HSP90 Shapes the Consequences of Human Genetic Variation.

HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90's buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an "experiment of nature" in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases.

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms" are functionally divergent (i.e., "functional alloforms").

Human gene-centered transcription factor networks for enhancers and disease variants.

Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping methods test one TF at a time and require the use of cells harboring the mutation(s) of interest, they are not suitable to identify TFs that bind to wild-type and mutant loci. Here, we use gene-centered yeast one-hybrid (eY1H) assays to interrogate binding of 1,086 human TFs to 246 enhancers, as well as to 109 non-coding disease mutations. We detect both loss and gain of TF interactions with mutant loci that are concordant with target gene expression changes. This work establishes eY1H assays as a powerful addition to the toolkit of mapping human GRNs and for the high-throughput characterization of genomic variants that are rapidly being identified by genome-wide association studies.

Widespread macromolecular interaction perturbations in human genetic disorders.

How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

A proteome-scale map of the human interactome network.

Just as reference genome sequences revolutionized human genetics, reference maps of interactome networks will be critical to fully understand genotype-phenotype relationships. Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. At equal quality, this map is ?30% larger than what is available from small-scale studies published in the literature in the last few decades. While currently available information is highly biased and only covers a relatively small portion of the proteome, our systematic map appears strikingly more homogeneous, revealing a "broader" human interactome network than currently appreciated. The map also uncovers significant interconnectivity between known and candidate cancer gene products, providing unbiased evidence for an expanded functional cancer landscape, while demonstrating how high-quality interactome models will help "connect the dots" of the genomic revolution.

Study of Sintering Behavior of Methane Hydrate Particles on the Wall Surface.

The sintering of hydrate aggregates on the pipe wall is a major form of hydrate deposition. Understanding the sintering behavior of hydrates on the wall is crucial for promoting hydrate safety management and preventing pipeline blockage. However, limited research currently exists on this topic. In this study, the cohesive force strength of hydrate particles on the wall surface under different conditions was directly measured using a high-pressure micromechanical force device (HP-MMF). Subsequently, the effects of subcooling and glycine on the cohesive force were investigated. The results indicate that the cohesive force is influenced by different growth states during the process of free water on the wall surface gradually growing into hydrate. Three states with larger measured values during the growth process were selected for research. Observation showed that increased subcooling strengthened sintering by accelerating the growth rate of the hydrate film, resulting in a significant increase in cohesive force. The role of glycine in the methane hydrate system was then evaluated. Glycine was found to reduce the degree of sintering by reducing the growth rate of the hydrate film, thereby decreasing the cohesive force. The optimal concentration in the system was determined to be 0.25 wt %. Moreover, compared with low subcooling (1 °C), glycine had a better effect at high subcooling (5 °C). At 5 °C subcooling and the optimal concentration, the cohesive force in the wall droplet state decreases from 677.38 to 489.02 mN/m, the cohesive force at the low-saturation state decreases from 951.79 to 543.32 mN/m, and the cohesive force at the high-saturation state decreases from 1194.95 to 641.76 mN/m. These findings contribute to a better understanding of the cohesive force behavior of gas hydrate on the inner wall of the pipeline and provide basic data for reducing the risk of hydrate blockage.

The nature of crystal facet effect of TiO2-supported Pd/Pt catalysts on selective hydrogenation of cinnamaldehyde: electron transfer process promoted by interfacial oxygen species.

Supported noble metal nanocatalysts typically exhibit strong crystal plane dependent catalytic behavior, but their working mechanism is still unclear. Herein, using anatase TiO2 with well-exposed crystal facets of {101}, {100} and {001} as a prototype support, Pd- and Pt-based supported TiO2 nanocatalysts (TiO2-Pd and TiO2-Pt) were prepared by chemical reduction with NaBH4 as reducer, and they showed a distinct metal-dependent crystal facet effect in the selective hydrogenation of cinamaldehyde (CAL). For Pd-based nanocatalysts, most Pd species on the {100} plane of TiO2 are present in the oxidized form with positive charges and unexpectedly show higher reactivity than the Pd species in the zero-valence state on the {101} and {001} planes. On the contrary, Pt species on all three crystal planes of TiO2 show zero-valence state, with relatively low conversion, but much better selectivity for hydrogenation of a CO bond than Pd-based catalysts. Well-designed experiments manipulating the stability and type of surface oxygen species confirmed that the essence of the crystal facet effect of the catalyst support actually creates a unique nanoconfined interface at the molecular level to construct a surface p-band intermediate state (PBIS), which provides a new alternative channel for surface electron transfer and consequently accelerates the reaction kinetics.

Gain-of-Function Mutations: An Emerging Advantage for Cancer Biology.

Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in cancer. Elucidating the functional pathways altered by loss-of-function (LOF) or gain-of-function (GOF) mutations will be crucial for prioritizing cancer-causing variants and their resultant therapeutic liabilities. In this review, we highlight the fundamental function of GOF mutations and discuss the potential mechanistic effects in the context of signaling networks. We also summarize advances in experimental and computational resources, which will dramatically help with studies on the functional and phenotypic consequences of mutations. Together, systematic investigations of the function of GOF mutations will provide an important missing piece for cancer biology and precision therapy.

Dynamics of parainfluenza virus among hospitalized children with acute respiratory tract infection under two-child policy and COVID-19 pandemic in Hubei Province, China, 2014-2022.

To analyze changes in the detection of parainfluenza virus (PIV) in children hospitalized with acute respiratory tract infection (ARTI) during 2014-2022 in Hubei Province, and explore the impact of the universal two-child policy and the public health measures against COVID-19 epidemic on the prevalence of PIV in China. The study was conducted at the Maternal and Child Health Hospital of Hubei Province. Children aged <18 years with ARTI admitted from January 2014 to June 2022 were enrolled. The infection of PIV was confirmed by the direct immunofluorescence method in nasopharyngeal specimens. Adjusted logistic regression models were used to analyze the influence of the universal two-child policy implementation and public health measurements against COVID-19 on PIV detection. Totally 75 128 inpatients meeting the criteria were enrolled in this study from January 2014 to June 2022 with an overall PIV positive rate of 5.5%. The epidemic seasons of PIV prevalence lagged substantially in 2020. A statistically significant higher positive rate of PIV was observed in 2017-2019 compared to that in 2014-2015 (6.12% vs 2.89%, risk ratio = 2.12, p < 0.001) after the implementation of the universal two-child policy in 2016. A steep decline occurred in PIV positive rate during the COVID-19 epidemic in 2020 (0.92% vs 6.92%, p < 0.001) and it rebounded during the regular epidemic prevention and control period in 2021-2022 (6.35%, p = 0.104). In Hubei Province, the implementation of the universal two-child policy might have led to an increase of PIV prevalence, and public health measures during the COVID-19 epidemic might have influenced the fluctuation in PIV detection since 2020.

Single-nucleus RNA sequencing and mRNA hybridization indicate key bud events and LcFT1 and LcTFL1-2 mRNA transportability during floral transition in litchi.

In flowering plants, floral induction signals intersect at the shoot apex to modulate meristem determinacy and growth form. Here, we report a single-nucleus RNA sequence analysis of litchi apical buds at different developmental stages. A total of 41 641 nuclei expressing 21 402 genes were analyzed, revealing 35 cell clusters corresponding to 12 broad populations. We identify genes associated with floral transition and propose a model that profiles the key events associated with litchi floral meristem identity by analyzing 567 identified floral meristem cells at single cell resolution. Interestingly, single-nucleus RNA-sequencing data indicated that all putative FT and TFL1 genes were not expressed in bud nuclei, but significant expression was detected in bud samples by RT-PCR. Based on the expression patterns and gene silencing results, we highlight the critical role of LcTFL1-2 in inhibiting flowering and propose that the LcFT1/LcTFL1-2 expression ratio may determine the success of floral transition. In addition, the transport of LcFT1 and LcTFL1-2 mRNA from the leaf to the shoot apical meristem is proposed based on in situ and dot-blot hybridization results. These findings allow a more comprehensive understanding of the molecular events during the litchi floral transition, as well as the identification of new regulators.

Epidemiological change of influenza virus in hospitalized children with acute respiratory tract infection during 2014-2022 in Hubei Province, China.

PURPOSE: Influenza virus (IFV) causes acute respiratory tract infection (ARTI) and leads to high morbidity and mortality annually. This study explored the epidemiological change of IFV after the implementation of the universal two-child policy and evaluated the impact of coronavirus disease 2019 (COVID-19) pandemic on the detection of IFV. METHODS: Hospitalized children under 18 years with ARTI were recruited from Hubei Maternal and Child Healthcare Hospital of Hubei Province from January 2014 to June 2022. The positive rates of IFV were compared among different periods by the implementation of the universal two-child policy and public health measures against COVID-19 pandemic. RESULTS: Among 75,128 hospitalized children with ARTI, the positive rate of IFV was 1.98% (1486/75128, 95% CI 1.88-2.01). Children aged 6-17 years had the highest positive rate of IFV (166/5504, 3.02%, 95% CI 2.58-3.50). The positive rate of IFV dropped to the lowest in 2015, then increased constantly and peaked in 2019. After the universal two-child policy implementation, the positive rate of IFV among all the hospitalized children increased from 0.40% during 2014-2015 to 2.70% during 2017-2019 (RR 6.72, 95% CI 4.94-9.13, P < 0.001), particularly children under one year shown a violent increasing trend from 0.20 to 2.01% (RR 10.26, 95% CI 5.47-19.23, P < 0.001). During the initial outbreak of COVID-19, the positive rate of IFV decreased sharply compared to that before COVID-19 (0.35% vs. 3.37%, RR 0.10, 95% CI 0.04-0.28, P < 0.001), and then rebounded to 0.91%, lower than the level before COVID-19 (RR 0.26, 95% CI 0.20-0.36, P < 0.001). CONCLUSION: IFV epidemiological pattern has changed after the implementation of the universal two-child policy. More attention should be emphasized to comprehend the health benefits generated by COVID-19 restrictions on IFV transmission in future.

Tetraalkoxysilane-Assisted Self-Emulsification Templating for Controlled Mesostructured Silica Nanoparticles.

Although mesoporous silica nanoparticles (MSNs) have been intensively investigated, their mesostructure and formation mechanism are still a topic of debate. Here, we show that MSNS are generated at the interface of the biphasic water-surfactant-triethanolamine-tetraalkoxysilane (TAOS) quaternary system. The spontaneous microemulsification of the hydrophobic TAOS generates microdroplets and direct micelles that both determine the particle size and the pore size. We confirmed also that the dendritic morphology with conical pores is an intermediate species, which readily transforms into regular MSNs concomitantly with the collapse of the microemulsion due to the continuous consumption of TAOS. The prominent effect of the microemulsion on the mechanism growth as a primary template is thoroughly investigated and named here tetraalkoxysilane-assisted self-emulsification templating.

Functional variomics and network perturbation: connecting genotype to phenotype in cancer.

Proteins interact with other macromolecules in complex cellular networks for signal transduction and biological function. In cancer, genetic aberrations have been traditionally thought to disrupt the entire gene function. It has been increasingly appreciated that each mutation of a gene could have a subtle but unique effect on protein function or network rewiring, contributing to diverse phenotypic consequences across cancer patient populations. In this Review, we discuss the current understanding of cancer genetic variants, including the broad spectrum of mutation classes and the wide range of mechanistic effects on gene function in the context of signalling networks. We highlight recent advances in computational and experimental strategies to study the diverse functional and phenotypic consequences of mutations at the base-pair resolution. Such information is crucial to understanding the complex pleiotropic effect of cancer genes and provides a possible link between genotype and phenotype in cancer.

Non-suicidal self-injury and professional psychological help-seeking among Chinese left-behind children: prevalence and influencing factors.

BACKGROUND: Non-suicidal self-injury (NSSI) is a risk factor for suicide. This study aimed to investigate the prevalence of NSSI and professional psychological help-seeking status and influencing factors among left-behind children (LBC) in China. METHODS: We implemented a population-based cross-sectional study in participants aged 10-18 years. Sociodemographic characteristics, NSSI, help-seeking status and coping style were measured by self-reported questionnaires. A total of 16,866 valid questionnaires were collected, including 6096 LBC. Binary logistic regression models were used to analyze the factors influencing NSSI and professional psychological help-seeking. RESULTS: The incidence of NSSI among LBC was 4.6%, significantly higher than that of non-left-behind children (NLBC). This incidence was higher among girls. Moreover, 53.9% of LBC with NSSI did not receive any treatment and only 22.0% sought professional psychological help. LBC often adopt emotion-oriented coping styles, specifically, those with NSSI. LBC with NSSI who seek professional help tend to adopt problem-oriented coping styles. Logistic regression analysis revealed that girls, learning stage, single-parent, remarried families, patience, and emotional venting were risk factors for NSSI in LBC, while problem-solving and social support seeking were protective factors. Moreover, problem-solving was also a predictor for seeking professional psychological help, patience will prevent it. LIMITATIONS: This was an online survey. CONCLUSIONS: The prevalence of NSSI in LBC is high. Gender, grade, family structure, and coping style affect the occurrence of NSSI among LBC. Only a few LBC with NSSI seek professional psychological help, while the coping style will affect the help-seeking behavior.

Self-reported sleep quality and oligo/astheno/teratozoospermia among men attending an infertility clinic: a longitudinal study.

OBJECTIVE: We aimed to examine the influence of sleep disturbances on the risk of oligo/astheno/teratozoospermia (OAT) in men attending an infertility clinic. METHODS: We consecutively enrolled men attending an infertility clinic from July 2020 to June 2021. Semen parameters were obtained at initial presentation, and the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale score, and the STOP-BANG Questionnair were completed to assess sleep quality. Embryo outcomes were evaluated after infertility treatment. RESULTS: Of 466 men enrolled, 119 had OAT (OAT group) and 347 had normozoospermia (NS group). There were no differences between the two groups regarding Epworth Sleepiness Scale and STOP-BANG Questionnaire scores. The prevalence of poor sleep quality (Pittsburgh Sleep Quality Index score ≥ 5) in the OAT group was significantly higher than that in the NS group (42% vs. 29%, p = 0.009). A higher rate of poor subjective sleep quality was observed in the OAT group compared with the NS group (p = 0.005) and Pearson's correlations revealed a negative relationship between subjective sleep quality and semen quality. Logistic regression found that subjective sleep quality was independently associated with an increased risk of OAT (adjusted odds ratio = 0.610, p = 0.007). CONCLUSIONS: Men with OAT attending an infertility clinic exhibited poor subjective sleep quality. Improving sleep disturbances may be a target intervention to reduce the risk of OAT. This possibility warrants further investigation.

Relationship between Obstructive Sleep Apnea and Liver Abnormalities in Older Patients: A Cross-Sectional Study.

Background: Older age is a risk factor for obstructive sleep apnea (OSA), which is associated with the development of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the correlation between OSA and liver injury among older patients. Study Design. This is a cross-sectional study. Methods: Consecutive older (≥60 years) snoring patients were included. Subjects were divided into no OSA, mild OSA, moderate OSA, and severe OSA groups according to the apnea-hypopnea index (AHI) and were also separated into liver injury and nonliver injury groups based on liver function. Logistic regression analysis was applied to analyze the independent risk factors for liver injury. Results: We studied 227 patients (155 male, 72 female). The prevalence of liver injury exhibited an increasing trend among groups with mild-to-severe OSA. In addition, body mass index, AHI, and TG showed significant differences between the liver injury and nonliver injury groups. Logistic regression analysis revealed that AHI and TG were the major contributing factors for liver injury in older patients (adjusted odds ratio [OR] = 1.055, p=0.013, and OR = 1.485, p=0.039, respectively). Conclusions: Older patients with OSA have an increased risk of liver injury and NAFLD, and sleep apnea and high TG are important factors in contributing to the development of liver injury.

Gene Regulatory Network Perturbation by Genetic and Epigenetic Variation.

Gene regulatory networks underlie biological function and cellular physiology. Alternative splicing (AS) is a fundamental step in gene regulatory networks and plays a key role in development and disease. In addition to the identification of aberrant AS events, an increasing number of studies are focusing on molecular determinants of AS, including genetic and epigenetic regulators. We review here recent efforts to identify various deregulated AS events as well as their molecular determinants that alter biological functions, and discuss clinical features of AS and their druggable potential.

Pathway perturbations in signaling networks: Linking genotype to phenotype.

Genes and gene products interact with each other to form signal transduction networks in the cell. The interactome networks are under intricate regulation in physiological conditions, but could go awry upon genome instability caused by genetic mutations. In the past decade with next-generation sequencing technologies, an increasing number of genomic mutations have been identified in a variety of disease patients and healthy individuals. As functional and systematic studies on these mutations leap forward, they begin to reveal insights into cellular homeostasis and disease mechanisms. In this review, we discuss recent advances in the field of network biology and signaling pathway perturbations upon genomic changes, and highlight the success of various omics datasets in unraveling genotype-to-phenotype relationships.

Rasmussen's encephalitis is characterized by relatively lower production of IFN-ß and activated cytotoxic T cell upon herpes viruses infection.

BACKGROUND: The etiology of Rasmussen's encephalitis (RE), a rare chronic neurological disorder characterized by CD8+ T cell infiltration and unihemispheric brain atrophy, is still unknown. Various human herpes viruses (HHVs) have been detected in RE brain, but their contribution to RE pathogenesis is unclear. METHODS: HHVs infection and relevant immune response were compared among brain tissues from RE, temporal lobe epilepsy (TLE) and traumatic brain injury (TBI) patients. Viral antigen or genome, CD8+ T cells, microglia and innate immunity molecules were analyzed by immunohistochemical staining, DNA dot blot assay or immunofluorescence double staining. Cytokines were measured by multiplex flow cytometry. Cell apoptosis was visualized by TUNEL staining. Viral infection, immune response and the severity of unihemispheric atrophy were subjected to correlation analysis. RESULTS: Antigens of various HHVs were prevalent in RE and TLE brains, and the cumulative viral score of HHVs positively correlated with the unihemispheric atrophy in RE patients. CD8+ T cells infiltration were observed in both RE and TLE brains and showed co-localization with HHV antigens, but their activation, as revealed by Granzyme B (GZMB) release and apoptosis, was found only in RE. In comparison to TLE, RE brain tissues contained higher level of inflammatory cytokines, but the interferon-ß level, which was negatively correlated with cumulative viral score, was relatively lower. In line with this, the DNA sensor STING and IFI16, rather than other innate immunity signaling molecules, were insufficiently activated in RE. CONCLUSIONS: Compared with TBI, both RE and TLE had prevalently HHV infection and immune response in brain tissues. However, in comparison to TLE, RE showed insufficient activation of antiviral innate immunity but overactivation of cytotoxic T cells. Our results show the relatively lower level of antiviral innate immunity and overactivation of cytotoxic T cells in RE cases upon HHV infection, the overactivated T cells might be a compensate to the innate immunity but the causative evidence is lack in our study and need more investigation in the future.

[UPLC fingerprint and indicator components of Boenninghausenia albiflora var. albiflora].

The fingerprint of Boenninghausenia albiflora var. albiflora was established by ultra performance liquid chromatography(UPLC), and the content of 12 active components including chlorogenic acid was determined. Multivariate statistical analysis was used to explore the indicator components of B. albiflora var. albiflora and a comprehensive evaluation system was created for the quality of B. albiflora var. albiflora. In this study, 33 batches of B. albiflora var. albiflora with different sources were collected and studied, and the UPLC fingerprint of B. albiflora var. albiflora was developed. There were 37 common peaks, of which 12 components were identified, and the content of these 12 components was measured. In combination of the common peaks and the content of chemical components, multivariate statistical analysis was performed, and the results showed that 6 components [daphnoretin, isoimperatorin, astragalin, imperatorin, neochlorogenic acid, and isoquercitrin(weight coefficient>0.1)] were selected as chemical markers for the quality of B. albiflora var. albiflora. Technique for order of preference by similarity to ideal solution(TOPSIS) analysis and chemometrics revealed that the quality of S32, S28 and S29 were superior, while that of S12, S7 and S16 were inferior. The quality evaluation method of B. albiflora var. albiflora constructed in this study was accurate and reliable, with simpleness and easiness to operate. It is suggested that the 6 above-mentioned active components could be used as indicator components for quality control of B. albiflora var. al-biflora. The samples were harvested during the flowering and fruiting period, which is from the beginning of July to the end of August.