The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling.

Viral infection often trigger an ATM serine/threonine kinase (ATM)-dependent DNA damage response in host cells that suppresses viral replication. Viruses evolved different strategies to counteract this antiviral surveillance system. Here, we report that human herpesvirus 6B (HHV-6B) infection causes genomic instability by suppressing ATM signaling in host cells. Expression of immediate-early protein 1 (IE1) phenocopies this phenotype and blocks homology-directed double-strand break repair. Mechanistically, IE1 interacts with NBS1, and inhibits ATM signaling through two distinct domains. HHV-6B seems to efficiently inhibit ATM signaling as further depletion of either NBS1 or ATM do not significantly boost viral replication in infected cells. Interestingly, viral integration of HHV-6B into the host's telomeres is not strictly dependent on NBS1, challenging current models where integration occurs through homology-directed repair. Given that spontaneous IE1 expression has been detected in cells of subjects with inherited chromosomally-integrated form of HHV-6B (iciHHV-6B), a condition associated with several health conditions, our results raise the possibility of a link between genomic instability and the development of iciHHV-6-associated diseases.

Sensitizing methicillin-resistant Staphylococcus aureus (MRSA) to cefuroxime: the synergic effect of bicarbonate and the wall teichoic acid inhibitor ticlopidine.

Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most ß-lactams, the first-line treatment for methicillin-susceptible S. aureus. A phenotype termed "NaHCO3-responsiveness" has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care ß-lactams in the presence of physiologically relevant concentrations of NaHCO3, in vitro and ex vivo; moreover, such "NaHCO3-responsive" isolates can be effectively cleared by ß-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO3 exposure on NaHCO3-responsive MRSA is to repress WTA synthesis. This NaHCO3 effect mimics the phenotype of tarO-deficient MRSA, including sensitization to the PBP2-targeting ß-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO3 exposure on CFX susceptibility in the presence and absence of a WTA synthesis inhibitor, ticlopidine (TCP), in a collection of clinical MRSA isolates from skin and soft tissue infections (SSTI) and bloodstream infections (BSI). NaHCO3 and/or TCP enhanced susceptibility to CFX in vitro, by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an ex vivo simulated endocarditis vegetations (SEV) model, in NaHCO3-responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO3), pre-exposure to TCP prior to infection sensitized the NaHCO3-responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO3 is acting similarly to WTA synthesis inhibitors, and that such inhibitors have potential translational applications in the treatment of certain MRSA strains in conjunction with specific ß-lactam agents.

Human Cytomegalovirus IE1 Impairs Neuronal Migration by Downregulating Connexin 43.

Human cytomegalovirus (HCMV) is a leading cause of congenital birth defects. Though the underlying mechanisms remain poorly characterized, mouse models of congenital CMV infection have demonstrated that the neuronal migration process is damaged. In this study, we evaluated the effects of HCMV infection on connexin 43 (Cx43), a crucial adhesion molecule mediating neuronal migration. We show in multiple cellular models that HCMV infection downregulated Cx43 posttranslationally. Further analysis identified the immediate early protein IE1 as the viral protein responsible for the reduction of Cx43. IE1 was found to bind the Cx43 C terminus and promote Cx43 degradation through the ubiquitin-proteasome pathway. Deletion of the Cx43-binding site in IE1 rendered it incapable of inducing Cx43 degradation. We validated the IE1-induced loss of Cx43 in vivo by introducing IE1 into the fetal mouse brain. Noteworthily, ectopic IE1 expression induced cortical atrophy and neuronal migration defects. Several lines of evidence suggest that these damages result from decreased Cx43, and restoration of Cx43 levels partially rescued IE1-induced interruption of neuronal migration. Taken together, the results of our investigation reveal a novel mechanism of HCMV-induced neural maldevelopment and identify a potential intervention target. IMPORTANCE Congenital CMV (cCMV) infection causes neurological sequelae in newborns. Recent studies of cCMV pathogenesis in animal models reveal ventriculomegaly and cortical atrophy associated with impaired neural progenitor cell (NPC) proliferation and migration. In this study, we investigated the mechanisms underlying these NPC abnormalities. We show that Cx43, a critical adhesion molecule mediating NPC migration, is downregulated by HCMV infection in vitro and HCMV-IE1 in vivo. We provide evidence that IE1 interacts with the C terminus of Cx43 to promote its ubiquitination and consequent degradation through the proteasome. Moreover, we demonstrate that introducing IE1 into mouse fetal brains led to neuronal migration defects, which was associated with Cx43 reduction. Deletion of the Cx43-binding region in IE1 or ectopic expression of Cx43 rescued the IE1-induced migration defects in vivo. Our study provides insight into how cCMV infection impairs neuronal migration and reveals a target for therapeutic interventions.

Upregulation of keratin 15 is required for varicella-zoster virus replication in keratinocytes and is attenuated in the live attenuated vOka vaccine strain.

Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles, diseases characterised by epidermal virus replication in skin and mucosa and the formation of blisters. We have previously shown that VZV infection has a profound effect on keratinocyte differentiation, altering the normal pattern of epidermal gene expression. In particular, VZV infection reduces expression of suprabasal keratins 1 and 10 and desmosomal proteins, disrupting epidermal structure to promote expression of a blistering phenotype. Here, we extend these findings to show that VZV infection upregulates the expression of keratin 15 (KRT15), a marker expressed by basal epidermal keratinocytes and hair follicles stem cells. We demonstrate that KRT15 is essential for VZV replication in the skin, since downregulation of KRT15 inhibits VZV replication in keratinocytes, while KRT15 exogenous overexpression supports viral replication. Importantly, our data show that VZV upregulation of KRT15 depends on the expression of the VZV immediate early gene ORF62. ORF62 is the only regulatory gene that is mutated in the live attenuated VZV vaccine and contains four of the five fixed mutations present in the VZV Oka vaccine. Our data indicate that the mutated vaccine ORF62 is not capable of upregulating KRT15, suggesting that this may contribute to the vaccine attenuation in skin. Taken together our data present a novel association between VZV and KRT15, which may open a new therapeutic window for a topical targeting of VZV replication in the skin via modulation of KRT15.

Antibiotic resistance of E. coli isolates from different water sources in Mbarara, Uganda.

Escherichia coli is widely used as an indicator of recent faecal pollution of water. Most E. coli strains are commensals; however, isolates in water samples have been shown to carry antibiotic resistance determinants. In total, 47 E. coli were isolated from selected drinking water sources in Mbarara, Uganda. The isolates were examined for their susceptibility to seven antibiotics and the presence of nine antibiotic-resistance genes (mostly ß-lactamase genes) and class 1 integrons. Isolates showed a high resistance to ampicillin of 55.5% and a high sensitivity to azithromycin and gentamicin at 98 and 96%, respectively. PCR analysis showed the presence of extended-spectrum ß-lactamase genes blaCTX-M-32 and blaCMY-2 in 64 and 36% of the isolates. The carbapenemase genes blaOXA-48, blaVIM-2, blaNDM-1, and blaKPC-3 were either not detected or only in a very small number of the isolates, whereas class 1 integrons were present in 68% of the isolates. This study proves that antimicrobial resistance exists in E. coli in water used for drinking purposes in Mbarara city. There is a need for public health actors to improve the surveillance of microbiological quality of drinking water to minimize health risks.

Chemical Complementarity of Blood-Sourced, Breast Cancer-Related TCR CDR3s and the CMV UL29 and IE1 Antigens is Associated with Worse Overall Survival.

Cytomegalovirus (CMV) infection is common and becomes a particular concern in immunocompromised patients. Understanding the potential role CMV plays in breast cancer patients' disease progression is important for providing more patient-specific treatments. In this study, we analyzed whether a breast cancer patient's blood-sourced T-cell receptor (TCR) complementarity determining-3 (CDR3) amino acid (AA) sequences could provide an indication of the impact of a systemic CMV infection. Specifically, we assessed the chemical complementarity of patient TCR CDR3 AAs and CMV antigens to determine whether patients with greater complementarity also represented different survival probabilities. Initially, we examined five distinct CMV antigens, of which two, IE1 and UL29, represented TCR (TRA+ RB)-CDR3-CMV antigen complementarity scores (CSs) whereby cases representing the upper 50th percentile of CSs had a worse overall survival (log-rank p = 5.034E-3, for IE1). Then, an analysis of CSs representing previously identified, TCR IE1 epitopes indicated that greater TRB CDR3-IE1 epitope complementarities represented a worse OS (log-rank p = 0.0111). These results raise the question of whether a systemic, anti-CMV response leads to increased systemic inflammation, which is either directly or indirectly supportive of tumor growth; or are patients succumbing to a direct impact of CMV functions on tumor growth or metastasis?

Assessing the impact of Medical Education's Innovation & Entrepreneurship Program in China.

OBJECTIVE: A growing number of clinical undergraduates are chosen to enter institutions for higher education biotechnology and industry workforce, though most need more laboratory experience training and business practice. Innovation and Entrepreneurship Program (I&E Program) can benefit from biological experiment and commercialization training largely absent from standard clinical medical educational curricula. Our study investigates the impact and status of the I&E Program in enhancing medical students' research and entrepreneurial abilities and provides recommendations for improving this program. METHODS: A cross-sectional study was applied by delivering a questionnaire to survey medical students from Central South University who participated in the I&E Program. The questionnaire consisted of three parts: basic information, the impact of the I&E Program on medical students' research and entrepreneurial abilities, and attitudes and recommendations regarding the I&E Program. RESULTS: Many students participating in the I&E Program have received competition awards and improved their academic experience, article writing, and application patents. Their research-related abilities have been enhanced, including in-lab techniques, theoretical research skills, data analysis knowledge, clinical research skills, experimental research skills, entrepreneurship, data analysis ability, teamwork, and communication. While 73.93% of students express satisfaction with the I&E Program, there are still several areas of improvement, including more robust practical components, increased support, and enhanced teamwork. CONCLUSION: The scale of the I&E Program is rapidly expanding to address scientific research or business skills needed by college students in the new era. However, more programs still need to be discontinued during their further study. The I&E Program significantly enhances research abilities and fosters confidence in their study. This analysis emphasizes the importance of research-oriented and interdisciplinary education for students' holistic development in medical schools compared with formal medical education.

Environmental occurrence and assessment of organic pollutants in surface sediments of South Peninsular Malaysia.

Organic pollution continues to be an important worldwide obstacle for tackling health and environmental concerns that require ongoing and prompt response. To identify the LAB content levels as molecular indicators for sewage pollution, surface sediments had obtained from the South region of Malaysia. The origins of the LABs were identified using gas chromatography-mass spectrometry (GC-MS). ANOVA and a Pearson correlation coefficient at p < 0.05 were used in the statistical analyses of the differences between the research locations. Internal to external (I/E) ratio, homologs C13/C12, and long to short (L/S) chains are used to identify the effectiveness of wastewater treatments. According to statistical analysis, the range of LAB level at the stations was 67.4 to 188.7 ng g-1dw. A significant difference was observed between LAB homologs (p < 0.05), with a higher level of C13 in most of the stations. The computed LAB ratio (I/E), which varied from 1.6 to 2.7, revealed the released wastewater from primary and secondary sources. LAB degradation varied between 33 and 49% in the areas that were evaluated. The treatment system of wastewater requires to be further improved, and using LAB markers to track anthropogenic contamination is imperative.

A young lady presenting with acute limb ischemia secondary to systemic lupus erythematosus, antiphospholipid syndrome and infective endocarditis.

We report a case of a 35 years old lady presenting with acute upper limb ischemia secondary to systemic lupus erythematosus (SLE), antiphospholipid syndrome (APLS) and infective endocarditis (IE). It is rare for SLE/APLS to present with acute limb ischemia (ALI) as the initial manifestation. The patient presented with high grade fever along with pain and numbness in her right upper limb. On examination her right upper limb was cold to touch and the peripheral pulses were not palpable. There was also an audible pansystolic murmur in the mitral area. CT Angiography confirmed a complete occlusion of the right axillary artery while echocardiogram revealed severe mitral regurgitation with large vegetations on the mitral valve leaflets, suggesting infective endocarditis. After the patient's clinical deterioration and considering the severity of the ischemic condition, additional investigations were conducted, which ultimately led to the diagnosis of SLE with APLS. Management included antibiotic therapy for IE and high dose of IV steroids and anticoagulants for SLE/APLS, to which she responded well. This case emphasizes the significance of conducting a comprehensive evaluation of all possible causes of acute limb ischemia, while considering the patient's medical history and physical examination findings.

A SLiM-dependent conformational change in baculovirus IE1 controls its focus formation ability.

The baculovirus IE1 gene encodes a multifunctional protein that is essential for both DNA replication and RNA transcription of the virus. Prior to viral DNA replication, IE1 promotes early gene transcription when localized in hr-dependent foci. During viral DNA replication, the IE1 foci expand and fuse to generate the virogenic stroma (VS) with IE1 found in the VS reticulum. To explore the IE1 structural features essential for this coordinated localization, we constructed various IE1 mutants based on three putative domains (N, I, and C). We determined that a BDI motif located in the intrinsic disorder region (IDR) between the N and I domains acts as a nuclear localization signal, whereas BDII and HLH in the C domain are required for VS localization in infected cells or for chromosomal association in uninfected mitotic cells. Deletion of the SLiM (short linear motif) located in the I domain restrains both nuclear- and VS localization. Intra-molecular fluorescence resonance energy transfer (FRET) probes of IE1 mutants revealed a conformational change of the I-C two-domain fragment during infection, which was inhibited by aphidicolin, suggesting that IE1 undergoes a stage-dependent conformational change. Further, homo-dimerization of the I domain and stage-dependent conformational changes require an intact SLiM. Mutational analysis of SLiM revealed that VS localization and chromosomal association were retained following S291A and S291E substitutions, but hr-dependent focus formation differed between the two mutations. These results suggest that coordinated IE1 localization is controlled by SLiM-dependent conformational changes that are potentially switched by the phosphorylation state of the SLiM.

Immunogenicity and Protection by DnaK and SpaA Recombinant Proteins Against Erysipelothrix Rhusiopathiae in a Murine Model.

BACKGROUND/AIMS: Swine erysipelas is a disease caused by Erysipelothrix rhusiopathiae, a Gram-positive bacillus, which has great economic importance because it leads to the loss of the swine herd. To control this disease, animals are immunized with a cellular vaccine of killed or attenuated E. rhusiopathiae, but even with herd vaccination, cases of swine erysipelas outbreaks have been reported in the United States, China and Japan, leading to the search for other antigenic components of the bacteria that may promote greater protection against E. rhusiopathiae. The surface protein SpaA from E. rhusiopathiae has been shown to be a candidate to constitute a subunit vaccine, since it has already been reported to induce a host immune response against the bacterium. DnaK, a hsp70 molecular chaperone, also seems to be a good candidate in the composition of a vaccine, as it has been demonstrated to be an antigenic protein of the bacteria. METHODS: This work evaluated the immunogenicity and protection induced by the E. rhusiopathiaee SpaA and DnaK recombinant proteins in a murine model, by intramuscular administration to mice with two doses of 100 µg at 21-day interval between them. The candidate proteins were tested either separately and together, compared with the commercial vaccine and the non-vaccination condition, and mice were challenged with a virulent strain of E. rhusiopathiae. Serum was collected to assess the produced antibodies and peripheral blood cells, whereas spleen and kidney tissues were assayed for E. rhusiopathiae presence by colony counting. RESULTS: A survival curve of the animals was performed, which confirmed the protection induced by the proteins. IgG antibodies increased in the animal serum inoculated with the proteins when compared to the control, and a significant delay in disease symptoms was observed. CONCLUSION: These results suggest that E. rhusiopathiae DnaK and SpaA are immunogenic in mice and interfere with the disease development.

Detection of Human cytomegalovirus UL55 Gene and IE/E Protein Expression in Colorectal Cancer Patients in Egypt.

BACKGROUND: A possible relation between Human cytomegalovirus (HCMV) and colorectal cancer (CRC) has been widely explored with an unclear role yet speculated. AIM: The study aimed at detecting HCMV UL55 gene, immediate early and early (IE/E) proteins in colorectal tumor tissues and adjacent non neoplastic tissues (ANNT). Also, it aimed to correlate HCMV presence with CRC clinicopathological features. SUBJECTS AND METHODS: A prospective study of 50 HCMV seropositive patients with resectable CRC were enrolled in the study. Demographic, clinical, and radiological findings were recorded. Pathological assessment was done. Paired CRC tumorous and ANNT were examined for HCMV UL55 by PCR and for IE/ E proteins by immunohistochemistry (IHC). RESULTS: 70% of CRC patients enrolled were females and 36% were elderly (> 60y). Adenocarcinoma was the prevalent histopathological type (92%) with Grade 2, higher stages, and nodal involvement accounting for (64%, 64% and 56%) respectively. HCMV detection was significantly higher in tumoral tissue versus ANNT by PCR and IHC (P < 0.001, P < 0.008) respectively. Moderate agreement was found between the two techniques (κ = 0.572, P < 0.001). Univariate analysis identified HCMV presence to be significantly higher in elderly patients, in tumors with higher stage and with nodal involvement (P = 0.041, P = 0.008, P = 0.018 respectively). In multivariate analysis, the latter two retained significance (P = 0.010, P = 0.008). CONCLUSION: CRC tumor tissues are more infected by HCMV than ANNT. A significant association of HCMV presence with a higher CRC tumor stage and nodal involvement in an age-dependent manner was detected. HCMV oncomodulatory and a disease progression role is suspected.

PcTrim prevents early infection with white spot syndrome virus by inhibiting AP1-induced endocytosis.

Viruses have evolved various strategies to achieve early infection by initiating transcription of their own early genes via host transcription factors, such as NF-κb, STAT, and AP1. How the host copes with this immune escape has been a topic of interest. Tripartite motif (TRIM) family proteins with RING-type domains have E3 ubiquitin ligase activity and are known as host restriction factors. Trim has been reported to be associated with phagocytosis and is also believed to be involved in the activation of autophagy. Preventing the virus from entering the host cell may be the most economical way for the host to resist virus infection. The role of TRIM in the early stage of virus infection in host cells remains to be further interpreted. In the current study, a crayfish TRIM with a RING-type domain, designated as PcTrim, was significantly upregulated under white spot syndrome virus (WSSV) infection in the red swamp crayfish (Procambarus clarkii). Recombinant PcTrim significantly inhibited WSSV replication in crayfish. RNAi targeting PcTrim or blocking PcTrim with an antibody promoted WSSV replication in crayfish. Pulldown and co-IP assays showed that PcTrim can interact with the virus protein VP26. PcTrim restricts the expression level of dynamin, which is involved in the regulation of phagocytosis, by inhibiting AP1 entry into the nucleus. AP1-RNAi effectively reduced the expression levels of dynamin and inhibited host cell endocytosis of WSSV in vivo. Our study demonstrated that PcTrim might reduce early WSSV infection by binding to VP26 and then inhibiting AP1 activation, resulting in reduced endocytosis of WSSV in crayfish hemocytes. Video Abstract.

Intracardiac echocardiogram to diagnose infective endocarditis after transcatheter aortic valve-in-valve implantation.

A 70-year-old man with history of transcatheter aortic valve-in-valve implantation was admitted because of suspected infective endocarditis (IE). Transesophageal echocardiogram did not reveal any vegetations, as the metallic stent frames caused significant artifacts. Position emission tomography was also negative. Intracardiac echocardiogram (ICE) was performed retrogradely through the ascending aorta, which showed clear vegetations over the stent frame of the transcatheter heart valve. Endocarditis after transcatheter aortic valve implantation was not uncommon. With increasing use of valve-in-valve procedures, echocardiographic diagnosis of IE would be more challenging. This case demonstrated the advantage of ICE over conventional echocardiography in visualizing the neo-aortic valve complex for diagnosing IE.

Host factors associated with either VP16 or VP16-induced complex differentially affect HSV-1 lytic infection.

Herpes simplex virus type 1 (HSV-1) is an important human pathogen with neurotropism. Following lytic infection in mucosal or skin epithelium, life-long latency is established mainly in sensory neurons, which can periodically reactivate by stress, leading to recurrent disease and virus transmission. During the virus's productive infection, the tegument protein VP16, a component of HSV-1 virion, is physically associated with two cellular factors, host cell factor-1 (HCF-1), and POU domain protein Oct-1, to construct the VP16-induced complex, which is essential to stimulate immediate early (IE)-gene transcription as well as initiate the lytic programme. Apart from HCF-1 and Oct-1, VP16 also associates with a series of other host factors, making a VP16-induced regulatory switch to either activate or inactivate virus gene transcription. In addition, VP16 has effects on distinct signalling pathways via binding to various host molecules that are essentially related to innate immune responses, RNA polymerases, molecular chaperones, and virus infection-induced host shutoff. VP16 also functionally compensates for given host factors, such as PPAR-γ and ß-catenin. In this review, we provide an overview of the updated insights on the interplay between VP16 and the host factors that coordinate virus infection.

Passive heat stress induces mitochondrial adaptations in skeletal muscle.

The mitochondria are central to skeletal muscle metabolic health. Impaired mitochondrial function is associated with various muscle pathologies, including insulin resistance and muscle atrophy. As a result, continuous efforts are made to find ways to improve mitochondrial health in the context of disuse and disease. While exercise is known to cause robust improvements in mitochondrial health, not all individuals are able to exercise. This creates a need for alternate interventions which elicit some of the same benefits as exercise. Passive heating (i.e., application of heat in the absence of muscle contractions) is one potential intervention which has been shown to increase mitochondrial enzyme content and activity, and to improve mitochondrial respiration. Associated with increases in mitochondrial content and/or function, passive heating can also improve insulin sensitivity in the context of type II diabetes and preserve muscle mass in the face of limb disuse. This area of research remains in its infancy, with many questions yet to be answered about how to maximize the benefits of passive heating and elucidate the mechanisms by which heat stress affects muscle mitochondria.

Predictions of optimal heating by magnetic reversal behavior of magnetic nanowires (MNWs) with different materials.

OBJECTIVE: Magnetic nanowires (MNWs) are potential candidates for heating in biomedical applications that require rapid and uniform heating rates, such as warming cryopreserved organs and hyperthermia treatment of cancer cells. Therefore, it is essential to determine which materials and geometries will provide the optimal heating using available alternating magnetic fields (AMF). METHOD: Micromagnetic simulations are used to investigate the heating ability of MNWs by predicting their hysteretic behavior. MNWs composed of iron (Fe), nickel (Ni), cobalt (Co) or permalloy (FeNi alloy, Py) with different diameters (10-200 nm) are simulated using object oriented micromagnetic framework (OOMMF). RESULTS: Hysteresis loops are obtained for each simulated MNW, and the 2D/3D magnetic moment map is simulated to show the reversal mechanism. The heating ability, in terms of specific loss power (SLP), is calculated from the area of the hysteresis loop times frequency for each MNW for comparison with others. CONCLUSION: It is estimated that a theoretical optimal heating ability of 2730 W/g can be provided by isolated Co MNWs with 50 nm diameters using a typical AMF system that can supply 72 kA/m field amplitude and 50 kHz in frequency. Generalized correlation between coercivity and size/material of MNWs is provided as a guidance for researchers to choose the most appropriate MNW as a heater for their AMF system and vice versa.

Racial and ethnic disparities in monthly trends in alcohol-induced mortality among US adults from January 2018 through December 2021.

Background: Historically, American Indians/Alaska Natives (AIANs), Blacks, and Hispanics have experienced higher alcohol-induced mortality rates. Given a disproportionate surge in unemployment rate and financial strain among racial and ethnic minorities and limited access to alcohol use disorder treatment during the COVID-19 pandemic, it is essential to examine monthly trends in alcohol-induced mortality in the United States during the pandemic.Objectives: This study estimates changes in monthly alcohol-induced mortality among US adults by age, sex, and race/ethnicity.Methods: Using monthly deaths from 2018-2021 national mortality files (N = 178,201 deaths, 71.5% male, 28.5% female) and census-based monthly population estimates, we calculated age-specific monthly alcohol-induced death rates and performed log-linear regression to derive monthly percent increases in mortality rates.Results: Alcohol-induced deaths among adults aged ≥25 years increased by 25.7% between 2019 (38,868 deaths) and 2020 (48,872 deaths). During 2018-2021, the estimated monthly percent change was higher for females (1.1% per month) than males (1.0%), and highest for AIANs (1.4%), followed by Blacks (1.2%), Hispanics (1.0%), non-Hispanic Whites (1.0%), and Asians (0.8%). In particular, between February 2020 and January 2021, alcohol-induced mortality increased by 43% for males, 53% for females, 107% for AIANs, the largest increase, followed by Blacks (58%), Hispanics (56%), Asians (44%), and non-Hispanic Whites (39%).Conclusions: During the peak months of the pandemic, the rising trends in alcohol-induced mortality differed substantially by race and ethnicity. Our findings indicate that behavioral and policy interventions and future investigation on underlying mechanisms should be considered to reduce alcohol-induced mortality among Blacks and AIANs.

iE-DAP Induced Inflammatory Response and Tight Junction Disruption in Bovine Mammary Epithelial Cells via NOD1-Dependent NF-κB and MLCK Signaling Pathway.

γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), a bacterial cell wall component, can trigger an inflammatory response. A mammary inflammatory response causes tight junction (TJ) dysfunction. This study aimed to explore the effects and involved mechanisms of iE-DAP-induced inflammatory response on the TJ integrity in bovine mammary epithelial cells (BMECs). The results showed that iE-DAP-induced inflammatory response and TJ disruption was associated with increased expression levels of inflammatory cytokines and decreased gene expression of ZO-1 and Occludin, as well as a reduction in transepithelial electrical resistance and elevation in paracellular dextran passage. While MLCK inhibitor ML-7 reversed the TJ disruption induced by iE-DAP. NF-κB inhibitor BAY 11-7085 hindered the activation of NF-κB and MLCK signaling pathways, the inflammatory response and TJ disruption induced by iE-DAP. NOD1-specific shRNA also inhibited the activation of the NOD1/NF-κB signaling pathway and reversed the inflammatory response and TJ injury in iE-DAP-treated BMECs. Above results suggest that iE-DAP activated the NF-κB and MLCK signaling pathway in NOD1-dependent manner, which promoted the transcription of inflammatory cytokines and altered the expression and distribution of tight junction proteins, finally caused inflammatory response and TJ disruption. This study might provide theoretical basis and scientific support for the prevention and treatment of mastitis.

Lateral distribution, environmental occurrence, and assessment of organic pollutants in surface sediments of the East Malaysia.

One of the molecular chemical markers used to identify anthropogenic inputs is linear alkylbenzenes (LABs) that cause serious impacts in the bays and coastal ecosystems. The surface sediments samples collected from the East Malaysia, including Brunei bay to estimate the LABs concentration and distribution as molecular markers of anthropogenic indicators. Gas chromatography-mass spectrometry (GC-MS) was used after purification, fractionation the hydrocarbons in the sediment samples to identify the sources of LABs. The analysis of variance (ANOVA) and Pearson correlation coefficient were applied to analyze the difference between sampling stations' significance at p < 0.05. Long to short chains L/S, homologs C13/C12, and internal to external (I/E) congeners have used to assess the LABs degradation rates as well as the effectiveness of sewage treatment. Results of this study showed that the LABs concentration ranged between 7.1 to 41.3 ng g-1 dw, in the investigated stations. The majority of sample sites exhibited a considerable input of C13-LABs homologs, and LABs homologs differed significantly. The estimated LABs ratios (I/E), which ranged between 0.6 and 2.2, demonstrated the effluents with primary and less secondary sources are released into the bay waters. The degradation of LABs were up to 42% in the interrogated locations. The conclusion is that the wastewater treatment system needs to be improved, and that LABs molecular markers are highly effective in tracing anthropogenic sewage contamination.