Listeria monocytogenes: possible mechanism of infection of goat uterus and its effects on uterine autophagy and cell apoptosis.

Listeriosis is highly prevalent in the animal farming industry, with Listeria monocytogenes as the causative pathogen. To identify potential therapeutic targets for LM infection, we investigated the mechanisms of LM infection in goat uteri. We inoculated a group of goats with LM via jugular vein injection, isolated and raised them, and subsequently collected sterile samples of their uterine tissue after they exhibited clinical symptoms of LM infection. We used Giemsa staining, immunohistochemical staining, real-time qPCR, and Western blotting as experimental methods.First, we investigated the mechanism of Listeria monocytogenes (LM) infection in the goat uterus by examining the expression levels of listeriolysin O, E-cadherin, and tyrosine kinase c-Met in the uterus.Furthermore, we investigated the impact of LM infection on uterine autophagy and cell apoptosis. The results indicate that the injection of LM into the goats' jugular veins leads to LM infection in the goats' uteri. During LM survival inside the goat uterine cells, there is a significant increase in the expression levels of LLO, E-cadherin, and c-Met in the host uterine tissue. This suggests that LM may potentially infect goat uteri through the InlA/E-cadherin and InlB/c-Met pathways. Furthermore, LM infection increases the levels of apoptosis and autophagy in goat uteri. Apoptosis genes Bcl-2 and Bax, as well as autophagy-related genes LC3B, PINK1, and Parkin, exhibit varying degrees of changes in localization and expression in goat uteri, mediating the occurrence of apoptotic and autophagic responses.

Future worldwide coronavirus disease 2019 epidemic predictions by Gaidai multivariate risk evaluation method.

Accurate estimation of pandemic likelihood in every US state of interest and at any time. Coronavirus disease 2019 (COVID-19) is an infectious illness with a high potential for global dissemination and low rates of fatality and morbidity, placing some strains on national public health systems. This research intends to benchmark a novel technique, that enables hazard assessment, based on available clinical data, and dynamically observed patient numbers while taking into account pertinent territorial and temporal mapping. Multicentre, population-based, and biostatistical strategies have been utilized to process raw/unfiltered medical survey data. The expansion of extreme value statistics from the univariate to the bivariate situation meets with numerous challenges. First, the univariate extreme value types theorem cannot be directly extended to the bivariate (2D) case,-not to mention challenges with system dimensionality higher than 2D. Assessing outbreak risks of future outbreaks in any nation/region of interest. Existing bio-statistical approaches do not always have the benefits of effectively handling large regional dimensionality and cross-correlation between various regional observations. These methods deal with temporal observations of multi-regional phenomena. Apply contemporary, novel statistical/reliability techniques directly to raw/unfiltered clinical data. The current study outlines a novel bio-system hazard assessment technique that is particularly suited for multi-regional environmental, bio, and public health systems, observed over a representative period. With the use of the Gaidai multivariate hazard assessment approach, epidemic outbreak spatiotemporal risks may be properly assessed. Based on raw/unfiltered clinical survey data, the Gaidai multivariate hazard assessment approach may be applied to a variety of public health applications. The study's primary finding was an assessment of the risks of epidemic outbreaks, along with a matching confidence range. Future global COVID-19/severe acute respiratory syndrome coronavirus 2 (SARS-COV2) epidemic risks have been examined in the current study; however, COVID-19/SARS-COV2 infection transmission mechanisms have not been discussed.

Pharmacokinetics and safety profiles of beinaglutide injection, a recombinant human GLP-1, in adults with overweight/obesity: results from a phase I clinical trial.

Background: Beinaglutide, whose active ingredient is rhGLP-1, has been widely used as a pharmacological therapy for T2DM. We explored the safety and pharmacokinetics of beinaglutide in Chinese overweight/obese volunteers to lay a foundation for clinical applications of beinaglutide as an anti-obesity drug. Methods: An open-label, single center, multiple ascending dose phase I clinical trial was conducted in 16 overweight/obese Chinese volunteers. The plasma concentrations of beinaglutide were determined by a validated ELISA method and the pharmacokinetic parameters were estimated via non-compartmental analysis methods. Adverse events were also recorded. Results: Beinaglutide sequentially multiple dosing (three times daily) at different doses were generally well tolerated, without serious AEs leading to discontinuation of the trial. After multiple subcutaneous injections of different doses (0.1, 0.14 and 0.2 mg), the average blood concentration of beinaglutide with or without baseline correction showed a similar trend among different dose groups on different study days. After reaching the peak concentration around 15 min, it began to decrease, and the median of Tmax and Tmax,adj was 10-15 min. The exposure in vivo increased in proportion to the dosage increment, demonstrating linear pharmacokinetic characteristics. There were no statistically significant differences in the main PK parameters and no accumulation of beinaglutide after multiple dosing. After multiple subcutaneous injections, a gender difference was observed, while no differences in BMI were found under the grouping conditions. Conclusion: The safety profile and pharmacokinetic properties support further development and clinical applications of beinaglutide as an anti-obesity drug. Systematic Review Registration: [https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000BPEI&selectaction=Edit&uid=U00050YQ&ts=2&cx=wy0ioj].

Growth, fusion and degradation of lipid droplets: advances in lipid droplet regulatory protein.

Context: An adequate supply of energy is essential for the proper functioning of all life activities in living organisms. As organelles that store neutral lipids, lipid droplets (LDs) are involved in the synthesis and metabolism of lipids in cells and are also an important source of energy supply.Methods and mechanisms: A comprehensive summary of the literature was first carried out to screen for relevant proteins affecting the morphological size of LDs.The size of milk fat globules (MFGs) is directly influenced by the morphological size of LDs, which also controls the energy storage capacity of LDs. In this review, we detail the progress of research into the role of some protein in regulating the morphological size of LDs.Conclusion: It has been discovered that the number of protein are involved in the control of LD growth and degradation, such as Rab18-mediated local synthesis of triacylglycerol (TAG), cell death-inducing DFF45-like effector family proteins (CIDEs)-mediated atypical fusion between LDs, Stomatin protein-mediated LD fusion and autophagy-related proteins (ATGs)-mediated autophagic degradation of LDs. However, more studies are needed in the future to enrich the network of mechanisms that regulate the morphological size of LDs.

A predictive model to explore risk factors for severe COVID-19.

With the rapid spread of the novel coronavirus (COVID-19), a sustained global pandemic has emerged. Globally, the cumulative death toll is in the millions. The rising number of COVID-19 infections and deaths has severely impacted the lives of people worldwide, healthcare systems, and economic development. We conducted a retrospective analysis of the characteristics of COVID-19 patients. This analysis includes clinical features upon initial hospital admission, relevant laboratory test results, and imaging findings. We aimed to identify risk factors for severe illness and to construct a predictive model for assessing the risk of severe COVID-19. We collected and analyzed electronic medical records of confirmed COVID-19 patients admitted to the Affiliated Hospital of Jiangsu University (Zhenjiang, China) between December 18, 2022, and February 28, 2023. According to the WHO diagnostic criteria for the novel coronavirus, we divided the patients into two groups: severe and non-severe, and compared their clinical, laboratory, and imaging data. Logistic regression analysis, the least absolute shrinkage and selection operator (LASSO) regression, and receiver operating characteristic (ROC) curve analysis were used to identify the relevant risk factors for severe COVID-19 patients. Patients were divided into a training cohort and a validation cohort. A nomogram model was constructed using the "rms" package in R software. Among the 346 patients, the severe group exhibited significantly higher respiratory rates, breathlessness, altered consciousness, neutrophil-to-lymphocyte ratio (NLR), and lactate dehydrogenase (LDH) levels compared to the non-severe group. Imaging findings indicated that the severe group had a higher proportion of bilateral pulmonary inflammation and ground-glass opacities compared to the non-severe group. NLR and LDH were identified as independent risk factors for severe patients. The diagnostic performance was maximized when NLR, respiratory rate (RR), and LDH were combined. Based on the statistical analysis results, we developed a COVID-19 severity risk prediction model. The total score is calculated by adding up the scores for each of the twelve independent variables. By mapping the total score to the lowest scale, we can estimate the risk of COVID-19 severity. In addition, the calibration plots and DCA analysis showed that the nomogram had better discrimination power for predicting the severity of COVID-19. Our results showed that the development and validation of the predictive nomogram had good predictive value for severe COVID-19.

The effects of BMP2 and the mechanisms involved in the invasion and angiogenesis of IDH1 mutant glioma cells.

PURPOSE: This study investigated the effect of an isocitrate dehydrogenase 1 (IDH1) mutation (mutIDH1) on the invasion and angiogenesis of human glioma cells. METHODS: Doxycycline was used to induce the expression of mutIDH1 in glioma cells. Transwell and wound healing assays were conducted to assess glioma cell migration and invasion. Western blotting and cell immunofluorescence were used to measure the expression levels of various proteins. The influence of bone morphogenetic protein 2 (BMP2) on invasion, angiogenesis-related factors, BMP2-related receptor expression, and changes in Smad signaling pathway-related proteins were evaluated after treatment with BMP2. Differential gene expression and reference transcription analysis were performed. RESULTS: Successful infection with recombinant lentivirus expressing mutIDH1 was demonstrated. The IDH1 mutation promoted glioma cell migration and invasion while positively regulating the expression of vascularization-related factors and BMP2-related receptors. BMP2 exhibited a positive regulatory effect on the migration, invasion, and angiogenesis of mutIDH1-glioma cells, possibly mediated by BMP2-induced alterations in Smad signaling pathway-related factors.After BMP2 treatment, the differential genes of MutIDH1-glioma cells are closely related to the regulation of cell migration and cell adhesion, especially the regulation of Smad-related proteins. KEGG analysis confirmed that it was related to BMP signaling pathway and TGF-ß signaling pathway and cell adhesion. Enrichment analysis of gene ontology and genome encyclopedia further confirmed the correlation of these pathways. CONCLUSION: Mutation of isocitrate dehydrogenase 1 promotes the migration, invasion, and angiogenesis of glioma cells, through its effects on the BMP2-driven Smad signaling pathway. In addition, BMP2 altered the transcriptional patterns of mutIDH1 glioma cells, enriching different gene loci in pathways associated with invasion, migration, and angiogenesis.

Camrelizumab, apatinib and hepatic artery infusion chemotherapy combined with microwave ablation for advanced hepatocellular carcinoma.

BACKGROUND: Hepatic arterial infusion chemotherapy and camrelizumab plus apatinib (TRIPLET protocol) is promising for advanced hepatocellular carcinoma (Ad-HCC). However, the usefulness of microwave ablation (MWA) after TRIPLET is still controversial. AIM: To compare the efficacy and safety of TRIPLET alone (T-A) vs TRIPLET-MWA (T-M) for Ad-HCC. METHODS: From January 2018 to March 2022, 217 Ad-HCC patients were retrospectively enrolled. Among them, 122 were included in the T-A group, and 95 were included in the T-M group. A propensity score matching (PSM) was applied to balance bias. Overall survival (OS) was compared using the Kaplan-Meier curve with the log-rank test. The overall objective response rate (ORR) and major complications were also assessed. RESULTS: After PSM, 82 patients were included both the T-A group and the T-M group. The ORR (85.4%) in the T-M group was significantly higher than that (65.9%) in the T-A group (P < 0.001). The cumulative 1-, 2-, and 3-year OS rates were 98.7%, 93.4%, and 82.0% in the T-M group and 85.1%, 63.1%, and 55.0% in the T-A group (hazard ratio = 0.22; 95% confidence interval: 0.10-0.49; P < 0.001). The incidence of major complications was 4.9% (6/122) in the T-A group and 5.3% (5/95) in the T-M group, which were not significantly different (P = 1.000). CONCLUSION: T-M can provide better survival outcomes and comparable safety for Ad-HCC than T-A.

How enterprise social media usage links to counterproductive work behavior: the mediating role of workplace loneliness and the moderating role of ICT hassle.

Work context transformed. Employees increasingly interact with enterprise social media, wherein employees may feel disconnected from workplace. Drawing on social affiliation theory, we develop and examine a moderated mediation model to explore the indirect effect of enterprise social media usage on counterproductive work behavior (CWB) via workplace loneliness and the moderating role of information and communication technology hassle (ICT hassle). We test hypotheses by conducting a three-wave survey of 345 knowledge workers. Results indicate that enterprise social media usage has a positive effect on workplace loneliness, and workplace loneliness mediated the indirect effect of enterprise social media usage on CWB. The moderated mediation analysis indicated that ICT hassle positively moderates the above mediation effect. We discuss the theoretical and practical implications of our findings.

[Efficiency of different large language models in China in response to consultations about PCa-related perioperative nursing and health education].

OBJECTIVE: To evaluate the efficiency of the four domestic language models, ERNIE Bot, ChatGLM2, Spark Desk and Qwen-14B-Chat, all with a massive user base and significant social attention, in response to consultations about PCa-related perioperative nursing and health education. METHODS: We designed a questionnaire that includes 15 questions commonly concerned by patients undergoing radical prostatectomy and 2 common nursing cases, and inputted the questions into each of the four language models for simulation consultation. Three nursing experts assessed the model responses based on a pre-designed Likert 5-point scale in terms of accuracy, comprehensiveness, understandability, humanistic care, and case analysis. We evaluated and compared the performance of the four models using visualization tools and statistical analyses. RESULTS: All the models generated high-quality texts with no misleading information and exhibited satisfactory performance. Qwen-14B-Chat scored the highest in all aspects and showed relatively stable outputs in multiple tests compared with ChatGLM2. Spark Desk performed well in terms of understandability but lacked comprehensiveness and humanistic care. Both Qwen-14B-Chat and ChatGLM2 demonstrated excellent performance in case analysis. The overall performance of ERNIE Bot was slightly inferior. All things considered, Qwen-14B-Chat was superior to the other three models in consultations about PCa-related perioperative nursing and health education. CONCLUSION: In PCa-related perioperative nursing, large language models represented by Qwen-14B-Chat are expected to become powerful auxiliary tools to provide patients with more medical expertise and information support, so as to improve the patient compliance and the quality of clinical treatment and nursing.

In Situ Intracellular Autocatalytic Hairpin Assembly of the Y-Shaped DNA Nanostructure for miR-155 Sensing and Gene Silencing.

miR-155 is a class of cancer markers closely related to cancer metastasis and invasion. Combining in situ detection with gene silencing not only helps to analyze the information on the abundance and spatial location of microRNA expression in the cell but also synergizes the therapy. In this work, we prepared HD@CM vesicles with three hairpin DNAs by using MCF-7 cell membranes. The hairpin DNAs can be triggered by endogenous miR-155, which opens the autocatalytic molecular circuit (ACHA) and obtains Y-shaped DNA nanostructures. This nanostructure not only detects endogenous miR-155 with high sensitivity for in situ imaging but also enables gene regulation of intracellular survivin mRNA. The levels of miR-155 in MDA-MB-231, MCF-7, Hela, and HEK-293T cells are found to be 7703, 3978, 1696, and 1229 copies/cell, respectively, as detected by HD@CMs. The fluorescence produced by HD@CM after coincubation with different cells is found to be proportional to the intracellular miR-155 content by confocal imaging. In addition, the gene regulatory function of the Y-shaped DNA structure resulted in significant inhibition of survivin protein expression and apoptosis rates of up to 83%. We look forward to the future application of our HD@CM platform for the precise diagnosis and programmable treatment of clinical cancers.

Recent Advances in Antimony Selenide Photodetectors.

Photodetectors (PDs) rapidly capture optical signals and convert them into electrical signals, making them indispensable in a variety of applications including imaging, optical communication, remote sensing, and biological detection. Recently, antimony selenide (Sb2Se3) has achieved remarkable progress due to its earth-abundant, low toxicity, low price, suitable bandgap width, high absorption coefficient, and unique structural characteristics. Sb2Se3 has been extensively studied in solar cells, but there's a lack of timely updates in the field of PDs. A literature review based on Sb2Se3 PDs is urgently warranted. This review aims to provide a concise understanding of the latest progress in Sb2Se3 PDs, with a focus on the basic characteristics and the performance optimization for Sb2Se3 photoconductive-type and photodiode-type detectors, including nanostructure regulation, process optimization, and stability improvement of flexible devices. Furthermore, the application progresses of Sb2Se3 PDs in heart rate monitoring, and monolithic-integrated matrix images are introduced. Finally, this review presents various strategies with potential and feasibility to address challenges for the rapid development and commercial application of Sb2Se3 PDs.

Correlations of PSGL-1 VNTR polymorphism with the susceptibility to severe HFMD associated with EV-71 and the immune status after infection.

Enterovirus 71 (EV-71) has strong neurotropism, and it is the main pathogen causing severe hand, foot, and mouth disease (HFMD). In clinical observations, significant differences were observed in the severity and prognosis of HFMD among children who were also infected with EV-71. Genetic differences among individuals could be one of the important causes of differences in susceptibility to EV-71-induced HFMD. As P-selectin glycoprotein ligand-1 (PSGL-1) is an important receptor of EV-71, the correlation between single-nucleotide polymorphisms (SNPs) in PSGL-1 and the susceptibility to severe HFMD following EV-71 infection is worth studying. Given the role of PSGL-1 in immunity, the correlations between PSGL-1 SNPs and the immune status after EV-71 infection are also worth studying. Meanwhile, PSGL-1 variable number of tandem repeats (VNTR) represents a research hotspot in cardiovascular and cerebrovascular diseases, but PSGL-1 VNTR polymorphism has not been investigated in HFMD caused by EV-71 infection. In this study, specific gene fragments were amplified by polymerase chain reaction, and PSGL-1 VNTR sequences were genotyped using an automatic nucleic acid analyzer. The correlations of PSGL-1 VNTR polymorphism with the susceptibility to EV-71-associated severe HFMD and the post-infection immune status were analyzed. The PSGL-1 VNTR A allele was identified as a susceptible SNP for severe HFMD. The risk of severe HFMD was higher for AA + AB genotype carriers than for BB genotype carriers. The counts of peripheral blood lymphocyte subsets were lower in AA + AB genotype carries than in BB genotype carries. In conclusion, PSGL-1 VNTR polymorphism is associated with the susceptibility to EV-71-induced severe HFMD and the immune status after infection. PSGL-1 VNTR might play a certain role in the pathogenesis of severe cases.

Oxygen electrocatalysis-driven electrochemiluminescence by hierarchical carbon nanoflower-supported copper-modulated cobalt sulfide for cytosensing.

A facile cation modulation strategy is proposed for the synthesis of copper/cobalt bimetallic sulfides dispersed on hierarchical carbon nanoflowers, which exhibit excellent oxygen electrocatalysis capacity to drive electrochemiluminescence for cytosensing.

Achieving High-Performance Polymer-Wrapper-Free Aligned Carbon Nanotube Field-Effect Transistors Through Degradable Polymer Wrapping and Efficient Removal Techniques.

Semiconducting carbon nanotubes (s-CNTs) have emerged as a promising alternative to traditional silicon for ultrascaled field-effect transistors (FETs), owing to their exceptional properties. Aligned s-CNTs (A-CNTs) are particularly favored for practical applications due to their ability to provide higher driving current and lower contact resistance compared with individual s-CNTs or random networks. Achieving high-semiconducting-purity A-CNTs typically involves conjugated polymer wrapping for selective separation of s-CNTs, followed by self-assembly techniques. However, the presence of the polymer wrapper on A-CNTs can adversely impact electrical contact, gating efficiency, carrier transport, and device-to-device variations, necessitating its complete removal. While various methods have been explored for polymer removal, accurately characterizing the extent of removal remains a challenge. Traditional techniques such as absorption spectroscopy and X-ray photoelectron spectroscopy (XPS) may not accurately depict the remaining polymer content on A-CNTs due to their inherent detection limits. Consequently, the performance of FETs based on pure polymer-wrapper-free A-CNTs is unclear. In this study, we present an approach for preparing high-semiconducting-purity and polymer-wrapper-free A-CNTs using poly[(9,9-dioctylfluorenyl-2,7-dinitrilomethine)-(9,9-dioctylfluorenyl-2,7-dimethine)] (PFO-N-PFO), a degradable polymer, in conjunction with a modified dimension-limited self-alignment process (m-DLSA). Comprehensive transmission electron microscopy (TEM) characterizations, complemented by absorption and XPS characterizations, provide robust evidence of the successful near-complete removal of the polymer wrapper via a cleaning procedure involving acidic degradation, hot solvent rinsing, and vacuum annealing. Furthermore, top-gated FETs based on these high-semiconducting-purity and polymer-wrapper-free A-CNTs exhibit good performance metrics, including an on-current (Ion) of 2.2 mA/µm, peak transconductance (gm) of 1.1 mS/µm, low contact resistance (Rc) of 191 Ω·µm, and negligible hysteresis, representing a significant advancement in the CNT-based FET technology.

Bioinformatics and validation reveal the potential target of curcumin in the treatment of diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common nerve-damaging complication of diabetes mellitus. Effective treatments are needed to alleviate and reverse diabetes-associated damage to the peripheral nerves. Curcumin is an effective neuroprotectant that plays a protective role in DPN promoted by Schwann cells (SCs) lesions. However, the potential molecular mechanism of curcumin remains unclear. Therefore, our aim is to study the detailed molecular mechanism of curcumin-mediated SCs repair in order to improve the efficacy of curcumin in the clinical treatment of DPN. First, candidate target genes of curcumin in rat SC line RSC96 cells stimulated by high glucose were identified by RNA sequencing and bioinformatic analyses. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was carried out by Metascape, followed by 8 algorithms on Cytoscape to determine 4 hub genes, namly Hmox1, Pten, Vegfa and Myc. Next, gene set enrichment analysis (GSEA) and Pearson function showed that Hmox1 was significantly correlated with apoptosis. Subsequently, qRT-PCR, MTT assay, flow cytometry, caspase-3 activity detection and westernblot showed that curcumin treatment increased RSC96 cell viability, reduced cell apoptosis, increased Hmox1, Pten, Vegfa and Myc expression, and up-regulated Akt phosphorylation level under high glucose environment. Finally, molecular docking predicted the binding site of curcumin to Hmox1. These results suggest that curcumin can reduce the apoptosis of SCs induced by high glucose, and Hmox1 is a potential target for curcumin. Our findings provide new insights about the mechanism of action of curcumin on SC as a potential treatment in DPN.

CYLD/HDAC6 signaling regulates the interplay between epithelial-mesenchymal transition and ciliary homeostasis during pulmonary fibrosis.

The primary cilium behaves as a platform for sensing and integrating extracellular cues to control a plethora of cellular activities. However, the functional interaction of this sensory organelle with epithelial-mesenchymal transition (EMT) during pulmonary fibrosis remains unclear. Here, we reveal a critical role for cylindromatosis (CYLD) in reciprocally linking the EMT program and ciliary homeostasis during pulmonary fibrosis. A close correlation between the EMT program and primary cilia is observed in bleomycin-induced pulmonary fibrosis as well as TGF-ß-induced EMT model. Mechanistic study reveals that downregulation of CYLD underlies the crosstalk between EMT and ciliary homeostasis by inactivating histone deacetylase 6 (HDAC6) during pulmonary fibrosis. Moreover, manipulation of primary cilia is an effective means to modulate the EMT program. Collectively, these results identify a pivotal role for the CYLD/HDAC6 signaling in regulating the reciprocal interplay between the EMT program and ciliary homeostasis during pulmonary fibrosis.

Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors.

BACKGROUND: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. METHODS: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). RESULTS: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. CONCLUSION: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).

Cadherin-18 loss in prospermatogonia and spermatogonial stem cells enhances cell adhesion through a compensatory mechanism.

Extracellular membrane proteins are crucial for mediating cell attachment, recognition, and signal transduction in the testicular microenvironment, particularly germline stem cells. Cadherin 18 (CDH18), a type II classical cadherin, is primarily expressed in the nervous and reproductive systems. Here, we investigated the expression of CDH18 in neonatal porcine prospermatogonia (ProSGs) and murine spermatogonial stem cells (SSCs). Disruption of CDH18 expression did not adversely affect cell morphology, proliferation, self-renewal, or differentiation in cultured porcine ProSGs, but enhanced cell adhesion and prolonged cell maintenance. Transcriptomic analysis indicated that the down-regulation of CDH18 in ProSGs significantly up-regulated genes and signaling pathways associated with cell adhesion. To further elucidate the function of CDH18 in germ cells, Cdh18 knockout mice were generated, which exhibited normal testicular morphology, histology, and spermatogenesis. Transcriptomic analysis showed increased expression of genes associated with adhesion, consistent with the observations in porcine ProSGs. The interaction of CDH18 with ß-catenin and JAK2 in both porcine ProSGs and murine SSCs suggested an inhibitory effect on the canonical Wnt and JAK-STAT signaling pathways during CDH18 deficiency. Collectively, these findings highlight the crucial role of CDH18 in regulating cell adhesion in porcine ProSGs and mouse SSCs. Understanding this regulatory mechanism provides significant insights into the testicular niche.

Artificial light at night decreases leaf herbivory in typical urban areas.

Artificial light at night (ALAN) is exerting growing pressure on natural ecosystems, but its impact on biological interactions remains unclear. This study aimed to assess how ALAN influences leaf functional traits and herbivory in two prevalent street tree species (Styphnolobium japonicum (L.) Schott and Fraxinus pennsylvanica) through field surveys and paired experiments in the urban areas of Beijing, China. We found that ALAN led to increased leaf toughness and decreased levels of leaf herbivory. Additionally, ALAN showed species-specific effects on leaf nutrients, size as well as defense substances. The findings illustrate that ALAN can significantly alter some key functional traits and ecological processes (nutrient cycling, energy flow). In general, we suggest that high ALAN intensity will be detrimental to the energy flow from urban plants to higher trophic levels, posing a potential threat to the maintenance of biodiversity (e.g., arthropod diversity, bird diversity) in urban ecosystems.

Chinese guidelines for integrated diagnosis and treatment of intestinal microecology technologies in tumor application (2024 Edition).

ABSTRACT: Intestinal microecology (IM) is the largest and most important microecological system of the human body. Furthermore, it is the key factor for activating and maintaining the physiological functions of the intestine. Numerous studies have investigated the effects of the gut microbiota on the different tissues and organs of the human body as well as their association with various diseases, and the findings are gradually being translated into clinical practice. The gut microbiota affects the occurrence, progression, treatment response, and toxic side effects of tumors. The deepening of research related to IM and tumors has opened a new chapter in IM research driven by methods and technologies such as second-generation sequencing and bioinformatics. The IM maintains the function of the host immune system and plays a pivotal role in tumor-control drug therapy. Increasing evidence has proven that the efficacy of tumor-control drugs largely depends on the IM balance, and strategies based on the IM technology show promising application prospects in the diagnosis and treatment of tumor. The Tumor and Microecology Professional Committee of the Chinese Anti-cancer Association gathered relevant experts to discuss and propose the "Chinese guidelines for integrated diagnosis and treatment of IM technologies in tumor application (2024 Edition)," which was established based on the research progress of the application of the IM technology in tumor to provide a basis for the standardization of the diagnosis and treatment of the IM technology in the tumor.