Osmosensor-mediated control of Ca2+ spiking in pollen germination.

Higher plants survive terrestrial water deficiency and fluctuation by arresting cellular activities (dehydration) and resuscitating processes (rehydration). However, how plants monitor water availability during rehydration is unknown. Although increases in hypo-osmolarity-induced cytosolic Ca2+ concentration (HOSCA) have long been postulated to be the mechanism for sensing hypo-osmolarity in rehydration1,2, the molecular basis remains unknown. Because osmolarity triggers membrane tension and the osmosensing specificity of osmosensing channels can only be determined in vivo3-5, these channels have been classified as a subtype of mechanosensors. Here we identify bona fide cell surface hypo-osmosensors in Arabidopsis and find that pollen Ca2+ spiking is controlled directly by water through these hypo-osmosensors-that is, Ca2+ spiking is the second messenger for water status. We developed a functional expression screen in Escherichia coli for hypo-osmosensitive channels and identified OSCA2.1, a member of the hyperosmolarity-gated calcium-permeable channel (OSCA) family of proteins6. We screened single and high-order OSCA mutants, and observed that the osca2.1/osca2.2 double-knockout mutant was impaired in pollen germination and HOSCA. OSCA2.1 and OSCA2.2 function as hypo-osmosensitive Ca2+-permeable channels in planta and in HEK293 cells. Decreasing osmolarity of the medium enhanced pollen Ca2+ oscillations, which were mediated by OSCA2.1 and OSCA2.2 and required for germination. OSCA2.1 and OSCA2.2 convert extracellular water status into Ca2+ spiking in pollen and may serve as essential hypo-osmosensors for tracking rehydration in plants.

Hydrogen peroxide sensor HPCA1 is an LRR receptor kinase in Arabidopsis.

Hydrogen peroxide (H2O2) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues1-4. H2O2 enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for H2O2 also exist on the cell surface remains unknown. In plant cells, H2O2 triggers an influx of Ca2+ ions, which is thought to be involved in H2O2 sensing and signalling. Here, by using forward genetic screens based on Ca2+ imaging, we isolated hydrogen-peroxide-induced Ca2+ increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by H2O2 via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates H2O2-induced activation of Ca2+ channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular H2O2 is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.

Plant cell-surface GIPC sphingolipids sense salt to trigger Ca2+ influx.

Salinity is detrimental to plant growth, crop production and food security worldwide. Excess salt triggers increases in cytosolic Ca2+ concentration, which activate Ca2+-binding proteins and upregulate the Na+/H+ antiporter in order to remove Na+. Salt-induced increases in Ca2+ have long been thought to be involved in the detection of salt stress, but the molecular components of the sensing machinery remain unknown. Here, using Ca2+-imaging-based forward genetic screens, we isolated the Arabidopsis thaliana mutant monocation-induced [Ca2+]i increases 1 (moca1), and identified MOCA1 as a glucuronosyltransferase for glycosyl inositol phosphorylceramide (GIPC) sphingolipids in the plasma membrane. MOCA1 is required for salt-induced depolarization of the cell-surface potential, Ca2+ spikes and waves, Na+/H+ antiporter activation, and regulation of growth. Na+ binds to GIPCs to gate Ca2+ influx channels. This salt-sensing mechanism might imply that plasma-membrane lipids are involved in adaption to various environmental salt levels, and could be used to improve salt resistance in crops.

Stereoselective Construction of Multifunctional C-Glycosides Enabled by Nickel-Catalyzed Tandem Borylation/Glycosylation.

Stereochemically pure saccharides have indispensable roles in fields ranging from medicinal chemistry to materials science and organic synthesis. However, the development of a simple, stereoselective, and efficient glycosylation protocol to access α- and ß-C-glycosides (particularly 2-deoxy entities) remains a persistent challenge. Existing studies have primarily focused on C1 modification of carbohydrates and transformation of glycosyl radical precursors. Here, we innovate by harnessing the in situ generated glycosyl-Ni species to achieve one-pot borylation and glycosylation in a cascade manner, which is enabled by an earth-abundant nickel-catalyzed carboboration of readily accessible glycals without any ligand. This work reveals the potential for the development of a modular and multifunctional glycosylation platform to facilitate the simultaneous introduction of C-C and C-B bonds at the stereogenic center of saccharides, a largely unexploited research area. Preliminary experimental and computational studies indicate that the endocyclic O and the C3 group play important roles in stereoseclectively forging glycosidic bonds. As a result, a diverse range of C-R (R = alkyl, aryl, and alkenyl) and 2-deoxygenated glycosides bearing modifiable boron groups could be rapidly made with excellent stereocontrol and exhibit remarkable functional group tolerance. The synthetic potential is underscored in the late-stage glycosylation of natural products and commercial drugs as well as the facile preparation of various rare sugars, bioactive conjugates, and key intermediates to prorocentin, phomonol, and aspergillide A.

Genome-wide identification of phasiRNAs in Arabidopsis thaliana, and insights into biogenesis, temperature sensitivity, and organ specificity.

The knowledge of biogenesis and target regulation of the phased small interfering RNAs (phasiRNAs) needs continuous update, since the phasiRNA loci are dynamically evolved in plants. Here, hundreds of phasiRNA loci of Arabidopsis thaliana were identified in distinct tissues and under different temperature. In flowers, most of the 24-nt loci are RNA-dependent RNA polymerase 2 (RDR2)-dependent, while the 21-nt loci are RDR6-dependent. Among the RDR-dependent loci, a significant portion is Dicer-like 1-dependent, indicating the involvement of microRNAs in their expression. Besides, two TAS candidates were discovered. Some interesting features of the phasiRNA loci were observed, such as the strong strand bias of phasiRNA generation, and the capacity of one locus for producing phasiRNAs by different increments. Both organ specificity and temperature sensitivity were observed for phasiRNA expression. In leaves, the TAS genes are highly activated under low temperature. Several trans-acting siRNA-target pairs are also temperature-sensitive. In many cases, the phasiRNA expression patterns correlate well with those of the processing signals. Analysis of the rRNA-depleted degradome uncovered several phasiRNA loci to be RNA polymerase II-independent. Our results should advance the understanding on phasiRNA biogenesis and regulation in plants.

A system review of central nervous system tumors on children in China: epidemiology and clinical characteristics.

BACKGROUND: Central nervous system (CNS) tumors are the most common solid tumors in children and the leading cause of cancer-related death in the latter. Currently, the incidence rate exceeds that of leukemia and ranks first in the incidence of malignant tumors in children. METHODS: The epidemiological data on childhood CNS tumors were collected from the Chinese Cancer Registry Annual Report. The annual percent change (APC) of incidence and mortality-rate changes were estimated via Joinpoint regression. Due to a lack of pertinent data, we performed a system review on the clinical-pathological characteristics in Chinese publications. RESULTS: There was no significant increase in the incidence rate (APC: -0.1, 95% CI: -1.5 to 1.3), but there was a significant increase in the mortality rate (APC: 1.8, 95% CI: 0.3 to 3.4) for childhood CNS tumors. In the subgroup analysis, there were significant increases in both the incidence and mortality rates in rural areas (APC in the incidence: 6.2, 95% CI: 2.4 to 10.2; APC in mortality: 4.4, 95% CI: 0.4 to 8.4). The most common location and type of childhood CNS were, respectively, the cerebral hemisphere (25.5%, 95% CI: 21.7% to 29.4%) and astrocytomas (26.8%, 95% CI: 23.9% to 29.6%). CONCLUSIONS: The epidemiological trends, and the relevant prediction, highlighted the need to pay continual attention to childhood CNS tumors, and the clinicopathology evinced its own distinctive characteristics. Timely detection and effective treatment must be further promoted regarding childhood CNS tumors with a view to decreasing the disease burden, especially in rural areas.

Semi-supervised segmentation of cardiac chambers from LGE-CMR using feature consistency awareness.

BACKGROUND: Late gadolinium enhancement cardiac magnetic resonance imaging (LGE-CMR) is a valuable cardiovascular imaging technique. Segmentation of cardiac chambers from LGE-CMR is a fundamental step in electrophysiological modeling and cardiovascular disease diagnosis. Deep learning methods have demonstrated extremely promising performance. However, excellent performance often depended on a large amount of finely annotated data. The purpose of this manuscript was to develop a semi-supervised segmentation method to use unlabeled data to improve model performance. METHODS: This manuscript proposed a semi-supervised network that integrates triple-consistency constraints (data-level, task-level, and feature-level) for cardiac chambers segmentation from LGE-CMR. Specifically, we designed a network that integrated segmentation and edge prediction tasks based on the mean teacher architecture. This addressed the problem of ignoring some challenging regions because of excluding low-confidence regions of previous research. We also applied a voxel-level contrastive learning strategy to achieve feature-level consistency, helping the model pay attention to the consistency between features overlooked in previous research. RESULTS: In terms of the Dice, Jaccard, Average Surface Distance (ASD), and 95% Hausdorff Distance (95HD) metrics, for the atrial segmentation dataset, the proposed method achieved scores of 88.34%, 79.30%, 7.92, and 2.02 when trained with 10% labeled data, and 90.70%, 83.09%, 6.41, and 1.72 when trained with 20% labeled data. For the ventricular segmentation task, the results were 87.22%, 77.95%, 2.27, and 0.61 with 10% labeled data, and 88.99%, 80.45%, 1.87, and 0.51 with 20% labeled data, respectively. CONCLUSION: Experiments demonstrated that our method outperforms previous semi-supervised methods, showing the potential of the proposed network for semi-supervised segmentation problems.

Unique association of anti-GABAA receptor encephalitis and myasthenia gravis in a patient with type A thymoma.

Association between anti-GABAAR encephalitis and myasthenia gravis is extremely rare with few reported cases. Herein, we report a case of a female patient diagnosed with anti-GABAAR encephalitis and thymoma at the first admission. She was administered glucocorticoids for long-term immunotherapy, and thymectomy with biopsy demonstrated a type A thymoma. After 4 months, the symptoms of encephalitis were relieved, but she then developed post-thymectomy myasthenia gravis with anti-AChR and anti-titin dual positivity. Antibodies to connective tissue (anti-ANA, anti-PCNA) and those characteristics of paraneoplastic syndrome (anti-Ma2/Ta) were also positive. She received oral glucocorticoids and tacrolimus as immunosuppressive therapy, and myasthenic symptoms were stable during a 2-year follow-up. Our case revealed that anti-GABAAR encephalitis and myasthenia gravis can appear in patient with type A thymoma at different periods, which alerts physicians to take long-term follow-up for anti-GABAAR encephalitis with thymoma, even after thymectomy. Concurrent positivity for more than one antibody after thymectomy is rarely observed, and their contribution to the clinical course and treatment decision remains to be further investigated.

Fluorine accumulation characteristics of 85 tea tree (Camellia sinensis) varieties and its potential risk assessment.

Tea tree is a fluorine (F)-enriched plant, leading to much concern about the safety of drinking tea from tea tree (Camellia sinensis (L.) Kuntze). Tea tree is a perennial leaf-harvested crop, and tea production in China is generally categorized as spring tea, summer tea and autumn tea in its annual growth rounds. However, the seasonally dynamic changes of F content and accumulation in the leaves and its drinking safety are poorly understood. In this study, 85 tea varieties cultivated under the same conditions were investigated to analyze the seasonal variation of F content and it's relationships with F accumulation, aluminum (Al), calcium (Ca) and manganese (Mn) and hazard quotient (HQ) in young leaves (one bud and two leaves, YL) and mature leaves (canopy leaves, ML). The average F contents and accumulations were 350 mg kg-1 and 203 g ha-1 in YL, and they were 2451 mg kg-1 and 2578 g ha-1 in ML, respectively, with F mainly accumulated in ML. As the growing season progresses, the F content showed a gradual increase in YL, while a decrease in ML, inferring that F may be redistributed from mature leaves to young leaves. Additionally, the F content was quite different among tea varieties which are suitable for processing oolong tea, green tea, and black tea, with higher F accumulation in oolong tea varieties than in green and black tea varieties. Moreover, F content and accumulation could be obviously affected by the geographical origin of the tea tree varieties, with significantly higher F content in the varieties from F rich fluorite belts than other regions. Furthermore, F content and accumulation showed a significant positive correlation with the content of Al and Mn (p < 0.05). Based on a daily tea consumption of 8.7 g, the HQ was investigated to show that the proportion of tea leaves with HQ<1 made from spring, summer and autumn tender leaves of 85 varieties was 100 %, 90.6 % and 50.6 %, respectively, indicating that the tea with the best drinking safety comes from spring, followed by summer, and then autumn. This result suggests that it could be necessary to avoid planting tea trees in fluorite mining areas, choose low F tea tree varieties, and control the tenderness of fresh leaves in order to ensure the safety of tea drinking.

Molecular mechanism of thiram-induced abnormal chondrocyte proliferation via lncRNA MSTRG.74.1-BNIP3 axis.

Thiram, a widely used organic pesticide in agriculture, exhibits both bactericidal and insecticidal effects. However, prolonged exposure to thiram has been linked to bone deformities and cartilage damage, contributing to the development of tibial dyschondroplasia (TD) in broilers and posing a significant threat to global agricultural production. TD, a prevalent nutritional metabolic disease, manifests as clinical symptoms like unstable standing, claudication, and sluggish movement in affected broilers. In recent years, there has been growing recognition of the regulatory role of long non-coding RNA (lncRNA) in tibial cartilage formation among broilers through diverse signaling pathways. This study employs in vitro experimental models, growth performance analysis, and clinical observation to assess broilers' susceptibility to thiram pollution. Transcriptome sequencing analysis revealed a significant elevation in the expression of lncRNA MSTRG.74.1 in both the con group and the thiram-induced in vitro group. The results showed that lncRNA MSTRG.74.1 plays a pivotal role in influencing the proliferation and abnormal differentiation of chondrocytes. This regulation occurs through the negative modulation of apoptotic genes, including Bax, Cytc, Bcl2, Apaf1, and Caspase3, along with genes Atg5, Beclin1, LC3b, and protein p62. Moreover, the overexpression of lncRNA MSTRG.74.1 was found to regulate broiler chondrocyte development by upregulating BNIP3. In summary, this research sheds light on thiram-induced abnormal chondrocyte proliferation in TD broilers, emphasizing the significant regulatory role of the lncRNA MSTRG.74.1-BNIP3 axis, which will contribute to our understanding of the molecular mechanisms underlying TD development in broilers exposed to thiram.

Molecular mechanism of miR-203a targeting Runx2 to regulate thiram induced-chondrocyte development.

Thiram is a kind of organic compound, which is commonly used for sterilization, insecticidal and deodorization in daily life. Its toxicology has been broadly studied. Recently, more and more microRNAs have been shown to participate in the regulation of cartilage development. However, the potential mechanism by which microRNA regulates chondrocyte growth is still unclear. Our experiments have demonstrated that thiram can hamper chondrocytes development and cause a significant increase in miR-203a content in vitro and in vivo trials. miR-203a mimic significantly decrease in mRNA and protein expression of Wnt4, Runx2, COL2A1, ß-catenin and ALP, and significantly enhance the mRNA and protein levels of GSK-3ß. It has been observed that overexpression of miR-203a hindered chondrocytes development. In addition, Runx2 was confirmed to be a direct target of miR-203a by dual luciferase report gene assay. Transfection of si-Runx2 into chondrocytes reveals that significant downregulation of genes is associated with cartilage development. Overall, these results suggest that overexpression of miR-203a inhibits the expression of Runx2. These findings are conducive to elucidate the mechanism of chondrocytes dysplasia induced by thiram and provide new research ideas for the toxicology of thiram.

Identification of Gonatophragmium mori Causing Mulberry Zonate Leaf Spot Disease and Characterization of Their Biological Enemies in Guangxi, China.

Mulberry zonate leaf spot disease (MZLSD) is an important fungal disease of mulberry trees, which seriously affects the productivity and quality of mulberry leaves. MZLSD has been widely reported in sericultural production areas in Guangxi, China, in recent years. In this study, the causal agent of MZLSD was isolated from symptomatic samples and identified as Gonatophragmium mori (Acrospermaceae) based on morphological characterization and molecular analyses using nucleotide sequences of the internal transcribed spacer (ITS) and large subunit ribosomal DNA (LSU rDNA). Pathogenicity tests confirmed that G. mori is the pathogen responsible for MZLSD. Furthermore, we isolated antagonistic endophytic bacteria (AEB) from healthy mulberry leaves. Plate confrontation experiments showed that the lipopeptide crude extracts (LPCE) of three endophytic bacteria can inhibit the growth of G. mori, and the diameter of the antibacterial circle reaches more than 60 mm when their concentration of LPCE is 200 mg/ml. Light microscopy and scanning electron microscopy revealed that LPCE caused drastic changes in mycelial morphology. Fluorescence microscopy and transmission electron microscopy showed that the LPCE-induced apoptosis-like cell death in G. mori hyphae. Finally, based on morphological and molecular features, we identified the three isolates as Bacillus subtilis DS07, B. subtilis DS32, and B. velezensis Q6, respectively. To our knowledge, this is the first time to identify G. mori by combining characterization and molecular analyses, and we provide timely information about the use of biocontrol agents for suppression of G. mori.

Changes of vertical distribution of Microcystis colonies driven by short-term rainfall: Disappearance and reformation of surface bloom.

Global climate warming and human activities have increased the magnitude and frequency of Microcystis surface blooms, posing significant threats to freshwater ecosystems and human health over recent decades. Heavy rainfall events have been reported to cause the disappearance of these blooms. Although some studies have employed turbulence models to analyze the movement characteristics of Microcystis colonies, the impact of rainfall is complex, comprehensive investigations on their vertical migration induced by short-term rainfall are still necessary. Utilizing monitoring data from eutrophic ponds and controlled simulation experiments, this study examines the short-term impacts of rainfall on the vertical distribution of Microcystis in the water column. Our findings indicate that rainfall contributes to the disappearance of Microcystis blooms by reducing the quantity of small to medium-sized colonies (0-100 µm) at the surface, subsequently decreasing the overall Microcystis biomass. As rainfall intensity increases, larger colonies migrate deeper into the water column. At a rainfall threshold of 666 mm, the difference in the median volume diameter (DV50) of Microcystis colonies between the surface and bottom reaches a minimal value of 3.09%. Post-rainfall, these colonies rapidly ascend, aggregate into larger formations, and re-establish surface blooms. The greater the rainfall, the smaller the resultant Microcystis biomass, albeit with larger aggregated colony sizes. When rainfall exceeds 222 mm, the recovery rate of surface Microcystis biomass remains below 100%, decreasing to 19.48% at 666 mm of rainfall, while the median volume diameter (DV50) of the colonies increases to 139.07% of its pre-rainfall level. Furthermore, compared to pre-rainfall conditions, the photosynthetic activity of the surface Microcystis colonies was enhanced and the secretion of EPS was increased under heavy rainfall conditions. Our results identify a critical response time of 30 min for Microcystis colonies to rainfall, after which the response ceases to intensify. These insights are crucial for predicting post-rain Microcystis bloom dynamics and aiding management authorities in timely interventions.

Association between phthalates and sleep problems in the U.S. adult females from NHANES 2011-2014.

There is little research on the relationship between phthalates exposure and sleep problems in adult females, with existing studies only assessing the association between exposure to individual phthalates with sleep problems. We aimed to analyse the relationship between phthalates and sleep problems in 1366 US females aged 20 years and older from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) by age stratification. Multivariate logistic regression showed that the fourth quartile of MECPP increased the risk of sleep problems in females aged 20-39 compared with the reference quartile (OR: 1.87, 95% CI: 1.14, 3.08). The WQS index was significantly associated with the sleep problems in females aged 20-39. In the BKMR, a positive overall trend between the mixture and sleep problems in females aged 20-39. In this study, we concluded that phthalates might increase the risk of sleep problems in females aged 20-39.

[Magnetically Induced Displacement Force Test Method for Ultralight Implants Based on Counterweight Correction Method].

ASTM (American Society for Testing and Materials) F2052-21 (Chinese corresponding standard titled as YY/T 0987.2) introduces a test method to measure the magnetically induced displacement force on medical devices in the magnetic resonance environment. This method has been widely accepted and utilized globally, which is intended for implantable medical devices that can be suspended from a string. The angular deflection of the string from the vertical is measured and thereby measuring out the magnitude of the magnetically induced deflection force relative to gravity. When applying this method on ultralight implants, it is practically almost impossible to use a suspension string that weighs less than 1% of the mass of the implant. That study proposes a method for measuring the magnetically induced displacement force on ultralight implants based on counterweight correction by using a string and clamp that exceed 1% of the weight of the implant. And then to measure the deflection angle according to the standard requirement, following that to correct the deflection angle by using the proportion of the mass of the implant under test to the total mass of the tested object, to obtain the measurement result. That study also provides theoretical calculations and experimental verification to the counterweight correction method, the results prove that the proposed method can effectively measure the magnetically induced displacement force on ultralight implants.

Single-cell RNA-sequencing analysis reveals divergent transcriptome events between platinum-sensitive and platinum-resistant high-grade serous ovarian carcinoma.

BACKGROUND: Tumor resistance is one of the main reasons leading to the failure of ovarian cancer treatment. Overcoming platinum resistance remains the greatest challenge in the management of high-grade serous ovarian carcinoma (HGSC). METHODS: Small conditional RNA-sequencing is a powerful method for exploring the complexity of the cellular components and their interactions in the tumor microenvironment. We profiled the transcriptomes of 35,042 cells from two platinum-sensitive and three platinum resistance HGSC clinical cases downloaded from Gene Expression Omnibus (GSE154600) and annotated tumor cells as platinum-resistant or sensitive based on the clinical trait. The study systematically investigated the inter-tumoral (using differential expression analysis, CellChat, and SCENIC) and intra-tumoral heterogeneity (using enrichment analysis such as gene set enrichment analysis, as well as gene set variation analysis, weighted gene correlation network analysis, and Pseudo-time analysis) of HGSC. RESULTS: A cellular map of HGSC generated by profiling 30,780 cells was revisualized using Uniform Manifold Approximation and Projection. The inter-tumoral heterogeneity was demonstrated with intercellular ligand-receptor interactions of major cell types and regulons networks. FN1, SPP1, and COLLAGEN play important roles in the cross-talk between tumor cells and the tumor microenvironment. HOXA7, HOXA9_extended, TBL1XR1_extended, KLF5, SOX17, and CTCFL regulons consistent with the distribution of platinum-resistant HGSC cells were the high activity regions. The intra-tumoral heterogeneity of HGSC was presented with corresponding functional pathway characteristics, tumor stemness features, and the cellular lineage transition from platinum-sensitive to resistant condition. Epithelial-mesenchymal transition played an important role in platinum resistance, whereas oxidative phosphorylation was the opposite. There was a small subset of cells in platinum-sensitive samples that had transcriptomic characteristics similar to platinum-resistant cells, suggesting that the progression of platinum resistance in ovarian cancer is inevitable. CONCLUSIONS: The present study describes a view of HGSC at single-cell resolution that reveals the characteristics of the HGSC heterogeneity and provides a useful framework for future investigation of platinum-resistant.

An LC-MS-based workflow measures the export activity of S1P transporters.

Sphingosine-1-phosphate (S1P) is an active signaling metabolite synthesized by blood cells, exported into blood stream, and can trigger many downstream signaling pathways with disease implications. Understanding how S1P is transported is of great values for dissecting the function of S1P, but most existing methods for measuring S1P transporter activity use radioactive substrates or involve multiple workup steps, hindering their broader uses. In this study, we develop a workflow combining sensitive LC-MS measurement and a cell-based transporter protein system to measure the export activity of S1P transporter proteins. Our workflow demonstrated good applications in studying different S1P transporters SPNS2 and MFSD2B, WT and mutated protein, and different protein substrates. In summary, we provide a simple yet versatile workflow for measuring the export activity of S1P transporters, facilitating future studies of S1P transport mechanism and drug development.

Role of kisspeptin in polycystic ovarian syndrome: A metabolomics study.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a pathophysiological disease affecting reproductive and metabolic indicators. Research has shown that kisspeptin might be involved in the regulation of pituitary hormone secretion and energy metabolism. The aim of this study was to investigate the relationship between serum kisspeptin levels and abnormal metabolism in PCOS. METHODS: Fifty patients with PCOS and 50 control patients were recruited for this study. Serum kisspeptin levels were measured via ELISA. High-performance liquid chromatography-tandem mass spectrometry metabolomics was used to study the changes in serum metabolism between the PCOS and control groups. RESULTS: Serum kisspeptin levels were significantly elevated in individuals with PCOS compared with those in healthy controls (p = 0.011) and positively correlated with LH, T, FFA, BA, and LEP levels (p < 0.05). Significantly dysregulated expression of several metabolites was observed in the intergroup comparisons of the high-kisspeptin PCOS, low-kisspeptin PCOS, and healthy control groups. These primarily consisted of lipid, amino acid, and carbohydrate metabolites, among which palmitic acid and N-formylkynurenine levels were lower in the high-kisspeptin group than in controls. Metabolite set enrichment analysis was also performed based on metabolites in the KEGG database. The results showed that owing to the differences in kisspeptin concentrations in individuals with PCOS, there was a significant difference in amino acid and pyruvate metabolism. CONCLUSIONS: Kisspeptin could be a potential biomarker for the diagnosis of PCOS and plays an important role in metabolic regulation in individuals with PCOS. In addition, metabolomics provides a promising method for the study of metabolic abnormalities in individuals with PCOS, which might contribute to our understanding of its mechanisms.

Effectiveness and safety of REBACIN as a non-invasive intervention for persistent high-risk human papillomavirus infection: A real-world prospective multicenter cohort study.

BACKGROUND: We previously reported that REBACIN effectively eliminates persistent high-risk human papillomavirus (hrHPV) infection. Here, we conducted a prospective multicenter cohort study to evaluate the safety and effectiveness of REBACIN, taking into account factors such as specific hrHPV subtype and patient's age. METHODS: According to inclusion/exclusion criteria and participant willingness, 3252 patients were divided into REBACIN group while 249 patients into control group. Patients in REBACIN group received one course treatment of intravaginal administration of REBACIN while no treatment in control group. After drug withdrawal, participants in both groups were followed up. RESULTS: The clearance rate of persistent hrHPV infection in REBACIN group was 60.64%, compared to 20.08% in control group. Specifically, the clearance rates for single-type infection of HPV16 or HPV18 were 70.62% and 69.23%, respectively, which was higher than that of HPV52 (59.04%) or HPV58 (62.64%). In addition, the single, double, and triple/triple+ infections had a clearance rate of 65.70%, 53.31%, and 38.30%, respectively. Moreover, 1635 patients under 40 years old had a clearance rate of 65.14%, while it was 55.08% for 1447 patients over 40 years old. No serious adverse effects were found. CONCLUSION: This study confirmed that REBACIN can effectively and safely eliminate persistent hrHPV infection, which the clearance rate of HPV16/18 is higher than that of HPV52/58, the clearance rate of single-type infection is higher than that of multiple-type infections, and the clearance rate in young patients is higher than that in elder patients, providing a guidance for REBACIN application in clearing hrHPV persistent infection in real-world settings. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry Registration Number: ChiCTR1800015617 http://www.chictr.org.cn/showproj.aspx?proj=26529 Date of Registration: 2018-04-11.

Analysis of clinical characteristics and treatment efficacy in two pediatric cases of ANKRD26-related thrombocytopenia.

ANKRD26-related thrombocytopenia (ANKRD26-RT or THC2, MIM 188 000), an autosomal dominant thrombocytopenia, is unresponsive to immunosuppressive therapy and susceptible to hematological malignancies. A large number of pediatric patients are diagnosed with immune thrombocytopenia (ITP) every year; however, thrombocytopenia of genetic origin is often missed. Extensive characterization of ANKRD26-RT will help prevent missed diagnosis and misdiagnosis. Furthermore, identification of ANKRD26-RT will help in the formulation of an accurate diagnosis and a treatment plan. In our study, we report cases of two Chinese pediatric patients with ANKRD26-RT and analyze their clinical characteristics, gene mutations, and treatment modalities. Both patients were 1-year-old and presented with mild bleeding (World Health Organization(WHO) score grade 1), different degrees of platelet reduction, normal mean platelet volume, and megakaryocyte maturation impairment not obvious. Genetic tests revealed that both patients had ANKRD26 gene mutations.Patient 1 had a mutation c.-140C>G of the 5' untranslated region (UTR), and patient 2 had a mutation of c.-127A>T of 5'UTR. Both patients were treated with eltrombopag, and the treatment was no response, with no adverse reactions.

What is the background? ANKRD26-RT is an autosomal dominant thrombocytopenia which is unresponsive to immunosuppressive therapy and susceptible to hematological malignancies.It is rare and lacks specific clinical features, making misdiagnosis easy.Some studies report that eltrombopag is safe and effective for short-term treatment of the disease; however, these reports are limited.What we did and summary of findings. We retrospectively studied the clinical manifestations and diagnosis process of ANKRD26-RT and discussed the treatment efficacy of immunosuppressants and eltrombopag for its management.We found two pediatric cases of patients with ANKRD26-RT with varying degrees of thrombocytopenia, mild bleeding, normal mean platelet volume, and megakaryocyte maturation impairment that was not obvious. Immunosuppressant treatment wasunresponsiveor temporarily responsivebut not sustained , and short-term administration of eltrombopag (25 mg/day) was safe, but it did not effectively improve the patients' platelet counts.What is the impact? If patients clinically diagnosed with immune thrombocytopenia do not respond  to immunosuppressive agents, genetic testing should be conducted to exclude hereditary thrombocytopenia, and a normal mean platelet volume should not exclude the possibility of the disease.For patients with ANKRD26-RT, eltrombopag is safe for short-term use;however, 25 mg/day treatment is unresponsive.Ourreport complements data on the diagnosis and management of ANKRD26-RT disease in children.