Estimating global annual gross primary production based on satellite-derived phenology and maximal carbon uptake capacity.

The high uncertainty regarding global gross primary production (GPP) remains unresolved. This study explored the relationships between phenology, physiology, and annual GPP to provide viable alternatives for accurate estimation. A statistical model of integrated phenology and physiology (SMIPP) was developed using GPP data from 145 FLUXNET sites to estimate the annual GPP for various vegetation types. By employing the SMIPP model driven by satellite-derived datasets of the global carbon uptake period (CUP) and maximal carbon uptake capacity (GPPmax), the global annual GPP was estimated for the period from 2001-2018. The results demonstrated that the SMIPP model accurately predicted annual GPP, with relative root mean square error values ranging from 11.20‒19.29% for forest types and 20.49‒35.71% for non-forest types. However, wetlands, shrublands, and evergreen forests exhibited relatively low accuracies. The average, trend, and interannual variation of global GPP during 2001-2018 were 132.6 Pg C yr-1, 0.25 Pg C yr-2, and 1.57 Pg C yr-1, respectively. They were within the ranges estimated in other global GPP products. Sensitivity analysis revealed that GPPmax had comparable effects to CUP in high-latitude regions but significantly greater impacts at the global scale, with sensitivity coefficients of 0.85 ± 0.23 for GPPmax and 0.46 ± 0.28 for CUP. This study provides a simple and practical method for estimating global annual GPP and highlights the influence of GPPmax and CUP on global-scale annual GPP.

Chronic exposure to tire rubber-derived contaminant 6PPD-quinone impairs sperm quality and induces the damage of reproductive capacity in male mice.

It has been reported that N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q), a derivative of the tire antioxidant, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD), exhibits acute toxicity towards organisms. However, the possible reproductive toxicity of 6PPD-Q in mammals has rarely been reported. In this study, the effects of 6PPD-Q on the reproductive toxicity of C57Bl/6 male mice were assessed after exposure to 6PPD-Q for 40 days at 4 mg/kg body weight (bw). Exposure to 6PPD-Q not only led to a decrease in testosterone levels but also adversely affected semen quality and in vitro fertilization (IVF) outcomes, thereby indicating impaired male fertility resulting from 6PPD-Q exposure. Additionally, transcriptomic and metabolomic analyses revealed that 6PPD-Q elicited differential expression of genes and metabolites primarily enriched in spermatogenesis, apoptosis, arginine biosynthesis, and sphingolipid metabolism in the testes of mice. In conclusion, our study reveals the toxicity of 6PPD-Q on the reproductive capacity concerning baseline endocrine disorders, sperm quality, germ cell apoptosis, and the sphingolipid signaling pathway in mice. These findings contribute to an enhanced understanding of the health hazards posed by 6PPD-Q to mammals, thereby facilitating the development of more robust safety regulations governing the utilization and disposal of rubber products.

Photocatalytic Unsymmetrical Diamination of Styrenes, Indoles, and Benzofurans Facilitated by Benzotriazolyl and Iminyl Radicals.

Utilizing energy transfer catalysis, this research employed the bifunctional reagents benzotriazole carboxylic acid oxime esters to simultaneously generate benzotriazole and imine radicals. The synthesis of two distinct C-N bonds in a single conversion is showcased through radical addition and radical-radical cross-coupling processes between benzotriazole carboxylic acid oxime ester and olefins. This process facilitates the intermolecular two-component unsymmetrical diamination reaction of olefins. Using this approach, more than 40 benzotriazole-containing molecules were successfully synthesized using styrene, indole, and benzofuran as acceptors, with yields ranging from moderate to excellent.

The Merger of Halogen Atom Transfer (XAT) and Energy Transfer Catalysis (EnT) for the Modular 1,2-Iminylalkylation of Diazenes.

The 1,2-iminylalkylation of diazenes using alkyl iodides in combination with an O-benzoyl oxime is reported. In this transformation, O-benzoyl oxime acted as a radical precursor and XAT mediator. In addition to common alkyl iodides, other alkyl iodides such as iodomethane, iodomethane-d3, trifluoroiodomethane, ethyl difluoroiodoacetate, and iodoalkanes containing unprotected hydroxyl and amide groups can also serve as C-radical precursors in the 1,2-iminylalkylation with electrophilic diazenes as radical acceptors.

Photoinduced Difunctionalization of Diazenes Enabled by N-N Radical Coupling.

In this study, a metal-free difunctionalization strategy for diazenes was developed using a range of bifunctionalization reagents. This strategy involves a unique N(sp3)-N(sp2) radical coupling between the hydrazine radical and the imine radical. More than 30 triazane core motifs were constructed by installing imines and various functional groups, including alkyl, phenyl, cyanoalkyl, and sulfonyl groups, on both ends of the nitrogen-nitrogen bond of diazenes in an efficient manner.

Comprehensive Analyses Revealed Eight Immune Related Signatures Correlated With Aberrant Methylations as Prognosis and Diagnosis Biomarkers for Kidney Renal Papillary Cell Carcinoma.

BACKGROUND: Kidney renal papillary cell carcinoma (KIRP) is a common type of renal cell carcinoma. DNA methylation plays an important role in the development of several cancers. The aim of our study was to identify differentially expressed genes associated with abnormal DNA methylation as biomarkers for predicting the outcome of KIRP. METHOD: We downloaded KIRP methylation data, RNA sequencing (RNAseq) data, and their corresponding clinical information from the Cancer Genome Atlas (TCGA) database. ChAMP and DEGseq2 packages in R software were used to screen differentially methylated probes (DMPs) and differentially expressed genes (DEGs). Univariate and multivariate Cox regression analyses were used to identify suitable immune related genes correlated with aberrant methylations as prognosis biomarkers. RESULTS: We identified 8 DEGs (Cysteine And Glycine Rich Protein 1 [CSRP1], major histocompatibility complex, Class II, DM Beta [HLA-DMB], LIF Receptor Subunit Alpha [LIFR], Leukotriene B4 receptor 2 [LTB4R2], Mitogen-Activated Protein Kinase Kinase Kinase 14 [MAP3K14], Nuclear Receptor Subfamily 2 Group F Member 1 [NR2F1], Secreted And Transmembrane 1 [SECTM1], and Vimentin [VIM]) that were independently associated with the overall survival (months) (OS) of KIRP. The time dependent area under the curve (AUC) for each receiver operating characteristic (ROC) of the risk assessment model at 1, 3, 5, and 10-years reached 0.8415, 0.8131, 0.7873, and 0.7667. The risk assessment model was correlated with several immune cells and factors. The AUC value of the diagnosis model using those 8 DEGs reached 0.99. CONCLUSIONS: The risk assessment model constructed by those 8 DEGs was well able to predict the prognosis and diagnose of KIRP. However, whether the prognosis and diagnosis model could be applied in clinical practice requires further study.

A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism.

Isolated hypogonadotropic hypogonadism (IHH) is a rare disease with hypogonadism and infertility caused by the defects in embryonic migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, hypothalamic GnRH secretion or GnRH signal transduction. PROKR2 gene, encoding a G-protein coupled receptor PROKR2, is one of the most frequently mutated genes identified in IHH patients. However, the functional consequences of several PROKR2 mutants remain elusive. In this study, we systematically analyzed the Gαq, Gαs and ERK1/2 signaling of 23 IHH-associated PROKR2 mutations which are yet to be functionally characterized. We demonstrate that blockage of Gαq, instead of MAPK/ERK pathway, inhibited PROK2-induced migration of PROKR2-expressing cells, implying that PROKR2-related IHH results primarily due to Gαq signaling pathway disruption. Combined with previous reports, we categorized a total of 63 IHH-associated PROKR2 mutations into four distinct groups according Gαq pathway functionality: (i) neutral (N, >80% activity); (ii) low pathogenicity (L, 50-80% activity); (iii) medium pathogenicity (M, 20-50% activity) and (iv) high pathogenicity (H, <20% activity). We further compared the cell-based functional results with in silico mutational prediction programs. Our results indicated that while Sorting Intolerant from Tolerant predictions were accurate for transmembrane region mutations, mutations localized in the intracellular and extracellular domains were accurately predicted by the Combined Annotation Dependent Depletion prediction tool. Our results thus provide a functional database that can be used to guide diagnosis and appropriate genetic counseling in IHH patients with PROKR2 mutations.

Reproductive Phenotypes and Genotypes in Men With IHH.

CONTEXT: Isolated hypogonadotropic hypogonadism (IHH) is phenotypically and genetically heterogeneous. OBJECTIVE: This work aimed to determine the correlation between genotypic severity with pubertal and neuroendocrine phenotypes in IHH men. METHODS: A retrospective study was conducted (1980-2020) examining olfaction (Kallmann syndrome [KS] vs normosmic IHH [nHH]), baseline testicular volume (absent vs partial puberty), neuroendocrine profiling (pulsatile vs apulsatile luteinizing hormone [LH] secretion), and genetic variants in 62 IHH-associated genes through exome sequencing (ES). RESULTS: In total, 242 men (KS: n = 131 [54%], nHH: n = 111 [46%]) were included. Men with absent puberty had significantly lower gonadotropin levels (P < .001) and were more likely to have undetectable LH (P < .001). Logistic regression showed partial puberty as a statistically significant predictor of pulsatile LH secretion (R2 = 0.71, P < .001, OR: 10.8; 95% CI, 3.6-38.6). Serum LH of 2.10 IU/L had a 95% true positive rate for predicting LH pulsatility. Genetic analyses in 204 of 242 IHH men with ES data available revealed 36 of 204 (18%) men carried protein-truncating variants (PTVs) in 12 IHH genes. Men with absent puberty and apulsatile LH were enriched for oligogenic PTVs (P < .001), with variants in ANOS1 being the predominant PTV in this genotype-phenotype association. Men with absent puberty were enriched for ANOS1 PTVs compared to partial puberty counterparts (P = .002). PTVs in other IHH genes imparted more variable reproductive phenotypic severity. CONCLUSION: Partial puberty and LH greater than or equal to 2.10 IU/L are proxies for pulsatile LH secretion. ANOS1 PTVs confer severe reproductive phenotypes. Variable phenotypic severity in the face of severe genetic variants in other IHH genes point to significant neuroendocrine plasticity of the HPG axis in IHH men.

SLIT2 Rare Sequencing Variants Identified in Idiopathic Hypogonadotropic Hypogonadism.

INTRODUCTION: Idiopathic hypogonadotropic hypogonadism (IHH) is a rare reproductive disorder resulting from gonadotropin-releasing hormone (GnRH) deficiency. However, in only approximately half of patients with IHH is it possible to identify a likely molecular diagnosis. Mice lacking Slit2 have a reduced number or altered patterning of GnRH neurons in the brain. In order to assess the contribution of SLIT2 to IHH, we carried out a candidate gene burden test analysis. METHODS: A total of 196 IHH probands and 2,362 ethic-matched controls were recruited for this study. The IHH probands and controls were subjected to whole-exome sequencing. In the IHH patients with SLIT2 variants and their available family members, detailed phenotyping and segregation analysis were performed. RESULTS: Nine heterozygous SLIT2 rare sequencing variants (RSVs) were identified in 13 probands, with a prevalence of 6.6%. Furthermore, we identified an increased mutational burden for SLIT2 in this cohort (odds ratio = 2.2, p = 0.021). The segregation analysis of available IHH families revealed that the majority of SLIT2 RSVs were inherited from unaffected or partially affected parents. CONCLUSION: Our study suggests SLIT2 as a new IHH-associated gene and expands the clinical and genetic spectrum of IHH. Furthermore, SLIT2 alone does not appear to be sufficient to cause the disorder, and it may interact with other IHH-associated genes to induce a clinical phenotype.

Incidence and Prevalence of Poststroke Shoulder Pain Among Different Regions of the World: A Systematic Review and Meta-Analysis.

Objectives: Poststroke shoulder pain (PSSP) is a common complication after stroke. This review aimed to provide updated information on the epidemiological characteristics of PSSP, reveal their trends over time and region. Study Design and Setting: We searched the PubMed, Embase, Cochrane Library and Web of Science databases from inception until Dec 31, 2020. Data were extracted from the eligible studies, and their quality was assessed. The pooled incidence and prevalence estimates of PSSP and their 95% confidence intervals (CIs) were calculated. We analyzed the incidence and prevalence of PSSP by different geographical regions and countries and separately calculated the annual incidence and prevalence (and 95% CIs) of PSSP. Results: A total of 21 studies were eligible for the meta-analysis. Eleven cohort studies were included to analyze the incidence of PSSP, and the estimated pooled incidence in 3,496 stroke patients was 0.29 (95% CI 0.21-0.36). Ten cross-sectional studies were included to analyze the prevalence of PSSP, and the pooled prevalence in 3,701 stroke patients was 0.33 (95% CI 0.22-0.43). In addition, we found that there were significant differences in the incidence and prevalence of PSSP between different geographical regions and different countries. Additionally, the incidence of PSSP fluctuated around 30%, and the prevalence had a downward trend over time. Conclusions: Current evidence suggests that the incidence and prevalence of PSSP are high and may be influenced by geographical region and time.

Analysis of PLXNA1, NRP1, and NRP2 variants in a cohort of patients with isolated hypogonadotropic hypogonadism.

BACKGROUND: Isolated hypogonadotropic hypogonadism (IHH) is a clinical syndrome described by failure of gonadal function secondary to defects on the synthesis, secretion, or action of the gonadotropin-releasing hormone (GnRH). The secreted glycoprotein SEMA3A binds its receptors NRP1 or NRP2 and PLXNA to participate in axonal projection, dendritic branching, synaptic formation, and neuronal migration. Deficiency in SEMA3A, NRP1, NRP2, and PLXNA1 have been related to abnormal GnRH neuron development in mice and IHH in humans. METHODS: The aim of this study was to examine the genotypic and phenotypic spectra of the NRP1, NRP2, and PLXNA1 genes in a large cohort of IHH probands from China. We screened NRP1, NRP2, and PLXNA1 variants in Chinese IHH patients by whole exome sequencing and pedigree analysis. RESULTS: We identified 10 heterozygous missense variants in PLXNA1, five heterozygous missense variants in NRP1, and two heterozygous missense variants in NRP2. NRP1 variants were found only in IHH patients with defective olfaction (i.e., Kallmann syndrome, KS). In addition, 85% (17/20) of patients harbored variants in other IHH-associated genes. CONCLUSION: Our study greatly enriched the genotypic and phenotypic spectra of PLXNA1, NRP1, and NRP2 in IHH. It may be conducive to the genetic counseling, diagnosis, and treatment of IHH with mutations in the PLXNA1, NRP1, and NRP2 genes. Furthermore, our results indicated that NRP1 were strongly linked to hearing loss.

A variant in the 3'-untranslated region of the MC2R gene decreases the risk of schizophrenia in a female Han Chinese population.

OBJECTIVE: Schizophrenia is a complex mental disorder with high heritability. The hypothalamic-pituitary-adrenal (HPA) axis, which is the stress system of the neuroendocrine system, is considered to impact psychotic disorders. We hypothesized that polymorphisms of HPA axis genes might be involved in the development of schizophrenia. METHODS: A case-control study comprising 234 patients with schizophrenia and 399 matched healthy controls was conducted to investigate the association between the human melanocortin 2 receptor (MC2R) gene and schizophrenia risk. Seven tag single nucleotide polymorphisms (SNPs) (rs16941303, rs16941314, rs2186944, rs28926188, rs7230126, rs948322, and rs948331) of MC2R were genotyped by direct sequencing. RESULTS: No significant associations were observed between any of the alleles, genotypes, or haplotypes examined within the MC2R gene and the risk of schizophrenia in the total group or in subgroups stratified by smoking or alcoholism. However, a subgroup analysis stratified by sex revealed that under the additive model, the C allele of the MC2R rs948331 SNP significantly decreased the risk of schizophrenia in females (odds ratio=0.18). CONCLUSION: The C allele of the MC2R rs948331 locus may be a protective factor, reducing the risk of schizophrenia in the female Han Chinese population.

Effect of Oral Motor Intervention on Oral Feeding in Preterm Infants: A Systematic Review and Meta-Analysis.

Objective This review article aimed to explore the effect of oral motor intervention on oral feeding in preterm infants through a meta-analysis. Method Eligible studies were retrieved from four databases (PubMed, Embase, Cochrane Library, and Web of Science) up to July 2020 and screened based on established selection criteria. Thereafter, relevant data were extracted and heterogeneity tests were conducted to select appropriate effect models according to the chi-square test and I 2 statistics. Assessment of risk of bias was performed among the included studies. Finally, a meta-analysis was carried out to evaluate the effect of oral motor intervention in preterm infants according to four clinical indicators: transition time for oral feeding, length of hospital stay, feeding efficiency, and weight gain. Results Eighteen randomized controlled trials with 848 participants were selected to evaluate the effect of oral motor intervention on preterm infants. The meta-analysis results revealed that oral motor intervention could effectively reduce the transition time to full oral feeds and the length of hospital stay as well as increase feeding efficiency and weight gain. Conclusions Oral motor intervention was an effective way to improve oral feeding in preterm infants. It is worthy to be used widely in hospitals to improve the clinical outcomes of preterm infants and reduce the economic burdens of families and society. Future studies should seek to identify detailed intervention processes and intervention durations for clinical application.

VPS4B deficiency causes early embryonic lethality and induces signal transduction disorders of cell endocytosis.

VPS4B (vacuolar protein sorting 4B), a member of the ATPase associated with diverse cellular activities (AAA) protein family, is a component of the endosomal sorting complexes required for transport machinery which regulates the internalization and lysosomal degradation of membrane proteins. We previously reported that VPS4B is one of the pathogenic genes related to dentin dysplasia type I, although its function was largely unknown. To investigate the role of VPS4B in tooth development, we deleted the Vps4b gene in mice. We found that heterozygous knockout mice (Vps4b+/- ) developed normally and were fertile. However, homozygous deletion of the Vps4b gene resulted in early embryonic lethality of Vps4b-/- mice at approximately embryonic day 9.5 (E9.5). To investigate the underlying molecular mechanisms, we examined the molecular functions of VPS4B in vivo and in vitro. Cell experiments showed that VPS4B influenced the proliferation, apoptosis, and cell cycle of transfected human neuroblastoma cells (IMR-32 cells) with over-expression or knockdown of VPS4B. Moreover, qRT-PCR detection showed that the mRNA expression levels of apoptosis-, cell cycle-, and endocytosis-related genes was significantly down or up-regulated in RNA interference-mediated knockdown of VPS4B in IMR-32 cells and Vps4b+/- E12.5 embryos. We accordingly speculated that signal transduction disorders of cell endocytosis are a contributing factor to the prenatal lethality of Vps4b-/- mice.

RNF216 regulates meiosis and PKA stability in the testes.

Spermatogenesis is a highly sophisticated process that comprises of mitosis, meiosis, and spermiogenesis. RNF216 (ring finger protein 216), an E3 ubiquitin ligase, has been reported to be essential for spermatogenesis and male fertility in mice. However, the stages affected by Rnf216 deficiency and its underlying molecular pathological mechanisms are still unknown. In this study, we generated Rnf216-deficient mice (Rnf216-/- ) using CRISPR-Cas9 technology. Knockout of Rnf216 led to infertility in male but not female mice. Rnf216 knockout affected the prophase of meiosis I, as no genotypic difference was observed until 12 dpp (days postpartum). Rnf216-/- spermatocytes were incompletely arrested at the zygotene stage and underwent apoptosis at approximately the pachytene stage. The proportion of zygotene spermatocytes was significantly increased, whereas the proportion of pachytene spermatocytes was significantly decreased in Rnf216-/- testes. Nevertheless, there was no significantly genotypic difference in the number of diplotene spermatocytes. We further revealed that the PKA catalytic subunit ß (PRKACB) was significantly increased, which subsequently resulted in elevated PKA activity in testes from adult as well as 9 dpp Rnf216-/- mice. RNF216 interacts with PRKACB and promotes its degradation through the ubiquitin-lysosome pathway. Collectively, our results revealed an important role for RNF216 in regulation of meiosis and PKA stability in the testes.

Clinical and Microbiological Characteristics of Invasive and Hypervirulent Klebsiella pneumoniae Infections in a Teaching Hospital in China.

PURPOSE: To investigate the clinical and microbiological characteristics of invasive and hypervirulent Klebsiella pneumoniae (HvKP) in a teaching hospital in Southern China. PATIENTS AND METHODS: A total of 495 non-repetitive K. pneumoniae strains were isolated from Dongguan People's Hospital affiliated to Southern Medical University in 2018. Multivariate analysis was performed using the patients' clinical data to identify the risk factors for HvKP. RESULTS: Eighty-one isolates were HvKP (16.4%, 81/495), of which 43 (53.1%) were invasive HvKP, whereas 38 (46.9%) were non-invasive HvKP. The incidence of extended spectrum beta-lactamases (ESBLs) in HvKP and classic K. pneumoniae (cKP) were 7.4% (6/81) and 28.0% (116/414), respectively (p<0.05). Multivariate analysis indicated that diabetes mellitus (odds ratio [OR]=12.849, 95% confidence interval [CI]: 1.494-110.511, P=0.020) was an independent risk factor for invasive HvKP infection. Altogether, 51.2% (22/43) of invasive HvKP infections were treated with antimicrobial therapy combined with surgical drainage, and achieved good prognosis. K1-ST23 HvKP accounted for a higher proportion of invasive infections than non-invasive infections (P<0.05), but there was no statistical difference in the prognosis between the two groups (P>0.05). The most prevalent virulence genes in HvKP were rmpA 98.7% (80/81), followed by rmpA2 (82.7%, 67/81), iroN (98.7%, 80/81), and iutA 90.1% (70/81). There was no significant difference in the distribution of virulence genes between invasive HvKP and non-invasive HvKP isolates (P>0.05). CONCLUSION: Invasive HvKP infection in this study was positively associated with diabetes as independent risk factors. Antibiotic therapy combined with surgical drainage is one of the most effective treatment measures of HvKP infection. Adequate attention should be paid to HvKP infection in clinical and microbiological laboratories.

Analysis of Metallo-ß-lactamases, oprD Mutation, and Multidrug Resistance of ß-lactam Antibiotic-Resistant Strains of Pseudomonas aeruginosa Isolated from Southern China.

The purpose of this study was to analyze the metallo-ß-lactamases (MBLs) genotype and oprD mutations of the ß-lactam antibiotic-resistant Pseudomonas aeruginosa (PA) strains isolated from southern China. We collected 110 strains of ß-lactam antibiotic-resistant PA from 2 hospitals during January 2016-December 2017 from Dongguan, South China. MBLs were detected, amplified, and typed using EDTA disc synergy test, PCR, and Sanger gene sequencing. The mutations and expression levels of oprD were detected using Sanger gene sequencing and qPCR. A total of 16.36% (18/110) ß-lactam antibiotic-resistant PA strains produced MBLs, and the main genotypes of MBLs were IMP-25, VIM-2, and SIM-2. Sanger gene sequencing results showed that 107 of the 110 strains harbored mutations in oprD sequence, while 3 strains were negative for oprD amplification (2.73%). Among the 107 strains with positive amplification (97.27%), the rate of intentional mutations (including deletions, insertions, and premature stop codons) was 93.46% (100/107) and that of no disrupted mutation was 6.54% (7/107). qPCR analysis confirmed that the expression level of the OprD protein in the 7 strains of no disrupted mutation was significantly reduced. Among the ß-lactam antibiotic-resistant PA strains in southern China, 16.36% were positive for MBLs. The loss rate of oprD was 2.73%, and almost all PA strains showed oprD amplification variation or transcription downregulation. Thus, impaired oprD expression and MBLs production may be some of the mechanisms of ß-lactam antibiotic-resistance of PA strains in southern China.

Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism.

OBJECTIVE: To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadotropic hypogonadism (CHH) and to assess the contribution of CCDC141 to CHH. DESIGN: Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible. METHODS: Whole-exome sequencing was performed in 177 CHH patients and 450 unrelated, ethnically matched controls from China. RESULTS: Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedigrees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated genes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showed that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of the patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex-steroid replacement. CONCLUSIONS: Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patients with CCDC141 RSVs is much wider than originally believed.

[Analysis of Human Herpes Viruses-Activated Infection Spectra in Patients with Various Immunodeficiencies].

OBJECTIVE: To study the epidemiologic characteristics of human herpes virus (HHV) activated infection in the diseases of blood system and patients received allo-HSCT by statistically analyzing the screening results of 8 human herpes viruses (HHVs) of 4164 patients in Hebei Yanda LU Dao-Pei Hospital from 2012 to 2017. METHODS: PCR was used to screen 8 HHVs. RESULTS: Two thousand and fifty-two patients (49.28%) were HHV-positive among 4164 patients screened. Among these patients screened, the infection spectra of 8 human HHVs in hematological diseases as well as patients received allogeneic hematopoietic stem cell transplantation of totally 2994 patients were summarized as follows: the positive rate of EBV (29.49%) was the highest, that of HCMV (23.15%), HHV-6 was 18.77% and HHV-7 was 17.64%, while the remaining 4 HHVs all≤2.1%. The rate of co-infection of various HHVs was significantly higher than that of single infection of HHV among all these disease groups except familial hemophagocytic lymphohistiocytosis, for which single EBV infection was the most common. The differences of positive rates among these 8 human HHVs in hematological diseases as well as patients received allogeneic hematopoietic stem cell transplantation were statistically significant by Chi-square test of R*C tables (χ2=54.99, P＜0.05). For each HHV, the differences of positive rates among the above-mentioned disease groups were also statistically significant except HHV-8 (P＜0.05). CONCLUSION: The patients with various blood diseases have different activated infection spectra of HHVs. EBV, HCMV, HHV-6 and HHV-7 are most common in HHVs infection. Different HHVs infections correlate with different hematologion diseases.

Functional analysis of SEMA3A variants identified in Chinese patients with isolated hypogonadotropic hypogonadism.

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder characterized by impaired sexual development and infertility, caused by the deficiency of hypothalamic gonadotropin-releasing hormone neurons. IHH is named Kallmann's syndrome (KS) or normosmic IHH (nIHH) when associated with a defective or normal sense of smell. Variants in SEMA3A have been recently identified in patients with KS. In this study, we screened SEMA3A variants in a cohort of Chinese patients with IHH by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two nIHH and one KS patients, respectively. Functional studies indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK (focal adhesion kinase) in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Our study further showed the contribution of SEMA3A loss-of-function variants to the pathogenesis of IHH.