DNA-functionalized artificial mechanoreceptor for de novo force-responsive signaling.

Synthetic signaling receptors enable programmable cellular responses coupling with customized inputs. However, engineering a designer force-sensing receptor to rewire mechanotransduction remains largely unexplored. Herein, we introduce nongenetically engineered artificial mechanoreceptors (AMRs) capable of reprogramming non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, enabling de novo-designed mechanotransduction. AMR is a modular DNA-protein chimera comprising a mechanosensing-and-transmitting DNA nanodevice grafted on natural RTKs via aptameric anchors. AMR senses intercellular tensile force via an allosteric DNA mechano-switch with tunable piconewton-sensitive force tolerance, actuating a force-triggered dynamic DNA assembly to manipulate RTK dimerization and activate intracellular signaling. By swapping the force-reception ligands, we demonstrate the AMR-mediated activation of c-Met, a representative RTK, in response to the cellular tensile forces mediated by cell-adhesion proteins (integrin, E-cadherin) or membrane protein endocytosis (CI-M6PR). Moreover, AMR also allows the reprogramming of FGFR1, another RTK, to customize mechanobiological function, for example, adhesion-mediated neural stem cell maintenance.

Regional centromere configuration in the fungal pathogens of the Pneumocystis genus.

Centromeres are constricted chromosomal regions that are essential for cell division. In eukaryotes, centromeres display a remarkable architectural and genetic diversity. The basis of centromere-accelerated evolution remains elusive. Here, we focused on Pneumocystis species, a group of mammalian-specific fungal pathogens that form a sister taxon with that of the Schizosaccharomyces pombe, an important genetic model for centromere biology research. Methods allowing reliable continuous culture of Pneumocystis species do not currently exist, precluding genetic manipulation. CENP-A, a variant of histone H3, is the epigenetic marker that defines centromeres in most eukaryotes. Using heterologous complementation, we show that the Pneumocystis CENP-A ortholog is functionally equivalent to CENP-ACnp1 of S. pombe. Using organisms from a short-term in vitro culture or infected animal models and chromatin immunoprecipitation (ChIP)-Seq, we identified CENP-A bound regions in two Pneumocystis species that diverged ~35 million years ago. Each species has a unique short regional centromere (<10 kb) flanked by heterochromatin in 16-17 monocentric chromosomes. They span active genes and lack conserved DNA sequence motifs and repeats. These features suggest an epigenetic specification of centromere function. Analysis of centromeric DNA across multiple Pneumocystis species suggests a vertical transmission at least 100 million years ago. The common ancestry of Pneumocystis and S. pombe centromeres is untraceable at the DNA level, but the overall architectural similarity could be the result of functional constraint for successful chromosomal segregation.IMPORTANCEPneumocystis species offer a suitable genetic system to study centromere evolution in pathogens because of their phylogenetic proximity with the non-pathogenic yeast S. pombe, a popular model for cell biology. We used this system to explore how centromeres have evolved after the divergence of the two clades ~ 460 million years ago. To address this question, we established a protocol combining short-term culture and ChIP-Seq to characterize centromeres in multiple Pneumocystis species. We show that Pneumocystis have short epigenetic centromeres that function differently from those in S. pombe.

Simultaneous suppression of As mobilization and N2O emission from NH4+/As-rich paddy soils by combined nitrate and birnessite amendment.

The environmental impacts of As mobilization and nitrous oxide (N2O) emission in flooded paddy soils are serious issues for food safety and agricultural greenhouse gas emissions. Several As immobilization strategies utilizing microbially-mediated nitrate reducing-As(III) oxidation (NRAO) and birnessite (δ-MnO2)-induced oxidation/adsorption have proven effective for mitigating As bioavailability in flooded paddy soils. However, several inefficiency and unsustainability issues still exist in these remediation approaches. In this study, the effects of a combined treatment of nitrate and birnessite were assessed for the simultaneous suppression of As(III) mobilization and N2O emission from flooded paddy soils. Microcosm incubations confirmed that the combined treatment achieved an effective suppression of As(III) mobilization and N2O emission, with virtually no As(T) released and at least a 87% decrease in N2O emission compared to nitrate treatment alone after incubating for 8 days. When nitrate and birnessite are co-amended to flooded paddy soils, the activities of denitrifying enzymes within the denitrification electron transport pathway were suppressed by MnO2. As a result, the majority of applied nitrate participated in nitrate-dependent microbial Mn(II) oxidation. The regenerated biogenetic MnO2 was available to facilitate subsequent cycles of As(III) immobilization and concomitant N2O emission suppression, sustainable remediation strategy. Moreover, the combined nitrate-birnessite amendment promoted the enrichment of Pseudomonas, Achromobacter and Cupriavidu, which are known to participate in the oxidation of As(III)/Mn(II). Our findings document strong efficacy for the combined nitrate/birnessite treatment as a remediation strategy to simultaneously mitigate As-pollution and N2O emission, thereby improving food safety and reducing greenhouse gas emissions from flooded paddy soils enriched with NH4+ and As.

Safety and Pharmacokinetics of HRS-2261, a P2X3 Receptor Antagonist, in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study.

BACKGROUND: P2X3 receptor antagonists hold promising potential as a therapeutic option for patients with refractory or unexplained chronic cough, a condition lacking approved therapies. This study assessed the safety, tolerability, and pharmacokinetics (PK) of HRS-2261, a novel selective P2X3 receptor antagonist, in healthy subjects. METHODS: This randomized, double-blinded, placebo-controlled phase 1 trial of HRS-2261 consisted of three phases: the single ascending dose (SAD) study phase, the food-effect study phase, and the multiple ascending dose (MAD) study phase. In the SAD phase, healthy subjects were randomly assigned to receive a single oral dose of HRS-2261 (25, 100, 200, 400, 800, and 1200 mg) or placebo. Subjects in the 200 mg group of the SAD phase progressed directly to the food-effect phase following safety evaluation. In the MAD phase, healthy subjects were randomized to receive HRS-2261 (50, 200, and 400 mg) or placebo twice daily for 14 consecutive days. The primary endpoints were safety and tolerability. RESULTS: A total of 62 and 30 subjects were enrolled in the SAD and MAD phases, respectively, with 12 subjects from the SAD phase transitioning to the food-effect phase. The incidence and severity of adverse events (AEs) were not dose dependent, and most AEs were mild except for one moderate AE (epididymitis, which was not related to treatment) in the 400 mg group. Dysgeusia was reported in nine subjects, including two from the SAD phase, one from the food-effect phase, and six from the MAD phase. The median Tmax and geometric mean t1/2 were 0.9-2.0 h and 4.1-8.5 h in the SAD, and 2.0-2.7 h and 4.6-5.0 h on day 14 in the MAD, respectively. Drug exposures in the SAD and MAD phases were both less than dose proportional. The accumulation of the drug was slight with repeated twice-daily dosing. Food-effect study results showed that food intake did not affect the plasma exposure of HRS-2261. CONCLUSIONS: HRS-2261 demonstrated good tolerability, with a low incidence of dysgeusia. The PK profile was favorable. This study supports further development of HRS-2261 as a potential P2X3 receptor antagonist for chronic cough. TRIAL REGISTRATION NUMBER: Clinical trials.gov, identifier: NCT05274516. Trial registration date: March 10, 2022.

Illuminated fulvic acid stimulates denitrification and As(III) immobilization in flooded paddy soils via an enhanced biophotoelectrochemical pathway.

Fulvic acid (FA) is a representative photosensitive dissolved organic matter (DOM) compound that occurs naturally in paddy soils. In this study, the effect of a FA + nitrate treatment (0, 4 and 8 mg/L FA + 20 mmol/L nitrate) on denitrification and As(III) immobilization in flooded paddy soils was assessed under dark and intermittently illuminated conditions (12 h light+12 h dark). The FA input stimulated denitrification in illuminated soils (~100 % of nitrate removal within 6 days) compared to dark conditions (~92 % nitrate removal after 6 days). Meanwhile, As(III) (initial concentration of 0.1 mmol/L) was nearly completely immobilized (~100 %) under illuminated conditions after 4 days for the FA + nitrate treatment compared to 90- 93 % retention in the dark. Denitrification and As immobilization were positively related to the FA dosage in the illuminated assays. The stronger denitrification in illuminated soils was ascribed to denitrifiers harvesting photoelectrons from photosensitive substrates/semiconducting minerals. FA addition also increased the activities of denitrifying enzymes (e.g., NAR, NIR and NOR) and the denitrification electron transport system by nearly 0.6-0.7 and 1.5-1.8 times that of the nitrate-alone treatment under illuminated and dark conditions, thereby fostering stronger denitrification. Upon irradiation, As(III) immobilization was not only stimulated by the interactions with the denitrification pathway whereby As(III) acts as an electron donor for denitrifiers, but was also modulated by Fe(III)/oxidative reactive species-derived photooxidation of As(III). Moreover, the FA + nitrate treatment promoted the enrichment of metal-oxidizing bacteria (e.g., Stenotrophomonas and Acidovorax) that are responsible for nitrate-dependent As(III)/Fe(II) oxidation. The results of this study enhance our understanding of interactions among the biogeochemical cycles of As, Fe, N and C, which are intricately linked by a biophotoelectrochemical pathway in flooded paddy soils.

Development of synthetic modulator enabling long-term propagation and neurogenesis of human embryonic stem cell-derived neural progenitor cells.

Neural progenitor cells (NPCs) are essential for in vitro drug screening and cell-based therapies for brain-related disorders, necessitating well-defined and reproducible culture systems. Current strategies employing protein growth factors pose challenges in terms of both reproducibility and cost. In this study, we developed a novel DNA-based modulator to regulate FGFR signaling in NPCs, thereby facilitating the long-term maintenance of stemness and promoting neurogenesis. This DNA-based FGFR-agonist effectively stimulated FGFR1 phosphorylation and activated the downstream ERK signaling pathway in human embryonic stem cell (HESC)-derived NPCs. We replaced the basic fibroblast growth factor (bFGF) in the culture medium with our DNA-based FGFR-agonist to artificially modulate FGFR signaling in NPCs. Utilizing a combination of cell experiments and bioinformatics analyses, we showed that our FGFR-agonist could enhance NPC proliferation, direct migration, and promote neurosphere formation, thus mimicking the functions of bFGF. Notably, transcriptomic analysis indicated that the FGFR-agonist could specifically influence the transcriptional program associated with stemness while maintaining the neuronal differentiation program, closely resembling the effects of bFGF. Furthermore, our culture conditions allowed for the successful propagation of NPCs through over 50 passages while retaining their ability to efficiently differentiate into neurons. Collectively, our approach offers a highly effective method for expanding NPCs, thereby providing new avenues for disease-in-dish research and drug screening aimed at combating neural degeneration.

Intestinal flora altered and correlated with interleukin-2/4 in patients with primary immune thrombocytopenia.

BACKGROUND: Little is known about the changes and mechanisms of intestinal flora in primary immune thrombocytopenia (ITP) patients. AIM: To explore the structural and functional differences of intestinal flora between ITP patients and healthy controls, and clarify the correlation between intestinal flora and Th1/Th2 imbalance. METHODS: Feces from ITP patients and healthy controls were studied by 16S rRNA and metagenomic techniques at phylum, genus, species or functional levels. Blood samples were collected for the detection of interleukin -2 (IL-2) and IL-4 concentrations. RESULTS: The following changes in ITP patients were found: a decrease of Bacteroidetes phylum, an increase of Proteobacteria phylum and alterations of ten genera and 1045 species. IL-2 and IL-4 were significantly correlated with six and five genera, respectively. Species of C. freundii, C. rodentium, and C. youngae were negatively correlated with bleeding scores, and S. infantis was positively related to platelet counts. Functionally, the intestinal flora of ITP patients changed mainly in terms of motility, chemotaxis, membrane transport, and metabolism. CONCLUSION: The mechanism underlying functional and structural changes of intestinal flora in ITP patients may be related to inflammation and immunity, providing possibilities of probiotics or fecal transplants for ITP.

Quinary RuRhPdPtAu high-entropy alloy as an efficient electrocatalyst for the hydrogen evolution reaction.

Quinary RuRhPdPtAu high-entropy alloy nanoparticles (HEA-NPs) were prepared for the first time from a deep eutectic solvent by an electrochemical method. Owing to the benefits of high entropy and abundant surface active sites, the RuRhPdPtAu HEA-NPs exhibit outstanding electrocatalytic performance for the hydrogen evolution reaction.

Genomic Analysis of Leptolyngbya boryana CZ1 Reveals Efficient Carbon Fixation Modules.

Cyanobacteria, one of the most widespread photoautotrophic microorganisms on Earth, have evolved an inorganic CO2-concentrating mechanism (CCM) to adapt to a variety of habitats, especially in CO2-limited environments. Leptolyngbya boryana, a filamentous cyanobacterium, is widespread in a variety of environments and is well adapted to low-inorganic-carbon environments. However, little is currently known about the CCM of L. boryana, in particular its efficient carbon fixation module. In this study, we isolated and purified the cyanobacterium CZ1 from the Xin'anjiang River basin and identified it as L. boryana by 16S rRNA sequencing. Genome analysis revealed that L. boryana CZ1 contains ß-carboxysome shell proteins and form 1B of Rubisco, which is classify it as belonging to the ß-cyanobacteria. Further analysis revealed that L. boryana CZ1 employs a fine CCM involving two CO2 uptake systems NDH-13 and NDH-14, three HCO3- transporters (SbtA, BicA, and BCT1), and two carboxysomal carbonic anhydrases. Notably, we found that NDH-13 and NDH-14 are located close to each other in the L. boryana CZ1 genome and are back-to-back with the ccm operon, which is a novel gene arrangement. In addition, L. boryana CZ1 encodes two high-affinity Na+/HCO3- symporters (SbtA1 and SbtA2), three low-affinity Na+-dependent HCO3- transporters (BicA1, BicA2, and BicA3), and a BCT1; it is rare for a single strain to encode all three bicarbonate transporters in such large numbers. Interestingly, L. boryana CZ1 also uniquely encodes two active carbonic anhydrases, CcaA1 and CcaA2, which are also rare. Taken together, all these results indicated that L. boryana CZ1 is more efficient at CO2 fixation. Moreover, compared with the reported CCM gene arrangement of cyanobacteria, the CCM-related gene distribution pattern of L. boryana CZ1 was completely different, indicating a novel gene organization structure. These results can enrich our understanding of the CCM-related gene arrangement of cyanobacteria, and provide data support for the subsequent improvement and increase in biomass through cyanobacterial photosynthesis.

Large Improvement of Thermoelectric Performance by Magnetism in Co-Based Full-Heusler Alloys.

Full-Heusler alloys (fHAs) exhibit high mechanical strength with earth-abundant elements, but their metallic properties tend to display small electron diffusion thermopower, limiting potential applications as excellent thermoelectric (TE) materials. Here, it is demonstrated that the Co-based fHAs Co2 XAl (X = Ti, V, Nb) exhibit relatively high thermoelectric performance due to spin and charge coupling. Thermopower contributions from different magnetic mechanisms, including spin fluctuation and magnon drag are extracted. A significant contribution to thermopower from magnetism compared to that from electron diffusion is demonstrated. In Co2 TiAl, the contribution to thermopower from spin fluctuation is higher than that from electron diffusion, resulting in an increment of 280 µW m-1  K-2 in the power factor value. Interestingly, the thermopower contribution from magnon drag can reach up to -47 µV K-1 , which is over 2400% larger than the electron diffusion thermopower. The power factor of Co2 TiAl can reach 4000 µW m-1  K-2 which is comparable to that of conventional semiconducting TE materials. Moreover, the corresponding figure of merit zT can reach ≈0.1 at room temperature, which is significantly larger than that of traditional metallic materials. The work shows a promising unconventional way to create and optimize TE materials by introducing magnetism.

The Host Adapted Fungal Pathogens of Pneumocystis Genus Utilize Genic Regional Centromeres.

Centromeres are genomic regions that coordinate accurate chromosomal segregation during mitosis and meiosis. Yet, despite their essential function, centromeres evolve rapidly across eukaryotes. Centromeres are often the sites of chromosomal breaks which contribute to genome shuffling and promote speciation by inhibiting gene flow. How centromeres form in strongly host-adapted fungal pathogens has yet to be investigated. Here, we characterized the centromere structures in closely related species of mammalian-specific pathogens of the fungal phylum of Ascomycota. Methods allowing reliable continuous culture of Pneumocystis species do not currently exist, precluding genetic manipulation. CENP-A, a variant of histone H3, is the epigenetic marker that defines centromeres in most eukaryotes. Using heterologous complementation, we show that the Pneumocystis CENP-A ortholog is functionally equivalent to CENP-ACnp1 of Schizosaccharomyces pombe. Using organisms from a short-term in vitro culture or infected animal models and ChIP-seq, we identified centromeres in three Pneumocystis species that diverged ~100 million years ago. Each species has a unique short regional centromere (< 10kb) flanked by heterochromatin in 16-17 monocentric chromosomes. They span active genes and lack conserved DNA sequence motifs and repeats. CENP-C, a scaffold protein that links the inner centromere to the kinetochore appears dispensable in one species, suggesting a kinetochore rewiring. Despite the loss of DNA methyltransferases, 5-methylcytosine DNA methylation occurs in these species, though not related to centromere function. These features suggest an epigenetic specification of centromere function.

An Extracellular miRNA-Responsive Artificial Receptor via Dynamic DNA Nano-assembly for Biomarker-Driven Therapy.

MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers and therapeutic targets in various diseases. However, there is currently a lack of molecular strategies that can effectively use disease-associated extracellular miRNAs as input signals to drive therapeutic functions. Herein, we present a modular and programmable miRNA-responsive chimeric DNA receptor (miRNA-CDR) capable of biomarker-driven therapy. By grafting a miRNA-responsive DNA nanodevice on a natural membrane receptor via aptamer anchoring, miRNA-CDR can sense extracellular miRNA levels and autonomously induce dimerization-mediated receptor activation via the complementary-mediated strand displacement reaction-induced dynamic DNA assembly. The sequence programmability of miRNA-CDR allows it to sense and respond to a user-defined miRNA with tunable sensitivity. Moreover, the miRNA-CDR is versatile and customizable to reprogram desirable signaling output via adapting a designated receptor, such as MET and FGFR1. Using a mouse model of drug-induced acute liver injury (DILI), we demonstrate the functionality of a designer miRNA-CDR in rewiring the recognition of the DILI-elevated miR-122 to promote MET signaling of hepatocytes for biomarker-driven in situ repair and liver function restoration. Our synthetic miRNA-CDR platform provides a novel molecular device enabling biomarker-driven therapeutic cellular response, potentially paving the way for improving the precision of cell therapy in regenerative medicine.

The Safety, Pharmacokinetics, and Pharmacodynamics of SHR2285, an Oral Small Molecule Factor XIa Inhibitor, in Healthy Chinese Volunteers.

BACKGROUND AND OBJECTIVE: There is an unmet need for a safer anticoagulant since bleeding remains a concern with currently approved anticoagulants. Coagulation factor XI (FXI) is an attractive anticoagulant drug target with limited a role in physiological hemostasis. The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in healthy Chinese volunteers. METHODS: The study consisted of single ascending doses part (part 1: 25-600 mg) and multiple ascending doses part (part 2: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo orally. Blood, urine and feces samples were collected to describe its pharmacokinetic and pharmacodynamic profile. RESULTS: In total, 103 healthy volunteers completed the study. SHR2285 was well tolerated. SHR2285 was absorbed rapidly with median time to maximum plasma concentration (Tmax) of 1.50 to 3.00 h. The geometric median half-life (t1/2) of SHR2285 varied from 8.74 to 12.1 h across 25-600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77- to 3.61-fold that of the parent drug. The plasma concentration of SHR2285 and SHR164471 reached steady state by the morning of Day 7, with low accumulation ratio (0.956-1.20 and 1.18-1.56, respectively). The increase in pharmacokinetic exposure of SHR2285 and SHR164471 was less than dose proportional. Food has minimal effect on the pharmacokinetics of SHR2285 and SHR164471. SHR2285 produced an exposure-dependent prolongation of activated partial thromboplastin time (APTT) and a decrease in FXI activity. The maximum FXI activity inhibition rate (geometric mean) at steady state was 73.27%, 85.58%, 87.77% and 86.27% for 100-400 mg, respectively. CONCLUSIONS: SHR2285 was generally safe and well tolerated in healthy subjects across a wide range of doses. SHR2285 exhibited a predictable pharmacokinetic profile and an exposure-related pharmacodynamic profile. CLINICALTRIALS: gov Identifier NCT04472819; registered on July 15, 2020.

Investigation and Analysis of Mental State and Coping Style of Psychiatric Nurses in Public Health Emergencies.

Objectives: In this study, we evaluated the evaluate the psychological loads of psychiatric nurses and analyzed the influencing factors of these loads in nurse-patient communication.Methods: We used a convenience sampling method to select 400 psychiatric nurses from 5 tertiary psychiatric hospitals in Hebei, Jiangsu and Guangdong between April 5, 2020 and March 5, 2022 to participate. All participants were interviewed using a self-developed psychiatric nurse-patient communication event questionnaire and a 12-item general health questionnaire (GHQ-12). Results: The nurses' mean GHQ-12 score for psychiatric nurse-patient communication was 5.12±3.89 points, and generally, the psychological load was at a moderately high level. Among them, 196 (49.00%) had a high psychological load. The top 5 types of violence from patients or families towards the psychiatric nurses in the past month were injuries, verbal abuse, difficulties, work obstruction, and threatening intimidation. The most frequent factors in nurse-patient communication stress events were being worried about errors and accidents at work, being worried about not facing patient's emotional problems properly, and concern that they lacked communication skills about specific psychiatric symptoms. A multiple linear regression analysis showed that the important predictors of a high psychological load in psychiatric nurses included being male, having greater education, having worked a high number of years, having a high nurse characteristic factor load score, having a high environmental and social support factor load score, and experiencing workplace violence. Conclusion: The psychological load of psychiatric nurses is generally at a moderately high level and is directly related to gender, the number of working years, whether nurses have received professional systematic training, the frequency of workplace violence factors, nurses' characteristics, and environmental and social support scores. Accordingly, we should take note of these areas and improve them.

Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance.

Mitochondrial dysfunction is a hallmark of heart failure. Mitochondrial transplantation has been demonstrated to be able to restore heart function, but its mechanism of action remains unresolved. Using an in-house optimized mitochondrial isolation method, we tested efficacy of mitochondria transplantation in two different heart failure models. First, using a doxorubicin-induced heart failure model, we demonstrate that mitochondrial transplantation before doxorubicin challenge protects cardiac function in vivo and prevents myocardial apoptosis, but contraction improvement relies on the metabolic compatibility between transplanted mitochondria and treated cardiomyocytes. Second, using a mutation-driven dilated cardiomyopathic human induced pluripotent stem cell-derived cardiomyocyte model, we demonstrate that mitochondrial transplantation preferentially boosts contraction in the ventricular myocytes. Last, using single-cell RNA-seq, we show that mitochondria transplantation boosts contractility in dystrophic cardiomyocytes with few transcriptomic alterations. Together, we provide evidence that mitochondria transplantation confers myocardial protection and may serve as a potential therapeutic option for heart failure.

Logic Nanodevice-Mediated Receptor Assembly for Nongenetic Regulation of Cell Behavior in Tumor-like Microenvironment.

The reprogramming of cell signaling and behavior through the artificial control of cell surface receptor oligomerization shows great promise in biomedical research and cell-based therapy. However, it remains challenging to achieve combinatorial recognition in a complicated environment and logical regulation of receptors for desirable cellular behavior. Herein, we develop a logic-gated DNA nanodevice with responsiveness to multiple environmental inputs for logically controlled assembly of heterogeneous receptors to modulate signaling. The "AND" gate nanodevice uses an i-motif and an ATP-binding aptamer as environmental cue-responsive units, which can successfully implement a logic operation to manipulate receptors on the cell surface. In the presence of both protons and ATP, the DNA nanodevice is activated to selectively assemble MET and CD71, which modulate the HGF/MET signaling, resulting in cytoskeletal reorganization to inhibit cancer cell motility in a tumor-like microenvironment. Our strategy would be highly promising for precision therapeutics, including controlled drug release and cancer treatment.

The signaling protein GIV/Girdin mediates the Nephrin-dependent insulin secretion of pancreatic islet ß cells in response to high glucose.

Glucose-stimulated insulin secretion of pancreatic ß cells is essential in maintaining glucose homeostasis. Recent evidence suggests that the Nephrin-mediated intercellular junction between ß cells is implicated in the regulation of insulin secretion. However, the underlying mechanisms are only partially characterized. Herein we report that GIV is a signaling mediator coordinating glucose-stimulated Nephrin phosphorylation and endocytosis with insulin secretion. We demonstrate that GIV is expressed in mouse islets and cultured ß cells. The loss of function study suggests that GIV is essential for the second phase of glucose-stimulated insulin secretion. Next, we demonstrate that GIV mediates the high glucose-stimulated tyrosine phosphorylation of GIV and Nephrin by recruiting Src kinase, which leads to the endocytosis of Nephrin. Subsequently, the glucose-induced GIV/Nephrin/Src signaling events trigger downstream Akt phosphorylation, which activates Rac1-mediated cytoskeleton reorganization, allowing insulin secretory granules to access the plasma membrane for the second-phase secretion. Finally, we found that GIV is downregulated in the islets isolated from diabetic mice, and rescue of GIV ameliorates the ß-cell dysfunction to restore the glucose-stimulated insulin secretion. We conclude that the GIV/Nephrin/Akt signaling axis is vital to regulate glucose-stimulated insulin secretion. This mechanism might be further targeted for therapeutic intervention of diabetic mellitus.

A Novel Data Augmentation Method Based on CoralGAN for Prediction of Part Surface Roughness.

Deep learning networks can be applied to the field of intelligent prediction of part surface roughness. However, the surface roughness samples of parts have the problems of high collection cost, unbalanced categories, and complicated data distribution, which inevitably limit the application of deep learning network models in the field of intelligent prediction of part surface roughness. To solve these problems, this article proposes a novel data augmentation method based on CoralGAN for prediction of part surface roughness, which introduces the domain adaptive method deep coral function to help optimize the network parameters of the generator of generative adversarial network (GAN). Specifically, the vibration signal collected during processing is converted into frequency spectrum data and input into CoralGAN. The training of the generator is guided by coral loss, that is, the distance between the covariances of the real samples and generated samples features, not just the statistical consistency of the traditional GAN. Experiments have been carried out on the three-axis vertical machining center. Research shows that the proposed method can improve the prediction accuracy of part surface roughness to 95.5%.

Large Magneto-Transverse and Longitudinal Thermoelectric Effects in the Magnetic Weyl Semimetal TbPtBi.

Magnetic topological semimetals provide new opportunities for power generation and solid-state cooling based on thermoelectric (TE) effect. The interplay between magnetism and nontrivial band topology prompts the magnetic topological semimetals to yield strong transverse TE effect, while the longitudinal TE performance is usually poor. Herein, it is demonstrated that the magnetic Weyl semimetal TbPtBi has high value for both transverse and longitudinal thermopower with large power factor (PF). At 300 K and 13.5 Tesla, the transverse thermopower and PF reach up to 214 µV K-1 and 35 µW cm-1  K-2 , respectively, which are comparable to those of state-of-the-art TE materials. Combining first-principles calculations, longitudinal magnetoresistance and planar Hall resistance measurements, and two-band model fitting, the large transverse thermopower and PF are attributed to both bipolar effect and large Hall angle. Moreover, the imperfectly compensated charge carriers and large transverse magnetoresistance induce the maximum magneto-longitudinal thermopower of 251 µV K-1 with a PF of 24 µW cm-1  K-2 at 150 K and 13.5 Tesla, which is two times higher than that at zero magnetic field. This work demonstrates the great potential of topological semimetals for TEs and offers a new excellent candidate for magneto-TEs.

Patients with von Willebrand disease in China: Results of an online survey.

INTRODUCTION: Little is known about the clinical characteristics of von Willebrand disease (VWD) patients in China, the impact of Covid-19 on them and their genetic mutation. AIM: To describe the clinical characteristics of a group of VWD patients in China, the impact of Covid-19 on them and their genetic mutation. METHODS: An online survey using a self-designed questionnaire was conducted among patients within a WeChat group of VWD patients in China. Data were analysed using t-test, the Chi-square test, Fisher's exact test and rank sum test. RESULTS: Data from a total of 96 patients were collected. Several important findings are yielded. Above all, type 3 patients accounted for over half of the surveyed patients. Secondly, a surprising rate (>40%) of patients had experience of being misdiagnosed. Thirdly, treatment regimens were dominated by cryoprecipitate, blood-derived FVIII and plasma, and only a small percentage of patients received prophylaxis. Fourthly, we identified 17 new von Willebrand factor (VWF) mutant genes which merit further investigation. Additionally, Covid-19 was found to pose some challenges for the patients. CONCLUSION: In China, the high rates of type 3 patients and misdiagnosis suggest that most of the VWD patients may never be diagnosed in China. When it comes to diagnosis and treatment, there is a large gap between developing countries like China and developed countries.