Arsenic methylation and microbial communities in paddy soils under alternating anoxic and oxic conditions.

Arsenic (As) methylation in soils affects the environmental behavior of As, excessive accumulation of dimethylarsenate (DMA) in rice plants leads to straighthead disease and a serious drop in crop yield. Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security. Here, soils including un-arsenic contaminated (N-As), low-arsenic (L-As), medium-arsenic (M-As), and high-arsenic (H-As) soils were incubated under continuous anoxic, continuous oxic, and consecutive anoxic/oxic treatments respectively, to profile arsenic methylating process and microbial species involved in the As cycle. Under anoxic-oxic (A-O) treatment, methylated arsenic was significantly increased once oxygen was introduced into the incubation system. The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic (A), oxic (O), and oxic-anoxic (O-A) treatments, under which arsenic was methylated slightly and then decreased in all four As concentration soils. In fact, the most plentiful arsenite S-adenosylmethionine methyltransferase genes (arsM) contributed to the increase in As methylation. Proteobacteria (40.8%-62.4%), Firmicutes (3.5%-15.7%), and Desulfobacterota (5.3%-13.3%) were the major microorganisms related to this process. These microbial increased markedly and played more important roles after oxygen was introduced, indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic (flooding) and oxic (drainage) environment. The novel findings provided new insights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.

Uncovering the mechanisms of Zhubi decoction against rheumatoid arthritis through an integrated study of network pharmacology, metabolomics, and intestinal flora.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhubi Decoction (ZBD) is a modified formulation derived from the classic traditional Chinese medicine prescription "Er-Xian Decoction" documented in the esteemed "Clinical Manual of Chinese Medical Prescription". While the utilization of ZBD has exhibited promising clinical outcomes in treating rheumatoid arthritis (RA), the precise bioactive chemical constituents and the underlying mechanisms involved in its therapeutic efficacy remain to be comprehensively determined. AIM OF THE STUDY: This study aims to systematically examine ZBD's pharmacological effects and molecular mechanisms for RA alleviation. MATERIALS AND METHODS: Utilizing the collagen-induced arthritis (CIA) rat model, we comprehensively evaluated the anti-rheumatoid arthritis effects of ZBD in vivo through various indices, such as paw edema, arthritis index, ankle diameter, inflammatory cytokine levels, pathological conditions, and micro-CT analysis. The UPLC-MS/MS technique was utilized to analyze the compounds of ZBD. The potential therapeutic targets and signaling pathways of ZBD in the management of RA were predicted using network pharmacology. To analyze comprehensive metabolic profiles and identify underlying metabolic pathways, we conducted a serum-based widely targeted metabolomics analysis utilizing LC-MS technology. Key targets and predicted pathways were further validated using immunofluorescent staining, which integrated findings from serum metabolomics and network pharmacology analysis. Additionally, we analyzed the gut microbiota composition in rats employing 16 S rDNA sequencing and investigated the effects of ZBD on the microbiota of CIA rats through bioinformatics and statistical methods. RESULTS: ZBD exhibited remarkable efficacy in alleviating RA symptoms in CIA rats without notable side effects. This included reduced paw redness and swelling, minimized joint damage, improved the histopathology of cartilage and synovium, mitigated the inflammatory state, and lowered serum concentrations of cytokines TNF-α, IL-1ß and IL-6. Notably, the effectiveness of ZBD was comparable to MTX. Network pharmacology analysis revealed inflammation and immunity-related signaling pathways, such as PI3K/AKT, MAPK, IL-17, and TNF signaling pathways, as vital mediators in the effectual mechanisms of ZBD. Immunofluorescence analysis validated ZBD's ability to inhibit PI3K/AKT pathway proteins. Serum metabolomics studies revealed that ZBD modulates 170 differential metabolites, partially restored disrupted metabolic profiles in CIA rats. With a notable impact on amino acids and their metabolites, and lipids and lipid-like molecules. Integrated analysis of metabolomics and network pharmacology identified 6 pivotal metabolite pathways and 3 crucial targets: PTGS2, GSTP1, and ALDH2. Additionally, 16 S rDNA sequencing illuminated that ZBD mitigated gut microbiota dysbiosis in the CIA group, highlighting key genera such as Ligilactobacillus, Prevotella_9, unclassified_Bacilli, and unclassified_rumen_bacterium_JW32. Correlation analysis disclosed a significant link between 47 distinct metabolites and specific bacterial species. CONCLUSION: ZBD is a safe and efficacious TCM formulation, demonstrates efficacy in treating RA through its multi-component, multi-target, and multi-pathway mechanisms. The regulation of inflammation and immunity-related signaling pathways constitutes a crucial mechanism of ZBD's efficacy. Furthermore, ZBD modulates host metabolism and intestinal flora. The integrated analysis presents experimental evidence of ZBD for the management of RA.

KLF15 suppresses stemness of pancreatic cancer by decreasing USP21-mediated Nanog stability.

The existence of cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) is considered to be the key factor for metastasis and chemoresistance. Thus, novel therapeutic strategies for eradicating CSCs are urgently needed. Here we aimed to explore the role of KLF15 in stemness and the feasibility of using KLF15 to inhibit CSCs and improve chemotherapy sensitivity in PDAC. In this study, we report that KLF15 is negatively associated with poor survival and advanced pathological staging of PDAC. Moreover, tumorous KLF15 suppresses the stemness of PDAC by promoting the degradation of Nanog, and KLF15 directly interacts with Nanog, inhibiting interaction between Nanog with USP21. We also demonstrate that the KLF15/Nanog complex inhibit the stemness in vivo and in PDX cells. Tazemetostat suppresses stemness and sensitizes PDAC cells to gemcitabine by promoting KLF15 expression in PDAC. In summary, the findings of our study confirm the value of KLF15 level in diagnosis and prognosis of PDAC, it is the first time to explore the inhibition role of KLF15 in stemness of PDAC and the regulation mechanism of Nanog, contributing to provide a new therapeutic strategy that using Tazemetostat sensitizes PDAC cells to gemcitabine by promoting KLF15 expression for PDAC.

Chest CT assess the impact of omalizumab treatment on airway remodeling in refractory asthma.

BACKGROUND: To evaluate the benefits of omalizumab treatment in patients through real-world follow-up and assess the impact of omalizumab treatment on airway remodeling using chest CT. METHODS: This is a single-center prospective, observational study included Chinese patients with refractory asthma who received omalizumab treatment from May 2021 to December 2022. We collected real-world clinical data, including their hospitalization information, pulmonary function, FENO, laboratory assessment, ACT scores, chest CT at baseline and every follow-up month. A comparison was made between the pre-treatment and post-treatment laboratory indicators, pulmonary function, airway parameters, and mucous plug scores under chest CT. RESULTS: This study included a total of 61 patients with refractory asthma treated with omalizumab. The study found that: ①regardless of whether the treatment lasted for a full four months or not, it significantly improved patient asthma control scores and reduced hospitalization costs and length of stay (p<0.05). ②After four months of treatment, pulmonary ventilation function examination revealed significant improvements (p<0.05) in MEF75, MEF50, MEF75/25, PEF, and FEV1/FVC. ③After four months of omalizumab treatment, the ratio of wall thickness and outer radius (T/D) and wall area percentage (WA%) of the bronchial wall decreased significantly (p<0.05). ④After medication, the expression of airway mucous plugs decreased. CONCLUSIONS: Omalizumab treatment can reduce airway wall thickness, decrease the percentage of airway wall area, and the expression of airway mucous plugs, thereby improving airflow limitation. Utilizing chest CT provides a novel and intuitive assessment of the efficacy of omalizumab treatment. TRIAL REGISTRATION: This study was registered in Chinese Clinical Trial Registry, the number is ChiCTR2100046343.

Dorsal raphe dopaminergic neurons target CaMKII+ neurons in dorsal bed nucleus of the stria terminalis for mediating depression-related behaviors.

Dopamine (DA) neurons play a crucial role in the development and manifestation of depression, as well as in response to antidepressant treatments. While the function of the predominantly distributed DA neurons in the ventral tegmental area (VTA) is well established, the contribution of a small fraction of DA neurons in the dorsal raphe nucleus (DRN) during depression remains unclear. In this study, we found that chronic unpredictable stress (CUS) induces depression-related behaviors and decreases spontaneous firing rates, excitatory and inhibitory postsynaptic currents of DA neurons in the DRN associated with reduced excitatory synaptic transmission in male and female mice. The chemogenetic inhibition of DA neurons in the DRN produces depressive phenotypes. Conversely, their activation completely reversed the anhedonic and despair behaviors induced by CUS. Furthermore, we showed that a DRN dopaminergic projecting to the dorsal bed nucleus of the stria terminalis (dBNST) selectively controls depressive behaviors by influencing the neural activity and N-methyl-D-aspartate receptor (NMDAR) mediating EPSC of calcium/calmodulin-dependent protein kinase II+ (CaMKII+) target neurons by regulating dopamine neurotransmitter and dopamine receptor 2 (DR2) in the dBNST. Overall, these findings highlight the essential role of the DRNDA → dBNSTCaMKII+ neural circuit in bi-directionally mediating stress-induced depression-related behaviors. Our findings indicate that DRN DA neurons are a key component of the neural circuitry involved in regulating depression-related behaviors, making them a potential therapeutic target for depression.

AI Prediction of Structural Stability of Nanoproteins Based on Structures and Residue Properties by Mean Pooled Dual Graph Convolutional Network.

The structural stability of proteins is an important topic in various fields such as biotechnology, pharmaceuticals, and enzymology. Specifically, understanding the structural stability of protein is crucial for protein design. Artificial design, while pursuing high thermodynamic stability and rigidity of proteins, inevitably sacrifices biological functions closely related to protein flexibility. The thermodynamic stability of proteins is not always optimal when they are highest to perfectly perform their biological functions. Extensive theoretical and experimental screening is often required to obtain stable protein structures. Thus, it becomes critically important to develop a stability prediction model based on the balance between protein stability and bioactivity. To design protein drugs with better functionality in a broader structural space, a novel protein structural stability predictor called PSSP has been developed in this study. PSSP is a mean pooled dual graph convolutional network (GCN) model based on sequence characteristics and secondary structure, distance matrix, graph, and residue properties of a nanoprotein to provide rapid prediction and judgment. This model exhibits excellent robustness in predicting the structural stability of nanoproteins. Comparing with previous artificial intelligence algorithms, the results indicate this model can provide a rapid and accurate assessment of the structural stability of artificially designed proteins, which shows the great promises for promoting the robust development of protein design.

Pharmacokinetics, Pharmacodynamics, and Safety of Intravenous Efgartigimod and Subcutaneous Efgartigimod PH20 in Healthy Chinese Participants.

BACKGROUND: Efgartigimod, a human immunoglobulin G (IgG)1-derived Fc fragment targeting the neonatal Fc receptor, has been developed into intravenous (IV) and subcutaneous (SC) formulations for treating generalized myasthenia gravis (gMG) and other autoimmune diseases. Data in the Chinese population were not available to date, and while both formulations have been approved in the USA, the EU, Japan and China for the treatment of gMG. OBJECTIVE: We present the pharmacokinetic, pharmacodynamic, and safety of IV and SC PH20 efgartigimod in healthy Chinese participants. METHODS: In two independent, double-blinded, placebo-controlled, phase I studies of the IV and SC formulations of efgartigimod, healthy Chinese adults were randomized 3:1 to receive active treatment or matching placebo once every 7 days for four doses. Primary endpoints were pharmacokinetic parameters. RESULTS: After the fourth IV infusion, a mean maximum observed concentration (Cmax) of 194 µg/mL was reached at the end of the 1 h infusion; the mean area under concentration-time curve from time zero to 168 h (AUC0-168h) was 5300 µg × h/mL. After the fourth SC injection, a mean Cmax of 42.1 µg/mL was achieved with a median Tmax of 47.74 h; the mean AUC0-168h was 4790 µg × h/mL. Maximal mean reductions from baseline in total IgG levels were reached approximately 24 days after the first dose (60.7%, IV formulation; 66.4%, SC formulation). Treatment-related adverse events (TRAEs) were reported in seven (58.3%) participants receiving SC efgartigimod, mostly injection-site reactions. No TRAEs or AEs of special interest were reported in the IV study. CONCLUSIONS: The efgartigimod IV and SC pharmacokinetic, pharmacodynamic, and safety profiles in Chinese participants were similar to the known profiles in non-Chinese participants. Both formulations effectively reduced total IgG levels by a similar percentage. CLINICAL TRIAL REGISTRATION: CTR20211952 and CTR20211805.

Oxygen extraction fraction mapping based combining quantitative susceptibility mapping and quantitative blood oxygenation level-dependent imaging model using multi-delay PCASL.

BACKGROUND AND PURPOSE: The oxygen extraction fraction is an essential biomarker for the assessment of brain metabolism. A recently proposed method combined with quantitative susceptibility mapping and quantitative blood oxygen level-dependent magnitude enables noninvasive mapping of the oxygen extraction fraction. Our study investigated the oxygen extraction fraction mapping variations of single-delay and multi-delay arterial spin-labeling. MATERIALS AND METHODS: A total of twenty healthy participants were enrolled. The multi-echo spoiled gradient-echo, multi-delay arterial spin-labeling, and magnetization-prepared rapid gradient echo sequences were acquired at 3.0 T. The mean oxygen extraction fraction was generated under a single delay time of 1780 ms, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume. The results were compared via paired t tests and the Wilcoxon test. Linear regression analyses were used to investigate the relationships among the oxygen extraction fraction, cerebral blood flow, and venous cerebral blood volume. RESULTS: The oxygen extraction fraction estimate with multi-delay arterial spin-labeling yielded a significantly lower value than that with single-delay arterial spin-labeling. The average values for the whole brain under single-delay arterial spin-labeling, multi-delay arterial spin-labeling of transit-corrected cerebral blood flow, and multi-delay arterial spin-labeling of arterial cerebral blood volume were 41.5 ±â€¯1.7 % (P < 0.05), 41.3 ±â€¯1.9 % (P < 0.001), and 40.9 ±â€¯1.9 % (N = 20), respectively. The oxygen extraction fraction also showed a significant inverse correlation with the venous cerebral blood volume under steady-state conditions when multi-delay arterial spin-labeling was used (r = 0.5834, p = 0.0069). CONCLUSION: These findings suggest that the oxygen extraction fraction is significantly impacted by the arterial spin-labeling methods used in the quantitative susceptibility mapping plus the quantitative blood oxygen level-dependent model, indicating that the differences should be accounted for when employing oxygen extraction fraction mapping based on this model in diseases.

PROTAC as a novel anti-cancer strategy by targeting aging-related signaling.

Aging and cancer share common cellular hallmarks, including cellular senescence, genomic instability, and abnormal cell death and proliferation, highlighting potential areas for therapeutic interventions. Recent advancements in targeted protein degradation technologies, notably Proteolysis-Targeting Chimeras (PROTACs), offer a promising approach to address these shared pathways. PROTACs leverage the ubiquitin-proteasome system to specifically degrade pathogenic proteins involved in cancer and aging, thus offering potential solutions to key oncogenic drivers and aging-related cellular dysfunction. This abstract summarizes the recent progress of PROTACs in targeting critical proteins implicated in both cancer progression and aging, and explores future perspectives in integrating these technologies for more effective cancer treatments.

Aging With Emerging Social Welfare and Disappearing Filial Piety: Chinese Migrant Workers' Pathways Toward Financial Retirement Planning.

This study examines the pathways and mechanisms linking Chinese migrant workers' migration experiences and their financial retirement planning. Using a mixed-methods approach with 1083 surveys and 32 interviews, this study finds that having a good financial status and social support system and maintaining a hopeful attitude toward retirement are direct pathways toward good financial retirement planning. Good health and hope for retirement are further enhanced by a good financial status and social support. Conversely, poor health and negative employment experiences are linked to poor financial retirement planning. The qualitative findings provide a contextual understanding of the pathways identified in the quantitative analyses. Migrant workers often face a dilemma between self-reliance for retirement and relying on filial piety. These findings apply not only to Chinese migrant workers but also to all migrant workers with limited access to healthcare and public pensions for retirement.

Delineating, Imaging, and Assessing Pulmonary Fibrosis Remodeling via Collagen Hybridization.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening disease with no early detection, few treatments, and dismal outcomes. Although collagen overdeposition is a hallmark of lung fibrosis, current research mostly focuses on the cellular aspect, leaving collagen, particularly its dynamic remodeling (i.e., degradation and turnover), largely unexplored. Here, using a collagen hybridizing peptide (CHP) that specifically binds unfolded collagen chains, we reveal vast collagen denaturation in human IPF lungs and delineate the spatiotemporal progression of collagen denaturation three-dimensionally within fibrotic lungs in mice. Transcriptomic analyses support that lung collagen denaturation is strongly associated with up-regulated collagen catabolism in mice and patients. We thus show that CHP probing differentiates remodeling responses to antifibrotics and highlights the resolution of established fibrosis by agents up-regulating collagen catabolism. We further develop a radioactive CHP that detects fibrosis in vivo in mice as early as 7 days postlung-injury (Ashcroft score: 2-3) by positron emission tomography (PET) imaging and ex vivo in clinical lung specimens. These findings establish collagen denaturation as a promising marker of fibrotic remodeling for the investigation, diagnosis, and therapeutic development of pulmonary fibrosis.

Carbothermal Reduction-Assisted Synthesis of a Carbon-Supported Highly Dispersed PtSn Nanoalloy for the Oxygen Reduction Reaction.

Exploring high-performance and low-platinum-based electrocatalysts to accelerate the oxygen reduction reaction (ORR) at the air cathode of zinc-air batteries remains crucial. Herein, by combining electroless deposition and carbothermal reduction, a nitrogen-doped carbon-supported highly dispersed PtSn alloy nanocatalyst (PtSn/NC) was prepared for a high-efficiency ORR process. Electrochemical measurements show that PtSn/NC exhibits excellent electrocatalytic ORR activity with a half-wave potential of 0.850 V versus reversible hydrogen electrode (RHE), which is higher than that of commercial Pt/C (0.815 V). The PtSn/NC-based (20 µgPt cm-2) rechargeable Zn-air battery exhibited astonishing performance with a maximum power density of up to 150.1 mW cm-2, as well as excellent rate performance and charge/discharge stability. Physical characterization reveals that carbothermal reduction could compel the transformation of Sn oxide into metallic Sn, which then alloys with the deposited Pt atoms to form the PtSn nanoalloy, in which electrons are transferred from Sn atoms to neighboring Pt atoms, thereby improving the ability of Pt-based active sites to catalyze the ORR process in PtSn/NC by optimizing the unoccupied d-band of Pt atoms. This work provides a reliable and innovative route for the rational design of highly dispersed Pt-based alloy ORR electrocatalysts.

Integrating multi-spectral imaging and Raman spectroscopy for in vivo endoscopic assessment of rat intestinal tract.

An integrated system for in vivo multi-spectral imaging (MSI) and Raman spectroscopy was developed to understand the external morphology and internal molecular information of biological tissues. The achieved MSI images were reconstructed by eighteen separated images from 400 nm to 760 nm, whose illumination bands were selected with six tri-channel band filters. Based on the spectral analysis algorithms, the spatial distribution patterns of blood volume, blood oxygen content and tissue scatterer volume fraction were visualized. In vivo Raman spectral measurements were executed by inserting specially designed optical probe into instrumental channel of endoscope. By this way, the molecular composition at selected sampling points could be identified with its fingerprint spectral information under the guidance of molecular imaging modality. Therefore, both structural and compositional features of intestinal membrane could be addressed without labeling and continuously. The achieved results testified that our presented methodology reveals insights not easily extracted from either MSI or Raman spectroscopy individually, which brings the enrichment of biological and chemical meanings for future in vivo studies.

Characterization of rimegepant drug-drug interactions using the cytochrome P450 probe drugs, itraconazole, rifampin, fluconazole, and midazolam.

OBJECTIVE: Reported here are the results of four rimegepant phase I studies, in healthy participants, aimed at determining the in vivo potential of rimegepant (75 mg) for cytochrome P450 (CYP) 3A4-related drug-drug interactions (DDIs). BACKGROUND: Rimegepant orally disintegrating tablet (Pfizer Inc., New York, NY, USA) is a calcitonin gene-related peptide receptor antagonist approved for acute treatment of migraine and preventive treatment of episodic migraine. People with migraine commonly use multiple drug treatments, with the potential for DDIs. METHODS: Each study was an open-label, single-arm, single-sequence, crossover study. Rimegepant was tested as a victim drug by separate co-administration of itraconazole (a strong CYP3A4 inhibitor and P-glycoprotein inhibitor) in Study 1, rifampin (a strong CYP3A4 inducer and moderate CYP2C9 inducer) in Study 2, and fluconazole (a strong CYP2C9 inhibitor and moderate CYP3A4 inhibitor) in Study 3, and as a perpetrator drug by co-administration with midazolam (a CYP3A4 substrate) in Study 4. RESULTS: Mean values of single-dose rimegepant maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC0-inf) increased with itraconazole co-administration (n = 22) by 1.42-fold (90% confidence interval [CI] 1.25-1.61) and by 4.14-fold (90% CI 3.87-4.44), respectively, and decreased with rifampin co-administration (n = 21) to 36% (90% CI 31.2-41.4%) and to 19% (90% CI 16.3-21.4%), respectively. Co-administration with fluconazole (n = 23) increased rimegepant mean AUC0-inf by 1.80-fold (90% CI 1.68-1.93), with no impact on Cmax (1.04-fold; 90% CI 0.94-1.15). Co-administration of rimegepant single dose (300 mg; n = 14) or multiple doses (150 mg/day; n = 14) increased the mean Cmax of midazolam by 1.38-fold (90% CI 1.13-1.67) and 1.53-fold (90% CI 1.32-1.78), respectively, and the AUC0-inf of midazolam by 1.86-fold (90% CI 1.58-2.19) and 1.91-fold (90% CI 1.63-2.25), respectively. CONCLUSIONS: Based on the magnitude of DDIs, these studies indicate the following: co-administration of rimegepant with a strong CYP3A4 inhibitor should be avoided; during co-administration with a moderate CYP3A4 inhibitor, another dose of rimegepant within 48 h should be avoided; co-administration of rimegepant with a strong or moderate CYP3A4 inducer should be avoided; CYP2C9 does not play a meaningful role in rimegepant metabolism; and there is no clinically meaningful CYP3A4 inhibition by rimegepant.

Assessment of pharmacokinetic and pharmacodynamic interactions between zavegepant and sumatriptan: A phase 1, randomized, placebo-controlled study in healthy adults.

OBJECTIVE: To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults. BACKGROUND: Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug-drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings. METHODS: This was a Phase 1, single-center, partially blind, randomized, placebo-controlled, single-arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre-specified time points. RESULTS: Forty-two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty-one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time-weighted average (TWA) of mean arterial pressure (MAP [sumatriptan + zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: -0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: -0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: -0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC0-inf and 104.1% (90% CI: 98.0%, 110.6%) for Cmax. A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC0-24 and 96.7% (90% CI: 88.9%, 105.2%) for Cmax. Overall, 90% (38/42) of participants experienced ≥ 1 treatment-emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated. CONCLUSION: Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults.

Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder.

This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.

Monitoring of Klebsiella pneumoniae Infection and Drug Resistance in 17 Pediatric Intensive Care Units in China from 2016 to 2022.

Objective: To investigate the characteristics and drug resistance patterns of Klebsiella pneumoniae (K. pneumoniae) infection in pediatric intensive care unit (PICU). Methods: K. pneumoniae strains from 17 domestic PICUs were analyzed for overall condition and drug resistance using WHO-NET software. Results: From 2016 to 2022, there was a linear increase in the detection rate of K. pneumoniae (P<0.05), with a total of 2591 (9.7%) strains detected. The primary sites of K. pneumoniae detection were the respiratory tract (71.1%), blood (8.6%), and urinary tract (7.1%). K. pneumoniae's resistance to penicillin drugs exceeded 90%, and are over 50% to cephalosporins. Resistance to cefoperazone-sulbactam decreased from 51.7% to 25.7%, and ranged from 9.1% to 20.8% for ceftolozane-tazobactam. Carbapenem-resistant K. pneumoniae strains constituted 32.3%. Resistance to imipenem and meropenem have decreased to 33.8% and 40.2%, while increased to 35.2% for ertapenem. Levofloxacin and amikacin resistance rates have decreased to 25.7% and 9.1%, but remain high at 63.8% for moxifloxacin and 44.6% for ciprofloxacin. K. pneumoniae demonstrated the lowest resistance rates to polymyxin B (0.9%), tigecycline (2.2%), and polymyxin E (3.1%). No strain of K. pneumoniae was resistant to both polymyxin B and meropenem. However, some strains showed co-resistance to meropenem with other antibiotics, including tigecycline (2%), imipenem (16%), amikacin (27%), colistin (37%), and levofloxacin (41%). Conclusion: The rates of isolation and drug resistance of K. pneumoniae in PICU have significantly increased over 7 years. Careful antibiotic use, infection control strategies, and appropriate antibiotic combinations are crucial in addressing this problem.

Herbal medicines for SOD1G93A mice of amyotrophic lateral sclerosis: preclinical evidence and possible immunologic mechanism.

Currently, there is no cure or effective treatment for Amyotrophic Lateral Sclerosis (ALS). The mechanisms underlying ALS remain unclear, with immunological factors potentially playing a significant role. Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), a systematic review of preclinical studies was conducted, searching seven databases including PubMed, covering literature from the inception of the databases to April 10, 2024. Methodological quality of the included literature was assessed using CAMARADES, while the risk of bias in the included studies was evaluated using SYRCLE's ROB tool. Review Manager 5.4.1 statistical software was used for meta-analysis of the outcomes. The scoping review followed the Joanna Briggs Institute Methodological Guidelines and reporting of this review followed the PRISMA-extension for Scoping Reviews (PRISMA -ScR) checklist to explore the immunological mechanisms of Herbal Medicine (HM) in treating ALS. This systematic review and meta-analysis involved 18 studies with a total of 443 animals. The studies scored between 4 to 8 for methodological quality and 3 to 7 for risk of bias, both summing up to 10.A remarkable effects of HM in ALS mice, including onset time(Standardized Mean Difference(SMD): 1.75, 95% Confidence Interval(CI) (1.14 ~ 2.36), Z = 5.60, P < 0.01), survival time(SMD = 1.42, 95% CI (0.79 ~ 2.04), Z = 4.44, P < 0.01), stride length(SMD=1.90, 95% CI (1.21 to 2.59), Z = 5.39, P < 0.01) and duration time (Mean Difference(MD)=6.79, 95% CI [-0.28, 13.87], Z=1.88, P =0.06), showing HM's certain efficiency in treating ALS mice. The scoping review ultimately included 35 articles for review. HMs may treat ALS through mechanisms such as combating oxidative stress, excitatory amino acid toxicity, and calcium cytotoxicity, understanding and exploring the mechanisms will bring hope to patients. Individual herbs and their formulations within HM address ALS through a variety of immune pathways, including safeguarding the blood-brain barrier, countering neuroinflammation, impeding complement system activation, mitigating natural killer cell toxicity, and regulating T cell-mediated immune pathways. The preclinical evidence supports the utilization of HM as a conventional treatment for ALS mice. Growing evidence indicates that HM may potentially delay neurological degeneration in ALS by activating diverse signaling pathways, especially immune pathways.

Machine Learning-Based Toxicological Modeling for Screening Environmental Obesogens.

The emerging presence of environmental obesogens, chemicals that disrupt energy balance and contribute to adipogenesis and obesity, has become a major public health challenge. Molecular initiating events (MIEs) describe biological outcomes resulting from chemical interactions with biomolecules. Machine learning models based on MIEs can predict complex toxic end points due to chemical exposure and improve the interpretability of models. In this study, a system was constructed that integrated six MIEs associated with adipogenesis and obesity. This system showed high accuracy in external validation, with an area under the receiver operating characteristic curve of 0.78. Molecular hydrophobicity (SlogP_VSA) and direct electrostatic interactions (PEOE_VSA) were identified as the two most critical molecular descriptors representing the obesogenic potential of chemicals. This system was further used to predict the obesogenic effects of chemicals on the candidate list of substances of very high concern (SVHCs). Results from 3T3-L1 adipogenesis assays verified that the system correctly predicted obesogenic or nonobesogenic effects of 10 of the 12 SVHCs tested, and identified four novel potential obesogens, including 2-benzotriazol-2-yl-4,6-ditert-butylphenol (UV-320), 4-(1,1,5-trimethylhexyl)phenol (p262-NP), 2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethanol (OP1EO) and endosulfan. These validation data suggest that the screening system has good performance in adipogenic prediction.

Myosin II tension sensors visualize force generation within the actin cytoskeleton in living cells.

Nonmuscle myosin II generates cytoskeletal forces that drive cell division, embryogenesis, muscle contraction, and many other cellular functions. However, at present there is no method that can directly measure the forces generated by myosins in living cells. Here we describe a Förster resonance energy transfer (FRET)-based tension sensor that can detect myosin associated force along the filamentous actin network. Fluorescence lifetime imaging microscopy (FLIM)-FRET measurements indicate that the forces generated by NMIIB exhibit significant spatial and temporal heterogeneity as a function of donor lifetime and fluorophore energy exchange. These measurements provide a proxy for inferred forces that vary widely along the actin cytoskeleton. This initial report highlights the potential utility of myosin-based tension sensors in elucidating the roles of cytoskeletal contractility in a wide variety of contexts.