Primary pulmonary myxoid sarcoma with EWSR1::CREB1 fusion: a literature review.

PURPOSE: This review primarily aims to review the epidemiology, clinical characteristics, imaging, pathology, immunohistochemistry, diagnosis, differential diagnosis, treatment, and prognosis of Primary pulmonary myxoid sarcoma (PPMS) with EWS RNA binding protein 1::cAMP response element binding protein 1 (EWSR1::CREB1) fusion. It provides reference for the diagnosis and treatment of this disease. METHODS: Retrospectively collected the literature about PPMS with EWSR1::CREB1 fusion, its clinical, radiology, histology, molecular characteristics and current treatment strategies were collated and analyzed. This review provides a detailed differential diagnosis of the disease. RESULTS: PPMS is an exceptionally rare, low-grade malignant tumor of the lung. This tumor commonly infiltrates lung tissue and develops within bronchial passages. It is identified by a genetic rearrangement involving the EWSR1 gene and a distinct chromosomal translocation t(2; 22)(q33; q12). Variants include EWSR1::CREB1 fusion and EWS RNA binding protein 1::activating transcription factors (EWSR1::ATF1) fusion. PPMS with EWSR1::CREB1 fusion is more prevalent among middle-aged individuals and affects both sexes almost equally. Clinical symptoms are relatively non-specific, primarily including cough, hemoptysis, and weight loss. Most patients undergo surgery and experience a favorable prognosis. Further research is required to validate the effectiveness of alternative treatments for PPMS with EWSR1::CREB1 fusion. CONCLUSION: EWSR1 rearrangement and EWSR1::CREB1 fusion are crucial genetic features of PPMS and serve as important diagnostic markers. Immunohistochemically, PPMS tests positive for EMA. In terms of treatment, surgery has been the primary approach in recent years. Therefore, the efficacy of other treatments still requires further investigation.

Astragalus polysaccharides attenuate rat aortic endothelial senescence via regulation of the SIRT-1/p53 signaling pathway.

BACKGROUND: Astragalus polysaccharides (APS) have been verified to have antioxidative and antiaging activities in the mouse liver and brain. However, the effect of APS on aortic endothelial senescence in old rats and its underlying mechanism are currently unclear. Here, we aimed to elucidate the effects of APS on rat aortic endothelial oxidative stress and senescence in vitro and in vivo and investigate the potential molecular targets. METHODS: Twenty-month-old natural aging male rats were treated with APS (200 mg/kg, 400 mg/kg, 800 mg/kg daily) for 3 months. Serum parameters were tested using corresponding assay kits. Aortic morphology was observed by staining with hematoxylin and eosin (H&E) and Verhoeff Van Gieson (VVG). Aging-related protein levels were evaluated using immunofluorescence and western blot analysis. Primary rat aortic endothelial cells (RAECs) were isolated by tissue explant method. RAEC mitochondrial function was evaluated by the mitochondrial membrane potential (MMP) measured with the fluorescent lipophilic cationic dye JC­1. Intracellular total antioxidant capacity (T-AOC) was detected by a commercial kit. Cellular senescence was assessed using senescence-associated-ß-galactosidase (SA-ß-Gal) staining. RESULTS: Treatment of APS for three months was found to lessen aortic wall thickness, renovate vascular elastic tissue, improve vascular endothelial function, and reduce oxidative stress levels in 20-month-old rats. Primary mechanism analysis showed that APS treatment enhanced Sirtuin 1 (SIRT-1) protein expression and decreased the levels of the aging marker proteins p53, p21 and p16 in rat aortic tissue. Furthermore, APS abated hydrogen peroxide (H2O2)-induced cell senescence and restored H2O2-induced impairment of the MMP and T-AOC in RAECs. Similarly, APS increased SIRT-1 and decreased p53, p21 and p16 protein levels in senescent RAECs isolated from old rats. Knockdown of SIRT-1 diminished the protective effect of APS against H2O2-induced RAEC senescence and T-AOC loss, increased the levels of the downstream proteins p53 and p21, and abolished the inhibitory effect of APS on the expression of these proteins in RAECs. CONCLUSION: APS may reduce rat aortic endothelial oxidative stress and senescence via the SIRT-1/p53 signaling pathway.

Fermented natto powder alleviates obesity by regulating LXR pathway and gut microbiota in obesity rats.

AIM: This study aimed to investigate the positive effect of natto powder on obese rats fed with a high-fat diet (HFD). METHODS AND RESULTS: Sprague-Dawley rats were fed with a HFD for 8 weeks continuously and gavaged with natto powder, respectively, for 8 weeks starting from the ninth week. The results showed that natto powder significantly reduced the body weight of rats and maintained the balance of cholesterol metabolism in the body by inhibiting the activity of liver X receptors (LXR) target genes, increasing the active expression of cholesterol 7 alpha-hydroxylase, and reducing the active expression of sterol-regulatory element-binding protein and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Furthermore, natto powder increased the relative abundance of potentially beneficial microbiota in gut and decreased the relative abundance of obesity-related harmful bacteria, and also increased the Bacteroidetes/Firmicutes ratio and improved the composition of gut microbiota. CONCLUSIONS: Natto powder maintains the balance of cholesterol metabolism by inhibiting the LXR pathway and regulating the gut microbiota.

Low-Temperature Adaptive Single-Atom Iron Nanozymes against Viruses in the Cold Chain.

Outbreaks of viral infectious diseases, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV), pose a great threat to human health. Viral spread is accelerated worldwide by the development of cold chain logistics; Therefore, an effective antiviral approach is required. In this study, it is aimed to develop a distinct antiviral strategy using nanozymes with low-temperature adaptability, suitable for cold chain logistics. Phosphorus (P) atoms are added to the remote counter position of Fe-N-C center to prepare FeN4P2-single-atom nanozymes (SAzymes), exhibiting lipid oxidase (OXD)-like activity at cold chain temperatures (-20, and 4 °C). This feature enables FeN4P2-SAzymes to disrupt multiple enveloped viruses (human, swine, and avian coronaviruses, and H1-H11 subtypes of IAV) by catalyzing lipid peroxidation of the viral lipid envelope. Under the simulated conditions of cold chain logistics, FeN4P2-SAzymes are successfully applied as antiviral coatings on outer packaging and personal protective equipment; Therefore, FeN4P2-SAzymes with low-temperature adaptability and broad-spectrum antiviral properties may serve as key materials for developing specific antiviral approaches to interrupt viral transmission through the cold chain.

Structural Characterization and Properties of Modified Soybean Meal Protein via Solid-State Fermentation by Bacillus subtilis.

Soybean meal (SBM) is a high-quality vegetable protein, whose application is greatly limited due to its high molecular weight and anti-nutritional properties. The aim of this study was to modify the protein of soybean meal via solid-state fermentation of Bacillus subtilis. The fermentation conditions were optimized as, finally, the best process parameters were obtained, namely fermentation temperature of 37 °C, inoculum amount of 12%, time of 47 h, and material-liquid ratio of 1:0.58, which improved the content of acid-soluble protein. To explore the utilization of modified SBM as a food ingredient, the protein structure and properties were investigated. Compared to SBM, the protein secondary structure of fermented soybean meal (FSBM) from the optimal process decreased by 8.3% for α-helix content, increased by 3.08% for ß-sheet, increased by 2.71% for ß-turn, and increased by 2.51% for random coil. SDS-PAGE patterns showed that its 25-250 KDa bands appeared to be significantly attenuated, with multiple newborn peptide bands smaller than 25 KDa. The analysis of particle size and zeta potential showed that fermentation reduced the average particle size and increased the absolute value of zeta potential. It was visualized by SEM and CLSM maps that the macromolecular proteins in FSBM were broken down into fragmented pieces with a folded and porous surface structure. Fermentation increased the solubility, decreased the hydrophobicity, increased the free sulfhydryl content, decreased the antigenicity, improved the protein properties of SBM, and promoted further processing and production of FSBM as a food ingredient.

Geotechnical Deformation Distributed Measuring Technology Research Based on Parallel Spiral Sensing Line.

The precursors that appear when geological disasters occur are geotechnical deformations. This paper studies the TDR (Time Domain Reflection) measurement technology for the distributed measurement of geotechnical deformation using parallel spiral wire as a sensor, which is used for monitoring and early warning detection of geological disasters. Based on the mechanism of the electromagnetic field distribution parameters of the parallel spiral sensing wire, the relationship between the stretching amount of the parallel spiral wire and the change in its characteristic impedance is analyzed. When the parallel spiral wire is buried in the soil, the geotechnical deformation causes the parallel spiral wire to be stretched, and according to its characteristic impedance change, the stretching position and the stretching degree can be obtained, thus realizing the distributed measurement of geotechnical deformation. Based on this principle, the TDR measurement system is developed, and a local single-point stretching amount and stretching positioning experiment are designed for the parallel spiral sensing line to verify the effectiveness of the sensing technology and the usability of the measurement system.

Bidirectionally Regulating Viral and Cellular Ferroptosis with Metastable Iron Sulfide Against Influenza Virus.

Influenza virus with numerous subtypes and frequent variation limits the development of high-efficacy and broad-spectrum antiviral strategy. Here, a novel multi-antiviral metastable iron sulfides (mFeS) against various influenza A/B subtype viruses is developed. This work finds that mFeS induces high levels of lipid peroxidation and •OH free radicals in the conservative viral envelope, which depends on Fe2+ . This phenomenon, termed as a viral ferroptosis, results in the loss of viral infectibility and pathogenicity in vitro and in vivo, respectively. Furthermore, the decoction of mFeS (Dc(mFeS)) inhibits cellular ferroptosis-dependent intracellular viral replication by correcting the virus-induced reprogrammed sulfur metabolism, a conserved cellular metabolism. Notably, personal protective equipment (PPE) that is loaded with mFeS provides good antiviral protection. Aerosol administration of mFeS combined with the decoction (mFeS&Dc) has a potential therapeutic effect against H1N1 lethal infection in mice. Collectively, mFeS represents an antiviral alternative with broad-spectrum activity against intracellular and extracellular influenza virus.

Analysis of clinical features and 7-year all-cause mortality in older male patients with non-thyroidal illness syndrome on general wards.

PURPOSE: Older patients with non-thyroidal illness syndrome (NTIS) have a poor prognosis. However, there are few studies on the association of NTIS and mortality among older inpatients on general wards. In a 7-year retrospective observational study, we aimed to investigate the clinical features of NTIS and the association of NTIS and all-cause mortality in older inpatients. METHODS: A total of 959 older male inpatients whose average age was 86.3 ± 8.1 years were enrolled and divided into the NTIS group and non-NTIS group. Cox models were performed to explore the association of thyroid hormone level and mortality. RESULTS: Patients had more respiratory disease and chronic kidney disease in the NTIS than in the non-NTIS group, especially in primary nursing care, respiratory failure and haemodialysis patients; serum total protein, albumin, prealbumin, haemoglobin, uric acid and high-density lipoprotein cholesterol levels were lower, and urea nitrogen and fasting blood glucose levels were higher, in the NTIS than in the non-NTIS group. Patients in the NTIS group had a lower survival rate over 7 years follow-up (P < 0.01). A lower free T3 level was associated with all-cause mortality with a HR of 1.50 (1.36, 1.66). Lower free T4 level was associated with reduced all-cause mortality with a HR of 0.91 (0.88, 0.94) even after adjusting for confounding factors (P < 0.01). CONCLUSIONS: Among older male inpatients, the survival rate was lower in the NTIS group. A reduced free T3 level with low albumin and Hb levels was associated with all-cause mortality; moreover, a higher free T4 in the normal range may be a strong predictor for long-term mortality risk in hospitalised older male patients.

Study on the fermentation effect of Rhodotorula glutinis utilizing tofu whey wastewater and the influence of Rhodotorula glutinis on laying hens.

Background: Tofu whey wastewater (TWW) is the wastewater of tofu processing, which is rich in a variety of nutrients. Rhodotorula glutinis can make full use of TWW to ferment and reproduce yeast cells, produce carotenoids and other nutrients, improve the utilization value of TWW, and reduce environmental pollution and resource waste. Methods: In this study, the nutrient composition changes of TWW treated by Rhodotorula glutinis were analyzed to reformulate TWW medium, and the optimal composition and proportion of TWW medium that can improve the biomass and carotenoids production of Rhodotorula glutinis were explored. Meanwhile, the Rhodotorula glutinis liquid obtained under these conditions was used to prepare biological feed for laying hens, and the effect of Rhodotorula glutinis growing on TWW as substrate on laying performance and egg quality of laying hens were verified. Results: The results showed that the zinc content of TWW after Rhodotorula glutinis fermentation increased by 62.30%, the phosphorus content decreased by 42.31%, and the contents of vitamin B1, B2 and B6 increased to varying degrees. The optimal fermentation conditions of Rhodotorula glutinis in the TWW medium were as follow: the initial pH was 6.40, the amount of soybean oil, glucose and zinc ions was 0.80 ml/L, 16.32 g/L, and 20.52 mg/L, respectively. Under this condition, the biomass of Rhodotorula glutinis reached 2.23 g/L, the carotenoids production was 832.86 µg/g, and the number of effective viable yeast count was 7.08 × 107 cfu/ml. In addition, the laying performance and egg quality of laying hens fed Rhodotorula glutinis biological feed were improved. Discussion: In this study, we analyzed the composition changes of TWW, optimized the fermentation conditions of Rhodotorula glutinis in TWW medium, explored the influence of Rhodotorula glutinis utilizing TWW on laying layers, and provided a new idea for the efficient utilization of TWW.

Optimization of Mixed Fermentation Conditions of Dietary Fiber from Soybean Residue and the Effect on Structure, Properties and Potential Biological Activity of Dietary Fiber from Soybean Residue.

Soybean residue is a by-product of soybean product production that is wasted unreasonably at present. Accomplishing the efficient utilization of soybean residue can save resources. A composite microbial system was constructed using lactic acid bacteria (LAB) and Saccharomyces cerevisiae (SC), and modified soybean residue was prepared by solid fermentation. In order to explore the value of modified soybean residue as a food raw material, its physical and chemical properties, adsorption properties, and antioxidant properties were studied. The results showed that the soluble dietary fiber (SDF) yield of mixed fermentation (MF) increased significantly. Both groups of soybean residues had representative polysaccharide infrared absorption peaks, and MF showed a looser structure and lower crystallinity. In terms of the adsorption capacity index, MF also has a higher adsorption capacity for water molecules, oil molecules, and cholesterol molecules. In addition, the in vitro antioxidant capacity of MF was also significantly higher than that of unfermented soybean residue (UF). In conclusion, our study shows that mixed fermentation could increase SDF content and improve the functional properties of soybean residue. Modified soybean residue prepared by mixed fermentation is the ideal food raw material.

PA-X protein of H9N2 subtype avian influenza virus suppresses the innate immunity of chicken bone marrow-derived dendritic cells.

H9N2 subtype avian influenza (AI) is an infectious disease associated with immunosuppression in poultry. Here, the regulation function of PA-X protein was determined on the host innate immune response of H9N2-infected chicken bone marrow-derived DCs (chBM-DCs). Based on 2 mutated viruses expressing PA-X protein (rTX) or deficient PA-X protein (rTX-FS), and the established culture system of chBM-DCs, results showed PA-X protein inhibited viral replication in chBM-DCs but not in non-immune chicken cells (DF-1). Moreover, PA-X protein downregulated the expression of phenotypic markers (CD40, CD86, and MHCII) and proinflammatory cytokine (IL-12 and IL-1ß) of chBM-DCs. The mixed lymphocyte reaction between chBM-DCs and chicken T cells showed PA-X protein significantly decreased H9N2-infected chBM-DCs to induce T cell proliferation, implying a suppression of the DC-induced downstream T cell response. Taken together, these findings indicated that PA-X protein is a key viral protein to help H9N2 subtype AIVs escape the innate immunity of chBM-DCs.

Parathyroid carcinoma: Report of 10 patients and literature review.

OBJECTIVE: Parathyroid carcinoma (PC) is a rare disease with high rates of misdiagnosis and recurrence. This report summarized the clinical and pathological characteristics of 10 patients with PC at our hospital, to improve the early recognition and prognosis of PC. METHODS: The clinical manifestations, imaging findings, pathological features, treatments, and prognostic data of 10 patients diagnosed with PC at the First Medical Center, Chinese PLA General Hospital from 2003 to 2021 were analyzed. RESULTS: There were 7 male and 3 female patients with PC whose average age was 41.4 ± 9.4 years. All patients had bone involvement (bone pain and/or osteoporosis), meanwhile 6 patients had kidney stones and 7 patients had palpable neck masses. Five patients presented with tumor metastasis, invading lymph nodes, lung, liver, or bone. Laboratory examinations revealed elevated serum total calcium (4.15 ± 0.81 mmol/L), parathyroid hormone (PTH, 1236.1 ± 519.9 pg/mL) and alkaline phosphatase (405.8 ± 219.0 IU/L) levels. Especially, hypercalcemic crisis occurred in 9 patients. The diagnosis of PC depended on histopathological features of the parathyroid tumor, including capsular and/or vascular invasion. All patients underwent at least en bloc resection. In the follow-up, six patients with relatively high preoperative PTH levels (1519.5 ± 436.8 pg/mL) relapsed postoperatively. Two patients with the Ki-67 index ≥ 10% in parathyroid tumor tissue and distant metastasis died within 2 years after the operation. CONCLUSION: Severe bone pain, kidney stones, hypercalcemic crisis, and markedly elevated PTH usually indicate PC. A markedly elevated PTH level, tumor metastasis, and the Ki-67 index ≥ 10% may be indicators of poor prognosis.

Recent development in hydrophilic interaction liquid chromatography stationary materials for glycopeptide analysis.

Protein glycosylation is one of the most important post-translational modifications, and aberrant glycosylation is associated with the occurrence and development of diseases. Deciphering abnormal glycosylation changes can identify disease-specific signatures to facilitate the discovery of potential disease biomarkers. However, glycosylation analysis is challenging due to the diversity of glycans, heterogeneity of glycosites, and poor electrospray ionization of mass spectrometry. To overcome these obstacles, glycosylation is often elucidated using enriched glycopeptides by removing highly abundant non-glycopeptides. Hydrophilic interaction liquid chromatography (HILIC) is widely used for glycopeptide enrichment due to its excellent selectivity and specificity to hydrophilic glycans and compatibility with mass spectrometry. However, the development of HILIC has lagged far behind hydrophobic interaction chromatography, so efforts to further improve the performance of HILIC are beneficial for glycosylation analysis. This review discusses recent developments in HILIC materials and their advanced applications. Based on the physiochemical properties of glycopeptides, the use of amino acids or peptides as stationary phases showed improved enrichment and separation of glycopeptides. We can envision that the use of glycopeptides as stationary phases would definitely further improve the selectivity and specificity of HILIC for glycosylation analysis.

Problems on polarization aberrations in large aperture dynamic interferometry based on the polarization phase shifting technique.

The polarization based phase shifting method is an effective way for dynamic measurements. However, when this technique is applied to the measurements of large optics, the interferometric results are easily limited by the birefringence of large optics. The birefringence changes the polarization states of reference light and test light, and brings constant polarization aberrations into the measurement results independent of the phase shifting procedure. In this article, the detailed theoretical analysis on the mechanism of polarization aberration is presented. Afterwards, we propose a new interferometric method to determine the birefringence effects by measuring the transmitted wavefronts of the large optics, which are considered as birefringent samples. Theoretical analysis shows that the polarization error in the linearly polarized system can be corrected by two independent measurements with orthogonal polarization states. The phase retardance can be obtained from the wavefront difference of the transmitted wavefronts when switching the polarization states of the incident lights. The birefringence distribution obtained is used to calibrate the polarization aberrations in the measurement result of a homemade large aperture measurement platform and the correction result is compared with the result via the wavelength tuning phase shifting method. The elimination of the polarization aberrations can be observed in the final results.

PA-X protein of H1N1 subtype influenza virus disables the nasal mucosal dendritic cells for strengthening virulence.

PA-X protein arises from a ribosomal frameshift in the PA of influenza A virus (IAV). However, the immune regulatory effect of the PA-X protein of H1N1 viruses on the nasal mucosal system remains unclear. Here, a PA-X deficient H1N1 rPR8 viral strain (rPR8-△PAX) was generated and its pathogenicity was determined. The results showed that PA-X was a pro-virulence factor in mice. Furthermore, it reduced the ability of H1N1 viruses to infect dendritic cells (DCs), the regulator of the mucosal immune system, but not non-immune cells (DF-1 and Calu-3). Following intranasal infection of mice, CCL20, a chemokine that monitors the recruitment of submucosal DCs, was downregulated by PA-X, resulting in an inhibition of the recruitment of CD11b+ DCs to submucosa. It also attenuated the migration of CCR7+ DCs to cervical lymph nodes and inhibited DC maturation with low MHC II and CD40 expression. Moreover, PA-X suppressed the maturation of phenotypic markers (CD80, CD86, CD40, and MHC II) and the levels of secreted pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) while enhancing endocytosis and levels of anti-inflammatory IL-10 in vitro, suggesting an impaired maturation of DCs that the key step for the activation of downstream immune responses. These findings suggested that the PA-X protein played a critical role in escaping the immune response of nasal mucosal DCs for increasing the virulence of H1N1 viruses.

The bidirectional association of C-peptide with cardiovascular risk in nondiabetic adults and patients with newly diagnosed type 2 diabetes mellitus: a retrospective cohort study.

BACKGROUND: Recent literature reported the biological role of C-peptide, but this role is still controversial and unclear. The primary aim of this study was to investigate associations between C-peptide and cardiovascular biomarkers as well as events. METHODS: A total of 55636 participants who had a health examination from 2017 to 2021 were included. Of them, 6727 participants visited the hospital at least twice. Cardiovascular biomarkers like high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured and their relationships with fasting C-peptide were evaluated for all participants. Cardiovascular events were obtained during the last visit and their associations with C-peptide were evaluated for those participants who visited the hospital at least twice. RESULTS: Among the included participants, 11.1% had a previous type 2 diabetes mellitus (T2DM). In the participants without previous T2DM, the relationships between fasting C-peptide and hs-CRP and hs-cTnT were negative if the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL. These relationships remained significant after adjusting for hemoglobin A1c, insulin resistance index, and its interaction with C-peptide, even if the participants were stratified by glucose metabolism status or levels of insulin resistance index. Hazard ratios of cardiovascular events were first decreased and then increased with the increasing of baseline C-peptide levels, though these associations became unsignificant using the multivariate Cox regression model. Unlike the participants without previous T2DM, the associations of C-peptide with cardiovascular biomarkers and events were not significant in the patients with previous T2DM. CONCLUSIONS: The associations of C-peptide with cardiovascular biomarkers and events were different between the participants without previous T2DM and those with previous T2DM. The effect of C-peptide on cardiovascular risk may be bidirectional, play a benefit role at a low level, and play a harmful role at a high level in the nondiabetic adults and the patients with newly diagnosed T2DM.

Phase unwrapping algorithm for a segmented phase based on iterative pseudo-phase inpainting.

Segmented phase unwrapping is an intractable problem in the phase-shifting technique. To solve the problem, this Letter presents an iterative pseudo-phase inpainting algorithm (IPPI). By means of image inpainting, the IPPI can be used to realize the pseudo-phases connecting each other among these phase islands. The error points in the pseudo-phases can be reduced by iterations of phase inpainting with the assistance of the reference pseudo-phase obtained by introducing the numerical carrier frequency and using the 2D Fourier transform. Compared with other methods, the proposed algorithm does not have to do any processing on the effective area of the wrapped phase, which ensures the authenticity of the result. The simulated and experimental verifications show that the proposed method not only possesses high precision, but also can be applied to a segmented phase with severe noise.

The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay.

PURPOSE: The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH). METHODS: A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay. RESULTS: Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities. CONCLUSION: This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.

Insights into behavior and mechanism of tetracycline adsorption on virgin and soil-exposed microplastics.

Microplastics (MPs), as vectors of pollutants, have attracted extensive attention because of their environmental effects. However, the adsorption behavior and antibiotic mechanism of environmentally exposed MPs is limited. Here, the adsorption of tetracycline (TC) onto virgin and soil-exposed polylactic acid (PLA), polyvinyl chloride (PVC) and polyethylene (PE) MPs showed that the adsorption capacity of MPs for TC increased after soil exposure, and PLA showed the strongest increase. Soil exposure increased the time to reach equilibrium, and the adsorption rate was controlled by both intraparticle diffusion and membrane diffusion. The isothermal adsorption results of soil-exposed PE and PLA indicated that TC adsorbed on heterogeneous surfaces was affected by the physicochemical adsorption process. The equilibrium absorption capacity of MPs for TC increased by 88% (PLA), 26% (PVC) and 15% (PE) after soil exposure. Soil dissolved organic matter promoted the desorption of TC from MPs, and TC speciation changed with pH. Soil-exposed MPs have the potential to promote TC degradation in solution without the addition of biological inhibitors. Moreover, density functional theory calculations verified that PE and PVC adsorbed TC through physical interactions, while hydrogen bonds were formed on PLA with TC. These results clarified the behavior and mechanisms of TC adsorption on virgin and soil-exposed MPs, which can help in the risk assessment of concomitant pollution of MPs and antibiotics.

H5N8 Subtype avian influenza virus isolated from migratory birds emerging in Eastern China possessed a high pathogenicity in mammals.

Novel H5N8 highly pathogenic avian influenza viruses (HPAIVs) bearing the clade 2.3.4.4b HA gene have been widely spread through wild migratory birds since 2020. One H5N8 HPAIV (A/Wild bird/Cixi/Cixi02/2020; here after Cixi02) was isolated from migratory birds in Zhejiang Province, Eastern China in 25 November 2020. However, its pathogenicity in avian and mammal remains unknown. Hemagglutinin gene genetic analysis indicated that Cixi02 virus belonged to the branch II of H5 clade 2.3.4.4b originated from Iraq in May 2020. Cixi02 virus showed a binding affinity to both SA α-2, 3-galactose (Gal) and SA α-2, 6 Gal receptors, good pH stability, thermostability, and replication ability in both avian and mammal cells. The poultry pathogenicity indicated that Cixi02 virus was lethal to chickens. Moreover, the mammalian pathogenicity showed that the 50% mouse lethal dose (MLD50 ) is 2.14 lgEID50 /50 µl, indicating a high pathogenicity in mice. Meanwhile, Cixi02 virus was widely detected in multiple organs, including heart, liver, spleen, lung, kidney, turbinate, and brain after nasal infection. In addition, we found high level gene expressions of TNF-α, IL-12p70, CXCL10, and IFN-α in lungs, IL-8 and IL-1ß in brains, and observed severe histopathological change in lungs and brains. Collectedly, this study provided new insights on the pathogenic and zoonotic features of an H5N8 subtype AIV isolated from migratory birds.