Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice

Infertility represents a significant health concern,with sperm quantity and quality being crucial determinants of male fertility.Oligoasthenoteratozoospermia(OAT)is characterized by reduced sperm motility,lower sperm concentration,and morphological abnormalities in sperm heads and flagella.Although variants in several genes have been implicated in OAT,its genetic etiologies and pathogenetic mechanisms remain inadequately understood.In this study,we identified a homozygous nonsense mutation(c.916C>T,p.Arg306*)in the coiled-coil domain containing 146(CCDC146)gene in an infertile male patient with OAT.This mutation resulted in the production of a truncated CCDC146 protein(amino acids 1-305),retaining only two out of five coiled-coil domains.To validate the pathogenicity of the CCDC146 mutation,we generated a mouse model(Ccdc146^(mut/mut))with a similar mutation to that of the patient.Consistently,the Ccdc146mut/mut mice exhibited infertility,characterized by significantly reduced sperm counts,diminished motility,and multiple defects in sperm heads and flagella.Furthermore,the levels of axonemal proteins,including DNAH17,DNAH1,and SPAG6,were significantly reduced in the sperm of Ccdc146^(mut/mut) mice.Additionally,both human and mouse CCDC146 interacted with intraflagellar transport protein 20(IFT20),but this interaction was lost in the mutated versions,leading to the degradation of IFT20.This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility,potentially by disrupting axonemal protein transportation.These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.

Computationally predicted pathogenic USP9X mutation identified in infertile men does not affect spermatogenesis in mice

Infertility is a major health issue,affecting approximately 15%of couples of child-bearing age.Although nearly half of idiopathic infertility cases are assumed to have a genetic basis,the underlying causes remain largely unknown in most infertile men.

A Fast Product of Conditional Reduction Method for System Failure Probability Sensitivity Evaluation

Systemreliability sensitivity analysis becomes difficult due to involving the issues of the correlation between failure modes whether using analytic method or numerical simulation methods.A fast conditional reduction method based on conditional probability theory is proposed to solve the sensitivity analysis based on the approximate analytic method.The relevant concepts are introduced to characterize the correlation between failure modes by the reliability index and correlation coefficient,and conditional normal fractile the for the multi-dimensional conditional failure analysis is proposed based on the two-dimensional normal distribution function.Thus the calculation of system failure probability can be represented as a summation of conditional probability terms,which is convenient to be computed by iterative solving sequentially.Further the system sensitivity solution is transformed into the derivation process of the failure probability correlation coefficient of each failure mode.Numerical examples results show that it is feasible to apply the idea of failure mode relevancy to failure probability sensitivity analysis,and it can avoid multi-dimension integral calculation and reduce complexity and difficulty.Compared with the product of conditional marginalmethod,a wider value range of correlation coefficient for reliability analysis is confirmed and an acceptable accuracy can be obtained with less computational cost.

Plasma membrane-localized Hsp40/DNAJ chaperone protein facilitates OsSUVH7-OsBAG4-OsMYB106 transcriptional complex formation for Os HKT1;5 activation

The salinization of irrigated land affects agricultural productivity.HIGH-AFFINITY POTASSIUM(K+)TRANSPORTER 1;5(OsHKT1;5)-dependent sodium(Na+)transport is a key salt tolerance mechanism during rice growth and development.Using a previously generated high-throughput activation tagging-based T-DNA insertion mutant pool,we isolated a mutant exhibiting salt stress-sensitive phenotype,caused by a reduction in OsHKT1;5transcripts.The salt stress-sensitive phenotype of this mutant results from the loss of function of OsDNAJ15,which encodes plasma membranelocalized heat shock protein 40(Hsp40).osdnaj15loss-of-function mutants show decreased plant height,increased leaf angle,and reduced grain number caused by shorter panicle length and fewer branches.On the other háand,OsDNAJ15-overexpression plants showed salt stress-tolerant phenotypes.Intriguingly,salt stress facilitates the nuclear relocation of OsDNAJ15 so that it can interact with OsBAG4,and OsDNAJ15 and OsBAG4synergistically facilitate the DNA-binding activity of OsMYB106 to positively regulate the expression of OsHKT1;5.Overall,our results reveal a novel function of plasma membrane-localized Hsp40protein in modulating,alongside chaperon regulator OsBAG4,transcriptional regulation under salinity stress tolerance.

Multivariate MOF for optimizing atmospheric water harvesting

Atmospheric water harvesting offers a powerful and promising solution to address the problem of global freshwater scarcity.In the past decade,significant progress has been achieved in utilizing hydrolytically stable metal-organic frameworks as recyclable water-sorbent materials under low relative humidity,especially in those arid areas.Recently,Yaghi's group has employed a combined crystallographic and theoretical technique to decipher the water filling mechanism in MOF-303,where the polar organic linkers rather than the inorganic units of MOF are demonstrated as the key factor.Hence,the hydrophilic strength of the water-binding pocket in MOFs can be optimized through the approach of multivariate modulations,resulting in enhanced water harvesting properties.

Type-B response regulator OsRR22 forms a transcriptional activation complex with OsSLR1 to modulate OsHKT2;1 expression in rice

Soil salinity severely limits crop yields and quality.Plants have evolved several strategies to mitigate the adverse effects of salinity,including redistribution and compartmentalization of toxic ions using ion-specific transporters.However,the mechanisms underlying the regulation of these ion transporters have not been fully elucidated.Loss-of-function mutants of OsHKT2;1,which is involved in sodium uptake,exhibit strong salt stress-resistant phenotypes.In this study,OsHKT2;1 was identified as a transcriptional target of the type-B response regulator OsRR22.Loss-of-function osrr22 mutants showed resilience to salt stress,and OsRR22-overexpression plants were sensitive to salt stress.OsRR22 was found to activate the expression of OsHKT2;1 by directly binding to the promoter region of OsHKT2;1 via a consensus cis-element of type-B response regulators.Moreover,rice DELLA protein OsSLR1 directly interacted with OsRR22 and functioned as a transcriptional co-activator.This study has uncovered a novel transcriptional regulatory mechanism by which a type-B response regulator controls sodium transport under salinity stress.

A recurrent homozygous missense mutation in CCDC103 causes asthenoteratozoospermia due to disorganized dynein arms

Asthenoteratozoospermia is one of the most severe types of qualitative sperm defects.Most cases are due to mutations in genes encoding the components of sperm flagella,which have an ultrastructure similar to that of motile cilia.Coiled-coil domain containing 103(CCDC103)is an outer dynein arm assembly factor,and pathogenic variants of CCDC103 cause primary ciliary dyskinesia(PCD).However,whether CCDC103 pathogenic variants cause severe asthenoteratozoospermia has yet to be determined.Whole-exome sequencing(WES)was performed for two individuals with nonsyndromic asthenoteratozoospermia in a consanguineous family.A homozygous CCDC103 variant segregating recessively with an infertility phenotype was identified(ENST00000035776.2,c.461A>C,p.His154Pro).CCDC103 p.His154Pro was previously reported as a high prevalence mutation causing PCD,though the reproductive phenotype of these PCD individuals is unknown.Transmission electron microscopy(TEM)of affected individuals’spermatozoa showed that the mid-piece was severely damaged with disorganized dynein arms,similar to the abnormal ultrastructure of respiratory ciliary of PCD individuals with the same mutation.Thus,our findings expand the phenotype spectrum of CCDC103 p.His154Pro as a novel pathogenic gene for nonsyndromic asthenospermia.