selected from published Genome-Wide Association Studies. The causal relationship between sleep-related traits and male fertility was evaluated using multiple methods, including inverse variance weighting (IVW), weighted median, Mendelian randomisation-Egger, weighted model, and simple model through two-sample Mendelian randomisation analysis. Mendelian randomisation-Egger regression was used to assess pleiotropy, Cochrane's Q test was employed to detect heterogeneity, and a leave-one-out sensitivity analysis was conducted. Results: Genetically-predicted chronotype (IVW,OR = 1.07; 95%CL = 1.04-1.12; p = 0.0002) was suggestively associated with bioavailable testosterone levels. However, using the IVW method, we found no evidence of a causal association between other sleep traits and male fertility. Conclusion: This study found that chronotype affects testosterone secretion levels. However, further studies are needed to explain this mechanism.