Structure-based discovery of a 4,5-Dihydropyrazole-cored PET ligand for imaging of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in the brain.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates programmed cell death and inflammation, contributing to a wide range of human pathologies, including inflammatory disorders, neurodegenerative conditions, and cancer. Despite this, no RIPK1 positron emission tomography (PET) ligand with significant in vivo specificity has been reported to date. In this work, we designed and synthesized a new family of dihydropyrazole-cored ligands suitable for 18F-labeling at the late stage. Among these, WL8 showed a strong binding affinity to RIPK1 (EC50 = 19.9 nM, Kd = 25 nM) and was successfully labeled with 18F in the 6-position of pyridine ring, yielding a high radiochemistry yield of 27.9 % (decay-corrected) and a high molar activity of 18.8-31.2 GBq/µmol. In in vitro autoradiography, [18F]WL8 showed some specific binding in the brain sections of rats and lipopolysaccharide (LPS) model mice. Preliminary PET studies in rat brains revealed that [18F]WL8 could efficiently penetrate the blood-brain barrier and was rapidly washed out. As anticipated, [18F]WL8 exhibited a high initial uptake (brain2min = 4.80 % ID/g) in mouse brains, followed by a rapid washout (brain60min = 0.14 % ID/g), although no clear specific binding to RIPK1 was observed. Moderate in vivo stability was noted for [18F]WL8 in mouse brains with 35.2 % of the parent fraction remaining after 30 min post-administration. Altogether, our work broadens the landscape and offers a new chemotype for RIPK1 PET ligand development.

Structure Tailoring of Hemicyanine Dyes for In Vivo Shortwave Infrared Imaging.

In vivo bioimaging using shortwave infrared (SWIR) (1000-2000 nm) molecular dyes enables deeper penetration and higher contrast compared to visible and near-infrared-I (NIR-I, 700-900 nm) dyes. Developing new SWIR molecules is still quite challenging. This study developed SRHCYs, a panel of fluorescent dyes based on hemicyanine, with adjustable absorbance (830-1144 nm) and emission (886-1217 nm) wavelength. The photophysical attributes of these dyes are precisely tailored by strengthening the donor parts and extending polymethine chains. SRHCY-3, with its clickable azido group, was chosen for high-performance imaging of blood vessels in living mice, enabling the precise detection of brain and lung cancer. The combination of these probes achieved in vivo multicolor imaging with negligible optical crosstalk. This report presents a series of SWIR hemicyanine dyes with promising spectroscopic properties for high-contrast bioimaging and multiplexing detection.

Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain.

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1-3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK'547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.

Clinical Insights into Brucella Peritonitis: A Comprehensive Analysis of Four Cases.

INTRODUCTION: Brucellosis, a globally distributed zoonotic disease, exhibits diverse clinical manifestations, with Brucella peritonitis being a rare but consequential complication. METHODS: Analyzing the medical records of four patients with Brucella peritonitis admitted to the First People's Hospital of Kashi Region from January 2022 to November 2023. A retrospective approach was used to analyze the general data, epidemiological history, clinical features, laboratory tests, and efficacy. All four patients with Brucella peritonitis were farmers. RESULTS: All of them were combined with decompensated stage of liver cirrhosis. The main manifestations were poor appetite, fatigue, bloating. Two patients were accompanied by moderate-high fever. All patients presented with mildly elevated C-reactive protein and procalcitonin < 0.25ng/ml. Brucella was cultured from blood in 2 cases, from pleural fluid in 1 case, and from ascitic fluid in another case. All patients had moderate-to-large amounts of ascites with elevated leukocytes in the ascites, predominantly mononuclear cells. Symptoms of the above patients were reduced or disappeared after effective anti-infection. CONCLUSION: When patients with decompensated cirrhosis present with exudative ascites dominated by elevated mononuclear cells, the possibility of Brucella peritonitis should also be considered in areas where brucellosis is endemic.

Incidence and Outcomes of Brucella Endocarditis in a High-Prevalence Area: A Single-Center Study.

OBJECTIVE: To analyze the clinical characteristics of Brucella endocarditis (BE) and observe the factors related to death to provide guidance for clinical treatment. METHODS: This study examined all patients with BE admitted to The First People's Hospital of Kashi Prefecture between January 2017 and November 2023. Clinical characteristics and follow-up outcomes were collected for analysis. RESULTS: This study revealed 774 cases of brucellosis and 14 cases of BE, with an overall incidence rate of 1.88%. Most of the patients were male (71.43%) and lived in areas where brucellosis is common. Patients ranged in age from 26 to 68 years. Common symptoms reported among patients included chest tightness and fatigue, and a significant portion also presented with congestive heart failure. Most patients exhibited normal white blood cell counts (WBC) but had elevated levels of C-reactive protein (CRP). Transthoracic ultrasound (TTE) revealed cardiac valve vegetation in all patients, along with positive blood cultures. Six patients (42.86%) completed heart surgery, and ten (71.43%) completed anti-infection treatment. Six patients died, five of whom did not undergo surgery. The other patient with Marfan syndrome died after surgery. Sex, WBC count, neutrophil (NEUT) and total bilirubin (TBIL) were significant factors associated with regression in BE patients (P < 0.05) according to univariate analysis. CONCLUSIONS: Patients with BE in Kashi have a severe clinical presentation at diagnosis, but early detection with improved cardiac ultrasound and aggressive treatment can improve the prognosis.

Characterization of a methyltransferase for iterative N-methylation at the leucinostatin termini in Purpureocillium lilacinum.

N-methyltransferase (NMT)-catalyzed methylation at the termini of nonribosomal peptides (NRPs) has rarely been reported. Here, we discover a fungal NMT LcsG for the iterative terminal N-methylation of a family of NRPs, leucinostatins. Gene deletion results suggest that LcsG is essential for leucinostatins methylation. Results from in vitro assays and HRESI-MS-MS analysis reveal the methylation sites as NH2, NHCH3 and N(CH3)2 in the C-terminus of various leucinostatins. LcsG catalysis yields new lipopeptides, some of which demonstrate effective antibiotic properties against the human pathogen Cryptococcus neoformans and the plant pathogen Phytophthora infestans. Multiple sequence alignments and site-directed mutagenesis of LcsG indicate the presence of a highly conserved SAM-binding pocket, along with two possible active site residues (D368 and D395). Molecular dynamics simulations show that the targeted N can dock between these two residues. Thus, this study suggests a method for increasing the variety of natural bioactivity of NPRs and a possible catalytic mechanism underlying the N-methylation of NRPs.

Can molecular hydrogen supplementation enhance physical performance in healthy adults? A systematic review and meta-analysis.

Background: Physical exertion during exercise often leads to increased oxidative stress and inflammatory responses, significantly affecting physical performance. Current strategies to mitigate these effects are limited by their effectiveness and potential side effects. Molecular hydrogen (H2) has gained attention for its antioxidant and anti-inflammatory properties. Studies have suggested that H2 supplementation contributes to antioxidant potential and anti-fatigue during exercise, but the variance in the observations and study protocols is presented across those studies. Objective: This systematic review and meta-analysis aimed to comprehensively characterize the effects of H2 supplementation on physical performance (i.e., endurance, muscular strength, and explosive power), providing knowledge that can inform strategies using H2 for enhancing physical performance. Methods: We conducted a literature search of six databases (PubMed, Web of Science, Medline, Sport-Discus, Embase, and PsycINFO) according to the PRISMA guidelines. The data were extracted from the included studies and converted into the standardized mean difference (SMD). After that, we performed random-effects meta-analyses and used the I 2 statistic to evaluate heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the quality of the evidence obtained from this meta-analysis. Results: In total, 27 publications consisting of 597 participants were included. The search finally included aerobic endurance, anaerobic endurance, muscular strength, lower limb explosive power, rating of perceived exertion (RPE), blood lactate (BLA), and average heart rate (HRavg) in the effect size (ES) synthesis. The ES of H2 on aerobic endurance, including V̇O2max (SMD = 0.09, p = 0.394; I 2 = 0%) and aerobic endurance exercise (SMD = 0.04, p = 0.687; I 2 = 0%), were not significant and trivial; the ES of H2 on 30 s maximal anaerobic endurance (SMD = 0.19, p = 0.239; I 2 = 0%) was not significant and trivial; the ES of H2 on muscular strength (SMD = 0.19, p = 0.265; I 2 = 0%) was not significant and trivial; but the ES of H2 on lower limb explosive power (SMD = 0.30, p = 0.018; I 2 = 0%) was significant and small. In addition, H2 reduces RPE (SMD = -0.37, p = 0.009; I 2 = 58.0%) and BLA (SMD = -0.37, p = 0.001; I 2 = 22.0%) during exercise, but not HRavg (SMD = -0.27, p = 0.094; I 2 = 0%). Conclusion: These findings suggest that H2 supplementation is favorable in healthy adults to improve lower limb explosive power, alleviate fatigue, and boost BLA clearance, but may not be effectively improving aerobic and anaerobic endurance and muscular strength. Future studies with more rigorous designs are thus needed to examine and confirm the effects of H2 on these important functionalities in humans. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO.

The Effect of 14-Day Consumption of Hydrogen-Rich Water Alleviates Fatigue but Does Not Ameliorate Dyspnea in Long-COVID Patients: A Pilot, Single-Blind, and Randomized, Controlled Trial.

(1) Background: Hydrogen (H2) may be a potential therapeutic agent for managing Long COVID symptoms due to its antioxidant and anti-inflammatory properties. However, more scientific literature is needed to describe the effects of H2 administration on treating symptoms. A study aimed to investigate the impact of hydrogen-rich water (HRW) administration on the fatigue and dyspnea of Long-COVID patients for 14 consecutive days. (2) Methods: In this randomized, single-blind, placebo-controlled study, 55 participants were recruited, and 23 of them were excluded. A total of 32 eligible participants were randomized into a hydrogen-rich water (HRW) group (n = 16) and a placebo water (PW) group (n = 16) in which they were instructed to consume hydrogen-rich water or placebo water for 14 days, respectively. The participants completed the Fatigue Severity Scale (FSS), Six-Minute Walk Test (6MWT), 30 s Chair Stand Test (30s-CST), Modified Medical Research Council Dyspnea Rating Scale (mMRC), Pittsburgh Sleep Quality Index (PSQI), and depression anxiety stress scale (DASS-21) before and after the intervention. A linear mixed-effects model was used to analyze the effects of HRW. Cohen's d values were used to assess the effect size when significance was observed. The mean change with 95% confidence intervals (95% CI) was also reported. (3) Results: The effects of HRW on lowering FSS scores (p = 0.046, [95% CI = -20.607, -0.198, d = 0.696] and improving total distance in the 6WMT (p < 0.001, [95% CI = 41.972, 61.891], d = 1.010), total time for the 30s-CST (p = 0.002, [95% CI = 1.570, 6.314], d = 1.190), and PSQI scores (p = 0.012, [95% CI = -5.169, 0.742], d = 1.274) compared to PW were of a significantly moderate effect size, while there was no significant difference in mMRC score (p = 0.556) or DASS-21 score (p > 0.143). (4) Conclusions: This study demonstrates that HRW might be an effective strategy for alleviating fatigue and improving cardiorespiratory endurance, musculoskeletal function, and sleep quality. Still, it does not ameliorate dyspnea among Long-COVID patients.

Can molecular hydrogen supplementation reduce exercise-induced oxidative stress in healthy adults? A systematic review and meta-analysis.

Objective: Exercise-induced oxidative stress affects multiple neurophysiological processes, diminishing the exercise performance. Hydrogen (H2) can selectively reduce excessive free radicals, but studies observed its "dual effects" on exercise-induced oxidative stress, that is, increasing or decreasing the oxidative stress. Therefore, we here conducted a systematic review and meta-analysis to quantitatively assess the influence of H2 on exercise-induced oxidative stress in healthy adults. Methods: We conducted a systematic review of publications across five databases. The following keywords were used for search strategy: ["hydrogen"[Mesh] or "molecular hydrogen" or "hydrogen rich water" or "hydrogen-rich water" or "hydrogen rich saline"] and ["Oxidative Stress"[Mesh] or "Antioxidative Stress" or "Oxidative Damage" or "Oxidative Injury" or "Oxidative Cleavage"] and ["randomized controlled trial"[Mesh] or "randomized" or "RCT"]. We included trials reporting the effects of H2 on exercise-induced oxidative stress and potential antioxidant capacity post-exercise in healthy adults. Additionally, subgroup analyses were conducted to explore how various elements of the intervention design affected those outcomes. Results: Six studies, encompassing seven experiments with a total of 76 participants, were included in our analysis. Among these studies, hydrogen-rich water, hydrogen bathing, and hydrogen-rich gas were three forms used in H2 administration. The H2 was applied in different timing, including before, during, or after exercise only, both before and after exercise, and repeatedly over days. Single-dose, multi-dose within 1 day and/or multiple-dose over days were implemented. It was observed that compared to placebo, the effects of H2 on oxidative stress (diacron-reactive oxygen metabolites, d-ROMs) was not significant (SMD = -0.01, 95%CI-0.42 to 0.39, p = 0.94). However, H2 induced greater improvement in antioxidant potential capacity (Biological Antioxidant Potential, BAP) (SMD = 0.29, 95% CI 0.04 to 0.54, p = 0.03) as compared to placebo. Subgroup analyses revealed that H2 supplementation showed greater improvement (SMD = 0.52, 95%CI 0.16 to 0.87, p = 0.02) in the antioxidant potential capacity of intermittent exercises than continuous exercise. Conclusion: H2 supplementation can help enhance antioxidant potential capacity in healthy adults, especially in intermittent exercise, but not directly diminish the levels of exercise-induced oxidative stress. Future studies with more rigorous design are needed to examine and confirm these findings. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=364123, Identifier CRD42022364123.

A Novel Coacervate Embolic Agent for Tumor Chemoembolization.

Transcatheter arterial chemoembolization (TACE) has proven effective in blocking tumor-supplied arteries and delivering localized chemotherapeutic treatment to combat tumors. However, traditional embolic TACE agents exhibit certain limitations, including insufficient chemotherapeutic drug-loading and sustained-release capabilities, non-biodegradability, susceptibility to aggregation, and unstable mechanical properties. This study introduces a novel approach to address these shortcomings by utilizing a complex coacervate as a liquid embolic agent for tumor chemoembolization. By mixing oppositely charged quaternized chitosan (QCS) and gum arabic (GA), a QCS/GA polymer complex coacervate with shear-thinning property is obtained. Furthermore, the incorporation of the contrast agent Iohexol (I) and the chemotherapeutic doxorubicin (DOX) into the coacervate leads to the development of an X-ray-opaque QCS/GA/I/DOX coacervate embolic agent capable of carrying drugs. This innovative formulation effectively embolizes the renal arteries without recanalization. More importantly, the QCS/GA/I/DOX coacervate can successfully embolize the supplying arteries of the VX2 tumors in rabbit ear and liver. Coacervates can locally release DOX to enhance its therapeutic effects, resulting in excellent antitumor efficacy. This coacervate embolic agent exhibits substantial potential for tumor chemoembolization due to its shear-thinning performance, excellent drug-loading and sustained-release capabilities, good biocompatibility, thrombogenicity, biodegradability, safe and effective embolic performance, and user-friendly application.

Basic concepts, recent advances, and future perspectives in the diagnosis of bovine mastitis.

Mastitis is one of the most widespread infectious diseases that adversely affects the profitability of the dairy industry worldwide. Accurate diagnosis and identification of pathogens early to cull infected animals and minimize the spread of infection in herds is critical for improving treatment effects and dairy farm welfare. The major pathogens causing mastitis and pathogenesis are assessed first. The most recent and advanced strategies for detecting mastitis, including genomics and proteomics approaches, are then evaluated . Finally, the advantages and disadvantages of each technique, potential research directions, and future perspectives are reported. This review provides a theoretical basis to help veterinarians select the most sensitive, specific, and cost-effective approach for detecting bovine mastitis early.

Mutational profiling of mitochondrial DNA reveals an epithelial ovarian cancer-specific evolutionary pattern contributing to high oxidative metabolism.

BACKGROUND: Epithelial ovarian cancer (EOC) heavily relies on oxidative phosphorylation (OXPHOS) and exhibits distinct mitochondrial metabolic reprogramming. Up to now, the evolutionary pattern of somatic mitochondrial DNA (mtDNA) mutations in EOC tissues and their potential roles in metabolic remodelling have not been systematically elucidated. METHODS: Based on a large somatic mtDNA mutation dataset from private and public EOC cohorts (239 and 118 patients, respectively), we most comprehensively characterised the EOC-specific evolutionary pattern of mtDNA mutations and investigated its biological implication. RESULTS: Mutational profiling revealed that the mitochondrial genome of EOC tissues was highly unstable compared with non-cancerous ovary tissues. Furthermore, our data indicated the delayed heteroplasmy accumulation of mtDNA control region (mtCTR) mutations and near-complete absence of mtCTR non-hypervariable segment (non-HVS) mutations in EOC tissues, which is consistent with stringent negative selection against mtCTR mutation. Additionally, we observed a bidirectional and region-specific evolutionary pattern of mtDNA coding region mutations, manifested as significant negative selection against mutations in complex V (ATP6/ATP8) and tRNA loop regions, and potential positive selection on mutations in complex III (MT-CYB). Meanwhile, EOC tissues showed higher mitochondrial biogenesis compared with non-cancerous ovary tissues. Further analysis revealed the significant association between mtDNA mutations and both mitochondrial biogenesis and overall survival of EOC patients. CONCLUSIONS: Our study presents a comprehensive delineation of EOC-specific evolutionary patterns of mtDNA mutations that aligned well with the specific mitochondrial metabolic remodelling, conferring novel insights into the functional roles of mtDNA mutations in EOC tumourigenesis and progression.

A High-Efficiency Capture-Based NGS Approach for Comprehensive Analysis of Mitochondrial Transcriptome.

The transcription of the mitochondrial genome is pivotal for maintenance of mitochondrial functions, and the deregulated mitochondrial transcriptome contributes to various pathological changes. Despite substantial progress having been achieved in uncovering the transcriptional complexity of the nuclear transcriptome, many unknowns and controversies remain for the mitochondrial transcriptome, partially owing to the lack of a highly efficient mitochondrial RNA (mtRNA) sequencing and analysis approach. Here, we first comprehensively evaluated the influence of essential experimental protocols, including strand-specific library construction, two RNA enrichment strategies, and optimal rRNA depletion, on accurately profiling mitochondrial transcriptome in whole-transcriptome sequencing (WTS) data. Based on these insights, we developed a highly efficient approach specifically suitable for targeted sequencing of whole mitochondrial transcriptome, termed capture-based mtRNA seq (CAP), in which strand-specific library construction and optimal rRNA depletion were applied. Compared with WTS, CAP has a great decrease of required data volume without affecting the sensitivity and accuracy of detection. In addition, CAP also characterized the unannotated mt-tRNA transcripts whose expression levels are below the detection limits of conventional WTS. As a proof-of-concept characterization of mtRNAs, the transcription initiation sites and mtRNA cleavage ratio were accurately identified in CAP data. Moreover, CAP had very reliable performance in plasma and single-cell samples, highlighting its wide application. Altogether, the present study has established a highly efficient pipeline for targeted sequencing of mtRNAs, which may pave the way toward functional annotation of mtRNAs and mtRNA-based diagnostic and therapeutic strategies in various diseases.

Effects of concurrent aerobic and resistance training on vascular health in type 2 diabetes: a systematic review and meta-analysis.

Objective: To determine the impacts of concurrent aerobic and resistance training on vascular structure (IMT) and function (PWV, FMD, NMD) in type 2 diabetes (T2D). Methods: The electronic databases PubMed, Web of Science Core Collection, Cochrane Library, Embase, Scopus, CINAHL, and SPORTDiscus were systematically searched for articles on "type 2 diabetes" and "concurrent training" published from inception to August 2, 2022. We included randomized controlled trials that examined the effects of concurrent training versus passive controls on IMT, PWV, FMD and NMD in T2D. Results: Ten studies were eligible, including a total of 361 participants. For IMT, concurrent training showed a slight decrease by 0.05 mm (95% CI -0.11 to 0.01, p > 0.05). concurrent training induced an overall significant improvement in FMD by 1.47% (95% CI 0.15 to 2.79, p < 0.05) and PWV by 0.66 m/s (95% CI -0.89 to -0.43, p < 0.01) in type 2 diabetics. However, concurrent training seemed to exaggerate the impaired NMD (WMD = -2.30%, 95% CI -4.02 to -0.58, p < 0.05). Conclusions: Concurrent training is an effective method to improve endothelial function and artery stiffness in T2D. However, within 24 weeks concurrent training exacerbates vascular smooth muscle dysfunction. More research is needed to explore whether longer and/or higher-intensity concurrent training interventions could enhance the vascular structure and smooth muscle function in this population. Systematic review registration: www.crd.york.ac.uk/PROSPERO/, identifier CRD42022350604.

Surface-decorated nanoliposomal leonurine targets activated fibroblast-like synoviocytes for efficient rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint destruction, leading to impaired life quality, disability, and even premature mortality. However, current medications suffer from limited clinical outcomes and severe side effects due to low bioavailability and non-specific distribution after administration. Herein, a targeting nanosystem (HAP-Lipo@Leo) was constructed for efficient RA treatment, which can precisely deliver a natural anti-arthritic drug leonurine (Leo) to the inflamed joint by HAP-1 peptide-mediated recognition of activated fibroblast-like synoviocytes (FLS). More specifically, HAP-Lipo@Leo was prepared by a combination of thin film hydration and high-pressure microfluidization and surface-decorated with HAP-1 peptide and PEG before encapsulating Leo by the ammonium sulfate gradient method. The as-obtained HAP-Lipo@Leo can be selectively internalized by activated FLS and impairs the lamellipodia formation and overexpression of inflammatory cytokines, both of which play detrimental roles in joint damage. Furthermore, HAP-Lipo@Leo demonstrated arthritic joint-specific distribution, significant inhibition of synovial inflammation, and reversal of cartilage and bone destruction in adjuvant-induced arthritis rats as evidenced by comprehensive investigations including ELISA tests, histopathology examinations, and micro-CT analysis. In addition, HAP-Lipo@Leo exhibited good biocompatibility and safety both in vitro and in vivo. Taken together, HAP-Lipo@Leo holds great potential for clinical RA management by integrating activated FLS targeting, long circulation, multifaceted therapeutic effects, and excellent biocompatibility.

A physiologically based pharmacokinetic model to optimize the dosage regimen and withdrawal time of cefquinome in pigs.

Cefquinome is widely used to treat respiratory tract diseases of swine. While extra-label dosages of cefquinome could improve clinical efficacy, they might lead to excessively high residues in animal-derived food. In this study, a physiologically based pharmacokinetic (PBPK) model was calibrated based on the published data and a microdialysis experiment to assess the dosage efficiency and food safety. For the microdialysis experiment, in vitro/in vivo relative recovery and concentration-time curves of cefquinome in the lung interstitium were investigated. This PBPK model is available to predict the drug concentrations in the muscle, kidney, liver, plasma, and lung interstitial fluid. Concentration-time curves of 1000 virtual animals in different tissues were simulated by applying sensitivity and Monte Carlo analyses. By integrating pharmacokinetic/pharmacodynamic target parameters, cefquinome delivered at 3-5 mg/kg twice daily is advised for the effective control of respiratory tract infections of nursery pig, which the bodyweight is around 25 kg. Based on the predicted cefquinome concentrations in edible tissues, the withdrawal interval is 2 and 3 days for label and the extra-label doses, respectively. This study provides a useful tool to optimize the dosage regimen of cefquinome against respiratory tract infections and predicts the concentration of cefquinome residues in edible tissues. This information would be helpful to improve the food safety and guide rational drug usage.

Metastatic pattern of ovarian cancer delineated by tracing the evolution of mitochondrial DNA mutations.

Ovarian cancer (OC) is the most lethal gynecologic tumor and is characterized by a high rate of metastasis. Challenges in accurately delineating the metastatic pattern have greatly restricted the improvement of treatment in OC patients. An increasing number of studies have leveraged mitochondrial DNA (mtDNA) mutations as efficient lineage-tracing markers of tumor clonality. We applied multiregional sampling and high-depth mtDNA sequencing to determine the metastatic patterns in advanced-stage OC patients. Somatic mtDNA mutations were profiled from a total of 195 primary and 200 metastatic tumor tissue samples from 35 OC patients. Our results revealed remarkable sample-level and patient-level heterogeneity. In addition, distinct mtDNA mutational patterns were observed between primary and metastatic OC tissues. Further analysis identified the different mutational spectra between shared and private mutations among primary and metastatic OC tissues. Analysis of the clonality index calculated based on mtDNA mutations supported a monoclonal tumor origin in 14 of 16 patients with bilateral ovarian cancers. Notably, mtDNA-based spatial phylogenetic analysis revealed distinct patterns of OC metastasis, in which a linear metastatic pattern exhibited a low degree of mtDNA mutation heterogeneity and a short evolutionary distance, whereas a parallel metastatic pattern showed the opposite trend. Moreover, a mtDNA-based tumor evolutionary score (MTEs) related to different metastatic patterns was defined. Our data showed that patients with different MTESs responded differently to combined debulking surgery and chemotherapy. Finally, we observed that tumor-derived mtDNA mutations were more likely to be detected in ascitic fluid than in plasma samples. Our study presents an explicit view of the OC metastatic pattern, which sheds light on efficient treatment for OC patients.

Salmonella antimicrobials inherited and the non-inherited resistance: mechanisms and alternative therapeutic strategies.

Salmonella spp. is one of the most important foodborne pathogens. Typhoid fever and enteritis caused by Salmonella enterica are associated with 16-33 million infections and 500,000 to 600,000 deaths annually worldwide. The eradication of Salmonella is becoming increasingly difficult because of its remarkable capacity to counter antimicrobial agents. In addition to the intrinsic and acquired resistance of Salmonella, increasing studies indicated that its non-inherited resistance, which commonly mentioned as biofilms and persister cells, plays a critical role in refractory infections and resistance evolution. These remind the urgent demand for new therapeutic strategies against Salmonella. This review starts with escape mechanisms of Salmonella against antimicrobial agents, with particular emphasis on the roles of the non-inherited resistance in antibiotic failure and resistance evolution. Then, drug design or therapeutic strategies that show impressive effects in overcoming Salmonella resistance and tolerance are summarized completely, such as overcoming the barrier of outer membrane by targeting MlaABC system, reducing persister cells by limiting hydrogen sulfide, and applying probiotics or predatory bacteria. Meanwhile, according to the clinical practice, the advantages and disadvantages of above strategies are discussed. Finally, we further analyze how to deal with this tricky problems, thus can promote above novel strategies to be applied in the clinic as soon as possible. We believed that this review will be helpful in understanding the relationships between tolerance phenotype and resistance of Salmonella as well as the efficient control of antibiotic resistance.

Fluorine-18-Labeled Diaryl-azines as Improved ß-Amyloid Imaging Tracers: From Bench to First-in-Human Studies.

The deposition of ß-amyloid (Aß) in the brain is a pathologic hallmark of Alzheimer's disease (AD), appearing years before the onset of symptoms, and its detection is incorporated into clinical diagnosis. Here, we have discovered and developed a class of diaryl-azine derivatives for detecting Aß plaques in the AD brain using PET imaging. After a set of comprehensive preclinical assessments, we screened out a promising Aß-PET tracer, [18F]92, with a high binding affinity to the Aß aggregates, significant binding ability with the AD brain sections, and optimal brain pharmacokinetic properties in rodents and non-human primates. The first-in-human PET study declared that [18F]92 displayed low white matter uptake and could bind to Aß pathology for distinguishing AD from healthy control subjects. All these results support that [18F]92 might become a promising PET tracer for visualizing Aß pathology in AD patients.