LMR-101, a novel derivative of propofol, exhibits potent anticonvulsant effects and possibly interacts with a novel target on γ-aminobutyric acid type A receptors.

OBJECTIVE: LMR-101 is a bisphenol derivative of propofol, a short-acting general anesthetic, which is also used to manage status epilepticus (SE). We evaluated the sedative and anticonvulsant effects of LMR-101 to discover its potential to manage epilepsy and SE in the clinic. METHODS: Comparative studies between LMR-101 and propofol were performed in mice to elucidate an appropriate dose range for LMR-101 that produced anticonvulsant effects without significant sedation. Then, the anticonvulsive efficacy for LMR-101 was evaluated using seizure models induced by pentylenetetrazol and (+)-bicuculline. The ability of LMR-101 to inhibit SE was assessed using a rat model of SE induced by pilocarpine. Radioligand binding assay profiles for LMR-101 were performed to evaluate the potential mechanisms of action underlying its anticonvulsant properties. RESULTS: In the mouse study, LMR-101 exhibited greater anticonvulsant and lesser sedative effect compared with propofol. LMR-101 completely inhibited pentylenetetrazol-induced seizures at a dose of 50 mg/kg and exhibited heavy sedation at 300 mg/kg. Propofol anesthetized all mice and only decreased the seizure rate at 25 mg/kg. LMR-101 also suppressed seizure behaviors evoked by (+)-bicuculline in mice in a dose-dependent manner. In the pilocarpine-induced SE model, LMR-101 significantly decreased the maximum seizure score and seizure duration in a dose-dependent manner. The median effective dose for LMR-101 was 14.30 mg/kg and 121.87 mg/kg to prevent and inhibit sustained SE, respectively. In binding assays, LMR-101 primarily inhibited tert-[35 S] butylbicyclophosphorothionate binding to γ-aminobutyric acid type A (GABAA ) receptors (half-maximal inhibitory concentration = 2.06 µmol·L-1 ), but it did not affect [3 H] flunitrazepam or [3 H] muscimol binding. SIGNIFICANCE: It is anticipated that LMR-101 might play an essential role in the clinical management of epilepsy and SE. LMR-101 also might bind to a novel target site on the GABAA receptor that is different from existing antiepileptic drugs. Further study of the mechanisms of action of LMR-101 would be of considerable value in the search for new active drug sites on GABAA receptors.

CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality globally. Discovering effective biomarkers for early diagnosis and prognosis is important to reduce the mortality rate and ensure efficient therapy for lung cancer patients. C-type lectin domain family 3 member B (CLEC3B) has been reported in various cancers, but its correlation with lung cancer remains elusive. METHODS: The GEO, TCGA and Oncomine databases were analyzed to examine the expression of CLEC3B in lung cancer. The CLEC3B mRNA levels in 15 patient tissue samples were detected by real-time PCR and the CLEC3B protein levels in 34 patient tissue samples were detected by immunohistochemistry. A Chi-square test was performed to analyze the correlation of CLEC3B expression and clinicopathological factors. The diagnostic value of CLEC3B was revealed by receiver operating characteristic (ROC) curves. Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots were used to evaluate the prognostic value of CLEC3B in lung cancer. The TIMER database was used to evaluate the correlation of CLEC3B and immune infiltration. Gene set enrichment analysis revealed tumor-associated biological processes related to CLEC3B. RESULTS: CLEC3B is significantly downregulated in lung cancer patients compared with nontumor controls according to database analysis and patient tissue sample detection (p < 0.001). Specifically, CLEC3B is significantly downregulated in stage IA lung cancer patients (p < 0.001) and has a high diagnostic accuracy (area under the receiver operating characteristic curve > 0.9). Moreover, low expression of CLEC3B is related to poor progression-free survival (HR = 0.60, 95% CI 0.49-0.74, p = 8.3e-07) and overall survival (HR = 0.66, 95% CI 0.58-0.75, p = 2.1e-10), indicating it as a risk factor for lung cancer. Multivariate analysis value showed that low expression of CLEC3B may be an independent risk factor for disease-free survival in lung cancer patients (HR = 0.655, 95% CI 0.430-0.996, Cox p = 0.048). In addition, we also investigated the potential role of CLEC3B in tumor-immune interactions and found that CLEC3B might be associated with the immune infiltration and immune activation of lung cancer, especially in squamous cell carcinoma. CONCLUSIONS: Our findings indicate that CLEC3B expression is downregulated in lung cancer and reveal the diagnostic and prognostic potential of CLEC3B in lung cancer and its potential as an immune-related therapeutic target in lung cancer.

A Retrospective Study on the Effects of Convalescent Plasma Therapy in 24 Patients Diagnosed with COVID-19 Pneumonia in February and March 2020 at 2 Centers in Wuhan, China.

BACKGROUND This retrospective study aimed to describe the effects of convalescent plasma therapy in 24 patients diagnosed with coronavirus disease 2019 (COVID-19) pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during February and March 2020 in Wuhan, China. MATERIAL AND METHODS The confirmation of SARS-CoV-2 infection was made by the reverse transcription-polymerase chain reaction test. We retrospectively analyzed the clinical data and laboratory test reports of patients with severe COVID-19 pneumonia who received a convalescent plasma transfusion. RESULTS A total of 24 patients with COVID-19 pneumonia who were transfused with ABO-compatible convalescent plasma were enrolled in the study. Convalescent plasma transfusion showed an effective clinical outcome in 14 of 24 patients (an effective rate of 58.3%). No patients had an adverse reaction to the transfusion. Compared with before convalescent plasma transfusion, the lymphocyte count after convalescent plasma transfusion increased to a normal level (median: 0.80×109/L vs. 1.12×109/L, P=0.004). Other laboratory indicators such as white blood cells, high-sensitivity C-reactive protein, procalcitonin, alanine aminotransferase, and aspartate transaminase showed a decreasing trend after transfusion. CONCLUSIONS This retrospective observational clinical study showed that convalescent plasma therapy could have beneficial effects on patient outcomes. Recently, regulatory authorization has been given for the use of convalescent plasma therapy, and clinical guidelines have been developed for the collection and use of convalescent plasma and hyperimmune immunoglobulin in patients with COVID-19.

Vaccine-Elicited Tier 2 HIV-1 Neutralizing Antibodies Bind to Quaternary Epitopes Involving Glycan-Deficient Patches Proximal to the CD4 Binding Site.

Eliciting broad tier 2 neutralizing antibodies (nAbs) is a major goal of HIV-1 vaccine research. Here we investigated the ability of native, membrane-expressed JR-FL Env trimers to elicit nAbs. Unusually potent nAb titers developed in 2 of 8 rabbits immunized with virus-like particles (VLPs) expressing trimers (trimer VLP sera) and in 1 of 20 rabbits immunized with DNA expressing native Env trimer, followed by a protein boost (DNA trimer sera). All 3 sera neutralized via quaternary epitopes and exploited natural gaps in the glycan defenses of the second conserved region of JR-FL gp120. Specifically, trimer VLP sera took advantage of the unusual absence of a glycan at residue 197 (present in 98.7% of Envs). Intriguingly, removing the N197 glycan (with no loss of tier 2 phenotype) rendered 50% or 16.7% (n = 18) of clade B tier 2 isolates sensitive to the two trimer VLP sera, showing broad neutralization via the surface masked by the N197 glycan. Neutralizing sera targeted epitopes that overlap with the CD4 binding site, consistent with the role of the N197 glycan in a putative "glycan fence" that limits access to this region. A bioinformatics analysis suggested shared features of one of the trimer VLP sera and monoclonal antibody PG9, consistent with its trimer-dependency. The neutralizing DNA trimer serum took advantage of the absence of a glycan at residue 230, also proximal to the CD4 binding site and suggesting an epitope similar to that of monoclonal antibody 8ANC195, albeit lacking tier 2 breadth. Taken together, our data show for the first time that strain-specific holes in the glycan fence can allow the development of tier 2 neutralizing antibodies to native spikes. Moreover, cross-neutralization can occur in the absence of protecting glycan. Overall, our observations provide new insights that may inform the future development of a neutralizing antibody vaccine.

Structure Determinants of Lagunamide A for Anticancer Activity and Its Molecular Mechanism of Mitochondrial Apoptosis.

Marine natural products are served as attractive source of anticancer therapeutics, with the great success of "first-in-class" drugs, such as Yondelis, Halaven, and Brentuximab vendotin. Lagunamides A-C from marine cyanobacterium, Lyngbya majuscula, exhibit exquisite growth inhibitory activities against cancer cells. In this study, we have systematically investigated the structure-activity relationships (SARs) of a concise collection of lagunamide A and its analogues constructed by total chemical synthesis against a broad panel of cancer cells derived from various tissues or organs, including A549, HeLa, U2OS, HepG2, BEL-7404, BGC-823, HCT116, MCF-7, HL-60, and A375. The R configuration of lagunamide A at C-39 position was found to be the structure determinant for anticancer activity. Further molecular mechanism study in A549 cells revealed that lagunamide A induced caspase-mediated mitochondrial apoptosis. Accompanied with the dissipation of mitochondrial membrane potential (Δφm) and overproduction of reactive oxygen species (ROS), lagunamide A led to mitochondrial dysfunction and finally caused cell death. Moreover, both anti- and pro-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins participated in lagunamide A-induced mitochondrial apoptosis, especially myeloid cell leukemia-1 (Mcl-1). Overexpression of Mcl-1 partly rescued A549 cells from lagunamide A-induced apoptosis. This study suggests that lagunamide A may exert anticancer property through mitochondrial apoptosis. Together, our findings would provide insightful information for the design of new anticancer drugs derived from lagunamides.

Optimal codons in Tremella fuciformis end in C/G, a strong difference with known Tremella species.

Tremella fuciformis is a popular edible fungus with fruiting bodies that can be produced in large quantities at low costs, while it is easy to transform and cultivate as yeast. This makes it an attractive potential bioreactor. Enhanced heterologous gene expression through codon optimization would be useful, but until now codon usage preferences in T. fuciformis remain unknown. To precisely determine the preferred codon usage of T. fuciformis we sequenced the genome of strain Tr26 resulting in a 24.2 Mb draft genome with 10,040 predicted genes. 3288 of the derived predicted proteins matched the UniProtKB/Swiss-Prot databases with 40% or more similarity. Corresponding gene models of this subset were subsequently optimized through repetitive comparison of alternative start codons and selection of best length matching gene models. For experimental confirmation of gene models, 96 random clones from an existing T. fuciformis cDNA library were sequenced, generating 80 complete CDSs. Calculated optimal codons for the 3288 predicted and the 80 cloned CDSs were highly similar, indicating sufficient accuracy of predicted gene models for codon usage analysis. T. fuciformis showed a strong preference for C and then G at the third base pair position of used codons, while average GC content of predicted genes was slightly higher than the total genome sequence average. Most optimal codons ended in C or G except for one, and an increased frequency of C ending codons was observed in genes with higher expression levels. Surprisingly, the preferred codon usage in T. fuciformis strongly differed from T. mesenterica and C. neoformans. Instead, optimal codon usage was similar to more distant related species such as Ustilago maydis and Neurospora crassa. Despite much higher overall sequence homology between T. fuciformis and T. mesenterica, only 7 out of 21 optimal codons were equal, whereas T. fuciformis shared up to 20 out of 21 optimal codons with other species. Clearly, codon usage in Tremella can differ largely and should be estimated for individual species. The precise identification of optimal and high expression related codons is therefore an important step in the development of T. fuciformis as a bioreactor system.

A novel single-tailed fusiform Sulfolobus virus STSV2 infecting model Sulfolobus species.

A newly isolated single-tailed fusiform virus, Sulfolobus tengchongensis spindle-shaped virus STSV2, from Hamazui, China, is characterised. It contains a double-stranded modified DNA genome of 76,107 bp and is enveloped by a lipid membrane structure. Virions exhibit a single coat protein that forms oligomers when isolated. STSV2 is related to the single-tailed fusiform virus STSV1 and, more distantly, to the two-tailed bicaudavirus ATV. The virus can be stably cultured over long periods in laboratory strains of Sulfolobus and no evidence was found for cell lysis under different stress conditions. Therefore, it constitutes an excellent model virus for archaeal virus-host studies.

Atomic model of a cypovirus built from cryo-EM structure provides insight into the mechanism of mRNA capping.

The cytoplasmic polyhedrosis virus (CPV) from the family Reoviridae belongs to a subgroup of "turreted" reoviruses, in which the mRNA capping activity occurs in a pentameric turret. We report a full atomic model of CPV built from a 3D density map obtained using cryoelectron microscopy. The image data for the 3D reconstruction were acquired exclusively from a CCD camera. Our structure shows that the enzymatic domains of the pentameric turret of CPV are topologically conserved and that there are five unique channels connecting the guanylyltransferase and methyltransferase regions. This structural organization reveals how the channels guide nascent mRNA sequentially to guanylyltransferase, 7-N-methyltransferase, and 2'-O-methyltransferase in the turret, undergoing the highly coordinated mRNA capping activity. Furthermore, by fitting the deduced amino acid sequence of the protein VP5 to 120 large protrusion proteins on the CPV capsid shell, we confirmed that this protrusion protein is encoded by CPV RNA segment 7.

STnc1280, a trans-coding sRNA is involved in virulence modulation via targeting gldA mRNA in Salmonella Typhimurium.

Introduction. Salmonella Typhimurium (STM) is a food-borne Gram-negative bacterium, which can infect humans and a wide range of livestock and poultry, causing a variety of diseases such as septicaemia, enteritis and abortion.Hypothesis/Gap Statement. We will decipher the impacts of sRNA STnc1280 on STM virulence and provide a theoretical basis to reveal the regulatory role and molecular mechanism of STnc1280.Aim. The main objective of this study was to clarify whether sRNA STnc1280 exerts regulatory roles on STM pathogenicity.Methodology. The STnc1280 gene was amplified and its molecular characteristics were analysed in this study. Then, STnc1280 gene deletion strain (STM-ΔSTnc1280) and the complementary strain (ΔSTnc1280/STnc1280) were constructed by λ-Red homologous recombination method, respectively, to analyse of adhesion and invasive ability and pathogenicity of different strains. Subsequently, the potential target gene regulated by STnc1280 was predicted using target RNA2 software, followed by the verification of the interaction between STnc1280 and target mRNA using the dual plasmid reporter system (DPRS). Furthermore, the mRNA and protein level of target gene was determined using qRT-PCR and Western blot, respectively.Results. The results revealed that the cell adhesion and invasive ability and pathogenicity of STM-ΔSTnc1280 were significantly reduced compared to STM-SL1344 strain, indicating that the deficiency of STnc1280 gene significantly influenced STM pathogenicity. The DPRS results showed that STnc1280 can interact with the mRNA of target gene gldA, thus suppressing the expression of lacZ gene. Furthermore, the level of gldA mRNA was not influenced in STM-ΔSTnc1280, but the expression of GldA protein decreased significantly.Conclusion. Combining the bioinformatic analysis, these findings suggested that STnc1280 may bind to the SD sequence of gldA mRNA, hindering the binding of ribosomes to gldA mRNA, thereby inhibiting the expression of GldA protein to modulate the virulence of STM.

Impaired autophagy in neurons after disinhibition of mammalian target of rapamycin and its contribution to epileptogenesis.

Certain mutations within the mammalian target of rapamycin (mTOR) pathway, most notably those affecting the tuberous sclerosis complex (TSC), lead to aberrant activation of mTOR and result in a high incidence of epilepsy in humans and animal models. Although hyperactivation of mTOR has been strongly linked to the development of epilepsy and, conversely, inhibition of mTOR by rapamycin treatment is protective against seizures in several models, the downstream epileptic mechanisms have remained elusive. Autophagy, a catabolic process that plays a vital role in cellular homeostasis by mediating the turnover of cytoplasmic constituents, is negatively regulated by mTOR. Here we demonstrate that autophagy is suppressed in brain tissues of forebrain-specific conditional TSC1 and phosphatase and tensin homlog knock-out mice, both of which display aberrant mTOR activation and seizures. In addition, we also discovered that autophagy is suppressed in the brains of human TSC patients. Moreover, conditional deletion of Atg7, an essential regulator of autophagy, in mouse forebrain neurons is sufficient to promote development of spontaneous seizures. Thus, our study suggests that impaired autophagy contributes to epileptogenesis, which may be of interest as a potential therapeutic target for epilepsy treatment and/or prevention.

HIV-1 virus-like particles produced by stably transfected Drosophila S2 cells: a desirable vaccine component.

The development of a successful vaccine against human immunodeficiency virus type 1 (HIV-1) likely requires immunogens that elicit both broadly neutralizing antibodies against envelope spikes and T cell responses that recognize multiple viral proteins. HIV-1 virus-like particles (VLP), because they display authentic envelope spikes on the particle surface, may be developed into such immunogens. However, in one way or the other current systems for HIV-1 VLP production have many limitations. To overcome these, in the present study we developed a novel strategy to produce HIV-1 VLP using stably transfected Drosophila S2 cells. We cotransfected S2 cells with plasmids encoding HIV-1 envelope, Gag, and Rev proteins and a selection marker. After stably transfected S2 clones were established, HIV-1 VLP and their immunogenicity in mice were carefully evaluated. Here, we report that HIV-1 envelope proteins are properly cleaved, glycosylated, and incorporated into VLP with Gag. The amount of VLP released into culture supernatants is comparable to those produced by insect cells infected with recombinant baculoviruses. Moreover, cryo-electron microscopy tomography revealed average 17 spikes per purified VLP, and antigenic epitopes on the spikes were recognized by the broadly neutralizing antibodies 2G12, b12, VRC01, and 4E10 but not by PG16. Finally, mice primed with DNA and boosted with VLP in the presence of CpG exhibited anti-envelope antibody responses, including ELISA-binding, neutralizing, antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated viral inhibition, as well as envelope and Gag-specific CD8 T cell responses. Thus, we conclude that HIV-1 VLP produced by the S2 expression system has many desirable features to be developed into a vaccine component against HIV-1.

Association between osteoprotegerin genetic variants and osteoporosis in Chinese postmenopausal women.

The objective of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) of osteoprotegerin gene (OPG) with bone mineral density (BMD) and osteoporosis. A total of 338 Chinese postmenopausal women with primary osteoporosis and 367 healthy controls were enrolled. The lumbar spine (L2₋4), total hip and femoral neck hip of BMD were assessed by dual-energy X-ray absorptiometry (DEXA). OPG genetic variants were genotyped through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), created restriction site-PCR (CRS-PCR) and DNA sequencing methods. In this study, the g.18861A>G and g.25548C>T SNPs were detected and our data suggested that the significant differences of spine BMD, femoral neck hip BMD and total hip BMD were found among different g.18861A>G genotype, subjects with the AA genotype were significantly higher than those of AG and GG genotypes (p < 0.05). The g.25548C>T variant was not significantly associated with spine BMD, femoral neck hip BMD and total hip BMD (p > 0.05), while almost reached at the significant level in total hip BMD (p = 0.061). These findings suggeste that OPG gene variants are related to BMD and osteoporosis in Chinese postmenopausal women.

Therapeutic Drug Monitoring of Imatinib and N-Desmethyl Imatinib in Chronic Myeloid Leukemia Patients Using LC-MS/MS in a Cohort Study.

Imatinib is an oral tyrosine kinase inhibitor (TKI) and first-line therapy for patients with chronic myeloid leukemia (CML). There is a positive correlation between serum imatinib concentrations and treatment response. However, the specific relationship between the blood concentration of imatinib and its influencing factors remains unclear. This study collected basic information from 102 patients using imatinib as first-line treatment for CML. Further, we analyzed the individual differences in imatinib concentration and explored its influencing factors. Through intra-day and inter-day precision studies, we found that the precision for the imatinib assay methodology was within ±13% and that the recovery rate was above 85%. There is notable individual variation in the blood concentration of imatinib; the recommended treatment concentration is 860-1500 ng/mL, with only 41.40% of patients achieving this concentration. Also, there was a negative correlation between age and imatinib trough concentration (Ctrough ), as is observed between age and N-desmethyl imatinib. Moreover, compared with the adolescent group, the serum imatinib Ctrough for groups aged 17-47 and 48-68 years was significantly reduced. Further analysis shows that imatinib Ctrough values reaching therapeutic concentrations (59%) increased dramatically for patients with CML aged 17-47 years. Moreover, groups dosed with 400 mg/day resulted in therapeutic imatinib concentrations for 68% of patients with CML, which was the best performance. The established method was validated, with acceptable accuracy, precision, linearity, and stability, as required, and then successfully applied to the therapeutic drug monitoring of imatinib. Age, dose, and metabolites can influence the imatinib concentration and its therapeutic effect in patients with CML.

Influencing factors of falls among older adults in Chinese retirement institutions: A systematic review and meta-analysis.

BACKGROUND: The incidence of falling has always been high among the elderly, and it was easy to cause injuries to the elderly and seriously affect their quality of life. There were many studies have been conducted on risk factors affecting the fall of the elderly, but the results widely, retirement institutions as a gathering place for the elderly, there was currently no comprehensive analysis of the factors related to elderly falls in pension institutions. This study aimed to explore the influencing factors of falls among older adults in Chinese nursing homes. METHODS: Chinese and English databases were searched for literature published from database inception to 5 April 2023 on the influencing factors of falls among older adults in Chinese nursing homes. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using RevMan 5.4 software. RESULTS: Eleven studies involving 3503 participants were included in the meta-analysis. The pooled estimate of falls among older adults in Chinese nursing homes was 32% [95% confidence interval (95%CI) (24.0%, 39.0%)]. The main influencing factors for falls among older adults in Chinese nursing homes were age (Odds Ratio (OR) = 1.53), gender (OR = 5.50), visual impairment (OR = 2.30), sedative-hypnotics (OR = 2.36), fear of falling (OR = 2.95), hypertension (OR = 3.72), static balance (OR = 2.02), three or more chronic diseases (OR = 5.63), cognitive status (OR = 2.64), walking aid use (OR = 1.98), fall-related chronic diseases (OR = 2.48), self-awareness of abilities (OR = 2.43), and frequent reminders for fall prevention (OR = 0.10). CONCLUSION: Falls among older adults in Chinese nursing homes were common, and there were many influencing factors. Timely screening and intervention should be implemented to reduce the adverse consequences of falls on older adults. TRIAL REGISTRATION: Registration number: CRD42023421099.

A Novel Clinical Tool to Detect Severe Obstructive Sleep Apnea.

Purpose: Obstructive sleep apnea (OSA) is a disease with high morbidity and is associated with adverse health outcomes. Screening potential severe OSA patients will improve the quality of patient management and prognosis, while the accuracy and feasibility of existing screening tools are not so satisfactory. The purpose of this study is to develop and validate a well-feasible clinical predictive model for screening potential severe OSA patients. Patients and Methods: We performed a retrospective cohort study including 1920 adults with overnight polysomnography among which 979 cases were diagnosed with severe OSA. Based on demography, symptoms, and hematological data, a multivariate logistic regression model was constructed and cross-validated and then a nomogram was developed to identify severe OSA. Moreover, we compared the performance of our model with the most commonly used screening tool, Stop-Bang Questionnaire (SBQ), among patients who completed the questionnaires. Results: Severe OSA was associated with male, BMI≥ 28 kg/m2, high blood pressure, choke, sleepiness, apnea, white blood cell count ≥9.5×109/L, hemoglobin ≥175g/L, triglycerides ≥1.7 mmol/L. The AUC of the final model was 0.76 (95% CI: 0.74-0.78), with sensitivity and specificity under the optimal threshold selected by maximizing Youden Index of 73% and 66%. Among patients having the information of SBQ, the AUC of our model was statistically significantly greater than that of SBQ (0.78 vs 0.66, P = 0.002). Conclusion: Based on common clinical examination of admission, we develop a novel model and a nomogram for identifying severe OSA from inpatient with suspected OSA, which provides physicians with a visual and easy-to-use tool for screening severe OSA.

The Small Non-coding RNA rli106 Contributes to the Environmental Adaptation and Pathogenicity of Listeria Monocytogenes.

Introduction: Listeria monocytogenes (LM) is an important food-borne pathogen, and the risk of its ingestion is a serious public health issue. The better its environmental adaptation mechanisms and pathogenicity are understood, the better the risk it poses can be countered. The regulatory role of the small non-coding RNA (sRNA) rli106 in the environmental adaptation and pathogenicity of LM is still unclear and this study investigated that role through its biological function. Material and Methods: An LM-Δrli106 gene deletion strain and an LM-Δrli106/rli106 gene complementation strain were constructed using the homologous recombination technique. Then, the adaptation of these strains to temperature, alkalinity, acidity, salinity, ethanol and oxidative stressors, their biofilm-forming ability and their pathogenicity in mice were investigated to show the regulatory roles of sRNA rli106 in LM. The target gene of rli106 was also predicted, and the interaction between it and rli106 was verified by a two-plasmid co-expressing system based on E.coli and Western blot analysis. Results: The adaptation of LM-Δrli106 to environmental stressors of pH 9, 5% NaCl and 8% NaCl, 3.8% ethanol and 5 mM H2O2 was significantly reduced when compared to the parental (LM EGD-e) and complementation strains. Also, the biofilm formation, cell adhesion, invasion, intracellular proliferation and pathogenicity of LM-Δrli106 in mice were significantly reduced. The results of two-plasmid co-expression and Western blot showed that rli106 can interact with the mRNA of the predicted DegU target gene. Conclusion: The sRNA rli106 may positively regulate the expression of the DegU gene in LM. This study sheds light on its regulatory roles in environmental adaptation and pathogenicity, providing new insights into the molecular mechanism of sRNA mediation in LM .

Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir.

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CLpro) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CLpro with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CLpro inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.

Chinese expert consensus on the management of patients with hematologic malignancies infected with SARS-CoV-2.

In December 2022, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became dominant in China due to its high infectivity and lower mortality rate. The risk of critical illness and mortality among patients with hematologic malignancies who contracted SARS-CoV-2 was particularly high. The aim of this study was to draft a consensus to facilitate effective treatments for these patients based on the type and severity of the disease. Following the outbreak of the novel coronavirus in China, a steering committee consisting of experienced hematologists was formed by the Specialized Committee of Oncology and Microecology of the Chinese Anti-Cancer Association. The expert group drafted a consensus on the management and intervention measures for different types of hematologic malignancies based on the clinical characteristics of the Omicron variant of the SARS-CoV-2 infection, along with relevant guidelines and literature. The expert group drafted independent recommendations on several important aspects based on the epidemiology of the Omicron variant in China and the unique vulnerability of patients with hematologic malignancies. These included prophylactic vaccinations for those with hematologic malignancies, the use of plasma from blood donors who recovered from the novel coronavirus infection, the establishment of negative pressure wards, the use of steady-state mobilization of peripheral blood hematopoietic stem cells, the provision of psychological support for patients and medical staff, and a focus on maintaining a healthy intestinal microecology.

Community Bargaining with Urban Growth: The Case of J Village in Guangzhou.

The past several decades have seen China undergo a rapid urbanization process. During periods of economic prosperity, cities expropriate outlying lands, often villages, for economic development with the support of various local and national government programs designed to encourage urban expansion. However, the autonomy of the villages has not been paid enough attention. How does incorporation into an urban development zone affect the community identity and autonomy of a village? How does the village bargain with external urban institutions? This research is based on ethnographic research and interviews conducted in 2013, 2014, 2017, and 2021. The results reveal that villagers are generally willing to accept the loss of their collective land in exchange for a larger share of the promised prosperity of industrialization, but over time they tend to find that the immediate benefits of expropriation are outweighed by long-term costs. They lose the support of the state and are exposed to new vulnerabilities, such as pollution and economic instability. Indeed, they agree to undertake unknown future risks in exchange for short-term gains. They cannot gain the right to the city, but gradually lose control of the village.

Association of admission blood glucose level and clinical outcomes in elderly community-acquired pneumonia patients with or without diabetes.

INTRODUCTION: Community-acquired pneumonia (CAP) is the major cause of infection-related mortality worldwide. Patients with CAP frequently present with admission hyperglycemia. OBJECTIVES: The aim of this study was to evaluate the association between admission blood glucose (ABG) level and clinical outcomes in elderly CAP patients (≥80 years of age) with or without diabetes. METHODS: In this single center retrospective study, 290 elderly patients diagnosed with CAP were included. Demographic and clinical information were collected and compared. The associations between admission blood glucose level and the 30-day mortality as well as intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) in elderly CAP patients with or without diabetes were assessed. RESULTS: Of the 290 eligible patients with CAP, 159 (66.5%) patients were male, and 64 (22.1%) had a known history of diabetes at hospital admission. After adjusting for age and sex, the logistic regression analysis had identified several risk factors that might be associated with clinical outcomes in elderly patients with CAP. Multivariable logistic regression analysis revealed that admission glucose level > 11.1 mmol/L was significant associated with ICU admission, IMV, and 30-day mortality both in non-diabetic and diabetic patients. Furthermore, Kaplan-Meier analysis indicated that patients with higher admission glucose level were correlated statistically significantly with 30-day mortality in patients with CAP (P < 0.001). CONCLUSION: Admission blood glucose is correlated with 30-day hospital mortality, ICU admission, and IMV of CAP in elderly patients with and without diabetes. Specially, admission glucose > 11.1 mmol/L was a significant risk factor for 30-day hospital mortality.