Diversification of the Rho transcription termination factor in bacteria.

Correct termination of transcription is essential for gene expression. In bacteria, factor-dependent termination relies on the Rho factor, that classically has three conserved domains. Some bacteria also have a functional insertion region. However, the variation in Rho structure among bacteria has not been analyzed in detail. This study determines the distribution, sequence conservation, and predicted features of Rho factors with diverse domain architectures by analyzing 2730 bacterial genomes. About half (49.8%) of the species analyzed have the typical Escherichia coli like Rho while most of the other species (39.8%) have diverse, atypical forms of Rho. Besides conservation of the main domains, we describe a duplicated RNA-binding domain present in specific species and novel variations in the bicyclomycin binding pocket. The additional regions observed in Rho proteins exhibit remarkable diversity. Commonly, however, they have exceptional amino acid compositions and are predicted to be intrinsically disordered, to undergo phase separation, or have prion-like behavior. Phase separation has recently been shown to play roles in Rho function and bacterial fitness during harsh conditions in one species and this study suggests a more widespread role. In conclusion, diverse atypical Rho factors are broadly distributed among bacteria, suggesting additional cellular roles.

Attentional Biases and Nonsuicidal Self-Injury Urges in Adolescents.

Importance: Nonsuicidal self-injury (NSSI) is a significant clinical concern among adolescents. Exposure to NSSI-related content on social media platforms has been suspected to potentially act as a trigger for NSSI. Objective: To use free-viewing eye-tracking and dot-probe paradigms to examine attentional bias and psychophysiological responses to NSSI-related pictorial and textual stimuli in adolescents with and without a history of NSSI. Design, Setting, and Participants: From June 2022 to April 2023, adolescent participants in Vienna, Austria with and without a history of NSSI were exposed to NSSI-related stimuli in this nonrandomized controlled trial. Data were analyzed from December 2023 to January 2024. Exposure: Exposure to NSSI-related stimuli. Main Outcomes and Measures: During both tasks, subjective arousal, NSSI urges, and autonomic nervous system activity were assessed. Results: A total of 50 adolescents in 2 groups, 25 who engaged in NSSI (mean [SD] age 15.86 [1.14] years; 19 female participants [76%]) and 25 who did not (mean [SD] age 16.40 [1.71] years; 19 female participants [76%]) were included. Adolescents with a history of NSSI-but not those without a history of NSSI-showed a clear attentional bias toward NSSI-related images during eye-tracking, as indicated by increased initial fixations (500 ms stimulus presentation mean difference, 28.64%; 95% CI, 18.31%-38.98%; P < .001; 1000 ms stimulus presentation mean difference, 18.50%; 95% CI, 9.05%-27.95%; P < .001) and longer fixation durations (500 ms mean difference, 29.51 ms; 95% CI, 4.3-54.72 ms; P < .001; 1000 ms mean difference, 39.83 ms; 95% CI, 6.90-72.76 ms; P < .001), regardless of stimulus duration. This bias was associated with a heightened urge to engage in NSSI (d = 1.22; 95% CI, 0.69-1.73; P < .001), a trend not seen in adolescents without a history of NSSI. Similarly, in the dot-probe task, only the NSSI group showed an attentional bias toward NSSI images but not toward trauma images, emphasizing the specificity of their attentional bias. Physiological measures revealed no significant differences, suggesting that viewing NSSI images is not associated with increased autonomic arousal. Textual NSSI content did not provoke an attentional bias or heighten NSSI urges in either group. Conclusions and Relevance: In this nonrandomized controlled trial of 50 adolescents, results highlighted a specific attentional bias toward NSSI-related pictorial stimuli in adolescents with a history of NSSI, particularly a difficulty in disengaging from NSSI images. These findings contribute to understanding maladaptive information processing in NSSI and suggest implications for clinical management and cognitive models addressing NSSI triggers. Trial Registration: German Clinical Trials Register identifier: DRKS00025905.

Alcaligenes faecalis corrects aberrant matrix metalloproteinase expression to promote reepithelialization of diabetic wounds.

Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here, we focused on Alcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds with A. faecalis accelerated healing during early stages. We investigated the underlying mechanisms and found that A. faecalis treatment promotes reepithelialization of diabetic keratinocytes, a process that is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found that A. faecalis treatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

A one-step low-cost molecular test for SARS-CoV-2 detection suitable for community testing using minimally processed saliva.

The gold standard for coronavirus disease 2019 diagnostic testing relies on RNA extraction from naso/oropharyngeal swab followed by amplification through reverse transcription-polymerase chain reaction (RT-PCR) with fluorogenic probes. While the test is extremely sensitive and specific, its high cost and the potential discomfort associated with specimen collection made it suboptimal for public health screening purposes. In this study, we developed an equally reliable, but cheaper and less invasive alternative test based on a one-step RT-PCR with the DNA-intercalating dye SYBR Green, which enables the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly from saliva samples or RNA isolated from nasopharyngeal (NP) swabs. Importantly, we found that this type of testing can be fine-tuned to discriminate SARS-CoV-2 variants of concern. The saliva RT-PCR SYBR Green test was successfully used in a mass-screening initiative targeting nearly 4500 asymptomatic children under the age of 12. Testing was performed at a reasonable cost, and in some cases, the saliva test outperformed NP rapid antigen tests in identifying infected children. Whole genome sequencing revealed that the antigen testing failure could not be attributed to a specific lineage of SARS-CoV-2. Overall, this work strongly supports the view that RT-PCR saliva tests based on DNA-intercalating dyes represent a powerful strategy for community screening of SARS-CoV-2. The tests can be easily applied to other infectious agents and, therefore, constitute a powerful resource for an effective response to future pandemics.

A Second Space Age Spanning Omics, Platforms, and Medicine Across Orbits.

The recent acceleration of commercial, private, and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit (LEO), concomitant with the highest-ever number of crewed missions entering space and preparations for exploration-class (>1 year) missions. Such rapid advancement into space from many new companies, countries, and space-related entities has enabled a"Second Space Age." This new era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, encompassing multi-omic, single-cell, and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring, and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics (PGx), as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this review, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration (NASA), Japan Aerospace Exploration Agency (JAXA), European Space Agency (ESA), and other space agencies, and also detail the commercial spaceflight sector's (e.g. SpaceX, Blue Origin, Axiom, Sierra Space) entrance into aerospace medicine and space biology, the first aerospace medicine biobank, and the myriad upcoming missions that will utilize these tools to ensure a permanent human presence beyond LEO, venturing out to other planets and moons.

Impact of device resistances in the performance of graphene-based terahertz photodetectors.

In recent years, graphene field-effect-transistors (GFETs) have demonstrated an outstanding potential for terahertz (THz) photodetection due to their fast response and high-sensitivity. Such features are essential to enable emerging THz applications, including 6G wireless communications, quantum information, bioimaging and security. However, the overall performance of these photodetectors may be utterly compromised by the impact of internal resistances presented in the device, so-called access or parasitic resistances. In this work, we provide a detailed study of the influence of internal device resistances in the photoresponse of high-mobility dual-gate GFET detectors. Such dual-gate architectures allow us to fine tune (decrease) the internal resistance of the device by an order of magnitude and consequently demonstrate an improved responsivity and noise-equivalent-power values of the photodetector, respectively. Our results can be well understood by a series resistance model, as shown by the excellent agreement found between the experimental data and theoretical calculations. These findings are therefore relevant to understand and improve the overall performance of existing high-mobility graphene photodetectors.

New RP-HPLC method for the simultaneous determination of process yield and percentage of encapsulation of Gallein in albumin nanoparticles.

A study was performed for the development and validation of a method of High Performance Liquid Chromatography (HPLC) for the identification and simultaneous quantification of Gallein and Human Serum Albumin (HSA). In addition, this work presents the development and physicochemical characterization of this new pharmaceutical formulation of HSA nanoparticles loaded with Gallein for potential use in the treatment of Alzheimer's disease. The method was developed with the purpose of determining the performance of the synthesis process of nanoparticles and the efficiency of encapsulation of the drug in the nanosystem. The HPLC mobile phase consisted of ACN:H2O:TEA:H3PO4 (50:49.8:0.1:0.1 v/v/v) pumped at a flow rate of 0.8 mL/min, isocratic mode, and the measurement were carried out at 220 nm. Chromatographic runs were performed on a C18 column (150 × 4.60 mm; 5 µm size particles). The HPLC-method was validated following the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and was used to simultaneously quantify the two components of the nanoformulation. Thus, the values obtained through the validated method were 43 % for drug encapsulation efficiency (% EE) and the synthesis performance (% yield) was 96 %. Moreover, the nanoformulation was characterized by DLS, the results showed that the average particle size was 217 nm, with a PDI of (0.085 ± 0.005) and a potential Z of -29.7 mV. Therefore, the developed method has proven useful in providing accurate simultaneous measurements of HSA and Gallein from albumin nanoparticles. It is advantageous since it is able to reduce the time and facilitate the determination of Gallein encapsulation efficiency and yield of albumin nanoparticles.

Pharmacological inhibition of receptor-interacting protein kinase 2 (RIPK2) elicits neuroprotective effects following experimental ischemic stroke.

Ischemic stroke induces a debilitating neurological insult, where inflammatory processes contribute greatly to the expansion and growth of the injury. Receptor-interacting protein kinase 2 (RIPK2) is most well-known for its role as the obligate kinase for NOD1/2 pattern recognition receptor signaling and is implicated in the pathology of various inflammatory conditions. Compared to a sham-operated control, ischemic stroke resulted in a dramatic increase in the active, phosphorylated form of RIPK2, indicating that RIPK2 may be implicated in the response to stroke injury. Here, we assessed the effects of pharmacological inhibition of RIPK2 to improve post-stroke outcomes in mice subjected to experimental ischemic stroke. We found that treatment at the onset of reperfusion with a RIPK2 inhibitor, which inhibits the phosphorylation and activation of RIPK2, resulted in marked improvements in post-stroke behavioral outcomes compared to the vehicle-administered group assessed 24 h after stroke. RIPK2 inhibitor-treated mice exhibited dramatic reductions in infarct volume, concurrent with reduced damage to the blood-brain barrier, as evidenced by reduced levels of active matrix metalloproteinase-9 (MMP-9) and leakage of blood-borne albumin in the ipsilateral cortex. To explore the protective mechanism of RIPK2 inhibition, we next pretreated mice with RIPK2 inhibitor or vehicle and examined transcriptomic alterations occurring in the ischemic brain 6 h after stroke. We observed a dramatic reduction in neuroinflammatory markers in the ipsilateral cortex of the inhibitor-treated group while also attaining a comprehensive view of the vast transcriptomic alterations occurring in the brain with inhibitor treatment through bulk RNA-sequencing of the injured cortex. Overall, we provide significant novel evidence that RIPK2 may represent a viable target for post-stroke pharmacotherapy and potentially other neuroinflammatory conditions.

Recent progress in the roles of microRNAs in pulmonary arterial hypertension associated with congenital heart disease.

Research on noncoding RNA, particularly microRNAs (miRNAs), is growing rapidly. Advances in genomic technologies have revealed the complex roles of miRNAs in pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). It has been demonstrated that the progression of PAH associated with CHD is characterized by particular dysregulation of miRNAs and is related to cardiovascular remodeling, cell death, and right ventricle dysfunction. This review provides a comprehensive overview of the current state of knowledge regarding the involvement of miRNAs in the pathogenesis and progression of PAH associated with CHD. We commence by explaining the process of miRNA synthesis and its mode of action, as well as the role of miRNA in PAH associated with CHD. Moreover, the article delves into current breakthroughs in research, potential clinical implications, and prospects for future investigations. The review provides the insight into novel approaches for diagnosis, prognosis, and therapy of PAH associated with CHD.

Effects of dietary fiber and biotic supplementation on apparent total tract macronutrient digestibility and the fecal characteristics, metabolites, and microbiota of healthy adult dogs.

Dietary fibers and biotics have been shown to support gastrointestinal health in dogs, but are usually tested individually. There is value in testing fiber-biotic combinations that are commonly used commercially. Therefore, this study was conducted to determine the apparent total tract macronutrient digestibility (ATTD) of diets supplemented with fibers or biotics and to evaluate their effects on the fecal characteristics, metabolites, microbiota, and immunoglobulin A (IgA) concentrations of dogs. Twelve healthy adult female beagle dogs (age = 6.2 ±â€…1.6 yr; body weight = 9.5 ±â€…1.1 kg) were used in a replicated 3 × 3 Latin square design to test three treatments: 1) control diet based on rice, chicken meal, tapioca starch, and cellulose + a placebo treat (CT); 2) diet based on rice, chicken meal, garbanzo beans, and cellulose + a placebo treat (GB); 3) diet based on rice, chicken meal, garbanzo beans, and a functional fiber/prebiotic blend + a probiotic-containing treat (GBPP). In each 28-d period, a 22-d diet adaptation was followed by a 5-d fecal collection phase. Fasted blood samples were collected on day 28. Data were analyzed using the Mixed Models procedure of SAS 9.4, with P < 0.05 being significant and P < 0.10 being trends. ATTD of dry matter (DM), organic matter, and energy were lower (P < 0.001) and DM fecal output was higher (P < 0.01) in dogs fed GBPP than CT or GB, whereas ATTD of crude protein was higher (P < 0.001) in dogs fed CT and GBPP than GB. ATTD of fat was higher (P < 0.001) and wet fecal output was lower (P < 0.01) in dogs fed CT than GB or GBPP. Fecal DM% was higher (P < 0.001) in dogs fed CT than GBPP or GB, and higher in dogs fed GBPP than GB. Fecal short-chain fatty acid concentrations were higher (P < 0.001) in dogs fed GB than CT or GBPP, and higher in dogs fed GB than GBPP. Fecal IgA concentrations were higher (P < 0.01) in dogs fed GB than CT. Fecal microbiota populations were affected by diet, with alpha diversity being higher (P < 0.01) in dogs fed GB than CT, and beta diversity shifting following dietary fiber and biotic supplementation. The relative abundance of 24 bacterial genera was altered in dogs fed GB or GBPP than CT. Serum triglyceride concentrations were lower in dogs fed GB than GBPP or CT. Our results demonstrate that legume-based dietary fibers, with or without prebiotics and probiotics, reduce ATTD, increase stool output, beneficially shift fecal metabolites and microbiota, and reduce blood lipids in adult dogs.

Functional fibers and biotics have demonstrated the potential to modulate the gut microbiome and improve gastrointestinal health in dogs, but are often tested individually. Research investigating unique fiber/biotic combinations is needed. Twelve dogs were used in a replicated 3 × 3 Latin square design to test the efficacy of three dietary treatments on apparent total tract macronutrient digestibility (ATTD) and the fecal characteristics, metabolites, microbiota, and immunoglobulin A concentrations of dogs. Treatments included a low-fiber control diet without prebiotics or probiotics + a placebo treat, a diet containing garbanzo beans + a placebo treat (GB), and a diet containing garbanzo beans and a prebiotic blend + a probiotic (Bacillus subtilis and Bacillus amyloliquefaciens) treat (GBPP). ATTD was reduced and stool output was greater in dogs fed GB or GBPP than controls. Fecal short-chain fatty acids were higher in dogs fed GB or GBPP than controls. Fecal immunoglobulin A was higher, while blood lipids were lower in dogs fed GB than control. Finally, GB and GBPP shifted fecal bacterial populations. Our results demonstrate that legume-based dietary fibers, with or without prebiotics and probiotics, reduce ATTD, increase stool output, beneficially shift fecal metabolites and microbiota, and reduce blood lipids in adult dogs.

Identifying priority sites for whale shark ship collision management globally.

The expansion of the world's merchant fleet poses a great threat to the ocean's biodiversity. Collisions between ships and marine megafauna can have population-level consequences for vulnerable species. The Endangered whale shark (Rhincodon typus) shares a circumglobal distribution with this expanding fleet and tracking of movement pathways has shown that large vessel collisions pose a major threat to the species. However, it is not yet known whether they are also at risk within aggregation sites, where up to 400 individuals can gather to feed on seasonal bursts of planktonic productivity. These "constellation" sites are of significant ecological, socio-economic and cultural value. Here, through expert elicitation, we gathered information from most known constellation sites for this species across the world (>50 constellations and >13,000 individual whale sharks). We defined the spatial boundaries of these sites and their overlap with shipping traffic. Sites were then ranked based on relative levels of potential collision danger posed to whale sharks in the area. Our results showed that researchers and resource managers may underestimate the threat posed by large ship collisions due to a lack of direct evidence, such as injuries or witness accounts, which are available for other, sub-lethal threat categories. We found that constellations in the Arabian Sea and adjacent waters, the Gulf of Mexico, the Gulf of California, and Southeast and East Asia, had the greatest level of collision threat. We also identified 39 sites where peaks in shipping activity coincided with peak seasonal occurrences of whale sharks, sometimes across several months. Simulated collision mitigation options estimated potentially minimal impact to industry, as most whale shark core habitat areas were small. Given the threat posed by vessel collisions, a coordinated, multi-national approach to mitigation is needed within priority whale shark habitats to ensure collision protection for the species.

From diagnosis to intervention: a review of telemedicine's role in skin cancer care.

Skin cancer treatment is a core aspect of dermatology that relies on accurate diagnosis and timely interventions. Teledermatology has emerged as a valuable asset across various stages of skin cancer care including triage, diagnosis, management, and surgical consultation. With the integration of traditional dermoscopy and store-and-forward technology, teledermatology facilitates the swift sharing of high-resolution images of suspicious skin lesions with consulting dermatologists all-over. Both live video conference and store-and-forward formats have played a pivotal role in bridging the care access gap between geographically isolated patients and dermatology providers. Notably, teledermatology demonstrates diagnostic accuracy rates that are often comparable to those achieved through traditional face-to-face consultations, underscoring its robust clinical utility. Technological advancements like artificial intelligence and reflectance confocal microscopy continue to enhance image quality and hold potential for increasing the diagnostic accuracy of virtual dermatologic care. While teledermatology serves as a valuable clinical tool for all patient populations including pediatric patients, it is not intended to fully replace in-person procedures like Mohs surgery and other necessary interventions. Nevertheless, its role in facilitating the evaluation of skin malignancies is gaining recognition within the dermatologic community and fostering high approval rates from patients due to its practicality and ability to provide timely access to specialized care.

Plant Protease Inhibitors as Emerging Antimicrobial Peptide Agents: A Comprehensive Review.

Antimicrobial peptides (AMPs) are important mediator molecules of the innate defense mechanisms in a wide range of living organisms, including bacteria, mammals, and plants. Among them, peptide protease inhibitors (PPIs) from plants play a central role in their defense mechanisms by directly attacking pathogens or by modulating the plant's defense response. The growing prevalence of microbial resistance to currently available antibiotics has intensified the interest concerning these molecules as novel antimicrobial agents. In this scenario, PPIs isolated from a variety of plants have shown potential in inhibiting the growth of pathogenic bacteria, protozoans, and fungal strains, either by interfering with essential biochemical or physiological processes or by altering the permeability of biological membranes of invading organisms. Moreover, these molecules are active inhibitors of a range of proteases, including aspartic, serine, and cysteine types, with some showing particular efficacy as trypsin and chymotrypsin inhibitors. In this review, we provide a comprehensive analysis of the potential of plant-derived PPIs as novel antimicrobial molecules, highlighting their broad-spectrum antimicrobial efficacy, specificity, and minimal toxicity. These natural compounds exhibit diverse mechanisms of action and often multifunctionality, positioning them as promising molecular scaffolds for developing new therapeutic antibacterial agents.

Predictors of damage accrual and its impact on health-related quality of life of thrombotic antiphospholipid syndrome: Independent validation of the damage index for antiphospholipid syndrome (DIAPS).

OBJECTIVES: We aim to independently assess the validity of the damage index for antiphospholipid syndrome (DIAPS) in thrombotic antiphospholipid syndrome (APS) patients by exploring the prevalence and risk factors of organ damage and evaluating its impact on health-related quality of life (HR-QoL). METHODS: Cross-sectional study including all thrombotic APS patients (Sydney criteria) attending a Portuguese tertiary centre. Damage was assessed using the DIAPS, and HR-QoL using the 3- and 5-level EuroQol HR-QoL (EQ-D5-3L and 5L), and Visual Analogue Scale (VAS) applied via a phone questionnaire. Spearman's correlation between DIAPS and the HR-QoL scales was performed. Risk factors for damage accrual and HR-QoL impairment were explored using univariate and multivariate logistic regression. RESULTS: Among the 108 patients (female, 65.7%; white, 90.7%; primary APS, 75.9%; median disease duration, 6 years), damage (DIAPS≥1) developed in 48.2% of patients (mean ± SD DIAPS, 3.08 ± 1.83). DIAPS's neuropsychiatric domain was the most affected (24.2%), followed by the peripheral vascular domain (20.3%). No clinical, demographic nor laboratory parameters were significantly associated with damage. Regarding HR-QoL, pain/discomfort, anxiety/depression and usual activities domains were the most frequently impaired in both scales. DIAPS's domains correlated similarly with the EQ-5D-3L and 5L scales' individual domains. Female sex, medical disorders, secondary APS and type of presenting thrombosis (arterial) increased the risk of HR-QoL impairment. Total DIAPS was associated with higher odds of mobility, self-care and pain/discomfort impairment in both EQ-5D-3L and 5L scales but lost its independent risk in multivariable analysis. CONCLUSION: This external validation of DIAPS reinforces the ability of the score to correlate with HR-QoL while also highlighting risk factors for HR-QoL impairment other than damage accrual.

Assessing Biomedical and Psychosocial Factors in a Cross-Sectional Study of School Dropouts Among Pregnant Adolescents and Young Mothers in Quito, Ecuador.

BACKGROUND: Over nearly three decades, Ecuador experienced a significant rise in adolescent motherhood. OBJECTIVES: By focusing on social, health, and psychological aspects, the research aims to reveal the complex factors influencing the decision to discontinue education. The emphasis on providing a platform for direct expression of personal experiences not only adds qualitative depth to the study but also ensures that the voices of those involved are heard authentically. METHODS: Employing a nonexperimental, descriptive, cross-sectional approach with qualitative and quantitative methods, the research delves into the interplay of biological, psychological, and social factors. Descriptive statistics, presented through tables and graphs, were used for variable analysis, complemented by inferential statistics to validate hypotheses. Focus group sessions, processed with ATLAS.ti (ATLAS.ti Scientific Software Development GmbH, Berlin, Germany) underwent a thorough review in workshops with Servicio de Atención Integral para Adolescentes (SAIA) experts. Adolescent participants were randomly recruited through the hospital's system. RESULTS: The findings unveiled a significant dropout rate among adolescents, where pregnancy was just one factor influencing their decision. Those discontinuing education often embraced a life project centered on motherhood and domestic roles, facing domestic violence and mental health disorders. In contrast, those persisting with education were driven by professional development, facing challenges but benefiting from family support. Despite unwanted pregnancies and low contraceptive use, many found personal growth and identity affirmation in motherhood. CONCLUSIONS: Our research highlights key insights into factors like pregnancy desire, contraception, reactions, and challenges. Urgent action is needed to address systemic problems and provide holistic support, acknowledging the resilience and validity of choices made by adolescent mothers in balancing motherhood with education and career goals.

The microbiota and T cells non-genetically modulate inherited phenotypes transgenerationally.

The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations.

White Paper: American Gastroenterological Association Position Statement: The Future of IBD Care in the United States-Removing Barriers and Embracing Opportunities.

Despite incredible growth in systems of care and rapidly expanding therapeutic options for people with inflammatory bowel disease, there are significant barriers that prevent patients from benefiting from these advances. These barriers include restrictions in the form of prior authorization, step therapy, and prescription drug coverage. Furthermore, inadequate use of multidisciplinary care and inflammatory bowel disease specialists limits patient access to high-quality care, particularly for medically vulnerable populations. However, there are opportunities to improve access to high-quality, patient-centered care. This position statement outlines the policy and advocacy goals that the American Gastroenterological Association will prioritize for collaborative efforts with patients, providers, and payors.

Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.

INTRODUCTION: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells. MATERIALS AND METHODS: To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. RESULTS: The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. CONCLUSION: YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.

Engineering models of head and neck and oral cancers on-a-chip.

Head and neck cancers (HNCs) rank as the sixth most common cancer globally and result in over 450 000 deaths annually. Despite considerable advancements in diagnostics and treatment, the 5-year survival rate for most types of HNCs remains below 50%. Poor prognoses are often attributed to tumor heterogeneity, drug resistance, and immunosuppression. These characteristics are difficult to replicate using in vitro or in vivo models, culminating in few effective approaches for early detection and therapeutic drug development. Organs-on-a-chip offer a promising avenue for studying HNCs, serving as microphysiological models that closely recapitulate the complexities of biological tissues within highly controllable microfluidic platforms. Such systems have gained interest as advanced experimental tools to investigate human pathophysiology and assess therapeutic efficacy, providing a deeper understanding of cancer pathophysiology. This review outlines current challenges and opportunities in replicating HNCs within microphysiological systems, focusing on mimicking the soft, glandular, and hard tissues of the head and neck. We further delve into the major applications of organ-on-a-chip models for HNCs, including fundamental research, drug discovery, translational approaches, and personalized medicine. This review emphasizes the integration of organs-on-a-chip into the repertoire of biological model systems available to researchers. This integration enables the exploration of unique aspects of HNCs, thereby accelerating discoveries with the potential to improve outcomes for HNC patients.

Approaches to risk-benefit assessment of seafood consumption: lessons learned from an evidence scan.

Qualitative and quantitative risk-benefit assessments (RBA) can be used to support public health decisions in food safety. We conducted an evidence scan to understand the state of the science regarding RBA in seafood to help inform seafood dietary advice in the United States. We collected published RBA studies assessing seafood consumption, designed inclusion and exclusion criteria to screen these studies, and conducted systematic data extraction for the relevant studies published since 2019. Our findings indicate the selection of health risks and benefits does not generally follow a systematic approach. Uncertainty and variability in RBAs is often not addressed, and quantitative RBAs making use of a single health metric generally have not been leveraged to directly support published regulatory decisions or dietary guidance. To elevate the role of RBA in supporting regulatory decision-making, risk assessors and risk managers must work together to set expectations and goals. We identified the need for a prioritization phase (e.g., multicriteria decision analysis model) to determine the risks and benefits of greatest public health impact to inform the RBA design. This prioritization would consider not only the degree of public health impact of each risk and benefit, but also the potential for risks and benefits to converge on common health outcomes and their importance to subpopulations. Including a prioritization could improve the utility of the RBAs to better inform risk management decisions and advance public health. Our work serves to guide the United States Food and Drug Administration's approaches to RBA in foods.