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.

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.

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.

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 over 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 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 % during 2009-2021. A novel frame paradigm based on supply-demand characteristics classified cities into "P recycling supply cities" with surplus recoverable P versus "P recycling self-sufficient cities". City-specific dynamics and possibilities of broader "city clusters" to match supply and demand should be considered for policies 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.

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.

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.

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.

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.

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.

The predictive value of CHA2DS2-VASc score on the prognosis of patients with atrial fibrillation based on a prospective cohort study.

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia encountered in clinical practice, and it is associated with an increased risk of mortality, stroke, and peripheral embolism. The risk of stroke in AF is heterogeneous and dependent on underlying clinical conditions included in current risk stratification schemes. Recently, the CHA2DS2-VASc score has been incorporated into guidelines to encompass common stroke risk factors observed in routine clinical practice. The aim of this study was to study the predictive value of CHA2DS2-VASc score on the prognosis of patients with AF to determine the correlation of major complications including cerebral infarction and intracranial hemorrhage in patients with AF with oral anticoagulant and antiplatelet aggregation drugs and to identify the risk factors for all-cause mortality. Methods: A prospective study was conducted on 181 patients with AF who underwent physical examinations at Hai'an Qutang Central Hospital from January 2020 to December 2020. The patient's general condition, chronic disease history, CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 years, and sex category (female)] score, left ventricular ejection fraction (LVEF), lipid metabolism, and oral anticoagulant and antiplatelet aggregation medication during physical examination were recorded. By using telephone meetings to complete the follow-up, we tracked the patient's cerebral infarction, intracranial hemorrhage, and survival status within 2 years of follow-up, statistically analyzed the relationship between AF complications and medication, and grouped patients with AF based on the CHA2DS2-VASc score to evaluate its predictive ability for mortality outcomes in these patients. Results: The patients were divided into four groups according to the medication situation, and the incidence of cerebral infarction in the combination group was significantly lower than that in the non-medication group (0.0% vs. 19.2%; P<0.01). The incidence of intracranial hemorrhage in the combination group was significantly higher than that in the non-drug group (13.8% vs. 0.0%; P<0.01). The logistic regression model indicated that patients with a history of cerebral infarction had an increased risk of death compared to those without a history of cerebral infarction [odds ratio (OR) =7.404; 95% confidence interval (CI): 2.255-24.309]. After grouping according to the CHA2DS2-VASc score, we found that there was a significant difference in the 2-year survival rate between patients with CHA2DS2-VASc score <5 and those with a score ≥5 (P<0.01). The characteristic curve analysis of the participants showed that the CHA2DS2-VASc score had good predictive ability for all-cause mortality in patients with AF (area under the curve =0.754), with a cutoff value of 4, a sensitivity of 62.50%, a specificity of 86.06%, and a 95% CI of 0.684-0.815. Conclusions: The CHA2DS2-VASc score demonstrated high predictive value for all-cause mortality in patients with AF.

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.

Discovery of 4-(isopentyloxy)-3-nitrobenzamide derivatives as xanthine oxidase inhibitors through a non-anthraquinone exploration.

In our previous study, we reported a series of N-(9,10-anthraquinone-2-carbonyl) amino acid derivatives as novel inhibitors of xanthine oxidase (XO). Recognizing the suboptimal drug-like properties associated with the anthraquinone moiety, we embarked on a nonanthraquinone medicinal chemistry exploration in the current investigation. Through systematic structure-activity relationship (SAR) studies, we identified a series of 4-(isopentyloxy)-3-nitrobenzamide derivatives exhibiting excellent in vitro potency against XO. The optimized compound, 4-isopentyloxy-N-(1H-pyrazol-3-yl)-3-nitrobenzamide (6k), demonstrated exceptional in vitro potency with an IC50 value of 0.13 µM. Compound 6k showed favorable drug-like characteristics with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.41 and 3.73, respectively. In comparison to the initial compound 1d, 6k exhibited a substantial 24-fold improvement in IC50, along with a 1.6-fold enhancement in LE and a 3.7-fold increase in LLE. Molecular modeling studies provided insights into the strong interactions of 6k with critical amino acid residues within the active site. Furthermore, in vivo hypouricemic investigations convincingly demonstrated that 6k significantly reduced serum uric acid levels in rats. The MTT results revealed that compound 6k is nontoxic to healthy cells. The gastric and intestinal stability assay demonstrated that compound 6k exhibits good stability in the gastric and intestinal environments. In conclusion, compound 6k emerges as a promising lead compound, showcasing both exceptional in vitro potency and favorable drug-like characteristics, thereby warranting further exploration.

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.

ß-hydroxybutyrate resensitizes colorectal cancer cells to oxaliplatin by suppressing H3K79 methylation in vitro and in vivo.

BACKGROUND: Ketone ß-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof. METHODS: CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro. RESULTS: Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function. CONCLUSIONS: ß-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.

The cytoarchitectonic landscape revealed by deep learning method facilitated precise positioning in mouse neocortex.

Neocortex is a complex structure with different cortical sublayers and regions. However, the precise positioning of cortical regions can be challenging due to the absence of distinct landmarks without special preparation. To address this challenge, we developed a cytoarchitectonic landmark identification pipeline. The fluorescence micro-optical sectioning tomography method was employed to image the whole mouse brain stained by general fluorescent nucleotide dye. A fast 3D convolution network was subsequently utilized to segment neuronal somas in entire neocortex. By approach, the cortical cytoarchitectonic profile and the neuronal morphology were analyzed in 3D, eliminating the influence of section angle. And the distribution maps were generated that visualized the number of neurons across diverse morphological types, revealing the cytoarchitectonic landscape which characterizes the landmarks of cortical regions, especially the typical signal pattern of barrel cortex. Furthermore, the cortical regions of various ages were aligned using the generated cytoarchitectonic landmarks suggesting the structural changes of barrel cortex during the aging process. Moreover, we observed the spatiotemporally gradient distributions of spindly neurons, concentrated in the deep layer of primary visual area, with their proportion decreased over time. These findings could improve structural understanding of neocortex, paving the way for further exploration with this method.