The Influence of Various Freezing-thawing Methods of Skin on Drug Permeation and Skin Barrier Function.

The selection of skin is crucial for the in vitro permeation test (IVPT). The purpose of this study was to investigate the influence of different freezing-thawing processes on the barrier function of skin and the transdermal permeability of granisetron and lidocaine. Rat and hairless mouse skins were thawed at three different conditions after being frozen at -20℃ for 9 days: thawed at 4℃, room temperature (RT), and 32℃. There were no significant differences in the steady-state fluxes of drugs between fresh and thawed samples, but compared with fresh skin there were significant differences in lag time for the permeation of granisetron in rat skins thawed at RT and 32℃. Histological research and scanning electron microscopy images showed no obvious structural damage on frozen/thawed skin, while immunohistochemical staining and enzyme-linked immunosorbent assay for the tight junction (TJ) protein Cldn-1 showed significantly impaired epidermal barrier. It was concluded that the freezing-thawing process increases the diffusion rate of hydrophilic drugs partly due to the functional degradation of TJs. It's recommended that hairless, inbred strains and identical animal donors should be used, and the selected thawing method of skin should be validated prior to IVPT, especially for hydrophilic drugs.

Mapping the distribution of Nipah virus infections: a geospatial modelling analysis.

BACKGROUND: Nipah virus is a zoonotic paramyxovirus responsible for disease outbreaks with high fatality rates in south and southeast Asia. However, knowledge of the potential geographical extent and risk patterns of the virus is poor. We aimed to establish an integrated spatiotemporal and phylogenetic database of Nipah virus infections in humans and animals across south and southeast Asia. METHODS: In this geospatial modelling analysis, we developed an integrated database containing information on the distribution of Nipah virus infections in humans and animals from 1998 to 2021. We conducted phylodynamic analysis to examine the evolution and migration pathways of the virus and meta-analyses to estimate the adjusted case-fatality rate. We used two boosted regression tree models to identify the potential ecological drivers of Nipah virus occurrences in spillover events and endemic areas, and mapped potential risk areas for Nipah virus endemicity. FINDINGS: 749 people and eight bat species across nine countries were documented as being infected with Nipah virus. On the basis of 66 complete genomes of the virus, we identified two clades-the Bangladesh clade and the Malaysia clade-with the time of the most recent common ancestor estimated to be 1863. Adjusted case-fatality rates varied widely between countries and were higher for the Bangladesh clade than for the Malaysia clade. Multivariable meta-regression analysis revealed significant relationships between case-fatality rate estimates and viral clade (p=0·0021), source country (p=0·016), proportion of male patients (p=0·036), and travel time to health-care facilities (p=0·036). Temperature-related bioclimate variables and the probability of occurrence of Pteropus medius were important contributors to both the spillover and the endemic infection models. INTERPRETATION: The suitable niches for Nipah virus are more extensive than previously reported. Future surveillance efforts should focus on high-risk areas informed by updated projections. Specifically, intensifying zoonotic surveillance efforts, enhancing laboratory testing capacity, and implementing public health education in projected high-risk areas where no human cases have been reported to date will be crucial. Additionally, strengthening wildlife surveillance and investigating potential modes of transmission in regions with documented human cases is needed. FUNDING: The Key Research and Development Program of China.

Inflammatory loop involving Staphylococcus aureus, IL-36γ, and cathepsin S drives immunity disorders in familial acne inversa keratinocytes.

Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an essential event in AI, the interaction between bacteria and keratinocytes in AI pathophysiology remains unclear. In this study, the NCSTN gene was suppressed using short hairpin RNA in HaCaT cells. Using RNA sequencing, real-time polymerase chain reaction, and western blotting, the expression of IL-36 cytokines was analyzed. The impact of Staphylococcus aureus on AI keratinocyte inflammation and underlying regulatory molecules was investigated by exposing the HaCaT cells to S. aureus. By stimulating NCSTN knockdown HaCaT cells with IFN-γ, the expression and regulatory mechanism of Cathepsin S (Cat S), an IL-36γ cleavage and activating protease, were investigated. After NCSTN knockdown, the IL-36α expression increased, and the IL-36Ra expression was downregulated. NCSTN/MEK/ERK impairment-induced Krüppel-like factor 4 (KLF4) up-regulation in concert with S. aureus-induced nuclear factor kappa B elevation acts synergistically to promote IL-36γ production with the subsequent IL-8 activation in HaCaT cells. NCSTN/MEK/ERK impairment was also observed in familial AI lesions. IFN-γ-induced Cat S in keratinocytes was enhanced after NCSTN knockdown. The expression of IFN-II pathway molecules was significantly upregulated in both NCSTN knockdown HaCaT cells and familial AI lesions. The Cat S expression was significantly elevated in the patient's AI lesions. Our findings suggested a synergistic relationship between S. aureus and NCSTN/MAPK/KLF4 axis in IL-36γ-induced familial AI keratinocytes.

Osteocyte-derived exosomes regulate the DLX2/wnt pathway to alleviate osteoarthritis by mediating cartilage repair.

BACKGROUND: Chondrocyte viability, apoptosis, and migration are closely related to cartilage injury in osteoarthritis (OA) joints. Exosomes are identified as potential therapeutic agents for OA. OBJECTIVE: This study aimed to investigate the role of exosomes derived from osteocytes in OA, particularly focusing on their effects on cartilage repair and molecular mechanisms. METHODS: An injury cell model was established by treating chondrocytes with IL-1ß. Cartilage repair was evaluated using cell counting kit-8, flow cytometry, scratch test, and Western Blot. Molecular mechanisms were analyzed using quantitative real-time PCR, bioinformatic analysis, and Western Blot. An OA mouse model was established to explore the role of exosomal DLX2 in vivo. RESULTS: Osteocyte-released exosomes promoted cell viability and migration, and inhibited apoptosis and extracellular matrix (ECM) deposition. Moreover, exosomes upregulated DLX2 expression, and knockdown of DLX2 activated the Wnt pathway. Additionally, exosomes attenuated OA in mice by transmitting DLX2. CONCLUSION: Osteocyte-derived exosomal DLX2 alleviated IL-1ß-induced cartilage repair and inactivated the Wnt pathway, thereby alleviating OA progression. The findings suggested that osteocyte-derived exosomes may hold promise as a treatment for OA.

Profiling lipid mediators in serum from children with H1N1 influenza.

Influenza A virus subtype H1N1 can cause severe acute respiratory distress syndrome and death in young children and elderly individuals. H1N1 initiates inflammatory responses that aim to contain and eliminate microbial invaders. Various lipid mediators (LMs) are biosynthesized and play a critical role in fighting viruses during inflammation; thus, by profiling the LMs in patients, researchers can obtain mechanistic insights into diseases, such as the pathways disrupted. To date, the relationship between molecular alterations in LMs and the pathogenesis of H1N1 influenza in children is poorly understood. Here, we employed a targeted liquid chromatography coupled with tandem mass spectrometry (LC‒MS/MS) to profile LMs in serum from children with H1N1 influenza (H1N1 children) and recovered children. We found that 22 LM species were altered in H1N1 children with mild symptoms. Analysis of the LM profiles of recovered children revealed a decrease in the levels of thromboxane B2 (TxB2) and thromboxane B3 (TxB3) and an increase in the levels of other 8 altered LM species associated with H1N1 influenza, including cytochrome P450 (CYP) enzyme-derived dihydroxyeicosatrienoic acids (DiHETrEs) and hydroxyeicosatetraenoic acids (HETEs) from arachidonic acid (AA), and epoxyoctadecamonoenoic acids (EpOMEs) from linoleic acid (LA). Taken together, the results of this study revealed that serum LMs change dynamically in H1N1 children with mild symptoms. The dramatically altered LMs in H1N1 children could serve as a basis for potential therapeutics or adjuvants against H1N1 influenza.

Unveiling the stochastic nature of human heteropolymer ferritin self-assembly mechanism.

Despite ferritin's critical role in regulating cellular and systemic iron levels, our understanding of the structure and assembly mechanism of isoferritins, discovered over eight decades ago, remains limited. Unveiling how the composition and molecular architecture of hetero-oligomeric ferritins confer distinct functionality to isoferritins is essential to understanding how the structural intricacies of H and L subunits influence their interactions with cellular machinery. In this study, ferritin heteropolymers with specific H to L subunit ratios were synthesized using a uniquely engineered plasmid design, followed by high-resolution cryo-electron microscopy analysis and deep learning-based amino acid modeling. Our structural examination revealed unique architectural features during the self-assembly mechanism of heteropolymer ferritins and demonstrated a significant preference for H-L heterodimer formation over H-H or L-L homodimers. Unexpectedly, while dimers seem essential building blocks in the protein self-assembly process, the overall mechanism of ferritin self-assembly is observed to proceed randomly through diverse pathways. The physiological significance of these findings is discussed including how ferritin microheterogeneity could represent a tissue-specific adaptation process that imparts distinctive tissue-specific functions to isoferritins.

AI and culture: Culturally dependent responses to AI systems.

This article synthesizes recent research connected to how cultural identity can determine responses to artificial intelligence. National differences in AI adoption imply that culturally-driven psychological differences may offer a nuanced understanding and interventions. Our review suggests that cultural identity shapes how individuals include AI in constructing the self in relation to others and determines the effect of AI on key decision-making processes. Individualists may be more prone to view AI as external to the self and interpret AI features to infringe upon their uniqueness, autonomy, and privacy. In contrast, collectivists may be more prone to view AI as an extension of the self and interpret AI features to facilitate conforming to consensus, respond to their environment, and protect privacy.

Mechanisms of the influence of proactive personality on nurses' sense of social responsibility: A structural equation modelling study.

AIM: To explore the mechanism of proactive personality influence on nurses' sense of social responsibility through a serial multiple mediation model of volunteering motivation and self-efficacy. DESIGN: Further analysis of a cross-sectional and survey-based study. METHODS: In June 2023, a study was conducted with 722 Chinese nurses from four hospitals. Data were collected using the Proactive Personality Scale, the Self-Efficacy Scale, the Motivation to Volunteer Scale and the Nurses' Sense of Social Responsibility Scale. Structural equation modelling was used to analyse the relationship between nurses' sense of social responsibility and its correlative factors. RESULTS: Structural equation modelling showed a good model fit. Proactive personality, self-efficacy and motivation to volunteer can directly influence nurses' sense of social responsibility (ß = .12, ß = .04, ß = .50, p < .05). According to the test of chained mediation effects, proactive personality was significant through a single mediation path of self-efficacy (Z = 2.33, p < .05) and motivation to volunteer (Z = 7.32, p < .05) and through successive mediation paths of both variables (Z = 3.33, p < .05). CONCLUSION: A proactive personality can motivate nurses' social responsibility. Therefore, prompting nurses to be more proactive can effectively enhance nurses' sense of social responsibility. REPORTING METHOD: This study was reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cross-sectional studies. PATIENT OR PUBLIC CONTRIBUTION: This study explored the mechanisms influencing nurses' sense of social responsibility at the end of the epidemic. The results may inform the maintenance of high levels of long-term effects of nurses' social responsibility and shed light on building a standing workforce for public health emergencies.

A new endophytic Penicillium oxalicum with aphicidal activity and its infection mechanism.

BACKGROUND: Aphid infestation adversely affects the yield and quality of crops. Rapid reproduction and insecticidal resistance have made controlling aphids in the field challenging. Therefore, the present study investigated the insecticidal property of Penicillium oxalicum (QLhf-1) and its mechanism of action against aphids, Hyalopterus arundimis Fabricius. RESULTS: Bioassay revealed that the control efficacy of the spores against aphids (86.30% and 89.05% on the third day and fifth day after infection, respectively) were higher than other components, such as the mycelium. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed that QLhf-1 invaded the aphid cuticle through spores and used the aphid tissues as a nutrient source for growth and reproduction, causing stiffness and atrophy and a final death. Three extracellular enzymes, lipase, protease, and chitinase had a synergistic effect with spores, and they acted together to complete the infection process by degrading the aphid body wall and accelerating the infection process. CONCLUSION: The newly discovered endophytic penicillin strain P. oxalicum 'QLhf-1' can effectively kill aphids. The results provided strong evidence for the biological control of aphids, and lay a foundation for the development and utilization of QLhf-1. © 2024 Society of Chemical Industry.

Ultra-Small High-Entropy Alloy as Multi-Functional Catalyst for Ammonia Based Fuel Cells.

Ammonia fuel cells using carbon-neutral ammonia as fuel are regarded as a fast, furious, and flexible next-generation carbon-free energy conversion technology, but it is limited by the kinetically sluggish ammonia oxidation reaction (AOR), oxygen reduction reaction (ORR), and hydrogen evolution reaction (HER). Platinum can efficiently drive these three types of reactions, but its scale-up application is limited by its susceptibility to poisoning and high cost. In order to reduce the cost and alleviate poisoning, incorporating Pt with various metals proves to be an efficient and feasible strategy. Herein, PtFeCoNiIr/C trifunctional high-entropy alloy (HEA) catalysts are prepared with uniform mixing and ultra-small size of 2 ± 0.5 nm by Joule heating method. PtFeCoNiIr/C exhibits efficient performance in AOR (Jpeak = 139.8 A g-1 PGM), ORR (E1/2 = 0.87 V), and HER (E10 = 20.3 mV), outperforming the benchmark Pt/C, and no loss in HER performance at 100 mA cm-2 for 200 h. The almost unchanged E1/2 in the anti-poisoning test indicates its promising application in real fuel cells powered by ammonia. This work opens up a new path for the development of multi-functional electrocatalysts and also makes a big leap toward the exploration of cost-effective device configurations for novel fuel cells.

The Chemokine CCL2 Promotes Excitatory Synaptic Transmission in Hippocampal Neurons via GluA1 Subunit Trafficking.

The CC chemokine ligand 2 (CCL2, also known as MCP-1) and its cognate receptor CCR2 have well-characterized roles in chemotaxis. CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability. However, the detailed molecular mechanism underlying this process remains largely unclear. In cultured hippocampal neurons, CCL2 application rapidly upregulated surface expression of GluA1, in a CCR2-dependent manner, assayed using SEP-GluA1 live imaging, surface GluA1 antibody staining, and electrophysiology. Using pharmacology and reporter assays, we further showed that CCL2 upregulated surface GluA1 expression primarily via Gαq- and CaMKII-dependent signaling. Consistently, using i.p. injection of lipopolysaccharide to induce neuroinflammation, we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus, an effect blocked in Ccr2-/- mice. Together, these results provide a mechanism through which CCL2, and other secreted molecules that signal through G-protein coupled receptors, can directly regulate synaptic transmission.

Transcriptomic analysis uncovers a biphasic response to precocious Eimeria acervulina infection in chicken duodenal tissue.

Live anticoccidial vaccines, either formulated with unattenuated or attenuated Eimeria parasites, are powerful stimulators of chicken intestinal immunity. Little is known about the dynamics of gene expression and the corresponding biological processes of chicken responses against infection with precocious line (PL) of Eimeria parasites. In the present study, we performed a time-series transcriptomic analysis of chicken duodenum across 15 time points from 6 to 156 hours post-infection (p.i.) with PL of E. acervulina. A high-quality profile showing two distinct changes in chicken duodenum mRNA expression was generated during the infection of Eimeria. Early response revealed that activation of the chicken immune response was detectable from 6 h.p.i., prominent genes triggered during the initiation of asexual and sexual parasite growth encompass immune regulatory effects, such as interferon gamma (IFN-γ), interferon regulatory factor 1 (IRF1), and interleukin-10 (IL10). The late response was identified significantly associating with maintaining cellular structure and activating lipid metabolic pathways. These analyses provide a detailed depiction of the biological response landscape in chickens infected by the PL of E. acervulina, contributing significant insights for the investigation of the host-parasite interactions and the management of parasitic diseases.

Cytology or Multiparameter Flow Cytometry Positivity in the Cerebrospinal Fluid Before Transplantation is Predictive of Poor Outcomes After Allotransplantation in Acute Myeloid Leukemia Patients.

INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.

Selective adhesion of nitrogen-containing toxic gasses on hexagonal boron phosphide monolayer: a computational study.

CONTEXT: Various toxic gasses are being released into the environment with the increasing industrialization. However, detecting these gasses at low concentrations has become one of the main challenges in environmental monitoring and protection. Thus, developing sensors with high performance to detect toxic gasses is of utmost significance. For this purpose, researchers have introduced 2D materials thanks to their unique electronic qualities and large specific surface area. Within this piece of research, a hexagonal boron phosphide monolayer (h-BPML) is employed as the substrate material. The adhesion behavior of ambient nitrogen-containing toxic gasses, i.e., N2O, NH3, NO2, and NO, onto the h-BPML is investigated through DFT computations. The adhesion energy values for gasses NO and NO2 were calculated to be - 0.509 and - 0.694 eV on the h-BPML, respectively. Meanwhile, the absorbed energy values for gasses NH3 and N2O were found to be - 0.326 and - 0.119 eV, respectively. The recovery time, DOS, workfunction, and Bader charges were computed based on four optimal adhesion structures. After the absorption of NO on the h-BPML, the value of workfunction of a monolayer decreased from 1.54 to 0.47 eV. This amount of decrease was the greatest among the other gasses absorbed. By comparing the investigated parameters, it can be concluded that the h-BPML has a greater tendency to interact with NO gas compared to other gasses, and it can be proposed as a sensor for NO gas. METHOD: Within this piece of research, the sensitivity of the h-BPML to four nitrogenous toxic gasses, namely, N2O, NH3, NO2, and NO, was investigated using the DFT with HSE06 hybrid functional by using GAMESS software. For this purpose, we computed the DOS, workfunction, and the Bader charges for the four adhesion systems with most stability.

Euphorbia factor L2 alleviated gouty inflammation by specifically suppressing both the priming and activation of NLRP3 inflammasome.

Euphorbia L. is a traditionally used herb and contains many newly identified compounds with novel chemical structures. Euphorbia factor L2 (EFL2), a diterpenoid derived from Euphorbia seeds, is reported to alleviate acute lung injury and arthritis by exerting anti-inflammatory effects. In this study, we aimed to test the therapeutic benefit and mechanisms of EFL2 in NLRP3 inflammasome-mediated gouty models and identified the potential molecular mechanism. A cell-based system was used to test the specific inhibitory effect of EFL2 on NLRP3-related inflammation. The gouty arthritis model and an air pouch inflammation model induced by monosodium urate monohydrate (MSU) crystals were used for in vivo experiments. Nlrp3-/- mice and in vitro studies were used for mechanistic exploration. Virtual molecular docking and biophysical assays were performed to identify the direct binding and regulatory target of EFL2. The inhibitory effect of EFL2 on inflammatory cell infiltration was determined by flow cytometry in vivo. The mechanism by which EFL2 activates the NLRP3 inflammasome signaling pathway was evaluated by immunological experiment and transmission electron microscopy. In vitro, EFL2 specifically reduced NLRP3 inflammasome-mediated IL-1ß production and alleviated MSU crystal-induced arthritis, as well as inflammatory cell infiltration. EFL2 downregulated NF-κB phosphorylation and NLRP3 inflammasome expression by binding to glucocorticoid receptors. Moreover, EFL2 could specifically suppress the lysosome damage-mediated NLRP3 inflammasome activation process. It is expected that this work may be useful to accelerate the development of anti-inflammatory drugs originated from traditional herbs and improve therapeutics in gout and its complications.

Pathological polarizations from microglia to astrocyte contributes to spatial memory deficit in methamphetamine abstinence mice.

Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.

First Report of Nigrospora oryzae Causing Leaf Spot Disease on Amorphophallus albus in Shaanxi Province of China.

Amorphophallus albus P. Y. Liu & J. F. Chen is a typical cash crop widely planted in southwest China (Gao et al., 2022). In early August of 2021, a peculiar leaf spot disease was first detected on A. albus in Ankang Academy of Agricultural Sciences manufacturing base (32°69'N, 109°02'E), Shaanxi, China. Small irregular yellow-brown spots (1 to 2 mm) were observed on the surface of A. albus leaf. Following infection of the leaf, it expanded (3 to 5 mm) and became necrotic. Nine planting bases were investigated, and approximately 75% of plants were symptomatic during the rapid expansion period of bulb growth in Hanyin, Langao and Hanbin counties, Ankang City, Shaanxi, China. Higher disease incidence was observed at temperatures above 30℃ and humidity above 80%. Twenty-seven symptomatic tissues of infected leaves were first surface sterilized by immersion in 75% ethanol for 1 minute, followed by rinsing three times in sterile distilled water. The tissues were then cut into 4-5 mm pieces, plated on 1.5% potato dextrose agar (PDA), and incubated at 28±2°C. The hyphal tip from the growing edge of colonies cultured for three days at 28±2℃ was transferred to PDA to obtain pure cultures. Fungal colonies were white, then grey to black with an unevenly distributed, fast-growing aerial mycelium covering the petri dish within five days at 28±2℃. The colony turned dark brown when maintained in the dark at 28±2℃ after seven days, then grayish brown upon sporulation after 15 days (Fig.1f-g). Conidia were brown or black, smooth, spherical to sub-spherical, single-celled (8-12 µm × 10-13µm, average 9-11.5 µm in diameter, n=5µm). The nutritional hyphae exhibited septa, and a portion of the aerial hyphae formed a long, rough conidium, giving rise to a nearly spherical apical sac (Fig.1h). The surface gave rise to several small peduncles bearing clusters of surfaced spherical conidia (Fig.1i). Surfaced spherical conidia were generated on the surface of the small peduncle (Fig.1j). These morphological features were consistent with Nigrospora oryzae (Li et al., 2017). Genomic DNA was extracted from mycelia of the pathogen using an Ezup column fungal genomic DNA extraction kit (Sangon Biotech, Shanghai, China). To confirm the identity of the pathogen, the genomic fragments for the internal transcribed spacer (ITS), LSU (28S) and BenA gene of the isolate were amplified by PCR (Wang et al., 2017) and sent for sequencing. The resultant sequence (GeneBank ID of gene ITS, LSU, BenA are OR723825, OR775345, OR277316, respectively) were compared with the voucher specimens. BLAST results showed >99% identity with those of N.oryzae (GeneBank ID of N.oryzae strain LC2707 ITS, LSU, BenA are KX985954, KY806242, KY019481, respectively). A neighbor joining phylogenetic tree with the concatenated sequences of these genes showed that A-pb169 had the closest match with N. oryzae (Fig. 2). For pathogenicity testing, fifty plants in a period of rapid expansion of bulb growth were selected. Four leaves per plant were inoculated by sprayed till runoff with a conidial suspension of the pathogen (50 µL, 1×106 conidia/ml sterile water), and incubated at 30±2℃ and 80 ± 5% humidity. Control plants received sterile water. On the third day after inoculation, a yellow-brown spot appeared on leave surfaces, the spot gradually expanded; the infection rate was 90 to 95%. Fifteen days after inoculation, infected leaves showed symptoms like those observed in the field, whereas 100 control leaves sprayed with sterile water remained symptomless (Fig.1 a-e). The pathogen was reisolated from infected leaves and confirmed as N. oryzae by morphology and molecular identification. To our knowledge, this is the first report of leaf spot disease of A. albus caused by N. oryzae in China. Since its one of the major cash crops of the southeastern China, further work is necessary to determine its spread and economic impact as well as developing sustainable disease management options.

Lingguizhugan Decoction Improved Obesity by Modulating the Gut Microbiota and its Metabolites in Mice.

BACKGROUND: The global obese population is rapidly increasing, urgently requiring the development of effective and safe weight-loss medications. The classic Chinese medicine formulation Lingguizhugan De-coction has exerted a significant anti-obesity effect. However, the underlying mechanism is still unclear. OBJECTIVE: This study aimed to explore the mechanism of LGZGD in the treatment of obesity based on the gut microbiota and its metabolites. METHODS: Three different dosages of LGZGD were gavaged to ob/ob mice for 8 weeks. Body mass and visceral fat mass were evaluated. Additionally, the changes in gut microbiota, fecal and plasma metabolites in mice after LGZGD treatment were analyzed by metagenomics and non-targeted metabolomics. RESULTS: The results demonstrated a significant anti-obesity effect of LGZGD treatment in ob/ob mice. Fur-thermore, the metagenomic analysis revealed that LGZGD reduced the ratio of Firmicutes / Bacteroidetes (F to B) in the gut, restored gut microbiota diversity, and identified 3 enriched KEGG pathways, including energy metabolism, lipid metabolism, and energy production and conversion pathways. Based on non-targeted metab-olomics analysis, 20 key metabolites in the feces and 30 key metabolites in the plasma responding to LGZGD treatment were identified, and the levels of Eicosapentaenoic acid (EPA) and Myristoleic acid (MA) might be the metabolites related to gut microbiota after LGZGD treatment. Their biological functions were mainly re-lated to the metabolism pathway. CONCLUSIONS: These findings suggested that LGZGD had therapeutic potential for obesity. The mechanism of LGZGD alleviating obesity was associated with improving dysbiosis of the gut microbiota. LDZGD affected gut microbiota-derived metabolites of EPA and MA and may act on energy metabolism pathways.

Risk factors for positive post-transplantation measurable residual disease in patients with acute lymphoblastic leukemia.

BACKGROUND: The level of measurable residual disease (MRD) before and after transplantation is related to inferior transplant outcomes, and post-hematopoietic stem cell transplantation measurable residual disease (post-HSCT MRD) has higher prognostic value in determining risk than pre-hematopoietic stem cell transplantation measurable residual disease (pre-HSCT MRD). However, only a few work has been devoted to the risk factors for positive post-HSCT MRD in patients with acute lymphoblastic leukemia (ALL). This study evaluated the risk factors for post-HSCT MRD positivity in patients with ALL who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 1683 ALL patients from Peking University People's Hospital between January 2009 and December 2019 were enrolled to evaluate the cumulative incidence of post-HSCT MRD. Cox proportional hazard regression models were built for time-to-event outcomes. Multivariate analysis was performed to determine independent influencing factors from the univariate analysis. RESULTS: Both in total patients and in T-cell ALL or B-cell ALL, pediatric or adult, human leukocyte antigen-matched sibling donor transplantation or haploidentical SCT subgroups, positive pre-HSCT MRD was a risk factor for post-HSCT MRD positivity (P <0.001 for all). Disease status (complete remission 1 [CR1] vs. ≥CR2) was also a risk factor for post-HSCT MRD positivity in all patients and in the B cell-ALL, pediatric, or haploidentical SCT subgroups (P = 0.027; P = 0.003; P = 0.035; P = 0.003, respectively). A risk score for post-HSCT MRD positivity was developed using the variables pre-HSCT MRD and disease status. The cumulative incidence of post-HSCT MRD positivity was 12.3%, 25.1%, and 38.8% for subjects with scores of 0, 1, and 2-3, respectively (P <0.001). Multivariate analysis confirmed the association of the risk score with the cumulative incidence of post-HSCT MRD positivity and relapse as well as leukemia-free survival and overall survival. CONCLUSION: Our results indicated that positive pre-MRD and disease status were two independent risk factors for post-HSCT MRD positivity in patients with ALL who underwent allo-HSCT.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.