Detection of H1N1 Influenza Virus in the Bile of a Severe Influenza Mouse Model.

AIMS: Influenza virus infection may lead to fatal complications including multi-organ failure and sepsis. The influenza virus was detected in various extra-pulmonary organs in autopsy studies during the 2009 pandemic. However, limited research has been conducted on the presence of viral particle or viral components in the peripheral blood. METHODS AND RESULTS: We established a mouse model for severe H1N1 influenza. The bile and blood samples were collected over time and inoculated into embryonated chicken eggs. We detected live influenza virus in bile and blood samples in early infection. Immunofluorescence showed influenza viral components in the liver tissue. No live virus was isolated in the bile in mice intragastrically administered with influenza virus, indicating that the virus was spread from the blood stream. Targeted metabolomics analysis of bile acid and liver tissues showed that a secondary bile acid (3-dehydrocholic acid) was decreased after influenza H1N1 infection. Genes related with fatty acid metabolism and bile secretion pathways were down-regulated in liver after influenza virus infection. CONCLUSION: Our study indicated that influenza virus viremia is present in severe influenza, and that the liver is a target organ for influenza viral sepsis.

Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane.

Rationale: An impairment of plasma membrane repair has been implicated in various diseases such as muscular dystrophy and ischemia/reperfusion injury. MOTS-c, a short peptide encoded by mitochondria, has been shown to pass through the plasma membrane into the bloodstream. This study determined whether this biological behavior was involved in membrane repair and its underlying mechanism. Methods and Results: In human participants, the level of MOTS-c was positively correlated with the abundance of mitochondria, and the membrane repair molecule TRIM72. In contrast to high-intensity eccentric exercise, moderate-intensity exercise improved sarcolemma integrity and physical performance, accompanied by an increase of mitochondria beneath the damaged sarcolemma and secretion of MOTS-c. Furthermore, moderate-intensity exercise increased the interaction between MOTS-c and TRIM72, and MOTS-c facilitated the trafficking of TRIM72 to the sarcolemma. In vitro studies demonstrated that MOTS-c attenuated membrane damage induced by hypotonic solution, which could be blocked by siRNA-TRIM72, but not AMPK inhibitor. Co-immunoprecipitation study showed that MOTS-c interacted with TRIM72 C-terminus, but not N-terminus. The dynamic membrane repair assay revealed that MOTS-c boosted the trafficking of TRIM72 to the injured membrane. However, MOTS-c itself had negligible effects on membrane repair, which was recapitulated in TRIM72-/- mice. Unexpectedly, MOTS-c still increased the fusion of vesicles with the membrane in TRIM72-/- mice, and dot blot analysis revealed an interaction between MOTS-c and phosphatidylinositol (4,5) bisphosphate [PtdIns (4,5) P2]. Finally, MOTS-c blunted ischemia/reperfusion-induced membrane disruption, and preserved heart function. Conclusions: MOTS-c/TRIM72-mediated membrane integrity improvement participates in mitochondria-triggered membrane repair. An interaction between MOTS-c and plasma lipid contributes to the fusion of vesicles with membrane. Our data provide a novel therapeutic strategy for rescuing organ function by facilitating membrane repair with MOTS-c.

Social Isolation Changes and Long-Term Outcomes Among Older Adults.

Importance: While the association between cross-sectional measures of social isolation and adverse health outcomes is well established, less is known about the association between changes in social isolation and health outcomes. Objective: To assess changes of social isolation and mortality, physical function, cognitive function, cardiovascular disease (CVD), and stroke. Design, Setting, and Participants: In a cohort design, social isolation changes in 4 years and subsequent risk of mortality and other outcomes were assessed using the 13 649 eligible Health and Retirement Study (HRS) respondents from the 2006 to 2020 waves. Data were analyzed from October 11, 2023, to April 26, 2024. Exposure: The main exposure was the change in social isolation measured by the Steptoe 5-item Social Isolation Index from the initial assessment to a second assessment conducted 4 years later. Participants were classified into decreased isolation, stable, or increased isolation groups, stratified by their baseline isolation status. Main Outcomes and Measures: The primary outcomes were mortality, self-reported dependencies in activities of daily living, Alzheimer disease and Alzheimer disease-related dementia, CVD, and stroke. Dementia, CVD, and stroke were assessed using HRS-linked Medicare records. Incidence rates (IRs) of each group were estimated and a Cox proportional hazards regression model was used, with inverse-probability treatment weighting to adjust for confounders. Results: Among 13 649 participants (mean [SD] age at baseline, 65.3 [9.5] years; 8011 [58.7%] women) isolated at baseline, those with increased isolation had higher mortality (n = 693; IR = 68.19; 95% CI, 60.89-76.36 per 1000 person-years) than those who were stable (n = 1796; IR = 44.02; 95% CI, 40.47-47.88 person-years) or had decreased isolation (n = 2067; IR = 37.77; 95% CI, 34.73-41.09 person-years) isolation. Increased isolation was associated with higher risks of mortality (adjusted hazard ratio [AHR], 1.29; 95% CI, 1.09-1.51), disability (AHR, 1.35; 95% CI, 1.09-1.67), and dementia (AHR, 1.40; 95% CI, 1.02-1.93) compared with stable isolation. Similar findings were observed among socially nonisolated participants at baseline. Conclusions and Relevance: In this cohort study, increased isolation was associated with elevated risks of mortality, disability, and dementia, irrespective of baseline isolation status. These results underscore the importance of interventions targeting the prevention of increased isolation among older adults to mitigate its adverse effects on mortality, as well as physical and cognitive function decline.

ALG5 Regulates STF-62247-Induced Milk Fat Synthesis via the mTOR Signaling Pathway.

Milk fat content is a critical indicator of milk quality. Exploring the key regulatory genes involved in milk fat synthesis is essential for enhancing milk fat content. STF-62247 (STF), a thiazolamide compound, has the potential to bind with ALG5 and upregulate lipid droplets in fat synthesis. However, the effect of STF on the process of milk fat synthesis and whether it acts through ALG5 remains unknown. In this study, the impact of ALG5 on milk fat synthesis and its underlying mechanism were investigated using bovine mammary epithelial cells (BMECs) and mouse models through real-time PCR, western blotting, Oil Red O staining, and triglyceride analysis. Experimental findings revealed a positive correlation between STF and ALG5 with the ability to synthesize milk fat. Silencing ALG5 led to decreased expression of FASN, SREBP1, and PPARγ in BMECs, as well as reduced phosphorylation levels in the PI3K/AKT/mTOR signaling pathway. Moreover, the phosphorylation levels of the PI3K/AKT/mTOR signaling pathway were restored when ALG5 silencing was followed by the addition of STF. These results suggest that STF regulates fatty acid synthesis in BMECs by affecting the PI3K/AKT/mTOR signaling pathway through ALG5. ALG5 is possibly a new factor in milk fat synthesis.

Structural basis for human Cav3.2 inhibition by selective antagonists.

The Cav3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Cav3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 Å to 3.2 Å. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity.

Quantum Light Generation Based on GaN Microring toward Fully On-Chip Source.

An integrated quantum light source is increasingly desirable in large-scale quantum information processing. Despite recent remarkable advances, a new material platform is constantly being explored for the fully on-chip integration of quantum light generation, active and passive manipulation, and detection. Here, for the first time, we demonstrate a gallium nitride (GaN) microring based quantum light generation in the telecom C-band, which has potential toward the monolithic integration of quantum light source. In our demonstration, the GaN microring has a free spectral range of 330 GHz and a near-zero anomalous dispersion region of over 100 nm. The generation of energy-time entangled photon pair is demonstrated with a typical raw two-photon interference visibility of 95.5±6.5%, which is further configured to generate a heralded single photon with a typical heralded second-order autocorrelation g_{H}^{(2)}(0) of 0.045±0.001. Our results pave the way for developing a chip-scale quantum photonic circuit.

Single-Shot Laser-Induced Switching of an Exchange Biased Antiferromagnet.

Ultrafast manipulation of magnetic order has challenged the understanding of the fundamental and dynamic properties of magnetic materials. So far single-shot magnetic switching has been limited to ferrimagnetic alloys, multilayers, and designed ferromagnetic (FM) heterostructures. In FM/antiferromagnetic (AFM) bilayers, exchange bias (He) arises from the interfacial exchange coupling between the two layers and reflects the microscopic orientation of the antiferromagnet. Here the possibility of single-shot switching of the antiferromagnet (change of the sign and amplitude of He) with a single femtosecond laser pulse in IrMn/CoGd bilayers is demonstrated. The manipulation is demonstrated in a wide range of fluences for different layer thicknesses and compositions. Atomistic simulations predict ultrafast switching and recovery of the AFM magnetization on a timescale of 2 ps. The results provide the fastest and the most energy-efficient method to set the exchange bias and pave the way to potential applications for ultrafast spintronic devices.

CGA alleviates LPS-induced inflammation and milk fat reduction in BMECs through the NF-κB signaling pathway.

Mastitis is an easy clinical disease in dairy cows, which seriously affects the milk yield and quality of dairy cows. Chlorogenic acid (CGA), a polyphenolic substance, is abundant in Eucommia ulmoides leaves and has anti-inflammatory and anti-oxidative stress effects. Here, we explore whether CGA attenuated lipopolysaccharide (LPS)-induced inflammation and decreased milk fat in bovine mammary epithelial cells (BMECs). 10 µg/mL LPS was used to induce mastitis in BMECs. QRT-PCR, Western blotting, oil red O staining, and triglyceride (TG) assay were used to examine the effects of CGA on BMECs, including inflammatory response, oxidative stress response, and milk fat synthesis. The results showed that CGA repaired LPS-induced inflammation in BMECs. The expression of IL-6, IL-8, TNF-α, IL-1ß, and iNOS was decreased, and the expression levels of CHOP, XCT, NRF2, and HO-1 were increased, which reduced the oxidative stress level of cells and alleviated the reduction of milk fat synthesis. In addition, the regulation of P65 phosphorylation by CGA suggests that CGA may exert its anti-inflammatory and anti-oxidative effects through the NF-κB signaling pathway. Our study showed that CGA attenuated LPS-induced inflammation and oxidative stress, and restored the decrease in milk fat content in BMECs by regulating the NF-κB signaling pathway.

Berbamine targets cancer stem cells and reverses cabazitaxel resistance via inhibiting IGF2BP1 and p-STAT3 in prostate cancer.

BACKGROUND: Cancer stem cells (CSCs) are a small subpopulation of tumor cells with the capability of self-renewal and drug resistance, leading to tumor progression and disease relapse. Our study aimed to investigate the antitumor effect of berbamine, extracted from berberis amurensis, on prostate CSCs. METHODS: Sphere formation was used to collect prostate CSCs. The viability, proliferation, invasion, migration, and apoptosis assays were used to evaluate the antitumor effect of berbamine on prostate CSCs. Prostate CSC markers were analyzed by flow cytometry and qRT-PCR. Small RNA sequencing analysis was conducted to analyse miRNAs. Exosomes were extracted using the ExoQuick-TC kit and verified by testing exosomal markers using western blot. RESULTS: Berbamine targets prostate CSCs. Additionally, berbamine enhanced the antitumor effect of cabazitaxel, a second-line chemotherapeutic drug for advanced prostate cancer, and re-sensitized Cabazitaxel-resistant PCa cells (CabaR-DU145) to cabazitaxel by inhibiting ABCG2, CXCR4, IGF2BP1, and p-STAT3. Berbamine enhanced the expression of let-7 miRNA family and miR-26b and influenced the downstream targets IGF2BP1 and p-STAT3, respectively. Silencing CXCR4 and ABCG2 downregulated the expression of IGF2BP1 and p-STAT3, respectively. Importantly, berbamine enhanced also levels of exosomal let-7 family and miR-26b, suggesting that berbamine possibly influences the expression of let-7 family and miR-26b through exosome delivery. Exosomes derived from berbamine-treated CabaR-DU145 cells re-sensitized the cells to cabazitaxel. CONCLUSION: Berbamine enhanced the toxic activity of cabazitaxel and reversed cabazitaxel resistance potentially through CXCR4/exosomal let-7/IGF2BP1 and ABCG2/exosomal miR-26b/p-STAT3 axes.

Effects of dissolved organic matter, pH and nutrient on ciprofloxacin bioaccumulation and toxicity in duckweed.

Water pollution induced by antibiotics has garnered considerable concern, necessitating urgent and effective removal methods. This study focused on exploring ciprofloxacin (CIP) removal by duckweed and assessing CIP bioaccumulation and toxic effects within duckweed under varying dissolved organic matter categories, pH levels, and nutrient (nitrogen (N) and phosphorus (P)) levels. The results revealed the proficient and rapid elimination of CIP from water by duckweed, resulting in 86.17 % to 92.82 % removal efficiency at the end of the 7-day experiment. Across all exposure groups, varying degrees of CIP bioaccumulation in duckweed were evident, with uptake established as a primary pathway for CIP elimination within this plant. Additionally, five CIP metabolites were identified in duckweed tissues. Interestingly, the presence of humic acid (HA) and fulvic acid (FA) reduced CIP absorption by duckweed, with FA yielding a more pronounced impact. Optimal CIP removal was recorded at a pH of 7.5, while duckweed displayed heightened physiological stress induced by CIP at pH 8.5. Although the influence of N and P concentrations on CIP removal by duckweed was modest, excessive N and P levels intensified the physiological strain of CIP on duckweed.

MSI2 Modulates Unsaturated Fatty Acid Metabolism by Binding FASN in Bovine Mammary Epithelial Cells.

The regulation of fatty acid metabolism is crucial for milk flavor and quality. Therefore, it is important to explore the genes that play a role in fatty acid metabolism and their mechanisms of action. The RNA-binding protein Musashi2 (MSI2) is involved in the regulation of numerous biological processes and plays a regulatory role in post-transcriptional translation. However, its role in the mammary glands of dairy cows has not been reported. The present study examined MSI2 expression in mammary glands from lactating and dry milk cows. Experimental results in bovine mammary epithelial cells (BMECs) showed that MSI2 was negatively correlated with the ability to synthesize milk fat and that MSI2 decreased the content of unsaturated fatty acids (UFAs) in BMECs. Silencing of Msi2 increased triglyceride accumulation in BMECs and increased the proportion of UFAs. MSI2 affects TAG synthesis and milk fat synthesis by regulating fatty acid synthase (FASN). In addition, RNA immunoprecipitation experiments in BMECs demonstrated for the first time that MSI2 can bind to the 3'-UTR of FASN mRNA to exert a regulatory effect. In conclusion, MSI2 affects milk fat synthesis and fatty acid metabolism by regulating the triglyceride synthesis and UFA content through binding FASN.

The development of a clinical research educational training for community health workers using the joint task force for clinical trial competency framework.

Introduction: The NYU Clinical & Translational Science Institute, in collaboration with a number of community-engaged initiatives, developed a training for community health workers (CHWs) to enhance health literacy about clinical research. This innovative research training provides CHWs with a basic level of competency in clinical research to convey the importance of research to communities and better advocate for their health needs. CHWs are an underutilized resource to engage diverse populations in clinical research. The training also addresses the need to expand and diversify the clinical research workforce-integrating CHWs into research teams and connecting underserved populations with research opportunities to enhance quality of care. Methods: Structured individual interviews and focus group sessions were held with CHWs as well as clinical research faculty and staff to identify knowledge gaps in clinical research and identify best practices for educating community members on research. Using the Joint Task Force (JTF) for Clinical Trial Competency framework, an online course was developed consisting of 28 modules offered asynchronously for internal and external audiences. Topics include the fundamentals of clinical research, scientific concepts and research design, research ethics, study management, clinical study operations, communications, and teamwork, as well as the importance of diversity and equity in research and the barriers to participation. Results: Learning was evaluated using multiple choice questions after each module to ensure the fundamental level of knowledge was obtained. A separate survey, completed at the conclusion of the course, evaluated the quality of training. Discussion: The course aims to enhance the knowledge and skills of CHWs to help promote greater understanding of clinical research within the communities they serve, including the risks and benefits of clinical research and opportunities for participation. As members of the research team, community stakeholders can help design interventions tailored to the unique needs, culture, and context of their communities. In addition, this research training equips trainees with skills to engage the community actively, involving them in the research process and ensuring community priorities are represented in research through more community engaged processes.

Occurrence, Bioaccumulation, Metabolism and Ecotoxicity of Fluoroquinolones in the Aquatic Environment: A Review.

In recent years, there has been growing concern about antibiotic contamination in water bodies, particularly the widespread presence of fluoroquinolones (FQs), which pose a serious threat to ecosystems due to their extensive use and the phenomenon of "pseudo-persistence". This article provides a comprehensive review of the literature on FQs in water bodies, summarizing and analyzing contamination levels of FQs in global surface water over the past three years, as well as the bioaccumulation and metabolism patterns of FQs in aquatic organisms, their ecological toxicity, and the influencing factors. The results show that FQs contamination is widespread in surface water across the surveyed 32 countries, with ciprofloxacin and norfloxacin being the most heavy contaminants. Furthermore, contamination levels are generally higher in developing and developed countries. It has been observed that compound types, species, and environmental factors influence the bioaccumulation, metabolism, and toxicity of FQs in aquatic organisms. FQs tend to accumulate more in organisms with higher lipid content, and toxicity experiments have shown that FQs exhibit the highest toxicity to bacteria and the weakest toxicity to mollusk. This article summarizes and analyzes the current research status and shortcomings of FQs, providing guidance and theoretical support for future research directions.

Preparation of chitosan/citral forward osmosis membrane via Schiff base reaction with enhanced anti-bacterial properties.

In this study, hydrogels generated by the Schiff base reaction between citral and chitosan (CS) were used for the first time to improve the anti-bacterial property of forward osmosis (FO) membranes. The composite membranes were characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), Water contact angle (WCA), Zeta potential and confocal laser scanning microscopic (CLSM). In the FO filtration experiment, the membrane performance of TFC-1 with 1 M sodium chloride solution as the draw solution and deionized water as the feed solution was the best, with the water flux of 25.54 ± 0.7 L m-2 h-1 and the reverse salt flux of 4.7 ± 0.4 g m-2 h-1. Although the hydrogel coating produced a certain hydraulic resistance, the flux of the modified membrane was only reduced by about 8%, compared with the unmodified membrane. However, the anti-bacterial property (Pseudomonas aeruginosa) and anti-fouling properties (bovine serum protein and lysozyme protein) of the modified membranes were improved, showing good antibacterial properties (99%) and flux recovery rate (over 90%). The modified method has the advantages of easy access to raw materials, simple operation and no risk of secondary pollution, which can effectively reduce the cost of chemical cleaning and extend the service life of the membrane. The modification of membrane by chitosan-based hydrogel is a promising option in the field of membrane anti-bacteria.

Corrigendum: The disease associated Tau35 fragment has an increased propensity to aggregate compared to full-length tau.

[This corrects the article DOI: 10.3389/fmolb.2021.779240.].

Occurrence and Health Risk Assessment of Sulfonamide Antibiotics in Different Freshwater Fish in Northeast China.

This study aimed to investigate the levels of 12 sulfonamide antibiotics in freshwater fish species obtained from three cities in northeastern China (Harbin, Changchun, and Shenyang). The analysis was conducted using HPLC-MS/MS to accurately quantify the antibiotic concentrations in the fish samples. The results showed that the average levels of sulfonamide antibiotics in fish samples from Harbin, Changchun, and Shenyang were 1.83 ng/g ww, 0.98 ng/g ww, and 1.60 ng/g ww, respectively. Sulfamethoxazole displayed the highest levels and detection rates in all three cities, whereas sulphapyridine exhibited the lowest concentrations in all the fish samples. The levels of sulfonamide antibiotic residues in the different fish species varied widely among the cities, and the highest level of antibiotic residues was found in the muscle of carnivorous fish. The results from a health risk evaluation on the consumption of these fish indicated that the risk from long-term antibiotic exposure to local residents from the intake of the sampled fish was small and not sufficient to pose a significant health risk to consumers.

Identification of a novel combination treatment strategy in clear cell renal cell carcinoma stem cells with shikonin and ipilimumab.

Background: Management of clear cell renal cell carcinoma (ccRCC) has changed rapidly in recent years with the advent of immune checkpoint inhibitors (ICIs). However, only a limited number of patients can sustainably respond to immune checkpoint inhibitors and many patients develop resistance to therapy, creating an additional need for therapeutic strategies to improve the efficacy of systemic therapies. Methods: Binding probability and target genes prediction using online databases, invasion, migration, and apoptosis assays as well as the inhibition of cancer stem cells (CSCs) markers in ccRCC cell lines were used to select the most promising phytochemicals (PTCs). Mixed lymphocyte tumor cell culture (MLTC) system and flow cytometry were performed to confirm the potential combination strategy. The potential immunotherapeutic targets and novel CSC markers were identified via the NanoString analysis. The mRNA and protein expression, immune signatures as well as survival characteristics of the marker in ccRCC were analyzed via bioinformation analysis. Results: Shikonin was selected as the most promising beneficial combination partner among 11 PTCs for ipilimumab for the treatment of ccRCC patients due to its strong inhibitory effect on CSCs, the significant reduction of FoxP3+ Treg cells in peripheral blood mononuclear cells (PBMCs) of patients and activation of the endogenous effector CD3+CD8+ and CD3+CD4+ T cells in response to the recognition of tumor specific antigens. Based on NanoString analysis VCAM1, CXCL1 and IL8 were explored as potential immunotherapeutic targets and novel CSC markers in ccRCC. The expression of VCAM1 was higher in the tumor tissue both at mRNA and protein levels in ccRCC compared with normal tissue, and was significantly positively correlated with immune signatures and survival characteristics in ccRCC patients. Conclusion: We propose that a combination of shikonin and ipilimumab could be a promising treatment strategy and VCAM1 a novel immunotherapeutic target for the treatment of ccRCC.

SEVERE BURN-INDUCED MITOCHONDRIAL RECRUITMENT OF CALPAIN CAUSES ABERRANT MITOCHONDRIAL DYNAMICS AND HEART DYSFUNCTION.

ABSTRACT: Mitochondrial damage is an important cause of heart dysfunction after severe burn injury. However, the pathophysiological process remains unclear. This study aims to examine the mitochondrial dynamics in the heart and the role of µ-calpain, a cysteine protease, in this scenario. Rats were subjected to severe burn injury treatment, and the calpain inhibitor MDL28170 was administered intravenously 1 h before or after burn injury. Rats in the burn group displayed weakened heart performance and decreased mean arterial pressure, which was accompanied by a diminishment of mitochondrial function. The animals also exhibited higher levels of calpain in mitochondria, as reflected by immunofluorescence staining and activity tests. In contrast, treatment with MDL28170 before any severe burn diminished these responses to a severe burn. Burn injury decreased the abundance of mitochondria and resulted in a lower percentage of small mitochondria and a higher percentage of large mitochondria. Furthermore, burn injury caused an increase in the fission protein DRP1 in the mitochondria and a decrease in the inner membrane fusion protein OPA1. Similarly, these alterations were also blocked by MDL28170. Of note, inhibition of calpain yielded the emergence of more elongated mitochondria along with membrane invagination in the middle of the longitude, which is an indicator of the fission process. Finally, MDL28170, administered 1 h after burn injury, preserved mitochondrial function and heart performance, and increased the survival rate. Overall, these results provided the first evidence that mitochondrial recruitment of calpain confers heart dysfunction after severe burn injury, which involves aberrant mitochondrial dynamics.

WITHDRAWN: RNA binding protein Musashi2 regulates dairy cows' mastitis by activating the TGFß signaling pathway.

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