From Individual to Population: Circuit Organization of Pyramidal Tract and Intratelencephalic Neurons in Mouse Sensorimotor Cortex.

The sensorimotor cortex participates in diverse functions with different reciprocally connected subregions and projection-defined pyramidal neuron types therein, while the fundamental organizational logic of its circuit elements at the single-cell level is still largely unclear. Here, using mouse Cre driver lines and high-resolution whole-brain imaging to selectively trace the axons and dendrites of cortical pyramidal tract (PT) and intratelencephalic (IT) neurons, we reconstructed the complete morphology of 1,023 pyramidal neurons and generated a projectome of 6 subregions within the sensorimotor cortex. Our morphological data revealed substantial hierarchical and layer differences in the axonal innervation patterns of pyramidal neurons. We found that neurons located in the medial motor cortex had more diverse projection patterns than those in the lateral motor and sensory cortices. The morphological characteristics of IT neurons in layer 5 were more complex than those in layer 2/3. Furthermore, the soma location and morphological characteristics of individual neurons exhibited topographic correspondence. Different subregions and layers were composed of different proportions of projection subtypes that innervate downstream areas differentially. While the axonal terminals of PT neuronal population in each cortical subregion were distributed in specific subdomains of the superior colliculus (SC) and zona incerta (ZI), single neurons selectively innervated a combination of these projection targets. Overall, our data provide a comprehensive list of projection types of pyramidal neurons in the sensorimotor cortex and begin to unveil the organizational principle of these projection types in different subregions and layers.

Long-term intermittent oral administration of selective COX-2 inhibitor improved the clinical outcomes of COVID-19 in patients with cirrhosis.

OBJECTIVES: Patients with cirrhosis are more susceptible to coronavirus disease 2019 (COVID-19) due to immune dysfunction. In this retrospective study we aimed to investigate whether suppression of mild systemic inflammation with selective cyclooxygenase-2 inhibitor (COX-2-I) during chronic care of cirrhotic patients would reduce the occurrence of acute decompensated events and improve patient prognosis of COVID-19. METHODS: Medical records of cirrhotic patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were sequentially reviewed. The patients were divided into the COX-2-I and control groups depending on whether they took oral selective COX-2-I for over 3 months or not. The primary outcomes included the occurrence of severe/critical COVID-19, acute decompensated events, and acute-on-chronic liver failure (ACLF). RESULTS: After propensity score matching analysis, there were 314 cases in the control group and 118 cases in the COX-2-I group. Compared with the control group, the risk of severe/critical COVID-19 in the COX-2-I group was significantly decreased by 83.1% (p = 0.004). Acute decompensated events and ACLF occurred in 23 (7.32%) and nine (2.87%) cases in the control group, but none in the COX-2-I group (p = 0.003 and 0.122). The rate of hospitalization in the COX-2-I group was significantly lower than that of the control group (3.39% vs 13.06%, p = 0.003). No patient in the COX-2-I group required intensive care unit admission. CONCLUSIONS: Long-term intermittent oral administration of selective COX-2-I in cirrhotic patients significantly reduces the occurrence of severe/critical COVID-19, acute decompensated events, and ACLF. It may also be used for systemic inflammation caused by other pathogens.

The clinical application value of multi-site mNGS detection of patients with sepsis in intensive care units.

BACKGROUND: Sepsis remains a leading cause of mortality in intensive care units, and rapid and accurate pathogen detection is crucial for effective treatment. This study evaluated the clinical application of multi-site metagenomic next-generation sequencing (mNGS) for the diagnosis of sepsis, comparing its performance against conventional methods. METHODS: A retrospective analysis was conducted on 69 patients with sepsis consecutively admitted to the Department of Intensive Care Medicine, Meizhou People's Hospital. Samples of peripheral blood and infection sites were collected for mNGS and conventional method tests to compare the positive rate of mNGS and traditional pathogen detection methods and the distribution of pathogens. The methods used in this study included a comprehensive analysis of pathogen consistency between peripheral blood and infection site samples. Additionally, the correlation between the pathogens detected and clinical outcomes was investigated. RESULTS: Of the patients with sepsis, 57.97% experienced dyspnea, and 65.2% had underlying diseases, with hypertension being the most common. mNGS demonstrated a significantly higher pathogen detection rate (88%) compared to the conventional method tests (26%). The pathogen consistency rate was 60% between plasma and bronchoalveolar lavage fluid samples, and that of plasma and local body fluid samples was 63%. The most frequently detected pathogens were gram-negative bacteria, and Klebsiella pneumonia. There were no significant differences in the clinical features between the pathogens. CONCLUSION: mNGS is significantly superior to conventional methods in pathogen detection. There was a notable high pathogen consistency detection between blood and local body fluid samples, supporting the clinical relevance of mNGS. This study highlights the superiority of mNGS in detecting a broad spectrum of pathogens quickly and accurately. TRIAL REGISTRATION: Not applicable.

A hierarchically annotated dataset drives tangled filament recognition in digital neuron reconstruction.

Reconstructing neuronal morphology is vital for classifying neurons and mapping brain connectivity. However, it remains a significant challenge due to its complex structure, dense distribution, and low image contrast. In particular, AI-assisted methods often yield numerous errors that require extensive manual intervention. Therefore, reconstructing hundreds of neurons is already a daunting task for general research projects. A key issue is the lack of specialized training for challenging regions due to inadequate data and training methods. This study extracted 2,800 challenging neuronal blocks and categorized them into multiple density levels. Furthermore, we enhanced images using an axial continuity-based network that improved three-dimensional voxel resolution while reducing the difficulty of neuron recognition. Comparing the pre- and post-enhancement results in automatic algorithms using fluorescence micro-optical sectioning tomography (fMOST) data, we observed a significant increase in the recall rate. Our study not only enhances the throughput of reconstruction but also provides a fundamental dataset for tangled neuron reconstruction.

A brainstem circuit amplifies aversion.

Dynamic gain control of aversive signals enables adaptive behavioral responses. Although the role of amygdalar circuits in aversive processing is well established, the neural pathway for amplifying aversion remains elusive. Here, we show that the brainstem circuit linking the interpeduncular nucleus (IPN) with the nucleus incertus (NI) amplifies aversion and promotes avoidant behaviors. IPN GABA neurons are activated by aversive stimuli and their predicting cues, with their response intensity closely tracking aversive values. Activating these neurons does not trigger aversive behavior on its own but rather amplifies responses to aversive stimuli, whereas their ablation or inhibition suppresses such responses. Detailed circuit dissection revealed anatomically distinct subgroups within the IPN GABA neuron population, highlighting the NI-projecting subgroup as the modulator of aversiveness related to fear and opioid withdrawal. These findings unveil the IPN-NI circuit as an aversion amplifier and suggest potential targets for interventions against affective disorders and opioid relapse.

Graph-based cell pattern recognition for merging the multi-modal optical microscopic image of neurons.

A deep understanding of neuron structure and function is crucial for elucidating brain mechanisms, diagnosing and treating diseases. Optical microscopy, pivotal in neuroscience, illuminates neuronal shapes, projections, and electrical activities. To explore the projection of specific functional neurons, scientists have been developing optical-based multimodal imaging strategies to simultaneously capture dynamic in vivo signals and static ex vivo structures from the same neuron. However, the original position of neurons is highly susceptible to displacement during ex vivo imaging, presenting a significant challenge for integrating multimodal information at the single-neuron level. This study introduces a graph-model-based approach for cell image matching, facilitating precise and automated pairing of sparsely labeled neurons across different optical microscopic images. It has been shown that utilizing neuron distribution as a matching feature can mitigate modal differences, the high-order graph model can address scale inconsistency, and the nonlinear iteration can resolve discrepancies in neuron density. This strategy was applied to the connectivity study of the mouse visual cortex, performing cell matching between the two-photon calcium image and the HD-fMOST brain-wide anatomical image sets. Experimental results demonstrate 96.67% precision, 85.29% recall rate, and 90.63% F1 Score, comparable to expert technicians. This study builds a bridge between functional and structural imaging, offering crucial technical support for neuron classification and circuitry analysis.

Amino-rich silicon quantum dots as efficient activator with intrinsic chemiluminescence for the detection of peroxydisulfate.

The specific detection of peroxydisulfate (S2O82-, PDS) is significant and challenging due to the rapid development of PDS-related technologies and their widespread application in multiple fields. However, traditional analytical methods are mainly based on their strong oxidizing properties, making it difficult to simultaneously achieve specific identification and high sensitivity for PDS detection in complex water environments. Here, we purposely prepared amino-rich SiQDs (N-SiQDs) as an effective catalyst and introduced H2O2 acts as a co-reactant for PDS activation and determination with strong intrinsic chemiluminescence (CL) emission. High yield of reactive active oxygen (mainly O2˙- and ˙OH) were generated during CL process, which trigger electron-hole annihilation between the N-SiQDs˙+ and N-SiQDs˙- accounted for extraordinary CL emission. On this basis, a new CL assay for PDS detection was fabricated with broad linear range of 5 × 10-7M-5 × 10-5 M and low detection limit (3.2 × 10-7 M). Due to the absence of SO4˙- involvement during CL emission, the sensing platform is sensitive enough, satisfactory selectivity and does not respond to transition-metal ions and inorganic anions that have interferences in the PDS CL sensors reported before. This work not only deepens insight into the mechanisms of nanomaterials assisted PDS activation but also provides a new perspective on the modified metal-free QDs CL probe for chemical species detection.

Spatial and temporal dynamics of sewage sludge phosphorus recovery potential in the cities of Yangtze River Zone in China: Implications for regional recycling policies.

Sewage sludge phosphorus (P) recovery presents opportunities to sustainably recycle P from cities to agriculture and alleviate global P scarcity. However, limited research explores sustainable recovery targets considering spatial-temporal variations in sludge generation and implications based on city-level local P demand. This study analyzed sludge production form 2009-2021 across 130 cities in China's Yangtze River Zone, which increased by almost 35 % from 2009 to 2021. Per capita gross domestic product (GDP), influent chemical oxygen demand (COD), and per capita drainage infrastructure were identified as the main significant influencing factors. City-level analysis revealed pronounced spatial-temporal disparities, with yearly sludge generation spanning five orders of magnitude (62-5.4 × 105 t/a). An indicator, "Potential of P recovery to local P demand", was defined, indicating the average city-level P recycle contribution increased from 5.3 % to 18.9 % from 2009-2021. A novel frame paradigm classified cities into six types based on the local P supply-demand characteristics, prioritizing sludge P recovery and implementing strategic management. City-specific dynamics and possibilities of broader "city clusters" to match supply and demand should be considered for policy implement. Recovering P from livestock manure and kitchen waste alongside sludge can further strengthen urban P cycles. This study provides novel city-scale analysis and strategic considerations for regional sludge P recycling policies in China and beyond.

A retrospective study of the safety and efficacy of clopidogrel versus aspirin monotherapy one year after coronary stent implantation.

BACKGROUND: The ideal single antiplatelet therapy for long-term maintenance after coronary stenting remains uncertain. In a head-to-head comparison, we aimed to evaluate the efficacy and safety profile of aspirin and clopidogrel as monotherapies in this patient cohort. METHOD: We reviewed 1044 patients who underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES) at the Department of Cardiovascular Medicine, Jinshan Hospital of Fudan University, between January 2019 and December 2021 and completed a 12-month Dual Antiplatelet Therapy (DAPT) treatment. They were divided into two groups: 582 were assigned to the aspirin group (100 mg/day) and 422 to the clopidogrel group (75 mg/day). The primary endpoint was the composite cardiac death, ischemic stroke, myocardial infarction, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater. Secondary endpoint events included all-cause death, ischemic stroke, myocardial infarction, bleeding (defined as a BARC type ≥ 2 bleeding), and gastrointestinal complications. RESULTS: After a mean observation period of 25 ± 8.4 months, the primary endpoint event occurred in 29 (6.8%) patients in the clopidogrel group and 30 (5.1%) in the aspirin group, with no difference between the two groups (P = 0.253). In BARC type 2 or greater bleeding events, there were 9 (1.5%) in the aspirin group compared to 7 (1.7%) in the clopidogrel group, with no difference between the two groups (P = 0.160). CONCLUSION: After 12-month DAPT in Chinese patients undergoing DES implantation, aspirin monotherapy versus clopidogrel monotherapy showed no significant difference between the two drugs in terms of safety and efficacy in terms of hemorrhage, myocardial infarction, ischemic stroke, cardiac death, and bleeding with BARC type 2 or greater.

Deciphering the cellular and molecular landscapes of Wnt/ß-catenin signaling in mouse embryonic kidney development.

Background: The Wnt/ß-catenin signaling pathway is critical in kidney development, yet its specific effects on gene expression in different embryonic kidney cell types are not fully understood. Methods: Wnt/ß-catenin signaling was activated in mouse E12.5 kidneys in vitro using CHIR99021, with RNA sequencing performed afterward, and the results were compared to DMSO controls (dataset GSE131240). Differential gene expression in ureteric buds and cap mesenchyme following pathway activation (datasets GSE20325 and GSE39583) was analyzed. Single-cell RNA-seq data from the Mouse Cell Atlas was used to link differentially expressed genes (DEGs) with kidney cell types. ß-catenin ChIP-seq data (GSE39837) identified direct transcriptional targets. Results: Activation of Wnt/ß-catenin signaling led to 917 significant DEGs, including the upregulation of Notum and Apcdd1 and the downregulation of Crym and Six2. These DEGs were involved in kidney development and immune response. Single-cell analysis identified 787 DEGs across nineteen cell subtypes, with Macrophage_Apoe high cells showing the most pronounced enrichment of Wnt/ß-catenin-activated genes. Gene expression profiles in ureteric buds and cap mesenchyme differed significantly upon ß-catenin manipulation, with cap mesenchyme showing a unique set of DEGs. Analysis of ß-catenin ChIP-seq data revealed 221 potential direct targets, including Dpp6 and Fgf12. Conclusion: This study maps the complex gene expression driven by Wnt/ß-catenin signaling in embryonic kidney cell types. The identified DEGs and ß-catenin targets elucidate the molecular details of kidney development and the pathway's role in immune processes, providing a foundation for further research into Wnt/ß-catenin signaling in kidney development and disease.

A Dataset of Distribution and Characterization of Underground Wastewater Treatment Plants in China.

Underground wastewater treatment plants (U-WWTPs) have emerged as a novel paradigm for urban wastewater pollutants management, offering benefits such as alleviating the Not-in-my-backyard (NIMBY) effect and utilizing land resources efficiently. China stands at the forefront, witnessing swift advancements in U-WWTP technology and deployment. However, the absence of a thorough understanding of their geographical distribution and operational characteristics could lead to misaligned planning and construction, resulting in inefficient resource allocation and treatment capacities for urban wastewater treatment. This dataset provides an up-to-date overview of the spatial distribution, process selection, and discharge standards for all U-WWTPs in China (with a total number of 201) constructed since 1995. To enhance comparative analysis, the dataset has been supplemented with information on conventional aboveground wastewater treatment plants (A-WWTPs), comprising a total of 2464 records, which enriches a more comprehensive evaluation of different wastewater treatment approaches. Utilizing this dataset can provide essential data support for the strategic management of urban wastewater systems and serve as a valuable reference for the paradigmatic renovation of existing wastewater treatment plants.

Miamiensis avidus, a Novel Scuticociliate Pathogen Isolated and Identified from Cultured Large Yellow Croaker (Larimichthys crocea).

Scuticociliates are recognized as the causative agents of mass mortalities in certain cultured marine fishes, resulting in enormous economic losses. This study aimed to investigate a fatal infection caused by scuticociliates in farmed large yellow croaker (Larimichthys crocea) in Fujian province, China. Microscopic examinations of focal organs, including the brain, eyes, gills, and skin, revealed the presence of parasites. Active masses of scuticociliates were observed in these organs, and the ciliates were subsequently isolated and maintained in vitro. An immersion challenge experiment revealed that L. crocea experienced cumulative mortalities reaching 73% within 7 d upon exposure to 1.0 × 104 ciliates mL-1. Based on the microscopic and PCR testing of infected fishes, the brain was comprehensively inferred as the main infection organ for the isolated strain. Microscopic and submicroscopic observations of the isolated scuticociliate, coupled with cortical ciliature patterns revealed through α-tubulin indirect immunofluorescence techniques, identified these scuticociliates as Miamiensis avidus. The sequencing of two genetic markers (small subunit ribosomal RNA, SSU rRNA and cytochrome c oxidase subunit I, COI) further confirmed that the isolated strains exhibited the highest sequence similarity to most M. avidus sequences in GenBank. However, significant differences in SSU sequences compared to the M. avidus strain Ma/2, and the lack of published COI and ITS (internal transcribed spacer) sequences for Ma/2, indicate the need for further molecular data to resolve whether there are potential cryptic species within the M. avidus complex.

Optogenetic Brain-Computer Interfaces.

The brain-computer interface (BCI) is one of the most powerful tools in neuroscience and generally includes a recording system, a processor system, and a stimulation system. Optogenetics has the advantages of bidirectional regulation, high spatiotemporal resolution, and cell-specific regulation, which expands the application scenarios of BCIs. In recent years, optogenetic BCIs have become widely used in the lab with the development of materials and software. The systems were designed to be more integrated, lightweight, biocompatible, and power efficient, as were the wireless transmission and chip-level embedded BCIs. The software is also constantly improving, with better real-time performance and accuracy and lower power consumption. On the other hand, as a cutting-edge technology spanning multidisciplinary fields including molecular biology, neuroscience, material engineering, and information processing, optogenetic BCIs have great application potential in neural decoding, enhancing brain function, and treating neural diseases. Here, we review the development and application of optogenetic BCIs. In the future, combined with other functional imaging techniques such as near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI), optogenetic BCIs can modulate the function of specific circuits, facilitate neurological rehabilitation, assist perception, establish a brain-to-brain interface, and be applied in wider application scenarios.

Stratified structure of membrane clogs observed in full scale cross-flow tubular ultrafiltration (UF) system: Fouling characterization and a proposed two-stage formation mechanism.

Membrane fouling remains a significant challenge in wastewater treatment, hindering both efficiency and lifespan. This study reports a distinct phenomenon of stratified membrane clogging observed in a full-scale cross-flow tubular ultrafiltration (UF) system treating sludge anaerobic digestion (AD) reject water. The distinct stratified structure, comprising inner and outer layers within the cake layer, has not been previously described. This research involved characterizing the filtration performance, analyzing membrane clog composition, and proposing a two-stage formation mechanism for the stratified clogs. It was revealed that higher inorganic and lower organic content in the outer layer compared to the inner layer. Acid and alkali treatments demonstrated the effectiveness of combined cleaning strategies. A mathematical model was developed to determine the critical conditions for stratified clog formation, influenced by membrane flux and cross-flow velocity (CFV). It is proposed that outer layer forms through long-term selective deposition, while the inner layer results from short-term dewatering within limited tubular space. High CFV (>2.5 m/s) prevents inner layer formation. Critical conditions for stratification occur at a flux of 18 L/m2/h with a CFV of 0.1 m/s or 65 L/m2/h with a CFV of 0.35 m/s. This study contributes a novel understanding of stratified membrane clogging, proposing a two-stage formation mechanism and identifying critical conditions, which provides insights for effective fouling control strategies and maintenance of operational efficiency for membrane systems.

Mapping sagittal-plane reference brain atlas of the cynomolgus macaque (Macaca fascicularis) based on consecutive cytoarchitectonic images.

The brain atlas is essential for exploring the anatomical structure and function of the brain. Non-human primates, such as cynomolgus macaque, have received increasing attention due to their genetic similarity to humans. However, current macaque brain atlases only offer coarse sections with intervals along the coronal direction, failing to meet the needs of single-cell resolution studies in functional and multi-omics research of the macaque brain. To address this issue, we utilized fluorescence micro-optical sectioning tomography to obtain sub-micron resolution cytoarchitectonic images of the macaque brain at the sagittal plane. Based on the obtained 8000 image sequences, a reference brain atlas comprising 45 sagittal sections was created, delineating 270 brain regions other than the cortex. Additionally, a website was established to share the reference atlas corresponding image data. This study is expected to provide an essential dataset and tool for scientists studying the macaque brain.

Efficacy of spray flushing in the reprocessing of flexible endoscopes: A randomized controlled trial.

BACKGROUND: Commonly used cleaning brushes in the reprocessing of flexible endoscopes often cause damage within the working channels. AIM: To develop a spray flushing system to achieving effective cleaning of the working channels while minimizing damage. METHODS: This prospective study included 60 used endoscopes and 60 Teflon tubes randomly divided into a control group (n = 30) and an experimental group (n = 30). The material of Teflon tubes was the same as that of the endoscope working channel. Endoscopes in the control group were manually cleaned using traditional cleaning brushes, while those in the experimental group were cleaned using the newly developed spray flushing system. ATP levels, cleanliness, and microbiological testing of the working channels were measured. Additionally, Teflon tubes in the control group underwent 500 passes with a cleaning brush, while those in the experimental group were subjected to the spray flushing system, and channel damage was evaluated. RESULTS: The ATP levels (RLU) in the two groups were 32.5 (13-66) and 26 (16-40), respectively (P > 0.05). Cleanliness scores were 1.5 (1-2) and 1 (1-2), respectively (P > 0.05). Debris was found in 73.3% of the control group, which was significantly higher than 46.7% in the experimental group (P < 0.05). Microbiological tests for both groups yielded negative results. Teflon tube damage in the control group was rated at 4 (4-5.25), which was significantly higher than in the experimental group 4 (3-4) (P < 0.01). CONCLUSION: The spray flushing system demonstrated superior efficacy in removing debris and resulted in less damage to the endoscope working channels compared with traditional cleaning brushes.

Effect of diode laser on oral pigmentation, pain, and wound healing in patients with gingival hyperpigmentation: a meta-analysis.

OBJECTIVES: Diode laser represent a practical clinical strategy for treating gingival hyperpigmentation. However, its effectiveness remains controversial. We conducted a meta-analysis evaluating the quantitative effects of diode laser therapy on gingival hyperpigmentation. METHOD AND MATERIALS: Pubmed, Embase, Web Of Science, and Cochrane Library were systematically searched for the use of diode laser in gingival hyperpigmentation. The primary outcomes assessed were the Dummett-Gupta Oral Pigmentation Index (DOPI), Visual Analog Scale (VAS) pain scores, and the Wound Healing Index (WHI) for overall evaluation. I2 index was calculated to identify heterogeneity and sensitivity analyses sources of heterogeneity. Funnel plots and Egger's test were utilized to evaluate publication bias. RESULTS: Thirteen randomized controlled trials (RCTs) involving a total of 233 participants were included in this study. The analysis demonstrated that diode laser had a significant effect on DOPI (standard mean difference [SMD] = -0.245, 95% CI = -0.415 to -0.040, P =.019) and VAS (SMD = -0.089, 95% CI = -1.332 to -0.285, P =.002), with no significant effect on WHI (SMD = -0.224, 95% CI = -1.100 to 0.653, P =.617). Despite the significant heterogeneity in VAS and WHI indicated by the I2 index statistic, the sensitivity analyses' results demonstrated the main findings' reliability. While no significant publication bias was detected for DOPI and WHI, the VAS results exhibited notable publication bias. CONCLUSION: The study demonstrated that diode laser prolongs gingival repigmentation time and reduces pain compared to other treatments. However, the efficacy in wound healing did not significantly promote.

The involvement of the Stat1/Nrf2 pathway in exacerbating Crizotinib-induced liver injury: implications for ferroptosis.

Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy.

HMGB1 as an extracellular pro-inflammatory cytokine: Implications for drug-induced organic damage.

Drug-induced organic damage encompasses various intricate mechanisms, wherein HMGB1, a non-histone chromosome-binding protein, assumes a significant role as a pivotal hub gene. The regulatory functions of HMGB1 within the nucleus and extracellular milieu are interlinked. HMGB1 exerts a crucial regulatory influence on key biological processes including cell survival, inflammatory regulation, and immune response. HMGB1 can be released extracellularly from the cell during these processes, where it functions as a pro-inflammation cytokine. HMGB1 interacts with multiple cell membrane receptors, primarily Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE), to stimulate immune cells and trigger inflammatory response. The excessive or uncontrolled HMGB1 release leads to heightened inflammatory responses and cellular demise, instigating inflammatory damage or exacerbating inflammation and cellular demise in different diseases. Therefore, a thorough review on the significance of HMGB1 in drug-induced organic damage is highly important for the advancement of pharmaceuticals, ensuring their effectiveness and safety in treating inflammation as well as immune-related diseases. In this review, we initially outline the characteristics and functions of HMGB1, emphasizing their relevance in disease pathology. Then, we comprehensively summarize the prospect of HMGB1 as a promising therapeutic target for treating drug-induced toxicity. Lastly, we discuss major challenges and propose potential avenues for advancing the development of HMGB1-based therapeutics.

Trends in Incidence of HIV and Syphilis Among Men Who Have Sex with Men - Tianjin Municipality, China, 2013-2022.

What is already known about this topic?: Given the common modes of transmission, outbreaks of both human immunodeficiency virus (HIV) and syphilis are primarily observed in men who have sex with men (MSM). However, minimal research has been conducted to concurrently evaluate the rates and trends of HIV and syphilis incidence within this community in China. What is added by this report?: This manuscript presents the incidence rates and associated factors of HIV and syphilis in MSM in Tianjin based on data derived from a decade-long cohort study. Intriguingly, it depicts a decreasing trend in HIV incidence juxtaposed with an increasing incidence of syphilis among this population in Tianjin. What are the implications for public health practice?: The interconnected risk factors for HIV and syphilis pose significant hindrances to disease control. Our study underscores the urgent need for improved intervention strategies specifically aimed at MSM to mitigate the propagation of both infections.