m6A modification controls the innate immune response to infection by targeting type I interferons.

N6-methyladenosine (m6A) is the most common mRNA modification. Recent studies have revealed that depletion of m6A machinery leads to alterations in the propagation of diverse viruses. These effects were proposed to be mediated through dysregulated methylation of viral RNA. Here we show that following viral infection or stimulation of cells with an inactivated virus, deletion of the m6A 'writer' METTL3 or 'reader' YTHDF2 led to an increase in the induction of interferon-stimulated genes. Consequently, propagation of different viruses was suppressed in an interferon-signaling-dependent manner. Significantly, the mRNA of IFNB, the gene encoding the main cytokine that drives the type I interferon response, was m6A modified and was stabilized following repression of METTL3 or YTHDF2. Furthermore, we show that m6A-mediated regulation of interferon genes was conserved in mice. Together, our findings uncover the role m6A serves as a negative regulator of interferon response by dictating the fast turnover of interferon mRNAs and consequently facilitating viral propagation.

Publisher Correction: m6A modification controls the innate immune response to infection by targeting type I interferons.

In the version of this article initially published, the penultimate sentence of the abstract included a typographical error ('cxgenes'). The correct word is 'genes'. The error has been corrected in the HTML and PDF version of the article.

Structural mechanism of CRL4-instructed STAT2 degradation via a novel cytomegaloviral DCAF receptor.

Human cytomegalovirus (CMV) is a ubiquitously distributed pathogen whose rodent counterparts such as mouse and rat CMV serve as common infection models. Here, we conducted global proteome profiling of rat CMV-infected cells and uncovered a pronounced loss of the transcription factor STAT2, which is crucial for antiviral interferon signalling. Via deletion mutagenesis, we found that the viral protein E27 is required for CMV-induced STAT2 depletion. Cellular and in vitro analyses showed that E27 exploits host-cell Cullin4-RING ubiquitin ligase (CRL4) complexes to induce poly-ubiquitylation and proteasomal degradation of STAT2. Cryo-electron microscopy revealed how E27 mimics molecular surface properties of cellular CRL4 substrate receptors called DCAFs (DDB1- and Cullin4-associated factors), thereby displacing them from the catalytic core of CRL4. Moreover, structural analyses showed that E27 recruits STAT2 through a bipartite binding interface, which partially overlaps with the IRF9 binding site. Structure-based mutations in M27, the murine CMV homologue of E27, impair the interferon-suppressing capacity and virus replication in mouse models, supporting the conserved importance of DCAF mimicry for CMV immune evasion.

Differential interferon-α subtype induced immune signatures are associated with suppression of SARS-CoV-2 infection.

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies, and have been successfully employed for the treatment of viral diseases. Humans express 12 IFN-alpha (α) subtypes, which activate downstream signaling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in IFN-I immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19; therefore, early administration of IFN-I may be protective against life-threatening disease. Here we comprehensively analyzed the antiviral activity of all IFNα subtypes against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate, and low antiviral IFNs. In particular, IFNα5 showed superior antiviral activity against SARS-CoV-2 infection in vitro and in SARS-CoV-2-infected mice in vivo. Dose dependency studies further displayed additive effects upon coadministration with the broad antiviral drug remdesivir in cell culture. Transcriptomic analysis of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting, and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in IFN-I signaling pathways, negative regulation of viral processes, and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multimodular definition of antiviral host responses mediated by defined IFN-I. This knowledge will support the development of novel therapeutic approaches against SARS-CoV-2.

UnCoVar: a reproducible and scalable workflow for transparent and robust virus variant calling and lineage assignment using SARS-CoV-2 as an example.

BACKGROUND: At a global scale, the SARS-CoV-2 virus did not remain in its initial genotype for a long period of time, with the first global reports of variants of concern (VOCs) in late 2020. Subsequently, genome sequencing has become an indispensable tool for characterizing the ongoing pandemic, particularly for typing SARS-CoV-2 samples obtained from patients or environmental surveillance. For such SARS-CoV-2 typing, various in vitro and in silico workflows exist, yet to date, no systematic cross-platform validation has been reported. RESULTS: In this work, we present the first comprehensive cross-platform evaluation and validation of in silico SARS-CoV-2 typing workflows. The evaluation relies on a dataset of 54 patient-derived samples sequenced with several different in vitro approaches on all relevant state-of-the-art sequencing platforms. Moreover, we present UnCoVar, a robust, production-grade reproducible SARS-CoV-2 typing workflow that outperforms all other tested approaches in terms of precision and recall. CONCLUSIONS: In many ways, the SARS-CoV-2 pandemic has accelerated the development of techniques and analytical approaches. We believe that this can serve as a blueprint for dealing with future pandemics. Accordingly, UnCoVar is easily generalizable towards other viral pathogens and future pandemics. The fully automated workflow assembles virus genomes from patient samples, identifies existing lineages, and provides high-resolution insights into individual mutations. UnCoVar includes extensive quality control and automatically generates interactive visual reports. UnCoVar is implemented as a Snakemake workflow. The open-source code is available under a BSD 2-clause license at github.com/IKIM-Essen/uncovar.

Electronic Health Record-Based Algorithm for Monitoring Respiratory Virus-Like Illness.

Viral respiratory illness surveillance has traditionally focused on single pathogens (e.g., influenza) and required fever to identify influenza-like illness (ILI). We developed an automated system applying both laboratory test and syndrome criteria to electronic health records from 3 practice groups in Massachusetts, USA, to monitor trends in respiratory viral-like illness (RAVIOLI) across multiple pathogens. We identified RAVIOLI syndrome using diagnosis codes associated with respiratory viral testing or positive respiratory viral assays or fever. After retrospectively applying RAVIOLI criteria to electronic health records, we observed annual winter peaks during 2015-2019, predominantly caused by influenza, followed by cyclic peaks corresponding to SARS-CoV-2 surges during 2020-2024, spikes in RSV in mid-2021 and late 2022, and recrudescent influenza in late 2022 and 2023. RAVIOLI rates were higher and fluctuations more pronounced compared with traditional ILI surveillance. RAVIOLI broadens the scope, granularity, sensitivity, and specificity of respiratory viral illness surveillance compared with traditional ILI surveillance.

Acute cytomegalovirus infection modulates the intestinal microbiota and targets intestinal epithelial cells.

Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive - in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high-titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro-inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet-derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.

Temperature-related emergency injury visits in Hanoi, Vietnam.

BACKGROUND: The short-term association between increasing temperatures and injury has been described in high-income countries, but less is known for low-income and-middle-income countries, including Vietnam. METHODS: We used emergency injury visits (EIV) data for 2017-2019 from 733 hospitals and clinics in Hanoi, Vietnam to examine the effects of daily temperature on EIV. Time-series analysis with quasi-Poisson models was used to estimate a linear relative risk increase (RRI) for overall populations and ones stratified by age and sex. Exposure-response curves estimated non-linear associations as an RR between daily temperature and injury. Models were adjusted for the day of week, holidays, daily relative humidity, daily particulate matter, and long-term and seasonal trends. RESULTS AND CONCLUSIONS: A total of 39 313 EIV were recorded averaging 36 injuries daily. Injuries more likely occurred in males and those aged 15-44, and aged 44-60. For linear effects, a 5°C increase in same day mean temperature was associated with an overall increased EIV (RRI 4.8; 95% CI 2.3 to 7.3) with males (RRI 5.9; 95% CI 3.0 to 8.9) experiencing a greater effect than females (RRI 3.0; 95% CI -0.5 to 6.5). Non-linear effects showed an increase in EIV at higher temperatures compared with the threshold temperature of 15°C, with the greatest effect at 33°C (RR 1.3; 95% CI 1.2 to 1.6). Further research to investigate temperature-injury among different populations and by the cause of injury is warranted.

Analysis of the Chloroplast Genome of Ficus simplicissima Lour Collected in Vietnam and Proposed Barcodes for Identifying Ficus Plants.

Ficus simplicissima Lour. is an Asian species of fig tree in the family Moraceae. The chloroplast (cp) genome of F. simplicissima m3 was sequenced using the Pacbio sequel platform. The F. simplicissima cpDNA has a size of 160,321 bp in length, of which GC content accounts for 36.13%. The cp genome of F. simplicissima consists of a single large copy (LSC) with a size of 91,346 bp, a single small copy (SSC) with a size of 20,131 bp, and a pair of inverted repeats with a size of 24,421 to 24,423 bp. The cp genome of F. simplicissima has 127 genes, including 85 protein-coding genes, eight rRNA genes, and 34 tRNA genes; 92 simple sequence repeats and 39 long repeats were detected in the cpDNA of F. simplicissim. A comparative cp genome analysis among six species in the Ficus genus indicated that the genome structure and gene content were highly conserved. The non-coding regions show more differentiation than the coding regions, and the LSC and SSC regions show more differences than the inverted repeat regions. Phylogenetic analysis supported that F. simplicissima m3 had a close relationship with F. hirta. The complete cp genome of F. simplicissima was proposed as a chloroplast DNA barcoding for genus-level in the Moraceae family and the psbA-trnH gene region for species-level identification.

Implementation studio: implementation support program to build the capacity of rural community health educators serving immigrant communities to implement evidence-based cancer prevention and control interventions.

PURPOSE: Rural community-based organizations (CBOs) serving immigrant communities are critical settings for implementing evidence-based interventions (EBIs). The Implementation Studio is a training and consultation program focused on facilitating the selection, adaptation, and implementation of cancer prevention and control EBIs. This paper describes implementation and evaluation of the Implementation Studio on CBO's capacity to implement EBIs and their clients' knowledge of colorectal cancer (CRC) screening and intention to screen. METHODS: Thirteen community health educators (CHEs) from two CBOs participated in the Implementation Studio. Both CBOs selected CRC EBIs during the Studio. The evaluation included two steps. The first step assessed the CHEs' capacity to select, adapt, and implement an EBI. The second step assessed the effect of the CHEs-delivered EBIs on clients' knowledge of CRC and intention to screen (n = 44). RESULTS: All CHEs were Hispanic and women. Pre/post-evaluation of the Studio showed an increase on CHEs knowledge about EBIs (pre: 23% to post: 75%; p < 0.001). CHEs' ability to select, adapt, and implement EBIs also increased, respectively: select EBI (pre: 21% to post: 92%; p < 0.001), adapt EBI (pre: 21% to post: 92%; p < 0.001), and implement EBI (pre: 29% to post: 75%; p = 0.003). Pre/post-evaluation of the CHE-delivered EBI showed an increase on CRC screening knowledge (p < 0.5) and intention to screen for CRC by their clients. CONCLUSION: Implementation Studio can address unique needs of low resource rural CBOs. An implementation support program with training and consultation has potential to build the capacity of rural CBOs serving immigrant communities to implementation of cancer prevention and control EBIs. CLINICAL TRIALS REGISTRATION NUMBER: NCT04208724 registered.

Prioritizing rural populations in state comprehensive cancer control plans: a qualitative assessment.

PURPOSE: The Centers for Disease Control and Prevention's National Comprehensive Cancer Control Program (NCCCP) requires that states develop comprehensive cancer control (CCC) plans and recommends that disparities related to rural residence are addressed in these plans. The objective of this study was to explore rural partner engagement and describe effective strategies for incorporating a rural focus in CCC plans. METHODS: States were selected for inclusion using stratified sampling based on state rurality and region. State cancer control leaders were interviewed about facilitators and barriers to engaging rural partners and strategies for prioritizing rural populations. Content analysis was conducted to identify themes across states. RESULTS: Interviews (n = 30) revealed themes in three domains related to rural inclusion in CCC plans. The first domain (barriers) included (1) designing CCC plans to be broad, (2) defining "rural populations," and (3) geographic distance. The second domain (successful strategies) included (1) collaborating with rural healthcare systems, (2) recruiting rural constituents, (3) leveraging rural community-academic partnerships, and (4) working jointly with Native nations. The third domain (strategies for future plan development) included (1) building relationships with rural communities, (2) engaging rural constituents in planning, (3) developing a better understanding of rural needs, and (4) considering resources for addressing rural disparities. CONCLUSION: Significant relationship building with rural communities, resource provision, and successful strategies used by others may improve inclusion of rural needs in state comprehensive cancer control plans and ultimately help plan developers directly address rural cancer health disparities.

The special sauce of the Cancer Prevention and Control Research Network: 20 years of lessons learned in developing the evidence base, building community capacity, and translating research into practice.

PURPOSE: The Cancer Prevention and Control Research Network (CPCRN) is a national network focused on accelerating the translation of cancer prevention and control research evidence into practice through collaborative, multicenter projects in partnership with diverse communities. From 2003 to 2022, the CPCRN included 613 members. METHODS: We: (1) characterize the extent and nature of collaborations through a bibliometric analysis of 20 years of Network publications; and (2) describe key features and functions of the CPCRN as related to organizational structure, productivity, impact, and focus on health equity, partnership development, and capacity building through analysis of 22 in-depth interviews and review of Network documentation. RESULTS: Searching Scopus for multicenter publications among the CPCRN members from their time of Network engagement yielded 1,074 collaborative publications involving two or more members. Both the overall number and content breadth of multicenter publications increased over time as the Network matured. Since 2004, members submitted 123 multicenter grant applications, of which 72 were funded (59%), totaling more than $77 million secured. Thematic analysis of interviews revealed that the CPCRN's success-in terms of publication and grant productivity, as well as the breadth and depth of partnerships, subject matter expertise, and content area foci-is attributable to: (1) its people-the inclusion of members representing diverse content-area interests, multidisciplinary perspectives, and geographic contexts; (2) dedicated centralized structures and processes to enable and evaluate collaboration; and (3) focused attention to strategically adapting to change. CONCLUSION: CPCRN's history highlights organizational, strategic, and practical lessons learned over two decades to optimize Network collaboration for enhanced collective impact in cancer prevention and control. These insights may be useful to others seeking to leverage collaborative networks to address public health problems.

The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing.

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.

Focal to bilateral tonic-clonic seizures predict pharmacoresistance in focal cortical dysplasia-related epilepsy.

OBJECTIVE: Focal cortical dysplasia (FCD) is the most common etiology of surgically-remediable epilepsy in children. Eighty-seven percent of patients with FCD develop epilepsy (75% is pharmacoresistant epilepsy [PRE]). Focal to bilateral tonic-clonic (FTBTC) seizures are associated with worse surgical outcomes. We hypothesized that children with FCD-related epilepsy with FTBTC seizures are more likely to develop PRE due to lesion interaction with restricted cortical neural networks. METHODS: Patients were selected retrospectively from radiology and surgical databases from Children's National Hospital. INCLUSION CRITERIA: 3T magnetic resonance imaging (MRI)-confirmed FCD from January 2011 to January 2020; ages 0 days to 22 years at MRI; and 18 months of documented follow-up. FCD dominant network (Yeo 7-network parcellation) was determined. Association of FTBTC seizures with epilepsy severity, surgical outcome, and dominant network was tested. Binomial regression was used to evaluate predictors (FTBTC seizures, age at seizure onset, pathology, hemisphere, lobe) of pharmacoresistance and Engel outcome. Regression was used to evaluate predictors (age at seizure onset, pathology, lobe, percentage default mode network [DMN] overlap) of FTBTC seizures. RESULTS: One hundred seventeen patients had a median age at seizure onset of 3.00 years (interquartile range [IQR] .42-5.59 years). Eighty-three patients had PRE (71%); 34 had pharmacosensitive epilepsy (PSE) (29%). Twenty patients (17%) had FTBTC seizures. Seventy-three patients underwent epilepsy surgery. Multivariate regression showed that FTBTC seizures are associated with an increased risk of PRE (odds ratio [OR] 6.41, 95% confidence interval [CI] 1.21-33.98, p = .02). FCD hemisphere/lobe was not associated with PRE. Percentage DMN overlap predicts FTBTC seizures. Seventy-two percent (n = 52) overall and 53% (n = 9) of patients with FTBTC seizures achieved Engel class I outcome. SIGNIFICANCE: In a heterogeneous population of surgical and non-operated patients with FCD-related epilepsy, the presence of FTBTC seizures is associated with a tremendous risk of PRE. This finding is a recognizable marker to help neurologists identify those children with FCD-related epilepsy at high risk of PRE and can flag patients for earlier consideration of potentially curative surgery. The FCD-dominant network also contributes to FTBTC seizure clinical expression.

Identification of efflux pump inhibitors for Pseudomonas aeruginosa MexAB-OprM via ligand-based pharmacophores, 2D-QSAR, molecular docking, and molecular dynamics approaches.

Efflux pumps have been reported as one of the significant mechanisms by which bacteria evade the effects of multiple antibiotics. The tripartite efflux pump MexAB-OprM in Pseudomonas aeruginosa is one of the most significant multidrug efflux systems due to its broad resistance to antibiotics such as chloramphenicol, fluoroquinolones, lipophilic ß-lactam antibiotics, nalidixic acid, novobiocin, rifampicin, and tetracycline. A promising strategy to overcome this resistance mechanism is to combine antibiotics with efflux pump inhibitors (EPIs), which can increase their intracellular concentration to enhance their biological activities. Based on 143 EPIs with chemically diverse skeletons, the 3D pharmacophore and 2D-QSAR modelings were developed and used for the virtual screening on 9.2 million compounds including ZINC15, DrugBank, and Traditional Chinese Medicine databases to identify new EPIs. The molecular docking was also performed to evaluate the binding affinity of potential EPIs to the distal-binding pocket of MexB and resulted in 611 potential EPIs. The structure-activity relationship analyses suggested that nitrogen heterocyclic compounds, piperazine and pyridine scaffolds, and amide derivatives are the most favorable chemically features for MexAB inhibitory activities. The results from molecular dynamics analysis in 100 ns indicated that ZINC009296881 and ZINC009200074 were the most potential MexB inhibitors with strong binding affinity to the distal pocket and MM/GBSA ∆Gbind values of - 38.97 and - 30.19 kcal mol-1, respectively. The predicted pharmacokinetic properties and toxicity of these compounds indicated their potential oral drugs. Multistep virtual screening of EPIs for MexAB-OprM, efflux pump multidrug resistant of P. aeruginosa.

A systematic review of interventions to promote HPV vaccination globally.

BACKGROUND: Despite the human papillomavirus (HPV) vaccine being a safe, effective cancer prevention method, its uptake is suboptimal in the United States (U.S.). Previous research has found a variety of intervention strategies (environmental and behavioral) to increase its uptake. The purpose of the study is to systematically review the literature on interventions that promote HPV vaccination from 2015 to 2020. METHODS: We updated a systematic review of interventions to promote HPV vaccine uptake globally. We ran keyword searches in six bibliographic databases. Target audience, design, level of intervention, components and outcomes were abstracted from the full-text articles in Excel databases. RESULTS: Of the 79 articles, most were conducted in the U.S. (72.2%) and in clinical (40.5%) or school settings (32.9%), and were directed at a single level (76.3%) of the socio-ecological model. Related to the intervention type, most were informational (n = 25, 31.6%) or patient-targeted decision support (n = 23, 29.1%). About 24% were multi-level interventions, with 16 (88.9%) combining two levels. Twenty-seven (33.8%) reported using theory in intervention development. Of those reporting HPV vaccine outcomes, post-intervention vaccine initiation ranged from 5% to 99.2%, while series completion ranged from 6.8% to 93.0%. Facilitators to implementation were the use of patient navigators and user-friendly resources, while barriers included costs, time to implement and difficulties of integrating interventions into the organizational workflow. CONCLUSIONS: There is a strong need to expand the implementation of HPV-vaccine promotion interventions beyond education alone and at a single level of intervention. Development and evaluation of effective strategies and multi-level interventions may increase the uptake of the HPV vaccine among adolescents and young adults.

Implementing Mailed Colorectal Cancer Fecal Screening Tests in Real-World Primary Care Settings: Promising Implementation Practices and Opportunities for Improvement.

Colorectal cancer (CRC) screening reduces morbidity and mortality, but screening rates in the USA remain suboptimal. The Colorectal Cancer Control Program (CRCCP) was established in 2009 to increase screening among groups disproportionately affected. The CRCCP utilizes implementation science to support health system change as a strategy to reduce disparities in CRC screening by directing resources to primary care clinics to implement evidence-based interventions (EBIs) proven to increase CRC screening. As COVID-19 continues to impede in-person healthcare visits and compel the unpredictable redirection of clinic priorities, understanding clinics' adoption and implementation of EBIs into routine care is crucial. Mailed fecal testing is an evidence-based screening approach that offers an alternative to in-person screening tests and represents a promising approach to reduce CRC screening disparities. However, little is known about how mailed fecal testing is implemented in real-world settings. In this retrospective, cross-sectional analysis, we assessed practices around mailed fecal testing implementation in 185 clinics across 62 US health systems. We sought to (1) determine whether clinics that do and do not implement mailed fecal testing differ with respect to characteristics (e.g., type, location, and proportion of uninsured patients) and (2) identify implementation practices among clinics that offer mailed fecal testing. Our findings revealed that over half (58%) of clinics implemented mailed fecal testing. These clinics were more likely to have a CRC screening policy than clinics that did not implement mailed fecal testing (p = 0.007) and to serve a larger patient population (p = 0.004), but less likely to have a large proportion of uninsured patients (p = 0.01). Clinics that implemented mailed fecal testing offered it in combination with EBIs, including patient reminders (92%), provider reminders (94%), and other activities to reduce structural barriers (95%). However, fewer clinics reported having the leadership support (58%) or funding stability (29%) to sustain mailed fecal testing. Mailed fecal testing was widely implemented alongside other EBIs in primary care clinics participating in the CRCCP, but multiple opportunities for enhancing its implementation exist. These include increasing the proportion of community health centers/federally qualified health centers offering mailed screening; increasing the proportion that provide pre-paid return mail supplies with the screening kit; increasing the proportion of clinics monitoring both screening kit distribution and return; ensuring patients with abnormal tests can obtain colonoscopy; and increasing sustainability planning and support.

Identification of herbal teas and their compounds eliciting antiviral activity against SARS-CoV-2 in vitro.

BACKGROUND: The SARS-CoV-2/COVID-19 pandemic has inflicted medical and socioeconomic havoc, and despite the current availability of vaccines and broad implementation of vaccination programs, more easily accessible and cost-effective acute treatment options preventing morbidity and mortality are urgently needed. Herbal teas have historically and recurrently been applied as self-medication for prophylaxis, therapy, and symptom alleviation in diverse diseases, including those caused by respiratory viruses, and have provided sources of natural products as basis for the development of therapeutic agents. To identify affordable, ubiquitously available, and effective treatments, we tested herbs consumed worldwide as herbal teas regarding their antiviral activity against SARS-CoV-2. RESULTS: Aqueous infusions prepared by boiling leaves of the Lamiaceae perilla and sage elicit potent and sustained antiviral activity against SARS-CoV-2 when applied after infection as well as prior to infection of cells. The herbal infusions exerted in vitro antiviral effects comparable to interferon-ß and remdesivir but outperformed convalescent sera and interferon-α2 upon short-term treatment early after infection. Based on protein fractionation analyses, we identified caffeic acid, perilla aldehyde, and perillyl alcohol as antiviral compounds. Global mass spectrometry (MS) analyses performed comparatively in two different cell culture infection models revealed changes of the proteome upon treatment with herbal infusions and provided insights into the mode of action. As inferred by the MS data, induction of heme oxygenase 1 (HMOX-1) was confirmed as effector mechanism by the antiviral activity of the HMOX-1-inducing compounds sulforaphane and fraxetin. CONCLUSIONS: In conclusion, herbal teas based on perilla and sage exhibit antiviral activity against SARS-CoV-2 including variants of concern such as Alpha, Beta, Delta, and Omicron, and we identified HMOX-1 as potential therapeutic target. Given that perilla and sage have been suggested as treatment options for various diseases, our dataset may constitute a valuable resource also for future research beyond virology.

Dysbindin Domain-Containing 1 in Prostate Cancer: New Insights into Bioinformatic Validation of Molecular and Immunological Features.

Prostate cancer (PCa) is one of the most prevalent cancers in men, yet its pathogenic pathways remain poorly understood. Transcriptomics and high-throughput sequencing can help uncover cancer diagnostic targets and understand biological circuits. Using prostate adenocarcinoma (PRAD) datasets of various web-based applications (GEPIA, UALCAN, cBioPortal, SR Plot, hTFtarget, Genome Browser, and MetaCore), we found that upregulated dysbindin domain-containing 1 (DBNDD1) expression in primary prostate tumors was strongly correlated with pathways involving the cell cycle, mitotic in KEGG, WIKI, and REACTOME database, and transcription factor-binding sites with the DBNDD1 gene in prostate samples. DBNDD1 gene expression was influenced by sample type, cancer stage, and promoter methylation levels of different cancers, such as PRAD, liver hepatocellular carcinoma (LIHC), and lung adenocarcinoma (LUAD). Regulation of glycogen synthase kinase (GSK)-3ß in bipolar disorder and ATP/ITP/GTP/XTP/TTP/CTP/UTP metabolic pathways was closely correlated with the DBNDD1 gene and its co-expressed genes in PCa. DBNDD1 gene expression was positively associated with immune infiltration of B cells, Myeloid-derived suppressor cell (MDSC), M2 macrophages, andneutrophil, whereas negatively correlated with CD8+ T cells, T follicular helper cells, M1 macrophages, and NK cells in PCa. These findings suggest that DBNDD1 may serve as a viable prognostic marker not only for early-stage PCa but also for immunotherapies.

Prophylactic and therapeutic HBV vaccination by an HBs-expressing cytomegalovirus vector lacking an interferon antagonist in mice.

Cytomegalovirus (CMV)-based vaccines show promising effects against chronic infections in nonhuman primates. Therefore, we examined the potential of hepatitis B virus (HBV) vaccines based on mouse CMV (MCMV) vectors expressing the small HBsAg. Immunological consequences of vaccine virus attenuation were addressed by either replacing the dispensable gene m157 ("MCMV-HBsȍ) or the gene M27 ("ΔM27-HBs"), the latter encodes a potent IFN antagonist targeting the transcription factor STAT2. M27 was chosen, since human CMV encodes an analogous gene product, which also induced proteasomal STAT2 degradation by exploiting Cullin RING ubiquitin ligases. Vaccinated mice were challenged with HBV through hydrodynamic injection. MCMV-HBs and ΔM27-HBs vaccination achieved accelerated HBV clearance in serum and liver as well as robust HBV-specific CD8+ T-cell responses. When we explored the therapeutic potential of MCMV-based vaccines, especially the combination of ΔM27-HBs prime and DNA boost vaccination resulted in increased intrahepatic HBs-specific CD8+ T-cell responses and HBV clearance in persistently infected mice. Our results demonstrated that vaccines based on a replication competent MCMV attenuated through the deletion of an IFN antagonist targeting STAT2 elicit robust anti-HBV immune responses and mediate HBV clearance in mice in prophylactic and therapeutic immunization regimes.