Alterations in synaptonemal complex coding genes and human infertility.

About 10% of reproductive-aged couples suffer from infertility. However, the genetic causes of human infertility cases are largely unknown. Meiosis produces haploid gametes for fertilization and errors in meiosis are associated with human infertility in both males and females. Successful meiosis relies on the assembly of the synaptonemal complex (SC) between paired homologous chromosomes during the meiotic prophase. The SC is ultrastructurally and functionally conserved, promoting inter-homologous recombination and crossover formation, thus critical for accurate meiotic chromosome segregation. With whole-genome/exome sequencing and mouse models, a list of mutations in SC coding genes has been linked to human infertility. Here we summarize those findings. We also analyzed SC gene variants present in the general population and presented complex interaction networks associated with SC components. Whether a combination of genetic variations and environmental factors causes human infertility demands further investigations.

Processing Laue Microdiffraction Raster Scanning Patterns with Machine Learning Algorithms: A Case Study with a Fatigued Polycrystalline Sample.

The massive amount of diffraction images collected in a raster scan of Laue microdiffraction calls for a fast treatment with little if any human intervention. The conventional method that has to index diffraction patterns one-by-one is laborious and can hardly give real-time feedback. In this work, a data mining protocol based on unsupervised machine learning algorithm was proposed to have a fast segmentation of the scanning grid from the diffraction patterns without indexation. The sole parameter that had to be set was the so-called "distance threshold" that determined the number of segments. A statistics-oriented criterion was proposed to set the "distance threshold". The protocol was applied to the scanning images of a fatigued polycrystalline sample and identified several regions that deserved further study with, for instance, differential aperture X-ray microscopy. The proposed data mining protocol is promising to help economize the limited beamtime.

The organization, regulation, and biological functions of the synaptonemal complex.

The synaptonemal complex (SC) is a meiosis-specific proteinaceous macromolecular structure that assembles between paired homologous chromosomes during meiosis in various eukaryotes. The SC has a highly conserved ultrastructure and plays critical roles in controlling multiple steps in meiotic recombination and crossover formation, ensuring accurate meiotic chromosome segregation. Recent studies in different organisms, facilitated by advances in super-resolution microscopy, have provided insights into the macromolecular structure of the SC, including the internal organization of the meiotic chromosome axis and SC central region, the regulatory pathways that control SC assembly and dynamics, and the biological functions exerted by the SC and its substructures. This review summarizes recent discoveries about how the SC is organized and regulated that help to explain the biological functions associated with this meiosis-specific structure.

SYP-5 regulates meiotic thermotolerance in Caenorhabditis elegans.

Meiosis produces the haploid gametes required by all sexually reproducing organisms, occurring in specific temperature ranges in different organisms. However, how meiotic thermotolerance is regulated remains largely unknown. Using the model organism Caenorhabditis elegans, here, we identified the synaptonemal complex (SC) protein SYP-5 as a critical regulator of meiotic thermotolerance. syp-5-null mutants maintained a high percentage of viable progeny at 20°C but produced significantly fewer viable progeny at 25°C, a permissive temperature in wild-type worms. Cytological analysis of meiotic events in the mutants revealed that while SC assembly and disassembly, as well as DNA double-strand break repair kinetics, were not affected by the elevated temperature, crossover designation, and bivalent formation were significantly affected. More severe homolog segregation errors were also observed at elevated temperature. A temperature switching assay revealed that late meiotic prophase events were not temperature-sensitive and that meiotic defects during pachytene stage were responsible for the reduced viability of syp-5 mutants at the elevated temperature. Moreover, SC polycomplex formation and hexanediol sensitivity analysis suggested that SYP-5 was required for the normal properties of the SC, and charge-interacting elements in SC components were involved in regulating meiotic thermotolerance. Together, these findings provide a novel molecular mechanism for meiotic thermotolerance regulation.

Determination and comparison of flavor (retronasal) threshold values of 19 flavor compounds in Baijiu.

Nineteen compounds, including ten esters, six acids, and three alcohols, were characterized and considered as significant tastants and aromas in Baijiu (Chinese Liquor). The flavor (retronasal) threshold values (FTVs) of these 19 compounds were determined by the 10 samples test method in hydroalcoholic solutions (46% v/v in ethanol). The FTVs of the compounds were calculated based on the best estimate threshold method. All the FTVs determined by the professional Chinese Baijiu tasters were lower than those by the nonprofessional tasters. For instance, the detection (2.31 mg/kg) and recognition (11.74 mg/kg) values of ethyl hexanoate determined by the nonprofessional group were higher than the respectively corresponding values 0.44 and 3.80 mg/kg determined by the professional group. All of the odor activity values (OAVs) of ethyl valerate (OAV: 1176.00 to 2321.17), ethyl octanoate (OAV: 6841.20 to 7851.60), and 1-butanol (OAV: 26.78 to 39.72) in Gujinggong Baijiu were more than 10-fold larger than their dose-over-threshold values (DoTs), for which the DoTs of ethyl valerate, ethyl octanoate, and 1-butanol were 92.84 to 183.25, 180.03 to 206.62, 1.18 to 1.75, respectively. On the contrary, the OAVs of ethyl heptanoate (OAV: 3.60 to 5.70) and isoamyl alcohol (OAV: 1.18 to 1.57) were lower than their corresponding DoTs at 152.62 to 241.63 and 12.26 to 16.41. The results demonstrated that it is necessary to consider and compare their DoTs and OAVs simultaneously on evaluating the contribution of flavor compounds in Baijiu. PRACTICAL APPLICATION: Sensory evaluation of threshold values of various flavor compounds could be significantly affected by their existing matrix. Most of the published results of the flavor threshold value of compounds were determined from the matrix such as beer, whiskey, red wine, rather than Chinese Baijiu. The results of this work not only could provide valuable information for flavor studies of Chinese Baijiu but also give useful information for the Baijiu industry to quality control.

High Strain Rate Response of In-Situ TiB2/7055 Composite by Taylor Impact.

The high strain rate deformation behavior and microstructure evolution of in situ TiB2 particle reinforced Al-Zn-Mg-Cu composite were investigated by means of Taylor impact. The dynamic tests were performed at three different impact velocities. Under three different velocities, no obvious shear failure occurred in the composite, indicating a good impact resistance. Compared to the quasi-static compression test, the dynamic yield strength increased obviously with the rise of velocity, even more than 1 GPa. The dislocation multiplication, phonon drag effect and ceramic reinforcement increased the flow stress of composite. Fine, equiaxed grain structure developed after impact, resulting from grain fragmentation or dynamic recrystallization. Finite element simulation of Taylor impact was qualitatively in agreement with the experiments, which was useful to elucidate the formation of equiaxed grain structure.

Hot Deformation Behavior and Workability of In Situ TiB2/7050Al Composites Fabricated by Powder Metallurgy.

Isothermal compression tests of in situ TiB2/7050Al composites fabricated by powder metallurgy were performed at 300-460 °C with the strain rate varying from 0.001 s-1 to 1 s-1. The Arrhenius constitutive equation and hot processing map of composites were established, presenting excellent hot workability with low activation energies and broad processing windows. Dramatic discontinuous/continuous dynamic recrystallization (DDRX/CDRX) and grain boundary sliding (GBS) take place in composites during deformation, depending on the Zener-Hollomon parameter (Z) values. It was found that initially uniform TiB2 particles and fine grain structures are beneficial to the DDRX, which is the major softening mechanism in composites at high Z values. With the Z value decreasing, dynamic recovery and CDRX around particles are enhanced, preventing the occurrence of DDRX. In addition, fine grain structures in composites are stable at elevated temperature thanks to the pinning of dense nanoparticles, which triggers the occurrence of GBS and ensures good workability at low Z values.

Corrigendum to "Five Novel Mutations in LOXHD1 Gene Were Identified to Cause Autosomal Recessive Nonsyndromic Hearing Loss in Four Chinese Families".

[This corrects the article DOI: 10.1155/2020/1685974.].

Asymmetrical effects of deafness-associated mitochondrial DNA 7516delA mutation on the processing of RNAs in the H-strand and L-strand polycistronic transcripts.

In this report, we investigated the molecular mechanism underlying a deafness-associated m.7516delA mutation affecting the 5' end processing sites of mitochondrial tRNAAsp and tRNASer(UCN). An in vitro processing experiment demonstrated that m.7516delA mutation caused the aberrant 5' end processing of tRNASer(UCN) and tRNAAsp precursors, catalyzed by RNase P. Using cytoplasmic hybrids (cybrids) derived from one hearing-impaired Chinese family bearing the m.7516delA mutation and control, we demonstrated the asymmetrical effects of m.7516delA mutation on the processing of tRNAs in the heavy (H)-strand and light (L)-strand polycistronic transcripts. Specially, the m.7516delA mutation caused the decreased levels of tRNASer(UCN) and downstream five tRNAs, including tRNATyr from the L-strand transcripts and tRNAAsp from the H-strand transcripts. Strikingly, mutant cybrids exhibited the lower level of COX2 mRNA and accumulation of longer and uncleaved precursors of COX2 from the H-strand transcripts. Aberrant RNA metabolisms yielded variable reductions in the mitochondrial proteins, especially marked reductions in the levels of ND4, ND5, CO1, CO2 and CO3. The impairment of mitochondrial translation caused the proteostasis stress and respiratory deficiency, diminished ATP production and membrane potential, increased production of reactive oxygen species and promoted apoptosis. Our findings provide new insights into the pathophysiology of deafness arising from mitochondrial tRNA processing defects.

Cochlear Implantation in a Patient with a Novel POU3F4 Mutation and Incomplete Partition Type-III Malformation.

Aims: This study is aimed at (1) analyzing the clinical manifestations and genetic features of a novel POU3F4 mutation in a nonsyndromic X-linked recessive hearing loss family and (2) reporting the outcomes of cochlear implantation in a patient with this mutation. Methods: A patient who was diagnosed as the IP-III malformation underwent cochlear implantation in our hospital. The genetic analysis was conducted in his family, including the whole-exome sequencing combined with Sanger sequencing and bioinformatic analysis. Clinical features, preoperative auditory and speech performances, and postoperative outcomes of cochlear implant (CI) were assessed on the proband and his family. Results: A novel variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was detected in the family, which was cosegregated with the hearing loss. This variant was absent in 200 normal-hearing persons. The phylogenetic analysis and structure modeling of Pou3f4 protein further confirmed that the novel mutation was pathogenic. The proband underwent cochlear implantation on the right ear at four years old and gained greatly auditory and speech improvement. However, the benefits of the CI declined about three and a half years postoperation. Though the right ear had been reimplanted, the outcomes were still worse than before. Conclusion: A novel frame shift variant c.400_401insACTC (p.Q136LfsX58) in the POU3F4 gene was identified in a Chinese family with X-linked inheritance hearing loss. A patient with this mutation and IP-III malformation could get good benefits from CI. However, the outcomes of the cochlear implantation might decline as the patient grows old.

A novel MYH14 mutation in a Chinese family with autosomal dominant nonsyndromic hearing loss.

BACKGROUND: MYH14 gene mutations have been suggested to be associated with nonsyndromic/syndromic sensorineural hearing loss. It has been reported that mutations in MYH14 can result in autosomal dominant nonsyndromic deafness-4A (DFNA4). METHODS: In this study, we examined a four-generation Han Chinese family with nonsyndromic hearing loss. Targeted next-generation sequencing of deafness genes was employed to identify the pathogenic variant. Sanger sequencing and PCR-RFLP analysis were performed in affected members of this family and 200 normal controls to further confirm the mutation. RESULTS: Four members of this family were diagnosed as nonsyndromic bilateral sensorineural hearing loss with postlingual onset and progressive impairment. A novel missense variant, c.5417C > A (p.A1806D), in MYH14 in the tail domain of NMH II C was successfully identified as the pathogenic cause in three affected individuals. The family member II-5 was suggested to have noise-induced deafness. CONCLUSION: In this study, a novel missense mutation, c.5417C > A (p.A1806D), in MYH14 that led to postlingual nonsyndromic autosomal dominant SNHL were identified. The findings broadened the phenotype spectrum of MYH14 and highlighted the combined application of gene capture and Sanger sequencing is an efficient approach to screen pathogenic variants associated with genetic diseases.

Identification of two novel mutations in POU4F3 gene associated with autosomal dominant hearing loss in Chinese families.

Autosomal dominant non-syndromic hearing loss is genetically heterogeneous with 47 genes identified to date, including POU4F3. In this study, by using a next-generation sequencing panel targeting 127 deafness genes, we identified a pathogenic frameshift mutation c.704_705del and a missense mutation c.593G>A in two three-generation Chinese families with late-onset progressive ADNSHL, respectively. The novel mutations of POU4F3 co-segregated with the deafness phenotype in these two families. c.704_705del caused a frameshift p.T235fs and c.593G>A caused an amino acid substitution of p.R198H. Both mutations led to an abnormal and incomplete protein structure. POU4F3 with either of the two mutations was transiently transfected into HEI-OC1 and HEK 293 cell lines and immunofluorescence assay was performed to investigate the subcellular localization of mutated protein. The results indicated that both c.704_705del (p.T235fs) and c.593G>A (p.R198H) could impair the nuclear localization function of POU4F3. The p.R198H POU4F3 protein was detected as a weak band of the correct molecular weight, indicating that the stability of p.R198H POU4F3 differed from that of the wild-type protein. While, the p.T235fs POU4F3 protein was expressed with a smaller molecular weight, implying this mutation result in a frameshift and premature termination of the POU4F3 protein. In summary, we report two novel mutations of POU4F3 associated with progressive ADNSHL and explored their effects on POU4F3 nuclear localization. These findings expanded the mutation spectrum of POU4F3 and provided new knowledge for the pathogenesis of POU4F3 in hearing loss.

Multivalent weak interactions between assembly units drive synaptonemal complex formation.

The synaptonemal complex (SC) is an ordered but highly dynamic structure assembled between homologous chromosomes to control interhomologous crossover formation, ensuring accurate meiotic chromosome segregation. However, the mechanisms regulating SC assembly and dynamics remain unclear. Here, we identified two new SC components, SYP-5 and SYP-6, in Caenorhabditis elegans that have distinct expression patterns and form distinct SC assembly units with other SYPs through stable interactions. SYP-5 and SYP-6 exhibit diverse in vivo SC regulatory functions and distinct phase separation properties in cells. Charge-interacting elements (CIEs) are enriched in SC intrinsically disordered regions (IDRs), and IDR deletion or CIE removal confirmed a requirement for these elements in SC regulation. Our data support the theory that multivalent weak interactions between the SC units drive SC formation and that CIEs confer multivalency to the assembly units.

Five Novel Mutations in LOXHD1 Gene Were Identified to Cause Autosomal Recessive Nonsyndromic Hearing Loss in Four Chinese Families.

Hearing loss is one of the most common sensory disorders in newborns and is mostly caused by genetic factors. Autosomal recessive nonsyndromic hearing loss (ARNSHL) is usually characterized as a severe-to-profound congenital sensorineural hearing loss and later can cause various degrees of defect in the language and intelligent development of newborns. The mutations in LOXHD1 gene have been shown to cause DFNB77, a type of ARNSHL. To date, there are limited reports about the association between LOXHD1 gene and ARNSHL. In this study, we reported six patients from four Chinese families suffering from severe-to-profound nonsyndromic hearing loss. We performed targeted next generation sequencing in the six affected members and identified five novel pathogenic mutations in LOXHD1 including c.277G>A (p.D93N), c.611-2A>T, c.1255+3A>G, c.2329C>T (p.Q777 ∗ ), and c.5888delG (p.G1963Afs ∗ 136). These mutations were confirmed to be cosegregated with the hearing impairment in the families by Sanger sequencing and were inherited in an autosomal recessive pattern. All of the five mutations were absent in 200 control subjects. There were no symptoms of Fuchs corneal dystrophy in the probands and their blood-related relatives. We concluded that these five novel mutations could be involved in the underlying mechanism resulting in the hearing loss, and this discovery expands the genotypic spectrum of LOXHD1 mutations.

Mutation spectrum and hotspots of the common deafness genes in 314 patients with nonsyndromic hearing loss in Heze area, China.

Background: Although, half of the childhood deafness is genetically related, the molecular etiology of hearing impairment has not been demonstrated explicitly. In addition, the mutation spectrums of deafness genes vary among different areas and ethnics. Objectives: To know more about the mutation spectrums of deafness genes in China, we tested the mutations of three common deafness genes (GJB2, SLC26A4, and mtDNA12SrRNA) in a particular deafness population from Heze area. Materials and methods: SNPscan technology was utilized to perform mutation screening for these three common deafness genes in 314 nonsyndromic deaf patients from Heze area. Results: 38.21% (120/314) of these 314 patients with nonsyndromic hearing loss from Heze area were related to the genetic defects in these three deafness genes, including 20.06% (63/314) for GJB2, 15.29% (48/314) for SLC26A4, and 2.87% (9/314) for mtDNA12SrRNA. Furthermore, the mutation hotspots in three deaf genes were GJB2 235delC, SLC26A4 c.919-2A > G, and mtDNA12SrRNA 1555A > G, respectively, distinct from hotspots reported in other regions worldwide. Conclusion: Our results disclosed a special and unique mutation spectrum of these three common deaf genes in Heze deaf population.

Strain measurement of particle-reinforced composites at the microscale: An approach towards concurrent characterization of strain and microstructure.

The mechanical behavior of particle-reinforced composites is largely determined by the interaction between the reinforcing particles and matrix. Although conventional digital image correlation (DIC) allows accurate measurements of strain at microscale, it usually requires preparation of synthetic pattern on the sample surface, which would affect the observation of reinforcing particles. An approach is proposed in this work that relies solely on the reinforcing particles as DIC pattern, thereby enabling concurrent microstructure observation and strain measurement. The main idea of the approach is that only the regions of high gray level contrast shall be correlated. The approach has been tested against the benchmarks taken from the images of rigidly translated and rotated sample, and the influence of image magnification has been discussed in detail. The approach has also been applied to actual tensile test and yielded qualitatively similar results as the conventional DIC approach.

Identification of a peptide for folate receptor alpha by phage display and its tumor targeting activity in ovary cancer xenograft.

The expression level of folate receptor alpha (FRα) is located highly rate in ovarian cancer though it is remained absent in normal tissues. This highly tumor restricted expression profile makes FRα a promising target for tumor therapy and diagnosis. In this research we report a FRα binding peptide C7(Met-His-Thr-Ala-Pro-Gly-Trp-Gly-Tyr-Arg-Leu-Ser) discovered by phage display and this peptide showed specific binding to FRα expressing cells by cell ELISA and flow cytometry. Tumor targeting ability of C7 was proved in vivo by both phage homing experiment and fluorescence imaging. C7 can be internalized by SKOV3 cells and its affinity to FRα was determined by MST. The molecular recognition was revealed by structure modeling, suggesting its binding mode with FRα.

Three MYO15A Mutations Identified in One Chinese Family with Autosomal Recessive Nonsyndromic Hearing Loss.

Hearing impairment is one of the most common sensory disease, of which more than 50% is attributed to a genetic etiology. The goal of this research is to explore the genetic cause of a Chinese deafness pedigree who was excluded of GJB2, SLC26A4, or MtDNA12SrRNA variants. Three variants, c.3971C>A (p.A1324D), c.4011insA (p.Q1337Qfs∗22), and c.9690+1G>A, in the MYO15A gene were identified by targeted capture sequencing and Sanger sequencing, and the first two of them were novel. These variants were cosegregated with the disease in this family and absent in 200 normal hearing persons. They were concluded to be pathogenic mutations by phylogenetic analysis and structure modeling. Thus, the combined use of SNPScan assay and targeted capture sequencing is a high-efficiency and cost-effective screening procedure for hereditary hearing loss. Genetic counseling would be important for this family, and our finding would be a great supplement to the mutation spectrum of MYO15A.

Hcp/fcc nucleation in bcc iron under different anisotropic compressions at high strain rate: Molecular dynamics study.

Previous researches have revealed the importance of shear and the orientation dependence in the structural transition of iron. In this work, we introduce a series of shear deformations by adjusting the strain ratio between the longitudinal ([001]) and transversal ([010] and [100]) directions, and then investigate this structural transition under different anisotropic compressions with molecular dynamics simulations. It is found that the shear deformation can lower the transition pressure notably, and even change the nucleation structure and morphology. Under 1D-dominated compression (along (001) direction), there only appears hcp nucleation with a few fcc stacking faults. For other cases, more equivalent planes will be activated and fcc structure begins to nucleate. Under 2D-dominated compression (along (010) and (001) directions), the fcc mass fraction is already over the hcp phase. At last, we compare the variations of shear stress and potential energy for different phases, and present the sliding mechanism under typical anisotropic compressions.

Effects of temperature and void on the dynamics and microstructure of structural transition in single crystal iron.

With classic molecular dynamics simulations, we investigate the effects of temperature and void on the bcc to hcp/fcc structural transition in single crystal iron driven by 1D ([0 0 1]) and 3D (uniform) compressions. The results show that the pressure threshold does not reduce monotonously with temperature. The pressure threshold firstly increases and then decreases in the range of 60-360 K under 1D compression, while the variation trend is just opposite under 3D compression. As expected, the initial defect may lower the pressure threshold via heterogenous nucleation. This effect is found to be more distinct at lower temperature, and the heterogenous nucleation mainly results in hcp structure. Under the condition of strain constraint, the products of structural transition will respectively form flaky hcp twin structure ((1 0 0) or (0 1 0)) and lamellar structure ({1 1 0}) of mixed phases under 1D and 3D compressions. During the structural transition, we find the shear stress (1D compression) of hcp phase is always lower than that of bcc phase. The cold energy calculations indicate that the hcp phase is the most stable under high pressure. However, we observe the evident metastable state of bcc phase, whose energy will be much higher than both hcp and fcc phases, and then provides the possibility for the occurrence of fcc nucleation.