Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients. METHODS: In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. RESULTS: In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan. CONCLUSIONS: Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).

GAABind: a geometry-aware attention-based network for accurate protein-ligand binding pose and binding affinity prediction.

Protein-ligand interactions are increasingly profiled at high-throughput, playing a vital role in lead compound discovery and drug optimization. Accurate prediction of binding pose and binding affinity constitutes a pivotal challenge in advancing our computational understanding of protein-ligand interactions. However, inherent limitations still exist, including high computational cost for conformational search sampling in traditional molecular docking tools, and the unsatisfactory molecular representation learning and intermolecular interaction modeling in deep learning-based methods. Here we propose a geometry-aware attention-based deep learning model, GAABind, which effectively predicts the pocket-ligand binding pose and binding affinity within a multi-task learning framework. Specifically, GAABind comprehensively captures the geometric and topological properties of both binding pockets and ligands, and employs expressive molecular representation learning to model intramolecular interactions. Moreover, GAABind proficiently learns the intermolecular many-body interactions and simulates the dynamic conformational adaptations of the ligand during its interaction with the protein through meticulously designed networks. We trained GAABind on the PDBbindv2020 and evaluated it on the CASF2016 dataset; the results indicate that GAABind achieves state-of-the-art performance in binding pose prediction and shows comparable binding affinity prediction performance. Notably, GAABind achieves a success rate of 82.8% in binding pose prediction, and the Pearson correlation between predicted and experimental binding affinities reaches up to 0.803. Additionally, we assessed GAABind's performance on the severe acute respiratory syndrome coronavirus 2 main protease cross-docking dataset. In this evaluation, GAABind demonstrates a notable success rate of 76.5% in binding pose prediction and achieves the highest Pearson correlation coefficient in binding affinity prediction compared with all baseline methods.

High-Entropy Polymer Electrolytes Derived from Multivalent Polymeric Ligands for Solid-State Lithium Metal Batteries with Accelerated Li+ Transport.

Solid-state polymer-based electrolytes (SSPEs) exhibit great possibilities in realizing high-energy-density solid-state lithium metal batteries (SSLMBs). However, current SSPEs suffer from low ionic conductivity and unsatisfactory interfacial compatibility with metallic Li because of the high crystallinity of polymers and sluggish Li+ movement in SSPEs. Herein, differing from common strategies of copolymerization, a new strategy of constructing a high-entropy SSPE from multivariant polymeric ligands is proposed. As a protocol, poly(vinylidene fluoride-co-hexafluoropropylene) (PH) chains are grafted to the demoed polyethylene imine (PEI) with abundant -NH2 groups via a click-like reaction (HE-PEIgPHE). Compared to a PH-based SSPE, our HE-PEIgPHE shows a higher modulus (6.75 vs 5.18 MPa), a higher ionic conductivity (2.14 × 10-4 vs 1.03 × 10-4 S cm-1), and a higher Li+ transference number (0.55 vs 0.42). A Li|HE-PEIgPHE|Li cell exhibits a long lifetime (1500 h), and a Li|HE-PEIgPHE|LiFePO4 cell delivers an initial capacity of 160 mAh g-1 and a capacity retention of 98.7%, demonstrating the potential of our HE-PEIgPHE for the SSLMBs.

In situ generated CdTe quantum dot-encapsulated hafnium polymer membrane to boost electrochemiluminescence analysis of tumor biomarkers.

Exploring the construction of an interface with bright emission, fabulous stability, and good function to develop high-performance electrochemiluminescence (ECL) biosensors for tumor biomarkers is in high demand but faces a huge challenge. Herein, we report an oriented attachment and in situ self-assembling strategy for one-step fabrication of CdTe QD-encapsulated Hf polymer membrane onto an ITO surface (Hf-CP/CdTe QDs/APS/ITO). Hf-CP/CdTe QDs/APS/ITO is fascinating with excellent stability, high ECL emission, and specific adsorption toward ssDNA against dsDNA and mononucleotides (mNs). These interesting properties make it an ideal interface to rationally develop an immobilization-free ECL biosensor for cancer antigen 125 (CA125), used as a proof-of-concept analyte, based on target-aptamer recognition-promoted exonuclease III (Exo III)-assisted digestion. The recognition of ON by CA125 leads to the formation of CA125@ON, which hybridizes with Fc-ssDNA to switch Exo III-assisted digestion, decreasing the amount of Fc groups anchored onto the electrode's surface and blocking electron transfer. As compared to the case where CA125 was absent, significant ECL emission recovery is determined and relies on CA125 concentration. Thus, highly sensitive analysis of CA125 against other biomarkers was achieved with a limit of detection down to 2.57 pg/mL. We envision this work will provide a new path to develop ECL biosensors with excellent properties, which shows great potential for early and accurate diagnosis of cancer.

The function and keystone microbiota in typical habitats under the influence of anthropogenic activities in Baiyangdian Lake.

Microbe is an essential driver in regulating the biochemical cycles of carbon, nitrogen, and sulfur. In freshwater lake, microbial communities and functions are influenced by multiple factors, especially anthropogenic activities. Baiyangdian Lake consisted of various habitats, and was frequently interfered with human activities. In this study, 16 S rRNA sequencing and metagenomic sequencing were performed to characterize the microbial communities, determine keystone taxa and reveal dominated metabolic functions in typical habitats in Baiyangdian Lake. The results showed that the diversity of microbial community was significantly higher in sediment compared with corresponding water sample. Microbial community showed strong spatial heterogeneity in sediment, and temporal heterogeneity in water. As for different habitats, significantly higher alpha diversity was observed in ecotone, where the interference of human activities was relatively weak. The shared OTUs were distinguished from the keystone taxa, which indicated the uniqueness of microbiota in different ecological habitat. Moreover, the interactions of microbial in ecological restoration area (abandoned fish pond) were relatively simple, suggesting that this ecosystem was relatively fragile compared with others. Based on the metagenomic sequencing, we recognized that the canal, open water, and abandoned fish pond were beneficial for methanogenic and the ecotone might be a hot zone for the oxidation of methane. Notably, most of the microbes that participated in these predominant metabolisms were unclassified, which indicated the hug potential for exploring functional microorganisms in Baiyangdian Lake. This study provided a comprehensive understanding of the ecology characteristics of microbiota in habitats undergoing various human interference in Baiyangdian Lake.

Biallelic truncating TTN variants in M-band encoding exons cause a fetal lethal titinopathy.

To report two novel TTN variants associated with fetal recessive titinopathy, thereby broadening the range of TTN variants that can lead to titinopathy. Clinical information on the fetus and parents was gathered, and genomic DNAs were extracted from the fetal tissue and family members' peripheral blood samples. Exome sequencing on fetal DNA was performed and following bioinformatics analysis, the suspected pathogenic variants were confirmed through Sanger sequencing. Prenatal ultrasound performed at 29 weeks of gestation revealed hydrops fetalis, decreased fetal movements, multiple joint contractures and polyhydramnios. Intrauterine fetal death was noted in the third trimester. Exome sequencing revealed compound heterozygous variants in the TTN gene: a paternally inherited allele c.101227C>T (p.Arg33743Ter) and a maternally inherited c.104254C>T (p.Gln34752Ter) allele. These variants have not been previously reported and are evaluated to be likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. We report a fetus with hydrops fetalis and arthrogryposis multiplex congenita associated with a compound heterozygote in the TTN gene. Our report broadens the clinical and genetic spectrum associated with the TTN-related conditions.

Synchronized measurement method of burning rate and combustion temperature of a solid propellant specimen.

To characterize the combustion properties of solid propellants, the synchronized measurement method of burning rate and combustion temperature is proposed combined shadow imaging and radiation imaging. Using spectroscopic and filtering imaging, shadow and radiation images of a solid propellant specimen are obtained synchronously. Burning rate is calculated by burning surface movement velocity of shadow images, and combustion temperature is calculated by radiation image thermometry. Measurement accuracies of burning rate and combustion temperature of the solid propellant specimen are validated by other independent measurement methods. On this basis, the synchronized measurements of burning rate and combustion temperature of different formulations of solid propellant specimens under different working conditions are carried out. The results show that the influence on burning rate and combustion temperature of pressure and formulas is different. Therefore, the synchronized measurement of burning rate and combustion temperature can provide more direct data support for the evaluation of solid propellant combustion performance.

Molecular analyses of exosome-derived miRNAs revealed reduced expression of miR-184-3p and decreased exosome concentration in patients with alveolar echinococcosis.

Both E. multilocularis and host-derived exosomes are involved in the pathogenic process of alveolar echinococcosis (AE). Exosomes secrete miRNAs that have regulatory roles in host-pathogen interactions in multiple ways. In the present study, we collected and purified supernatants of E. multilocularis cultures, as well as human plasma exosomes. High-throughput sequencing showed the identities of 45 exosomal miRNAs in E. multilocularis. The lengths of these miRNAs ranged from 19 to 25 nucleotides (nt), with the majority (n = 18) measuring 22 nt. Notably, emu-let-7-5p emerged as the most abundant among these miRNAs, with a detected count of 33,097 and also length of 22 nt. Nanoparticle tracking analysis (NTA) showed that the concentration of exosomes in the plasma of AE patients was lower compared to that in the healthy individuals. This result suggested that the concentration of plasma exosomes was able to distinguish AE patients from healthy individuals. Using qRT-PCR to assess the relative expression of 10 miRNAs of E. multilocularis, we showed that the expression of miR-184-3p was downregulated significantly in the exosomes of plasma from AE patients compared to that in the control group. In summary, this study indicates that AE induces a reduction in the concentration of human plasma exosomes, as well as downregulating miR-184-3p in infected individuals.

A comparative cadaveric study for percutaneous scaphoid fixation: robotic vs freehand.

PURPOSES: To compare the robotic-assisted and the traditional freehand percutaneous scaphoid fixation in number of guidewire attempts, duration of fluoroscopy time, amount of radiation dose, and screw centrality. METHODS: Twenty cadaveric specimens were randomized into either the robotic or freehand group. The scaphoids in both groups were fixed by either the same attending or resident from our hand surgery department. The operation duration, amount of radiation from intraoperative fluoroscopy, total fluoroscopy time, and the number of guidewire attempts were documented and compared. Postoperatively, all the specimens had a computed tomography (CT) scan performed, and the difference in the final position of the screw and the central axis of the scaphoid was examined. RESULTS: In the robotic group, all the guide wires were satisfactorily positioned within a single attempt, while the median number of attempts in the traditional freehand group was 18 (quaternion 14-65). This also meant that the surgeon in the robotic group experienced significantly lower radiation exposure dose and time as compared to the freehand group. There were no significant differences in the final screw position as compared to the central axis of the scaphoid in both groups. Although there was no difference in surgeon performance in the robotic group, the operative time for the attending was significantly lower as compared to the resident in the freehand group. CONCLUSION: Robotic-assisted surgery for scaphoid fracture fixation is superior to the traditional freehand method as it facilitates accurate screw placement with lower radiation exposure and fewer guide wire attempts.

Examining the Significance of Intercultural Communicative Competence Development in Trainees during Pre-service Training.

The aim of this study is to discuss the need for improved intercultural communicative competence (ICC) training for pre-service Chinese as a Second Language (CSL) teachers who travel abroad to teach. Previous studies have shown that pre-service CSL teachers often struggle with intercultural communication, and this study investigates the reasons behind their difficulties and suggests ways to address them. The researchers used the Intercultural Sensitivity Scale (ISS) and the Intercultural Effectiveness Scale (IES) to measure the ICC of 217 pre-service CSL teachers. The study found that while pre-service CSL teachers have strong intercultural communicative emotional ability, their behavioral ability in intercultural communication is weak. In particular, they lacked skills in interactive control, interactive relaxation, identity management, information skills, and behavioral flexibility. The study proposes several strategies to improve ICC training for pre-service CSL teachers. One potential approach is the use of Computer Assisted Language Learning to provide teacher-trainee students with opportunities to practice intercultural communication skills in simulated contexts, receive personalized feedback, and engage with authentic materials and cultural information relevant to their host country. CALL could also facilitate communication between pre-service CSL teachers and former CSL teachers, providing a platform for information exchange and additional psychological support. The study also suggests that pre-service training should distinguish between foreign language learning and intercultural communication skills training. Specifically, it recommends that foreign language proficiency should be improved, while training should focus on educational culture and work culture in the host country, rather than providing a general introduction to the national conditions of the country. Finally, the study proposes that pre-service training should establish contact between pre-service CSL teachers and former CSL teachers as early as possible so that trainees can learn specific relevant information in advance, which can help them get ready, avoid intercultural communication mistakes, and obtain additional psychological support. By incorporating CALL and addressing the areas of weakness identified in the study, pre-service CSL teachers can be better prepared to navigate the challenges of intercultural communication and provide effective and culturally sensitive instruction abroad.

Directionally In Situ Self-Assembled Iridium(III)-Polyimine Complex-Encapsulated Metal-Organic Framework Two-Dimensional Nanosheet Electrode To Boost Electrochemiluminescence Sensing.

Manufacturing electrochemiluminescence (ECL) electrodes to detect analytes with high performance in the aqueous phase for water-insoluble metal complexes is a great challenge. Here, a directional self-assembling avenue for in situ fabricating iridium(III)-polyimine complex-encapsulated metal-organic framework (MOF) two-dimensional electrode Hf-MOF/Ir2PD/APS/ITO is developed. The electrode displayed bright red ECL emission with high stability in the aqueous phase and specific adsorption toward ssDNA against dsDNA and mNs. That is to say, a "high-performance and multifunctional ECL electrode" is presented and explored for sensitive detection of acetamiprid (Ace) with a limit of detection of 0.0025 nM, where Ace-aptamer recognition-switched Exonuclease III-mediated digestion to make large numbers of Fc-labeled ssDNA transform into Fc-mNs. Furthermore, the proposed method was triumphantly employed to monitor the change in the residual concentration of Ace in pakchoi. This work breaks through the bottleneck of metal complex-based ECL emission in organic solvents and provides a novel strategy to develop high-performance ECL sensors.

Comparative effectiveness of multiple different treatment regimens for nonalcoholic fatty liver disease with type 2 diabetes mellitus: a systematic review and Bayesian network meta-analysis of randomised controlled trials.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are closely related and mutually contribute to the disease's development. There are many treatment options available to patients. We provide a comprehensive overview of the evidence on the treatment effects of several potential interventions for NAFLD with T2DM. METHODS: This systematic review and network meta-analysis included searches of PubMed, Embase, Cochrane Library, and Web of Science from inception to June 30, 2023, for randomised controlled trials of treatment of NAFLD with T2DM. We performed Bayesian network meta-analyses to summarise effect estimates of comparisons between interventions. We applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks to rate all comparative outcomes' certainty in effect estimates, categorise interventions, and present the findings. This study was registered with PROSPERO, CRD42022342373. RESULTS: Four thousand three hundred and sixty-nine records were retrieved from the database and other methods, of which 24 records were eligible for studies enrolling 1589 participants. Eight clinical indicators and 14 interventions were finally in focus. Referring to the lower surface under the cumulative ranking curves (SUCRA) and the league matrix table, exenatide and liraglutide, which are also glucagon-like peptide-1 receptor agonists (GLP-1RAs), showed excellent potential to reduce liver fat content, control glycemia, reduce body weight, and improve liver function and insulin resistance. Exenatide was more effective in reducing glycated haemoglobin (HbA1c) (mean difference (MD) 0.32, 95%CI 0.12 to 0.52), lowering BMI (MD 0.81, 95%CI 0.18 to 1.45), and lowering alanine transaminase (ALT) (MD 10.96, 95%CI 5.27 to 16.66) compared to liraglutide. However, this evidence was assessed as low certainty. Omega-3 was the only intervention that did not have a tendency to lower HbA1c, with standard-treatment (STA-TRE) as reference (MD - 0.17, 95%CI - 0.42 to 0.07). Glimepiride is the only intervention that causes an increase in ALT levels, with standard-treatment (STA-TRE) as reference (MD - 11.72, 95%CI - 17.82 to - 5.57). Based on the available evidence, the treatment effects of pioglitazone, dapagliflozin, and liraglutide have a high degree of confidence. CONCLUSIONS: The high confidence mandates the confident application of these findings as guides for clinical practice. Dapagliflozin and pioglitazone are used for glycaemic control in patients with NAFLD combined with T2DM, and liraglutide is used for weight loss therapy in patients with abdominal obesity. The available evidence does not demonstrate the credibility of the effectiveness of other interventions in reducing liver fat content, visceral fat area, ALT, and insulin resistance. Future studies should focus on the clinical application of GLP-1Ras and the long-term prognosis of patients.

Controllable Preparation of 2D V2 O5 Peroxidase-Mimetic Nanozyme to Develop Portable Paper-Based Analytical Device for Intelligent Pesticide Assay.

Given severe harmfulness of pesticides, unique characteristics of peroxidase-mimetic nanozymes, and favorable prospects of paper-based analytical devices (PADs), it is highly desirable to construct a nanozyme-based PAD for intelligent analysis of pesticide without enzyme/aptamer/antibody and interference of O2 . Herein, 2D nanosheet-like V2 O5 (2D-VONz) with exclusive peroxidase-mimetic activity is controllably prepared under the optimal reactants concentration and reaction temperature. Experimental characterizations demonstrate that 2D-VONz exhibits high affinity and catalytic rate, and catalytic oxidation is dependent on •OH yielded from the decomposition of H2 O2 catalyzed by 2D-VONz, and the catalytic performance is relevant to π-π stacking force-controlled surface zeta potential of 2D-VONz changed by substrates, giving a comprehensive understand of the inherent mechanism. Interestingly, 2D-VONz activity is inhibited by pesticide glyphosate (Gly), and then is exploited to develop a PAD, on which, Gly declines 2D-VONz activity to prevent it from catalyzing the oxidation of 3,3',5,5'-tetramethylbenzidine, contributing to rapid, naked-eye, and portable analysis of pesticide using a smartphone. The current strategy on preparing exclusive peroxidase-mimetic 2D nanozyme, investigating catalytic mechanism, developing nanozyme-based PAD, and achieving direct pesticide sensing will set up new avenues to improve the analytical performance, strengthen the practicability, and broaden the application scope of nanozymes.

Transcription factor WRKY28 curbs WRKY33-mediated resistance to Sclerotinia sclerotiorum in Brassica napus.

Sclerotinia sclerotiorum causes substantial damage and loss of yield in oilseed rape (Brassica napus). The molecular mechanisms of oilseed rape defense against Sclerotinia remain elusive. In this study, we found that in the early stages of B. napus infection a conserved mitogen-activated protein kinase (MAPK) cascade mediated by BnaA03.MKK5-BnaA06.MPK3/BnaC03.MPK3 module phosphorylates the substrate BnWRKY33, enhancing its transcriptional activity. The activated BnWRKY33 binds to its own promoter and triggers a transcriptional burst of BnWRKY33, thus helping plants effectively resist the pathogenic fungi by enhancing the expression of phytoalexin synthesis-related genes. The expression of BnWRKY33 is fine-tuned during defense. Ongoing Sclerotinia infection induces BnaA03.WRKY28 and BnaA09.VQ12 expression. BnaA09.VQ12 interacts physically with BnaA03.WRKY28 to form a protein complex, causing BnaA03.WRKY28 to outcompete BnWRKY33 and bind to the BnWRKY33 promoter. BnaA03.WRKY28 induction suppresses BnWRKY33 expression in the later stages of infection but promotes branch formation in the leaf axils by regulating the expression of branching-related genes such as BnBRC1. BnaA03.WRKY28 participates in the trade-off between defense and growth. These findings suggest that oilseed rape plants may modulate defense-response strength and develop alternative reproduction and survival strategies in the face of lethal pathogens.

Association of Androgen-Receptor Gene Mutations with the Copy Number of Androgen-Receptor Silk Protein A Complex and Glutathione-S-Transferases T1 and M1 in Prostate Cancer Patients.

Objective: The purpose of our work was to explore the association of mutations in the androgen receptor gene and copy numbers of the androgen-receptor silk protein A complex with glutathione-S-transferases T1 and M1 in prostate cancer patients. Materials and Methods: Eighty-five patients with PC and 85 healthy controls were included in the study. Fasting peripheral venous blood was collected, whole blood genomic DNA was extracted, and AR gene-receptor genotype was detected by a high-resolution melting curve analysis detection technology. Expression levels of androgen receptor (AR) and filamin protein A (FlnA) were detected by Western blotting. RT-PCR was used to detect the copy number of T1 and M1 glutathione-S-transferases. Results: The wild-type androgen receptor gene rs5918762 is of TT type. The frequencies of CC and TC genes in the prostate cancer group were significantly higher than those in the normal control group (P < 0.05). Compared with TT-type PC patients, PC patients with TC-type and CC-type had higher expression levels of sex hormone receptor silk protein A complex and higher copy numbers of GSTT1 and GSTM1 (P < 0.05). Androgen-receptor gene mutation (T ⟶ C) was significantly positively correlated with the expression level of androgen-receptor silk protein A complex and the copy number of GSTT1 and GSTM1. Conclusion: Androgen-receptor gene polymorphisms were significantly associated with expression levels of androgen receptor complex A and silk proteins, and copy numbers of T1 and M1 glutathione-S-transferases. A combination of four factors can be used to identify prostate cancer susceptibility and disease progression.

Synthesis of quinazolinones via Cp*Co(III)-catalyzed C-H functionalization of primary amides with oxadiazolones.

Multi-heteroatom heterocycle synthesis through direct C-H bond activation is methodologically appealing but synthetically challenging. An efficient double C-N bond formation sequence to prepare quinazolinones utilizing primary amides and oxadiazolones in a catalytic redox-neutral [CoCp*(CO)I2]/AgSbF6 system, where oxadiazolone could function as an internal oxidant to maintain the catalytic cycle, is reported. Amide-directed C-H bond activation and oxadiazolone decarboxylation are key to the success of this traceless, atom- and step-economic, and cascade approach for the construction of the quinazolinone skeleton.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) alleviate paclitaxel-induced spermatogenesis defects and maintain male fertility.

Chemotherapeutic drugs can cause reproductive damage by affecting sperm quality and other aspects of male fertility. Stem cells are thought to alleviate the damage caused by chemotherapy drugs and to play roles in reproductive protection and treatment. This study aimed to explore the effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on alleviating paclitaxel (PTX)-induced spermatogenesis and male fertility defects. An in vivo PTX-induced mice model was constructed to evaluate the reproductive toxicity and protective roles of hUC-MSCs in male fertility improvement. A 14 day PTX treatment regimen significantly attenuated mice spermatogenesis and sperm quality, including affecting spermatogenesis, reducing sperm counts, and decreasing sperm motility. hUC-MSCs treatment could significantly improve sperm functional indicators. Mating experiments with normal female mice and examination of embryo development at 7.5 days post-coitum (dpc) showed that hUC-MSCs restored male mouse fertility that was reduced by PTX. In IVF experiments, PTX impaired sperm fertility and blastocyst development, but hUC-MSCs treatment rescued these indicators. hUC-MSCs' protective role was also displayed through the increased expression of the fertility-related proteins HSPA2 and HSPA4L in testes with decreased expression in the PTX-treated group. These changes might be related to the PTX-induced decreases in expression of the germ cell proliferation protein PCNA and the meiosis proteins SYCP3, MLH1, and STRA8, which were restored after hUC-MSCs treatment. In the PTX-treated group, the expression of testicular antioxidant proteins SIRT1, NRF2, CAT, SOD1, and PRDX6 was significantly decreased, but hUC-MSCs could maintain these expressions and reverse PTX-related increases in BAX/BCL2 ratios. hUC-MSCs may be a promising agent with antioxidant and anti-apoptosis characteristics that can maintain sperm quality following chemotherapy treatment.

Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration.

Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration in Caenorhabditis elegans, the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1-dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells.

Effects of Probiotic Supplementation on Nutrient Intake, Ghrelin, and Adiponectin Concentrations in Diabetic Hemodialysis Patients.

Objective: The paper aimed to explore the effect of probiotic supplementation on nutrient intake, Ghrelin, and adiponectin concentrations in diabetic hemodialysis patients. Methods: A total of 86 patients with diabetic nephropathy who received hemodialysis treatment in the Department of Nephrology of the First People's Hospital of Shanghai from May 2019 to March 2021 were selected as the research subjects, including 52 male patients and 34 female patients, with an average age of 56.57 ± 4.28. According to the research protocol, the patients were divided into the control group (n = 30) and the observation group (n = 56). In the control group, dietary soybean milk was used as a placebo. In the observation group, capsules containing probiotics Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium were taken with soybean milk. All patients signed an informed consent form before being included in the study. The results of the experimental biochemical analysis and the archived data counted the general data of the patients. Plasma adiponectin concentrations were measured with a commercially available human enzyme immunoassay kit. Ghrelin concentrations were estimated by specific commercial methods. Correlation software was used to calculate patient nutritional intake data. Serum creatinine, insulin resistance, fasting blood glucose, and levels of oxidative stress and inflammatory factors were measured using appropriate biochemical assays. Results: There was no difference in baseline characteristics between the two groups (P > .05). Before treatment, there was no difference in serum adiponectin concentration between the two groups (P > .05). After treatment, the serum adiponectin concentration in the observation group was lower than in the control group (P < .05). Before treatment, there was no difference in serum ghrelin levels between the two groups (P > .05). After treatment, serum ghrelin levels in the observation group were higher than in the control group (P < .05). Before treatment, there was no difference in nutrient intake between the two groups (P > .05). After treatment, the nutrient intake in the observation group was higher than in the control group (P < .05). Serum creatinine, fasting blood glucose, urine protein/creatinine ratio, and HOMA-IR in the observation group were lower than in the control group (P < .05). The serum levels of malondialdehyde, C-reactive protein, and TNF-α in the observation group were lower than those in the control group (P < .05), and the levels of glutathione in the observation group were higher than those in the control group (P < .05). Conclusion: Supplementation of probiotics in DN dialysis patients can increase serum ghrelin concentration, increase nutrient intake through appetite regulation, and reduce adiponectin level, which is beneficial to blood sugar control, insulin resistance, and renal function.

Single-cell sequencing reveals the new existence form of dermal papilla cells in the hair follicle regeneration of cashmere goats.

The problem of human hair loss has caused widespread concern, however, such research is difficult because the periodicity is not obvious and the deeper levels knowledge of dermal papilla (DP) stem cells' differentiation are limited. Here, cashmere goats which have obvious periodicity of hair follicles were used, based on unbiased scRNA sequencing, we constructed DP cell lineage differentiation trajectory and revealed the key genes, signals and functions involved in cell fate decisions. And then we revealed the molecular landscape of hair follicle on regeneration. Revealed that DP cells differentiate into four intermediate cell states at different periodicity: Intermediate-cell-10 showed important functions in the growth and maintenance of cashmere; intermediate-cell-1 acting on apoptosis and cashmere shedding; intermediate-cell-0 initiated new follicular cycles, the migration of hair follicles and the occurrence of cashmere; and intermediate-cell-15 are suggested to be DP progenitor cells. In general, we provide new insights for hair regrowth. At the same time, it provides a new research ideas, directions and molecular landscape for the mechanism of dermal papilla cells.