Population-based genetic analysis in infertile men reveals novel mutations of ADAD family members in patients with impaired spermatogenesis.

The testis-specific adenosine deaminase domain-containing (ADAD) protein family, including ADAD1 and ADAD2, has been confirmed to be essential in mouse male fertility. However, the roles of ADAD1 and ADAD2 in human reproductive biology are unclear. Herein, whole-exome sequencing was conducted for 337 infertile patients to detect pathogenic variants in ADAD1 and ADAD2. Importantly, a novel deleterious biallelic variant of NM_001159285.2:c.1408G > T (p.V470F) and NM_001159285.2:c.1418A > G (p.E473G) in ADAD1 and a pathogenic homozygous missense variant of NM_001145400.2:c.1381C > T (p.R461W) in ADAD2 were identified in this infertile cohort with frequencies of 0.29 (1/337) and 0.59% (2/337), respectively. Electron microscopy revealed an abnormal morphology and severely disorganized ultrastructure of sperm from the patients. Immunofluorescence and western blotting showed a sharp decrease in ADAD1 and ADAD2 expression in sperm from the patients. Mechanistically, bioinformatics analysis suggested that ADAD2 interacts with DNAH17. Furthermore, we demonstrated that the expression of DNAH17 was markedly downregulated in the sperm of patients harboring ADAD2 variants. In addition, the expression of several autophagy regulators was significantly disrupted in the sperm of patients harboring ADAD2 variants. In conclusion, we identified novel ADAD1 and ADAD2 variants in three infertile patients from a large infertile cohort, first providing evidence that ADAD1 and ADAD2 variants might be a candidate genetic cause of human male infertility. Moreover, an important new dimension to our understanding of the genotype-phenotype correlations between the ADAD gene family and male infertility in humans has been uncovered, providing valuable information for the genetic diagnosis of male infertility.

Maternal CHD7 gonosomal mosaicism in a fetus with CHARGE syndrome.

Parental mosaicism is important in families with de novo mutations. Herein, we report a case of fetal CHARGE syndrome (CS) with a CHD7 variant inherited from maternal CHD7 gonosomal mosaicism. The variant was detected through trio-based whole-exome sequencing and Sanger sequencing. High-depth whole-exome sequencing was performed for the identification of parental mosaicism. A novel heterozygous CHD7 nonsense mutation (c.5794G>T/ p.E1932*) was detected in the tissue from the aborted fetus. The parents were wild-type, indicating that the mutation was a de novo variant. The mutation was suspected to be the cause of the fetal CS. However, high-depth whole-exome sequencing revealed maternal gonosomal mosaicism at a variant allele frequency of 3.2%-23.3%. The variant was identified in various tissues (peripheral blood, hair follicles, buccal epithelia, and pharyngeal epithelia) from the asymptomatic mother. We confirmed maternal CHD7 gonosomal mosaicism as a genetic cause of fetal CS. Our results emphasize the importance of clinical analysis in accurately determining the parents' status in detecting the CHD7 de novo variant in fetal CS, as this analysis has vital implications for evaluating the recurrence risk for genetic counseling.

Current understanding of essential trace elements in intrahepatic cholestasis of pregnancy.

Trace elements are important components in the body and have fundamental roles in maintaining a healthy and balanced pregnancy process. Either deficiency or excess of trace elements, including selenium, iron, zinc, copper, and magnesium can lead to pregnancy complications. As a rare disorder during pregnancy of unknown aetiology, intrahepatic cholestasis of pregnancy (ICP) poses a significant risk to the fetus of perinatal mortality. ICP is a multifactorial complication of which the pathogenesis is still an enigma. Epidemiological studies have demonstrated the association of ICP with some trace elements. Evidence from retrospective studies in humans further revealed the possible contributing roles of trace elements in the pathogenesis of ICP. The published literature on the association of trace elements with ICP was reviewed. Recent advances in molecular biological techniques from animal studies have helped to elucidate the possible mechanisms by how these trace elements function in regulating oxidative reactions, inflammatory reactions and immune balance in the maternal-fetal interface, as well as the influence on hepato-intestinal circulation of bile acid. The scenario regarding the role of trace elements in the pathogenesis of ICP is still developing. The administration or depletion of these trace elements may have promising effects in alleviating the symptoms and improving the pregnancy outcomes of ICP.

Sequencing of the ZMYND15 gene in a cohort of infertile Chinese men reveals novel mutations in patients with teratozoospermia.

BACKGROUND: The information of ZMYND15 in human reproduction is very limited, resulting in the unclear link between ZMYND15 variants and male infertility. METHODS: Whole exome sequencing and Sanger sequencing to identify the potential pathogenic variation of ZMYND15 in infertile men, Papanicolaou staining and electron microscopy to investigate the spermatozoa morphology, western blotting and immunofluorescence staining to confirm the pathogenicity of the identified variants, and proteomic analysis and coimmunoprecipitation to clarify the potential molecular mechanism. RESULTS: A total of 31 ZMYND15 variants were identified in 227 infertile patients. Three deleterious biallelic variants, including a novel compound heterozygous variant of c.1105delG (p.A369Qfs*15) and c.1853T>C (p.F618S), a new homozygous splicing mutation of c.1297+5G>A and a reported homozygous nonsense mutation of c.1209T>A (p.Y403*), were detected in three affected individuals with oligoasthenoteratozoospermia, showing a biallelic pathogenic mutation frequency of 1.3% (3/227). No biallelic pathogenic mutation was found in 692 fertile men. Morphology analysis showed abnormalities in sperm morphology in the patients harbouring ZMYND15 mutations. Western blotting and immunofluorescence staining confirmed the nearly absent ZMYND15 expression in the sperm of the patients. Mechanistically, ZMYND15 might regulate spermatogenesis by interacting with key molecules involved in sperm development, such as DPY19L2, AKAP4 and FSIP2, and might also mediate the expression of the autophagy-associated protein SPATA33 to maintain sperm individualisation and unnecessary cytoplasm removal. CONCLUSION: Our findings broaden the variant and phenotype spectrum of ZMYND15 in male infertility, and reveal the potential signalling pathway of ZMYND15 regulating spermatogenesis, finally confirming the essential role of ZMYND15 in human fertility.

Identification of nonfunctional SPATA20 causing acephalic spermatozoa syndrome in humans.

Acephalic spermatozoa syndrome (ASS) is a rare and severe type of teratozoospermia characterized by the predominance of headless spermatozoa in the ejaculate. However, knowledge about the causative genes associated with ASS in humans is limited. Loss-of-function of SPATA20 has been suggested to result in the separation of the sperm head and flagellum in mice, whereas there have been no cases reporting SPATA20 variants leading to human male infertility. In this study, a nonsense mutation in SPATA20 (c.619C > T, p.Arg207*) was first identified in an ASS patient. Moreover, this variant contributed to the degradation of SPATA20 and was associated with decreased expression of SPATA6, which plays a vital role in the assembly of the sperm head-tail conjunction in humans. In addition, the infertility caused by loss-of-function mutation of SPATA20 might not be rescued by intracytoplasmic sperm injection (ICSI). Collectively, our findings suggested that SPATA20 might be required for sperm head-tail conjunction formation in humans, the nonfunction of which may lead to male infertility related to ASS. The discovery of the loss-of-function mutation in SPATA20 enriches the gene variant spectrum of human ASS, further contributing to improved diagnosis, genetic counseling and prognosis for male infertility.

Identification of POLR3B biallelic mutations-associated hypomyelinating leukodystrophy-8 in two siblings.

POLR3B gene encodes the 2nd largest catalytic subunit and affects the function of RNA polymerase III enzymes in transcription. Bi-allelic variants in POLR3B pathogenically cause hypomyelinating leukodystrophy-8 (HLD8). Herein, we recruited a family with two patients, who presented clinically with cerebellar atrophy, intellectual disability, hypogonadotropic hypogonadism, and visual problems. We identified the two affected siblings carrying the compound heterozygous variations (c.165_167del; c.1615G>T) in POLR3B by trio-whole-exome sequencing (trio-WES). The qPCR and western blot showed that both transcriptional and translational levels of the mutation (c.165_167del, p.I55_K56delinsM) were sharply attenuated. Following that, a thorough functional examination of a zebrafish line disrupted for human POLR3B validated the pathogenic effects of the two mutations. Our research broadens the spectrum of HLD8-related pathogenic POLR3B mutations and provides new molecular and animal evidence.

Identification of nonfunctional PABPC1L causing oocyte maturation abnormalities and early embryonic arrest in female primary infertility.

Oocyte maturation arrest, fertilization failure, and early embryonic arrest are important causes of female infertility, whereas the genetic events that contribute to these processes are largely unknown. Loss-of-function of PABPC1L in mice has been suggested to cause female infertility involved in the absence of mature oocytes or embryos in vivo or in vitro. However, the role of PABPC1L in human female reproduction remains largely elusive. In this study, we identified a homozygous missense mutation (c.536G>A, p.R179Q) and a compound heterozygous mutation (c.793C>T, p.R265W; c.1201C>T, p.Q401*) in PABPC1L in two unrelated infertile females characterized by recurrent oocyte maturation abnormalities and early embryonic arrest. These variants resulted in nonfunctional PABPC1L protein and were associated with impaired chromatin configuration and transcriptional silencing in GV oocytes. Moreover, the binding capacity of mutant PABPC1L to mRNAs related to oocyte maturation and early embryonic development was decreased significantly. Our findings revealed novel PABPC1L mutations causing oocyte maturation abnormalities and early embryonic arrest, confirming the essential role of PABPC1L in human female fertility.

A Soybean Sucrose Non-Fermenting Protein Kinase 1 Gene, GmSNF1, Positively Regulates Plant Response to Salt and Salt-Alkali Stress in Transgenic Plants.

Soybean is one of the most widely grown oilseed crops worldwide. Several unfavorable factors, including salt and salt-alkali stress caused by soil salinization, affect soybean yield and quality. Therefore, exploring the molecular basis of salt tolerance in plants and developing genetic resources for genetic breeding is important. Sucrose non-fermentable protein kinase 1 (SnRK1) belongs to a class of Ser/Thr protein kinases that are evolutionarily highly conserved direct homologs of yeast SNF1 and animal AMPKs and are involved in various abiotic stresses in plants. The GmPKS4 gene was experimentally shown to be involved with salinity tolerance. First, using the yeast two-hybrid technique and bimolecular fluorescence complementation (BiFC) technique, the GmSNF1 protein was shown to interact with the GmPKS4 protein. Second, the GmSNF1 gene responded positively to salt and salt-alkali stress according to qRT-PCR analysis, and the GmSNF1 protein was localized in the nucleus and cytoplasm using subcellular localization assay. The GmSNF1 gene was then heterologously expressed in yeast, and the GmSNF1 gene was tentatively identified as having salt and salt-alkali tolerance function. Finally, the salt-alkali tolerance function of the GmSNF1 gene was demonstrated by transgenic Arabidopsis thaliana, soybean hairy root complex plants overexpressing GmSNF1 and GmSNF1 gene-silenced soybean using VIGS. These results indicated that GmSNF1 might be useful in genetic engineering to improve plant salt and salt-alkali tolerance.

Impaired Function of a Rare Mutation in the MMUT Gene Causes Methylmalonic Acidemia in a Chinese Patient.

Methylmalonic acidemia (MMA) is an autosomal recessive metabolic disorder mainly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MMUT) and leads to the reduced activity of MCM. In this study, a 3-year-old girl was diagnosed with carnitine deficiency secondary to methylmalonic acidemia by tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GS/MS). Whole-exome sequencing (WES) was performed on the patient and identified two compound heterozygous mutations in MMUT: c.554C>T (p. S185F) and c.729-730insTT (p. D244Lfs ∗ 39). Bioinformatics analysis predicted that the rare missense mutation of c.554C>T would be damaging. Moreover, this rare mutation resulted in the reduced levels of MMUT mRNA and MMUT protein. Collectively, our findings provide a greater understanding of the effects of MMUT variants and will facilitate the diagnosis and treatment of patients with MMA.

Radiographic measurement of the posterior tibial slope in normal Chinese adults: a retrospective cohort study.

BACKGROUND: Measurement of the posterior tibial slope (PTS) angle has important applications in total knee replacement surgery, high tibial osteotomy, and anterior cruciate ligament reconstruction. This study aimed to determine the mean PTS of knee joints in healthy Chinese adults, and provide data to guide knee surgery in China. METHODS: A retrospective analysis of 1257 (n = 1233, 50.4% male) plain X-ray films of participants aged 25-59 years was performed. The picture archiving and communication system was used for PTS measurement. The PTS was defined as the angle between the vertical line of the tangent of the anterior tibial cortex of the proximal tibia, and the tangent line of the tibial cortex. Two imaging physicians conducted the PTS measurements independently, and both the inter- and intraclass correlation coefficients (ICCs) were calculated. RESULTS: The mean PTS value was 7.68 ± 3.84° (range: 0-21°). The left PTS was significantly smaller in males than in females (7.22 ± 3.89 vs 8.05 ± 3.60; P = 0.005). Additionally, the PTS in participants aged 25-29 years was significantly larger than that in the other age groups (Left side: 8.64 ± 3.73 vs 6.92 ± 3.42, 7.42 ± 3.75, 7.53 ± 3.98; P <  0.001 and Right side: 8.68 ± 3.84 vs 7.48 ± 4.21, 7.13 ± 3.64, 7.66 ± 3.80; P = 0.004). There were no significant differences in PTS between the left and right sides. Two-way analysis of variance suggested that the differences in PTS between age groups were not affected by sex. The interobserver ICC was 0.91 (95% confidence interval [CI]: 0.85-0.94), and the intraobserver ICC was 0.90 (95% CI: 0.82-0.94). CONCLUSIONS: This study demonstrated that there were significant differences in PTS based on sex and age, highlighting the need to provide individualized treatment for knee surgery. It provided valuable information regarding the normal PTS values in Chinese adults and presented regionalised data to guide knee surgery.

Acute changes in knee cartilage and meniscus following long-distance running in habituate runners: a systematic review on studies using quantitative magnetic resonance imaging.

OBJECTIVE: Running is among the most popular recreational activities; nonetheless, the acute post-race changes of cartilage or meniscus have rarely been determined. The current study aimed to review the acute changes in knee cartilage and meniscus among habituate runners following long-distance running detected by using quantitative magnetic resonance imaging (MRI). MATERIALS AND METHODS: Systematic literature search was performed on those dominate clinical databases which including MEDLINE, Cochrane, Embase, ScienceDirect, and Web of Science. Included studies should be conducted on healthy marathon runners, and the participants should be examined before and after running by using MRI. Intervention studies were excluded. RESULTS: A total number of 14 studies were finally included in this review which all examined the cartilage or meniscus by using MRI functional sequences. Among them, six studies quantitatively measured the changes regarding volume of the knee cartilage or/and meniscus. Five studies found that the volume would decrease initially after running. Ten studies reported T2 (T2*) would decrease after running and returned to the baseline in a short term, while T1ρ may remain increased in months. Five studies measured subareas for T2 (T2*) value, and found that the superficial and medial subarea changed more vastly than other regions after running. CONCLUSION: Runners experience transient changes in the volume and signals of knee cartilage and meniscus after long-distance running. A liquid exchange and material interaction in cartilage and meniscus was observed after running. Superficial and medial areas of knee cartilage and meniscus might be more susceptible to mechanical loading.

Efficient markerless gene deletions in Pseudomonas protegens Pf-5 using a upp-based counterselective system.

OBJECTIVES: Developing a counterselective system for efficient markerless gene deletions in biocontrol strain P. protegens Pf-5. RESULTS: We successfully implemented a markerless deletion of upp in Pf-5 to obtain the 5-FU resistant strain Pf5139. With this strain, we performed markerless gene deletions for each component of Gac/Rsm system and a 17 kb DNA fragment with the deletion ratio of 20 to 50%, and efficiently constructed a strain with triple deletions based on the suicide plasmid pJQ200UPP. In addition, there is no obvious connection between the deleted fragment length and the deletion ratio. CONCLUSION: The upp-based counterselective system in this study is efficient and valuable for markerless gene deletions in Pf-5, indicating that it has great potential in the study of gene function and in the application of genome reduction for Pseudomonas strains.

Perspectives of healthcare providers on withdrawal of life-sustaining treatment and advanced directives for unresponsive wakefulness syndrome in China.

Objectives: We performed the current research to describe healthcare providers' perspectives toward withdrawal of life-sustaining treatment (WLST) and advanced directive (AD) of patients with unresponsive wakefulness syndrome (UWS) and to identify influencing factors of their perspectives. Methods: Healthcare providers were recruited during a professional conference on disorders of consciousness (DoC). Participants completed self-administered questionnaires which included demographics, personal perspectives regarding WLST and the perception of ADs. Results: A total of 230 Chinese healthcare providers (female: 69.7%) were included. Only a small proportion reported positive attitudes toward withdrawing artificial nutrition and hydration (35.2%), antibiotics (30.9%), and do-not-resuscitation orders (23.5%) in UWS patients. As for predictors' identification, religion was significantly associated with the positive attitude toward DNR order (p = 0.004). Moreover, although 47.4% of the participants had never heard of ADs before of conference, almost all of them would consider ADs (95.7%) thereafter, especially for non-neurologists (p = 0.033). Conclusion: The propensity to WLST for UWS in China is low and perspective on WLST is significantly associated with individual characteristics. The attitudes of healthcare providers toward integrating ADs in the decisional process are positive. Future research regarding ADs and their predictors should be carried out to improve the quality of end-of-life care of UWS in China.

Changes in inflammatory edema and fat fraction of thigh muscles following a half-marathon in recreational marathon runners.

It is known that microtrauma exists in the thigh muscles after long-distance running such as the half-marathon. Moreover, training characteristics of long-distance runners may influence the specificity of the distribution of muscle fiber types in the thigh and affect muscle responses to lipid metabolism. However, the specific changes in microtrauma and intramuscular lipid in thigh muscles after a half-marathon are unknown. A cohort of 20 healthy recreational marathon runners was recruited to complete a half-marathon. MRI T2 mapping and 6-echo q-Dixon sequences were employed at baseline (P1), 2-3 h after running (P2), and 1 day after running (P3). Inflammatory markers (the T2 values) and intramuscular fat fraction (the proton density fat fraction, PDFF) were measured in thigh muscles to detect microtrauma and intramuscular lipid changes, respectively. One-way analysis of variance showed significant time effects for T2 values and PDFF. Post hoc analysis of the 14 datasets collected at three time points revealed significantly higher T2 values in all thigh muscles after running (all p < 0.05). Significant differences in T2 values persisted for all thigh muscles at P3 compared to P1 (all p < 0.05). The PDFF of the vastus lateralis and vastus medialis was significantly decreased at P2 compared to P1 (p < 0.05). No significant differences in PDFF were observed for the thigh muscles at P3 compared to P1. The manifestations of inflammation edema and intramuscular lipid investigated through MRI may offer valuable insights for recreational marathon runners regarding the lower limb movement characteristics during half-marathon running.

Impact of Running Exercise on Intervertebral Disc: A Systematic Review.

CONTEXT: Running is one of the most popular sports worldwide. However, controversies exist regarding how running affects runner's intervertebral discs (IVD). OBJECTIVE: The purpose of this study was to systematically review studies that evaluated IVD morphology or composition changes in response to running exercise, to determine the impact of running exercise on IVD. DATA SOURCES: A systematic literature search was performed for 4 major databases: PubMed, Cochrane, Embase, and Web of Science. STUDY SELECTION: Inclusion criteria were as follows: (1) healthy people without known IVD disease or major complications such as tuberculosis (IVD degeneration or low back pain are considered as minor complications); (2) subjects performed 1-time or regular running exercises; (3) pre and post comparison of runners or comparison between runners and healthy control subjects; (4) direct or indirect IVD morphology or composition measured; (5) IVD assessed before and after either acute or chronic running exercise, or compared cross-sectionally between runners and controls. Exclusion criteria were as follows: (1) reviews, editorials, letters or abstracts only; (2) animal studies; (3) subjects performed exercise other than running. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 3. DATA EXTRACTION: The extracted data included study design and primary outcomes of the included studies. The Newcastle-Ottawa scale (NOS) was used to evaluate study quality and risk of bias. RESULTS: A total of 13 studies with 632 participants were included in the final analysis; 4 studies measured IVD changes using stature or spinal height, and the other 9 measured IVD changes using magnetic resonance imaging; 6 studies found that running acutely and negatively impacts IVD; 3 out of 5 cross-sectional studies found that IVD parameters are better for runners than controls; 1 longitudinal study found no significant difference in IVD before and after training for marathon in runners; 1 longitudinal study found no significant difference in changes of IVD between runners and controls after 15 years of follow-up. CONCLUSION: Negative changes in IVD exist for a short period of time after running, which may be due to the temporary compression pushing water content out of the disc. Cross-sectional studies suggest that long-term running exerts a mild positive effect on IVD; however, this inference has not been confirmed by high-quality longitudinal studies.

Prediction of half-marathon performance of male recreational marathon runners using nomogram.

BACKGROUND: Long-distance running is a popular competitive sport. We performed the current research as to develop an easily accessible and applicable model to predict half-marathon performance in male recreational half-marathon runners by nomogram. METHODS: Male recreational half-marathon runners in Zhejiang Province, China were recruited. A set of literature-based and panel-reviewed questionnaires were used to assess the epidemiological conditions of the recruited runners. Descriptive and binary regression analyses were done for the profiling and identification of predictors related to higher half-marathon performance (completing time ≤ 105 min). Participants were assigned to the training set (n = 141) and the testing set (n = 61) randomly. A nomogram was used to visually predict the half-marathon performance, and the receiver operating characteristic (ROC) was used to evaluate the predictive ability of the nomogram. RESULTS: A total of 202 participants (median age: 49 years; higher half-marathon performance: 33.7%) were included. After multivariate analysis, three variables remained as significant predictors: longer monthly running distance [adjusted odds ratio (AOR) = 0.992, 95% confidence interval (CI): 0.988 to 0.996, p < 0.001], faster mean training pace (AOR = 2.151, 95% CI: 1.275 to 3.630, p < 0.001), and better sleep quality [the Pittsburgh Sleep Quality Index (PSQI), AOR = 2.390, 95% CI: 1.164 to 4.907, p = 0.018]. The AUC of the training and testing sets in nomogram were 0.750 and 0.743, respectively. Further ternary and linear regression analyses corroborated the primary findings. CONCLUSIONS: This study developed a nomogram with good potential to predict the half-marathon performance of recreational runners. Our results suggest that longer monthly running distance, faster mean training pace and better sleep quality notably contribute to better half-marathon performance.

Effects of long-term running on the structure and biochemical composition of knee cartilage in males: a cross-sectional study.

Background: Running has been widely recognized as a beneficial activity for improving physical fitness, but it can also increase the risk of running-related injuries (RRIs). This study aims to assess the impact of long-term running on the structural and biochemical composition of the knee. Methods: This study recruited a total of 32 participants, including 16 male recreational runners, aged 28-49 years, with a running experience of 2-7 years, and 16 matched sedentary controls. Magnetic resonance (MR) scans of T2* mapping and three-dimensional double-echo steady-state (3D-DESS) were performed on all participants. The volumes, thickness, and T2* values of joint articular cartilage were obtained via automatic segmentation software. Results: Compared with the sedentary controls, runners exhibited significant increases in the volumes of both the femoral medial articular cartilage and the tibial medial articular cartilage. Additionally, there were significant increases in the thickness of several cartilage regions, including femoral medial cartilage, femoral medial articular cartilage, femoral medial thickness, femoral lateral cartilage, and tibial medial articular cartilage. Notably, the T2* values in the femoral lateral and tibial lateral cartilage of runners decreased significantly, while those in the patellar cartilage and medial tibial cartilage increased significantly. Runner pace was negatively correlated with the overall knee cartilage thickness (r=-0.556; P=0.02), femoral cartilage thickness (r=-0.533; P=0.03), and volume (r=-0.532; P=0.03) but positively correlated with the T2* value of the patellar cartilage (r=0.577; P=0.01). Conclusions: Our study suggests that long-term mechanical stress from running may lead to increased thickness and volume in certain knee joint cartilage regions, possibly enhancing the functional adaptability of knee cartilage. The varying changes in T2* value in the tibial and fibular cartilage areas may indicate differing adaptability to pressure.

The Effects of Ketogenic Diets and Ketone Supplements on the Aerobic Performance of Endurance Runners: A Systematic Review.

CONTEXT: Ketogenic diets and ketone supplements have gained popularity among endurance runners given their purported effects: potentially delaying the onset of fatigue by enabling the increased utilization of the body's fat reserve or external ketone bodies during prolonged running. OBJECTIVE: This systematic review was conducted to evaluate the effects of ketogenic diets (>60% fat and <10% carbohydrates/<50 g carbohydrates per day) or ketone supplements (ketone esters or ketone salts, medium-chain triglycerides or 1,3-butadiol) on the aerobic performance of endurance runners. DATA SOURCES: A systematic search was conducted in PubMed, Web of Science, Pro Quest, and Science Direct for publications up to October 2023. STUDY SELECTION: Human studies on the effects of ketogenic diets or ketone supplements on the aerobic performance of adult endurance runners were included after independent screening by 2 reviewers. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 3. DATA EXTRACTION: Primary outcomes were markers of aerobic performance (maximal oxygen uptake [VO2max], race time, time to exhaustion and rate of perceived exertion). RESULTS: VO2max was assessed by incremental test to exhaustion. Endurance performance was assessed by time trials, 180-minute running trials, or run-to-exhaustion trials; 5 studies on ketogenic diets and 7 studies on ketone supplements involving a total of 132 endurance runners were included. Despite the heterogeneity in study design and protocol, none reported benefits of ketogenic diets or ketone supplements on selected markers of aerobic performance compared with controls. Reduction in bodyweight and fat while preserving lean mass and improved glycemic control were reported in some included studies on ketogenic diets. CONCLUSION: This review did not identify any significant advantages or disadvantages of ketogenic diets or ketone supplements for the aerobic performance of endurance runners. Further trials with larger sample sizes, more gender-balanced participants, longer ketogenic diet interventions, and follow-up on metabolic health are warranted.

Deficiency of IQCH causes male infertility in humans and mice.

IQ motif-containing proteins can be recognized by calmodulin (CaM) and are essential for many biological processes. However, the role of IQ motif-containing proteins in spermatogenesis is largely unknown. In this study, we identified a loss-of-function mutation in the novel gene IQ motif-containing H (IQCH) in a Chinese family with male infertility characterized by a cracked flagellar axoneme and abnormal mitochondrial structure. To verify the function of IQCH, Iqch knockout (KO) mice were generated via CRISPR-Cas9 technology. As expected, the Iqch KO male mice exhibited impaired fertility, which was related to deficient acrosome activity and abnormal structures of the axoneme and mitochondria, mirroring the patient phenotypes. Mechanistically, IQCH can bind to CaM and subsequently regulate the expression of RNA-binding proteins (especially HNRPAB), which are indispensable for spermatogenesis. Overall, this study revealed the function of IQCH, expanded the role of IQ motif-containing proteins in reproductive processes, and provided important guidance for genetic counseling and genetic diagnosis of male infertility.