Effects of Kv1.3 knockout on pyramidal neuron excitability and synaptic plasticity in piriform cortex of mice.

Kv1.3 belongs to the voltage-gated potassium (Kv) channel family, which is widely expressed in the central nervous system and associated with a variety of neuropsychiatric disorders. Kv1.3 is highly expressed in the olfactory bulb and piriform cortex and involved in the process of odor perception and nutrient metabolism in animals. Previous studies have explored the function of Kv1.3 in olfactory bulb, while the role of Kv1.3 in piriform cortex was less known. In this study, we investigated the neuronal changes of piriform cortex and feeding behavior after smell stimulation, thus revealing a link between the olfactory sensation and body weight in Kv1.3 KO mice. Coronal slices including the anterior piriform cortex were prepared, whole-cell recording and Ca2+ imaging of pyramidal neurons were conducted. We showed that the firing frequency evoked by depolarization pulses and Ca2+ influx evoked by high K+ solution were significantly increased in pyramidal neurons of Kv1.3 knockout (KO) mice compared to WT mice. Western blotting and immunofluorescence analyses revealed that the downstream signaling molecules CaMKII and PKCα were activated in piriform cortex of Kv1.3 KO mice. Pyramidal neurons in Kv1.3 KO mice exhibited significantly reduced paired-pulse ratio and increased presynaptic Cav2.1 expression, proving that the presynaptic vesicle release might be elevated by Ca2+ influx. Using Golgi staining, we found significantly increased dendritic spine density of pyramidal neurons in Kv1.3 KO mice, supporting the stronger postsynaptic responses in these neurons. In olfactory recognition and feeding behavior tests, we showed that Kv1.3 conditional knockout or cannula injection of 5-(4-phenoxybutoxy) psoralen, a Kv1.3 channel blocker, in piriform cortex both elevated the olfactory recognition index and altered the feeding behavior in mice. In summary, Kv1.3 is a key molecule in regulating neuronal activity of the piriform cortex, which may lay a foundation for the treatment of diseases related to piriform cortex and olfactory detection.

[Treatment of ornithine transcarbamylase deficiency in a child with glyceryl phenylbutyrate]. / è‹¯ä¸é ¸ç”˜æ²¹é ¯æ²»ç–—å„¿ç«¥é¸Ÿæ°¨é ¸æ°¨ç”²é °åŸºè½¬ç§»é ¶ç¼ºä¹ç—‡1例.

Glyceryl phenylbutyrate (GPB) serves as a long-term management medication for Ornithine transcarbamylase deficiency (OTCD), effectively controlling hyperammonemia, but there is a lack of experience in using this medicine in China. This article retrospectively analyzes the case of a child diagnosed with OTCD at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, including a review of related literature. After diagnosis, the patient was treated with GPB, followed by efficacy follow-up and pharmacological monitoring. The 6-year and 6-month-old male patient exhibited poor speech development, disobedience, temper tantrums, and aggressive behavior. Blood ammonia levels peaked at 327 µmol/L; urine organic acid analysis indicated elevated uracil levels; cranial MRI showed extensive abnormal signals in both cerebral hemispheres. Genetic testing revealed de novo mutation in the OTC gene (c.241T>C, p.S81P). Blood ammonia levels were approximately 43, 80, and 56 µmol/L at 1, 2, and 3 months after starting GPB treatment, respectively. During treatment, blood ammonia was well-controlled without drug-related adverse effects. The patient showed improvement in developmental delays, obedience, temperament, and absence of aggressive behavior.

Fungal Prenyltransferase AnaPT and Its F265 Mutants Catalyze the Dimethylallylation at the Nonaromatic Carbon of Phloretin.

Phloretin is widely found in fruit and shows various biological activities. Here, we demonstrate the dimethylallylation, geranylation, and farnesylation, particularly the first dimethylallylation at the nonaromatic carbon of phloretin (1) by the fungal prenyltransferase AnaPT and its mutants. F265 was identified as a key amino acid residue related to dimethylallylation at the nonaromatic carbon of phloretin. Mutants AnaPT_F265D, AnaPT_F265G, AnaPT_F265P, AnaPT_F265C, and AnaPT_F265Y were discovered to generally increase prenylation activity toward 1. AnaPT_F265G catalyzes the O-geranylation selectively at the C-2' hydroxyl group, which involves an intramolecular hydrogen bond with the carbonyl group of 1. Seven products, 1D5, 1D7-1D9, 1G2, 1G4, and 1F2, have not been reported prior to this study. Twelve compounds, 1D3-1D9, 1G1-1G3, and 1F1-1F2, exhibited potential inhibitory effects on α-glucosidase with IC50 values ranging from 11.45 ± 0.87 to 193.80 ± 6.52 µg/mL. Among them, 1G1 with an IC50 value of 11.45 ± 0.87 µg/mL was the most potential α-glucosidase inhibitor, which is about 30 times stronger than the positive control acarbose with an IC50 value of 346.63 ± 15.65 µg/mL.

[Characteristics of drug resistance and biofilm formation in carbapenem-resistant Acinetobacter baumannii in hospitalized children]. / 住院患儿耐碳青霉烯类鲍曼不动杆菌的耐药及生物膜特征分析.

OBJECTIVES: To study the distribution, drug resistance, and biofilm characteristics of carbapenem-resistant Acinetobacter baumannii (CRAB) isolated from hospitalized children, providing a reference for the prevention and treatment of CRAB infections in hospitalized children. METHODS: Forty-eight CRAB strains isolated from January 2019 to December 2022 were classified into epidemic and sporadic strains using repetitive extragenic palindromic sequence-based polymerase chain reaction. The drug resistance, biofilm phenotypes, and gene carriage of these two types of strains were compared. RESULTS: Both the 22 epidemic strains and the 26 sporadic strains were producers of Class D carbapenemases or extended-spectrum ß-lactamases with downregulated outer membrane porins, harboring the VIM, OXA-23, and OXA-51 genes. The biofilm formation capability of the sporadic strains was stronger than that of the epidemic strains (P<0.05). Genes related to biofilm formation, including Bap, bfs, OmpA, CsuE, and intI1, were detected in both epidemic and sporadic strains, with a higher detection rate of the intI1 gene in epidemic strains (P<0.05). CONCLUSIONS: CRAB strains are colonized in the hospital, with sporadic strains having a stronger ability to form biofilms, suggesting the potential for forming new clonal transmissions in the hospital. Continuous monitoring of the epidemic trends of CRAB and early warning of the distribution of epidemic strains are necessary to reduce the risk of CRAB infections in hospitalized children.

Endogenous IAA affected fluoranthene accumulation by regulating H+-ATPase and SOD activity in ryegrass.

This study explores the role of endogenous indole-3-acetic acid (IAA) in modulating plant responses to pollution stress and its effect on pollutant accumulation, with a focus on fluoranthene (Flu) in ryegrass. To elucidate the mechanism, we employed an IAA promoter (α-aminobutyric acid [α-AB]) and an IAA inhibitor (naphthylphthalamic acid [NPA]) to regulate IAA levels and analyze Flu uptake characteristics. The experimental setup included a Flu treatment group (ryegrass with Flu addition) and a control group (ryegrass without Flu). Our findings demonstrate that Flu treatment enhanced IAA content and plant growth in ryegrass compared to the control. The Flu+AB treatment further enhanced these effects, while the Flu+NPA treatment exhibited a contrasting trend. Moreover, Flu+AB treatment led to increased Flu accumulation, in contrast to the inhibitory effect observed with Flu+NPA treatment. Flu treatment also enhanced the activities of key antioxidant enzymes (SOD, POD, CAT) and increased soluble sugar and protein levels, indicative of enzymatic and nonenzymatic defense responses, respectively. The Flu+AB treatment amplified these responses, whereas the Flu+NPA treatment attenuated them. Significantly, Flu treatment raised H+-ATPase activity compared to the control, an effect further elevated by Flu+AB treatment and diminished by Flu+NPA treatment. A random forest analysis suggested that Flu accumulation dependency varied under different treatments: it relied more on H+-ATPase activity under Flu+AB treatment and more on SOD activity under Flu+NPA treatment. Additionally, Flu+AB treatment boosted the transpiration rate in ryegrass, thereby increasing the Flu translocation factor, a trend reversed by Flu+NPA treatment. This research highlights crucial factors influencing Flu accumulation in ryegrass, offering potential new avenues for controlling the gathering of contaminants within plant systems.

Synergistic Activation of Electric Furnace Ferronickel Slag by Mechanical Grinding and Chemical Activators to Prepare Cementitious Composites.

The use of electric furnace ferronickel slag (FNS) as a supplementary cementitious material is the current focus of research. This study investigates the effect of mechanical grinding and chemical additives on the activity excition of FNS, as well as the associated synergistic mechanisms. This study shows that the addition of triethanolamine (TEA) increases the fine-grained content in FNS powder, which facilitates the depolymerization of FNS and the early hydration of aluminum tricalcium. Furthermore, the addition of Ca(OH)2 raises the alkalinity of the cementitious system, which promotes the availability of Ca2+ ions and accelerates the hydration process, resulting in the generation of additional hydration products. The enhancement of late hydration of C3S by TEA and its combination with the secondary hydration of Ca2+ at high alkalinity are the pivotal factors to improve the strength of cementitious composite. A mixture of FNS and 0.03% TEA is subjected to grinding for 90 min, using the obtained micropowder which replaces 20% of the cement, and subsequently, after being excited with 3% Ca(OH)2, the FNS micropowder reaches the quality standards of S95 slag powder. It is worth remarking that the micropowder prepared by mixing FNS with 3% Ca(OH)2 and 0.03% TEA and grinding it for 81 min also meets the S95 standard for slag powder. The larger dosage of FNS in cement is supported by the observed synergy between TEA and Ca(OH)2. This research will provide valuable insights for the expanded application of FNS in construction materials.

Spatiotemporal heterogeneity in meteorological and hydrological drought patterns and propagations influenced by climatic variability, LULC change, and human regulations.

This study aims to quantify meteorological-hydrological drought propagations and examine the potential impacts by climatic variability, LULC change (LULC), and human regulations. An integrated observation-modeling framework quantifies drought propagation intervals and assesses mechanisms influencing hydrological droughts. Meteorological droughts are characterized using the Standardized Precipitation Evapotranspiration Index (SPEI), and hydrological droughts are assessed through the Standardized Streamflow Index (SSI) across diverse climatic zones. Cross-correlation analysis between SPEI and SSI time series identifies the lag time associated with the highest correlation as the drought propagation interval. Mechanisms are investigated via a coupled empirical-process modeling framework incorporating the Soil and Water Assessment Tool (SWAT). Discrepancies between simulated and observed SSI time series help quantify the extent of human regulation impacts on hydrological drought characteristics and propagation. The Yellow River Basin (YRB), divided into six subzones based on climate characteristics, is selected as the case study. Key findings include: (1) Meteorological droughts were extremely severe across most YRB during the 1990s, while the 2000s showed some mitigation primarily due to precipitation increases. (2) Hydrological droughts and propagation times from meteorology to hydrology demonstrated substantial spatiotemporal variability. In general, summer propagation times were shorter than other seasons. (3) Propagation times were shorter in arid regions with cropland or built-up land cover versus grassland and woodland, while the reverse held for humid regions. (4) Human regulations prolonged propagation times, likely due to reservoir regulations designed to overcome water deficits. While the YRB is the focus of this paper, the methodologies and findings are applicable to other regions worldwide to enhance drought forecasting and water resource management. In various hydrological and climatic contexts worldwide.

A comparative study of genotyping and antimicrobial resistance between carbapenem-resistant Klebsiella pneumoniae and Acinetobacter baumannii isolates at a tertiary pediatric hospital in China.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolations have rapidly increased in pediatric patients. To investigate a possible health care-associated infections of CRKP in a tertiary pediatric hospital, the circulating clones and carbapenem-resistant pattern between CRKP and carbapenem-resistant Acinetobacter baumannii (CRAB) isolates were compared to classify their epidemiological characteristics. The results will help to identify the epidemic pattern of the CRKP transmission in the hospital. Methods: Ninety-six CRKP and forty-eight CRAB isolates were collected in Kunming Children's Hospital from 2019 through 2022. These isolates were genotyped using repetitive extragenic palindromic-PCR (REP-PCR). Carbapenemase phenotypic and genetic characterization were investigated using a disk diffusion test and singleplex PCR, respectively. In addition, these characteristics of the two pathogens were compared. Results: The rates of CRKP and CRAB ranged from 15.8% to 37.0% at the hospital. Forty-nine and sixteen REP genotypes were identified among the 96 and 48 CRKP and CRAB isolates tested, respectively. The CRKP isolates showed more genetic diversity than the CRAB isolates. Of the 96 CRKP isolates, 69 (72%) produced Class B carbapenemases. However, all 48 CRAB isolates produced Class D carbapenemase or extended-spectrum ß-lactamases (ESBL) combined with the downregulation of membrane pore proteins. Furthermore, the carbapenemase genes bla KPC, bla IMP, and bla NDM were detected in CRKP isolates. However, CRAB isolates were all positive for the bla VIM, bla OXA-23, and bla OXA-51 genes. Conclusions: These CRKP isolates exhibited different biological and genetic characteristics with dynamic changes, suggesting widespread communities. Continuous epidemiological surveillance and multicenter research should be carried out to strengthen the prevention and control of infections.

Bottom-up and top-down controls on Alteromonas macleodii lead to different dissolved organic matter compositions.

The effects of both bottom-up (e.g. substrate) and top-down (e.g. viral lysis) controls on the molecular composition of dissolved organic matter have not been investigated. In this study, we investigated the dissolved organic matter composition of the model bacterium Alteromonas macleodii ATCC 27126 growing on different substrates (glucose, laminarin, extracts from a Synechococcus culture, oligotrophic seawater, and eutrophic seawater), and infected with a lytic phage. The ultra-high resolution mass spectrometry analysis showed that when growing on different substrates Alteromonas macleodii preferred to use reduced, saturated nitrogen-containing molecules (i.e. O4 formula species) and released or preserved oxidized, unsaturated sulfur-containing molecules (i.e. O7 formula species). However, when infected with the lytic phage, Alteromonas macleodii produced organic molecules with higher hydrogen saturation, and more nitrogen- or sulfur-containing molecules. Our results demonstrate that bottom-up (i.e. varying substrates) and top-down (i.e. viral lysis) controls leave different molecular fingerprints in the produced dissolved organic matter.

Advancements in the Research of GEF-H1: Biological Functions and Tumor Associations.

Guanine nucleotide exchange factor H1 (GEF-H1) is a unique protein modulated by the GDP/GTP exchange. As a regulator of the Rho-GTPase family, GEF-H1 can be activated through a microtubule-depended mechanism and phosphorylation regulation, enabling it to perform various pivotal biological functions across multiple cellular activities. These include the regulation of Rho-GTPase, cytoskeleton formation, cellular barrier, cell cycle, mitosis, cell differentiation, and vesicle trafficking. Recent studies have revealed its crucial effect on the tumor microenvironment (TME) components, promoting tumor initiation and progress. Consequently, an in-depth exploration of GEF-H1's biological roles and association with tumors holds promise for its potential as a valuable molecular target in tumor treatment.

Identification and expression analysis of expansin gene family in Salvia miltiorrhiza.

BACKGROUND: Expansins (EXP) are important enzymes that are involved in the extension of plant cells and regulation of root configurations, which play important roles in resisting various stresses. As a model medicinal plant, Salvia miltiorrhiza is well recognized for treating coronary heart disease, myocardial infection, and other cardiovascular and cerebrovascular diseases; however, the SmEXP gene family has not yet been analyzed. METHODS: The SmEXP family was systematically analyzed using bioinformatics. Quantitative real-time PCR was employed to analyze the tissue expression patterns of the SmEXP family, as well as its expression under abscisic acid (ABA) treatment and abiotic stress. Subcellular localization assay revealed the localization of SmEXLA1, SmEXLB1, and SmEXPA2. RESULTS: This study identified 29 SmEXP that belonged to four different subfamilies. SmEXP promoter analysis suggested that it may be involved in the growth, development, and stress adaptation of S. miltiorrhiza. An analysis of the expression patterns of SmEXP revealed that ABA, Cu2+, and NaCl had regulatory effects on its expression. A subcellular localization assay showed that SmEXLA1 and SmEXLB1 were located on the nucleus and cell membrane, while SmEXPA2 was located on the cell wall. CONCLUSION: For this study, the SmEXP family was systematically analyzed for the first time, which lays a foundation for further elucidating its physiological and biological functionality.

Reliability, validity, and simplification of the Chinese version of the Global Pain Scale in patients with rheumatoid arthritis.

BACKGROUND: Persistent pain is the most reported symptom in patients with rheumatoid arthritis (RA); however, effective and brief assessment tools are lacking. We validated the Chinese version of the Global Pain Scale (C-GPS) in Chinese patients with RA and proposed a short version of the C-GPS (s-C-GPS). METHOD: The study was conducted using a face-to-face questionnaire survey with a multicenter cross-sectional design from March to December 2019. Patients aged > 18 years who met the RA diagnostic criteria were included. Based on the classical test theory (CTT) and the item response theory (IRT), we assessed the validity and reliability of the C-GPS and the adaptability of each item. An s-C-GPS was developed using IRT-based computerized adaptive testing (CAT) analytics. RESULTS: In total, 580 patients with RA (mean age, 51.04 ± 24.65 years; mean BMI, 22.36 ± 4.07 kg/m2), including 513 (88.4%) women, were included. Most participants lived in a suburb (49.3%), were employed (72.2%) and married (91.2%), reported 9-12 years of education (66.9%), and had partial medical insurance (57.8%). Approximately 88.1% smoked and 84.5% drank alcohol. Analysis of the CTT demonstrated that all items in the C-GPS were positively correlated with the total scale score, and the factor loadings of all these items were > 0.870. A significant positive relationship was found between the Visual Analog Scale (VAS) and the C-GPS. IRT analysis showed that discrimination of the C-GPS was between 2.271 and 3.312, and items 6, 8, 13, 14, and 16 provided a large amount of information. Based on the CAT and clinical practice, six items covering four dimensions were included to form the s-C-GPS, all of which had very high discrimination. The s-C-GPS positively correlated with the VAS. CONCLUSION: The C-GPS has good reliability and validity and can be used to evaluate pain in RA patients from a Chinese cultural background. The s-C-GPS, which contains six items, has good criterion validity and may be suitable for pain assessment in busy clinical practice. TRIAL REGISTRATION: This cross-sectional study was registered in the Chinese Clinical Trial Registry (ChiCTR1800020343), granted on December 25, 2018.

Mefloquine improves pulmonary fibrosis by inhibiting the KCNH2/Jak2/Stat3 signaling pathway in macrophages.

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease characterized by severe pulmonary fibrosis, for which there is an urgent need for effective therapeutic agents. Mefloquine (Mef) is a quinoline compound primarily used for the treatment of malaria. However, high doses (>25 mg/kg) may lead to side effects such as cardiotoxicity and psychiatric disorders. Here, we found that low-dose Mef (5 mg/kg) can safely and effectively treat IPF mice. Functionally, Mef can improve the pulmonary function of IPF mice (PIF, PEF, EF50, VT, MV, PENH), alleviating pulmonary inflammation and fibrosis by inhibiting macrophage activity. Mechanically, Mef probably regulates the Jak2/Stat3 signaling pathway by binding to the 492HIS site of Potassium voltage-gated channel subfamily H member 2 (KCNH2) protein in macrophages, inhibiting the secretion of macrophage inflammatory and fibrotic factors. In summary, Mef may inhibit macrophage activity by binding to KCNH2 protein, thereby slowing down the progress of IPF.

The Putative Effects of Neoadjuvant Chemotherapy on the Immune System of Advanced Epithelial Ovarian Carcinoma.

The epithelial ovarian carcinoma (EOC) is one of leading causes of cancer-related mortality in females. For some patients, complete resection cannot be achieved, thus neoadjuvant chemotherapy (NACT) following interval debulking surgery (IDS) could be an alternative choice. In general-held belief, cytotoxic chemotherapy is assumed to be immunosuppressive, because of its toxicity to dividing cells in the bone marrow and peripheral lymphoid tissues. However, increasing evidence highlighted that the anticancer activity of chemotherapy may also be related to its ability to act as an immune modulator. NACT not only changed the morphology of cancer cells, but also changed the transcriptomic and genomic profile of EOC, induced proliferation of cancer stem-like cells, gene mutation, and tumor-related adaptive immune response. This review will provide a comprehensive overview of recent studies evaluating the impact of NACT on cancer cells and immune system of advanced EOC and their relationship to clinical outcome. This information could help us understand the change of immune system during NACT, which might provide new strategies in future investigation of immuno-therapy for maintenance treatment of EOC.

Characteristics of CXE family of Salvia miltiorrhiza and identification of interactions between SmGID1s and SmDELLAs.

Carboxylesterase (CXE) is a class of hydrolases that contain an α/ß folding domain, which plays critical roles in plant growth, development, and stress responses. Based on the genomic and transcriptomic data of Salvia miltiorrhiza, the SmCXE family was systematically analyzed using bioinformatics. The results revealed 34 SmCXE family members in S. miltiorrhiza, and the SmCXE family could be divided into five groups (Group I, Group II, Group III, Group IV, and Group V). Cis-regulatory elements indicated that the SmCXE promoter region contained tissue-specific and development-related, hormone-related, stress-related, and photoresponsive elements. Transcriptome analysis revealed that the expression levels of SmCXE2 were highest in roots and flowers (SmCXE8 was highest in stems and SmCXE19 was highest in leaves). Further, two GA receptors SmCXE1 (SmGID1A) and SmCXE2 (SmGID1B) were isolated from the SmCXE family, which are homologous to other plants. SmGID1A and SmGID1B have conserved HGGSF motifs and active amino acid sites (Ser-Asp-Val/IIe), which are required to maintain their GA-binding activities. SmGID1A and SmGID1B were significantly responsive to gibberellic acid (GA3) and methyl jasmonate (MeJA) treatment. A subcellular assay revealed that SmCXE1 and SmCXE2 resided within the nucleus. SmGID1B can interact with SmDELLAs regardless of whether GA3 exists, whereas SmGID1A can only interact with SmDELLAs in the presence of GA3. A Further assay showed that the GRAS domain mediated the interactions between SmGID1s and SmDELLAs. This study lays a foundation for further elucidating the role of SmCXE in the growth and development of S. miltiorrhiza.

Quarantine experience of healthcare workers in close contact with COVID-19 patients in China: a qualitative study.

BACKGROUND: This study investigated the experiences of front-line healthcare workers who had been in close contact with COVID-19 patients and had been quarantined in order to provide guidance on quarantine measures with more humanistic care when dealing with future public health emergencies. METHODS: We conducted a qualitative study using semistructured, qualitative, in-depth interviews between April and June 2022. The interviews were recorded and transcribed, followed by a thematic analysis. The study followed the Standards for Reporting Qualitative Research. RESULTS: This study identified the following four themes: (1) personal psychological changes, (2) increased reflection on life and work during quarantine, (3) the important role of others' support and (4) different types of demands during quarantine and isolation. Each theme is supported by several subthemes that further illustrate the participants' experiences. CONCLUSIONS: Quarantine of close contacts is necessary to prevent outbreaks. Front-line doctors and nurses are at a greater risk of COVID-19 infection than others. The results showed the psychological reactions of ordinary close contacts, and the unique feelings and experiences of doctors and nurses during the epidemic. Therefore, future research should cooperate with multiple departments to assess their needs, provide them with individualised care and love and give them incentives in order to reduce their psychological burden, improve their quality of life and allow them to engage in healthcare with a healthy mind.

Elevational characteristics of soil bacterial community and their responses to soil translocation at a mountainside in northwest Sichuan, China.

How the soil bacterial communities vary with elevation is context-dependent, and the effect of soil translocation between elevations on bacterial community structure and metabolic function was not fully understood yet. Here, the bacterial community composition and diversity at five elevations along a 1600-3000 m elevation gradient on a mountainside in northwest Sichuan were characterized, and the responses of soil bacterial community to simulated climate changes were further studied by soil translocation reciprocally at three elevations for 12 months. Significant differences were found in soil temperature and moisture at different elevations, but there was no observed change in bacterial alpha diversity. The relative abundance of bacterial phyla was significantly different among the five elevations except for Proteobacteria (the dominant bacterial phyla in five elevation), and most bacterial phyla correlated with soil temperature, moisture, pH and soil bulk density. The direct effect of soil properties (pH, soil nutrients and soil bulk density) on soil bacterial community was stronger than the direct effect of temperature and moisture. Soil translocation changed the relative abundance of some bacterial phyla, and taxonomic groups with significant changes were mainly non-dominant phyla rather than the dominant phyla. Metabolism was the primary function of bacterial community at all elevations, which accounted for ~ 80% of relative abundance, and soil translocation had little effect on metabolic function. These findings indicated that soil bacterial dominant taxa and soil bacterial metabolic functions are relatively stable, which contribute to the stability of the ecosystem when response to the climate change in the future.

OTUB1's role in promoting OSCC development by stabilizing RACK1 involves cell proliferation, migration, invasion, and tumor-associated macrophage M1 polarization.

Ovarian tumor domain, ubiquitin aldehyde binding 1 (OTUB1), a deubiquitinating enzyme known to regulate the stability of downstream proteins, has been reported to regulate various cancers tumorigenesis, yet its direct effects on oral squamous cell carcinoma (OSCC) progression are unclear. Bioinformatics analysis was performed to screen for genes of interest, and in vitro and in vivo studies were carried out to investigate the function and mechanism of OTUB1 in OSCC. We found that OTUB1 was abnormally elevated in OSCC tissues and positively associated with the pathological stage and tumor stage. Knockdown of OTUB1 impaired the malignance of OSCC cells - suppressed cell proliferation, invasion, migration, and xenografted tumor growth. OTUB1 silencing also drove tumor-associated macrophage M1 polarization but suppressed M2 polarization, and the induction of M1 polarization inhibited the survival of OSCC cells. However, OTUB1 overexpression exerted the opposite effects. Furthermore, the protein network that interacted with the OTUB1 protein was constructed based on the GeneMANIA website. Receptor for activated C kinase 1 (RACK1), a facilitator of OSCC progression, was identified as a potential target of the OTUB1 protein. We revealed that OTUB1 positively regulated RACK1 expression and inhibited RACK1 ubiquitination. Additionally, RACK1 upregulation reversed the effects of OTUB1 knockdown on OSCC progression. Overall, we demonstrated that OTUB1 might regulate OSCC progression by maintaining the stability of the RACK1 protein. These findings highlight the potential roles of the OTUB1/RACK1 axis as a potential therapeutic target in OSCC.

Autonomous ratcheting by stochastic resetting.

We propose a generalization of the stochastic resetting mechanism for a Brownian particle diffusing in a one-dimensional periodic potential: randomly in time, the particle gets reset at the bottom of the potential well it was in. Numerical simulations show that in mirror asymmetric potentials, stochastic resetting rectifies the particle's dynamics, with a maximum drift speed for an optimal average resetting time. Accordingly, an unbiased Brownian tracer diffusing on an asymmetric substrate can rectify its motion by adopting an adaptive stop-and-go strategy. Our proposed ratchet mechanism can model the directed autonomous motion of molecular motors and micro-organisms.

Donafenib and GSK-J4 Synergistically Induce Ferroptosis in Liver Cancer by Upregulating HMOX1 Expression.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. Donafenib is a multi-receptor tyrosine kinase inhibitor approved for the treatment of patients with advanced HCC, but its clinical effect is very limited. Here, through integrated screening of a small-molecule inhibitor library and a druggable CRISPR library, that GSK-J4 is synthetically lethal with donafenib in liver cancer is shown. This synergistic lethality is validated in multiple HCC models, including xenograft, orthotopically induced HCC, patient-derived xenograft, and organoid models. Furthermore, co-treatment with donafenib and GSK-J4 resulted in cell death mainly via ferroptosis. Mechanistically, through integrated RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) analyses, that donafenib and GSK-J4 synergistically promoted the expression of HMOX1 and increased the intracellular Fe2+ level is found, eventually leading to ferroptosis. Additionally, through cleavage under targets & tagmentation followed by sequencing (CUT&Tag-seq), it is found that the enhancer regions upstream of HMOX1 promoter significantly increased under donafenib and GSK-J4 co-treatment. A chromosome conformation capture assay confirmed that the increased expression of HMOX1 is caused by the significantly enhanced interaction between the promoter and upstream enhancer under dual-drug combination. Taken together, this study elucidates a new synergistic lethal interaction in liver cancer.