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Purpose: Pitch variations (tone productions) have been reported as a measure to differentiate Cantonese-speaking children with and without childhood apraxia of speech (CAS). This study aims to examine fundamental frequency (F0) changes within syllables and the effects of syllable structure, lexical status, and syllable positions on F0 in Cantonese-speaking preschool children with and without CAS. Method: Six children with CAS, six children with non-CAS speech sound disorder plus language disorder (S&LD), 22 children with speech sound disorder only (SSD), and 63 children with typical speech-language development (TD) performed the tone sequencing task (TST). Growth curve analysis was employed to analyze and compare the F0 values within syllables with three Cantonese tones (high level, high rising, and low falling). The analysis considered the effects of syllable structure (vowel and consonant-vowel), lexical status (word and nonword), and syllable position (initial, medial, and final) on F0, as well as comparisons within and between groups. Results: Within each group, the effects of syllable structure and position on F0 values were found with different patterns. Between-group comparisons showed that the CAS group had reduced F0 contrasts. The CAS group could be differentiated from the control groups based on interactions of F0 with syllable structure and position, but not lexical status. The dissimilarity of F0 values detected between the CAS and SSD/TD groups was more prominent than that observed between the CAS and S&LD groups. Conclusions: This study demonstrated that Cantonese-speaking children with CAS had difficulty in varying F0 within syllables as compared to those without CAS, suggesting pitch variation difficulty and language-specific impairment profiles in CAS. Future investigations of objective measures for identifying Cantonese speakers with CAS and cross-linguistic investigations using growth curve analysis and the TST are suggested.

ABSTRACT Background Previous studies reveal inconsistent associations between serum lipid traits and the risks of fractures and osteoporosis in the general population. Methods This prospective cohort study analysed data from 414 302 UK Biobank participants (223 060 women and 191 242 men, aged 37–73 years) with serum lipid measurements: apolipoprotein A (Apo A), apolipoprotein B (Apo B), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG) and lipoprotein A (Lp(a)). Multivariable Cox proportional hazard models with penalized cubic splines were used to explore potential nonlinear associations of each lipid trait with the risks of fractures and osteoporosis. Subgroup analyses by age, sex, BMI categories and pre‐existing cardiovascular disease were conducted. Mediation analyses using the g‐formula were performed to quantify to which extent bone mineral density (BMD) may mediate the association between serum lipids and fracture risk. Results Over a median follow‐up period of 13.8 years, 25 918 (6.8%) of the 383 530 participants without prior fracture had incident fracture cases, and 7591 (4.1%) of the 184 919 participants with primary care data and without baseline osteoporosis were diagnosed with osteoporosis. TG had nonlinear associations with fractures and osteoporosis, whereas Apo B, TC and LDL‐C had linear associations. There were also nonlinear associations of Apo A and HDL‐C with fractures. Individuals in the highest quintiles for Apo A (fracture: HR 1.15 [95% CI 1.10, 1.21]; osteoporosis: HR 1.13 [1.02, 1.25]) and HDL‐C (fracture: HR 1.27 [1.20, 1.34]; osteoporosis: HR 1.31 [1.18, 1.46]) were associated with higher risks of fractures and osteoporosis. Conversely, those in the highest quintile for Apo B (fracture: HR 0.85 [0.81, 0.89]; osteoporosis: HR 0.86 [0.79, 0.94]), LDL‐C (fracture: HR 0.89 [0.85, 0.93]; osteoporosis: HR 0.91 [0.83, 1.00]) and TG (fracture: HR 0.78 [0.74, 0.82]; osteoporosis: HR 0.75 [0.68, 0.82]) were associated with lower risks. The associations of Apo A (ratio of HR [RHR] 1.05 [1.02, 1.09]) and HDL‐C (RHR 1.06 [1.03, 1.09]) with fracture risk were more pronounced in men compared to women. Except for TG and Lp(a), the associations between serum lipids and fractures appear to be partially mediated through BMD (mediation proportions: 5.30% to 40.30%), assuming causality. Conclusions Our study reveals a complex interplay between different lipid markers and skeletal health, potentially partially mediated through BMD. Routine lipid profile assessments, including HDL‐C and Apo A among other lipid traits, may be integrated into the strategies for fracture risk stratification.

Abstract Background Early in the coronavirus disease 2019 (COVID-19) pandemic, Sunda pangolins (Manis javanica) involved in the illegal wildlife trade in mainland China were identified as hosts of severe acute respiratory syndrome-related coronaviruses (SARSr-CoVs). Although it is unconfirmed whether pangolins or other traded wildlife served as intermediate hosts for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the trafficking of pangolins presents a clear risk for transmission of viruses with zoonotic and epizootic potential regardless. We have investigated the origins of pangolin carcasses seized in Hong Kong and have evaluated their potential exposure to SARSr-CoVs, other coronaviruses, and paramyxoviruses, aiming to address a gap in our knowledge with regard to the role of wildlife trade in the maintenance and emergence of pathogens with zoonotic and epizootic potential. Results Using a combination of virological and wildlife forensics tools, we investigated 89 Sunda pangolin carcasses seized by Hong Kong authorities during anti-smuggling operations in the territory conducted in 2013 (n = 1) and 2018 (n = 88). Swabs, organ tissues, blood, and other body fluids were collected during post-mortem examination. Two enzyme-linked immunosorbent assays (ELISAs), which employ a double-antigen sandwich format, were used to detect antibodies reactive against SARSr-CoVs. One individual was found to be seropositive with support from both methods, while five individuals exhibited a putatively seropositive result from one ELISA method. Polymerase chain reaction (PCR) screening for coronavirus and paramyxovirus ribonucleic acid (RNA) did not yield any positives. Based on genomic data, the seropositive individual was determined to have likely originated from Java, while the putatively seropositive individuals were determined to have originated from populations in Borneo, Java, and Singapore/Sumatra. Conclusions While the role of pangolins in the evolution and ecology of SARS-CoV-2 is uncertain, our results suggest susceptibility and potential exposure of pangolins to SARSr-CoVs, occurring naturally or associated with the illegal trafficking of these animals. Complex dynamics between natural populations, traded individuals, and pathogen susceptibility complicate conclusions about the role of pangolins, as well as other host species, in the ecology of SARSr-CoVs and potentially zoonotic viruses with risk of future emergence.

Abstract Background Fusobacterium nucleatum (F. nucleatum) is one of the key tumorigenic bacteria in colorectal cancer (CRC), yet how F. nucleatum is involved in colorectal cancer carcinogenesis remains unknown. Results In the present study, we carried out PathSeq analysis on RNA sequencing data from the 430 primary colon adenocarcinomas in TCGA database to assess the relationship between patients’ survival and F. nucleatum abundance. Among patients with cecum and ascending colon tumors, we found that F. nucleatum transcriptome abundance is positively correlated with mutation load. We further demonstrated that patients with both high tumoral abundance of F. nucleatum and high mutation load exhibited poorer survival and DNA damage. We furthermore determined that F. nucleatum-conditioned medium (Fn. CM) induces DNA damage in both in vitro and in vivo studies. In addition, two F. nucleatum-secreted mutagens, namely DL-homocystine and allantoic acid, were identified to lead to DNA damage. Conclusions Our finding delineates the genotoxicity of F.nucleatum-secreted mutagens, which provides a basis for further work to investigate the role of F. nucleatum in the pathogenicity of CRC.

Abstract Background The COVID-19 pandemic had a significant impact on both the clinical practice and the psychological states of frontline physicians in the emergency department. Trainees, at the beginning of their careers and thus still developing their practice styles and identities as physicians, were uniquely affected. Objective In this qualitative study, we sought to explore how the pandemic environment shaped the experiences of emergency medicine resident physicians. Methods This was a qualitative study. We conducted in-depth interviews with emergency medicine faculty, resident physicians, and staff at a single emergency department based at an urban academic institution in the northeastern United States. Interviews were audio recorded and transcribed, and transcripts were then analyzed in an iterative process by our coding team for recurring themes related to the resident experience. Results We reached data saturation with 27 individuals. Of those who were interviewed, 10 were resident physicians [6 senior residents (PGY-3 or PGY-4) and 4 junior residents (PGY-1 or PGY-2)]. Three major recurring themes regarding resident physician experience emerged during our analysis of the interviews: (1) novel educational experiences dampened by negative structural forces from the pandemic, (2) fracturing of social interactions and mitigation through ad-hoc support systems and community of practice, and (3) development of negative emotions and psychological trauma including fear, resentment, and moral injury causing lasting harm. Conclusions Our results suggest that emergency medicine resident physicians training during the COVID-19 pandemic faced unique experiences concerning their education, social support systems, and emotional states. While the educational and social experiences were described as having both negative and positive impacts, the emotional experiences were largely negative. Residency program leadership may use these insights to improve resident preparation, wellness, and resilience in the face of future adverse events.

Awareness and interest in engineering entrepreneurship education has been steadily increasing, yet questions remain on what should be taught. There is a need for research to examine the impact of engineering entrepreneurship education with reference to existing theory and research, and from perspectives of different stakeholders. This study investigates the expectations and perspectives of multiple stakeholders towards learning outcomes in engineering entrepreneurship education, mainly including students from first and final years of higher education, along with educators and industry professionals. A survey instrument was adopted to investigate student expectations towards engineering entrepreneurship education learning outcomes. The quantitative phase offered preliminary findings to support the next phase of individual interviews with students, educators, and professionals from the engineering industry. Findings revealed diverse expectations, needs and preferences across individuals and stakeholder groups. Implications are offered for curriculum design and implementation of teaching and learning practices in this field.

This article explores the issue of internationalisation in the teaching of political science at universities. We first provide an overview of the mix of courses in terms of geographical focus offered by high-ranking political science departments. Second, with survey data from students, we assess the factors affecting their attitudes towards area-specific and general politics courses. The results indicate that, compared to local students who prefer local politics courses, international students are most interested in those with a mid-range scope such as those containing cross-case comparisons. This paper encourages integrating comparative elements even in area-specific politics courses to enhance student engagement.

ObjectiveAutism spectrum disorder (ASD) is a common neurodevelopmental disorder. Increasing evidence suggests that it is potentially related to gut microbiota, but no prior bibliometric analysis has been performed to explore the most influential works in the relationships between ASD and gut microbiota. In this study, we conducted an in-depth analysis of the most-cited articles in this field, aiming to provide insights to the existing body of research and guide future directions.MethodsA search strategy was constructed and conducted in the Web of Science database to identify the 100 most-cited papers in ASD and gut microbiota. The Biblioshiny package in R was used to analyze and visualize the relevant information, including citation counts, country distributions, authors, journals, and thematic analysis. Correlation and comparison analyses were performed using SPSS software.ResultsThe top 100 influential manuscripts were published between 2000 and 2021, with a total citation of 40,662. The average number of citations annually increased over the years and was significantly correlated to the year of publication (r = 0.481, p < 0.01, Spearman’s rho test). The United States was involved in the highest number of publications (n = 42). The number of publications in the journal was not significantly related to the journal’s latest impact factor (r = 0.016, p > 0.05, Spearman’s rho test). Co-occurrence network and thematic analysis identified several important areas, such as microbial metabolites of short-chain fatty acids and overlaps with irritable bowel syndrome.ConclusionThis bibliometric analysis provides the key information of the most influential studies in the area of ASD and gut microbiota, and suggests the hot topics and future directions. The findings of this study can serve as a valuable reference for researchers and policymakers, guiding the development and implementation of the scientific research strategies in this area.

Category: Trauma; Ankle Introduction/Purpose: The direct anterior (DA) approach is commonly used for reconstructive procedures to treat posttraumatic ankle osteoarthritis (PTOA), however, literature investigating utilization of the DA approach (defined as the interval between the tibialis anterior tendon and extensor hallucis longus tendon) for initial fixation of pilon fractures is lacking. This retrospective study of patients undergoing fixation of pilon fractures hypothesizes that there is no difference in reoperation rate for patients whose pilon fractures were treated with DA approach. Methods: A retrospective radiographic and chart review of patients undergoing surgical fixation of tibial plafond fractures over a nine year period (2013-2022) at an urban, level 1 trauma center was undertaken. Review of operative notes for reoperation for infection, PTOA, nonunion and symptomatic hardware was utilized to determine reoperation rates. Injuries were radiographically stratified by AO/OTA classification, and quality of fracture reduction was assessed via measurement of the lateral distal tibial angle (LDTA) and lateral talar station (LTS) at the first postoperative radiograph. Likelihood of reoperation within one year of index surgery was analyzed using Kaplan-Meier estimations. Reoperation risk factors were determined with multivariable logistic regression analyses created using a backwards stepwise process. Results: 135 fractures in 130 patients met inclusion criteria; 44 fractures were treated via a DA approach, 91 treated via all other approaches, many in combination. Between groups, AO/OTA classification, demographics, injury characteristics and operative time were no different. Overall reoperation rate was 40.7%. There was no significant difference between DA and all other approaches in rate of reoperation for infection (2.3% vs. 10%, p=0.21), nonunion (15.9% vs. 16.5%, p=1), PTOA (9.1% vs. 7.8%, p=1) and removal of symptomatic hardware (25% vs. 36.3%, P=0.27). Multivariable regression showed DA approach was associated with lower risk of reoperation within one year (OR 0.25, 95% CI 0.07-0.71, P=0.02). The DA group lateral talar station (LTS) was significantly greater (more anterior) by 0.9mm (2.75mm DA vs. 1.85mm all others, P=0.01). Conclusion: Utilization of the direct anterior approach to the ankle for initial fixation of pilon fractures has no difference in overall reoperation rates and a lower likelihood of reoperation within one year compared to all other combinations of approaches to the tibial plafond. Radiographic outcomes were different between groups, but the clinical significance of this is unclear. The DA approach should be considered for fracture patterns amenable to its use and may offer benefit should reconstructive procedures become necessary.

ABSTRACTRepeated exposure to antibiotics and changes in the diet and environment shift the gut microbial diversity and composition, making the host susceptible to pathogenic infection. The emergence and ongoing spread of AMR pathogens is a challenging public health issue. Recent evidence showed that probiotics and prebiotics may play a role in decolonizing drug-resistant pathogens by enhancing the colonization resistance in the gut. This review aims to analyze available evidence from human-controlled trials to determine the effect size of probiotic interventions in decolonizing AMR pathogenic bacteria from the gut. We further studied the effects of prebiotics in human and animal studies. PubMed, Embase, Web of Science, Scopus, and CINAHL were used to collect articles. The random-effects model meta-analysis was used to pool the data. GRADE Pro and Cochrane collaboration tools were used to assess the bias and quality of evidence. Out of 1395 citations, 29 RCTs were eligible, involving 2871 subjects who underwent either probiotics or placebo treatment to decolonize AMR pathogens. The persistence of pathogenic bacteria after treatment was 22%(probiotics) and 30.8%(placebo). The pooled odds ratio was 0.59(95% CI:0.43–0.81), favoring probiotics with moderate certainty (p = 0.0001) and low heterogeneity (I2 = 49.2%, p = 0.0001). The funnel plot showed no asymmetry in the study distribution (Kendall’sTau = −1.06, p = 0.445). In subgroup, C. difficile showed the highest decolonization (82.4%) in probiotics group. Lactobacillus-based probiotics and Saccharomyces boulardii decolonize 71% and 77% of pathogens effectively. The types of probiotics (p

Abstract Background Uveal melanoma is the most common non-cutaneous melanoma and is an intraocular malignancy affecting nearly 7,000 individuals per year worldwide. Of these, approximately 50% will progress to metastatic disease for which there are currently no effective curative therapies. Despite advances in molecular profiling and metastatic stratification of uveal melanoma tumors, little is known regarding their underlying biology of metastasis. Our group has identified a disseminated neoplastic cell population characterized by co-expression of immune and melanoma proteins, circulating hybrid cells (hybrids), in patients with uveal melanoma. Compared to circulating tumor cells, which lack expression of immune proteins, hybrids are detected at an increased prevalence in peripheral blood and can be used as a non-invasive biomarker to predict metastatic progression. Methods To ascertain mechanisms underlying enhanced hybrid cell dissemination we identified hybrid cells within primary uveal melanoma tumors using single cell RNA sequencing (n = 8) and evaluated their gene expression and predicted ligand-receptor interactions in relation to other melanoma and immune cells within the primary tumor. We then verified expression of upregulated hybrid pathways within patient-matched tumor and peripheral blood hybrids (n = 4) using cyclic immunofluorescence and quantified their protein expression relative to other non-hybrid tumor and disseminated tumor cells. Results Among the top upregulated genes and pathways in hybrid cells were those involved in enhanced cell motility and cytoskeletal rearrangement, immune evasion, and altered cellular metabolism. In patient-matched tumor and peripheral blood, we verified gene expression by examining concordant protein expression for each pathway category: TMSB10 (cell motility), CD74 (immune evasion) and GPX1 (metabolism). Both TMSB10 and GPX1 were expressed on significantly higher numbers of disseminated hybrid cells compared to circulating tumor cells, and CD74 and GPX1 were expressed on more disseminated hybrids than tumor-resident hybrids. Lastly, we identified that hybrid cells express ligand-receptor signaling pathways implicated in promoting metastasis including GAS6-AXL, CXCL12-CXCR4, LGALS9-P4HB and IGF1-IGFR1. Conclusion These findings highlight the importance of TMSB10, GPX1 and CD74 for successful hybrid cell dissemination and survival in circulation. Our results contribute to the understanding of uveal melanoma tumor progression and interactions between tumor cells and immune cells in the tumor microenvironment that may promote metastasis.

Introduction: Alcohol flushing syndrome (AFS) is experienced by up to 46% of East Asians. This study aimed to review the risk of cancers in AFS patients, elucidate an exposure-response relationship, and understand risk associated with alcohol intake and cancer. Method: An electronic database search of PubMed, Embase, Scopus and Cochrane Library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. Observational studies on AFS’ effects and all cancers risk were included. Studies including patients with existing malignancy were excluded. Dichotomous variables were pooled using the Mantel-Haenszel method with a random effects model. Sensitivity and subgroup analyses were performed. PROSPERO (CRD42023392916) protocol was followed. Results: A total of 18 articles were included in the final analysis with a total of 387,521 participants. AFS was associated with an increased risk of all cancers (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.06–1.34), esophageal squamous cell carcinoma (OR 1.47, 95% CI 1.05–2.05) and gastric adenocarcinoma (OR 1.40, 95% CI 1.14–1.72). Men with AFS exhibited an increased risk of all cancers (OR 1.34, 95% CI 1.13–1.59). However, this was not observed in women. All cancers risk was associated with AFS in those who consumed drink (i.e. consumed alcohol) more than 200 g of pure ethanol/week (OR 1.68, 95% CI 1.20–2.37) but not those who consumed less than 200 g of pure ethanol/week (OR 1.27, 95% CI 0.90–1.79) or non-drinkers (OR 0.99, 95% CI 0.67–1.47). Conclusion: AFS is associated with an increased risk of all cancers, particularly esophageal squamous cell carcinoma and gastric adenocarcinoma.

Abstract Currently there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in paediatric patients with SARS-CoV-2 infection. This target trial emulation study aims to address this gap by evaluating the use of nirmatrelvir/ritonavir in non-hospitalized paediatric patients aged 12–17 years with SARS-CoV-2 Omicron variant infection. Among paediatric patients diagnosed between 16th March 2022 and 5th February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or COVID-19 diagnosis. Primary outcome was 28 day all-cause mortality or all-cause hospitalization, while secondary outcomes were 28 day in-hospital disease progression, 28 day COVID-19-specific hospitalization, multisystem inflammatory syndrome in children (MIS-C), acute liver injury, acute renal failure, and acute respiratory distress syndrome. Overall, 49,378 eligible paediatric patients were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28 day all-cause hospitalization (absolute risk reduction = 0.23%, 95%CI = 0.19%–0.31%; relative risk = 0.66, 95%CI = 0.56–0.71). No events of mortality, in-hospital disease progression, or adverse clinical outcomes were observed among nirmatrelvir/ritonavir users. The findings confirmed the effectiveness of nirmatrelvir/ritonavir in reducing all-cause hospitalization risk among non-hospitalized pediatric patients with SARS-CoV-2 Omicron variant infection.

Abstract Background Buprenorphine is an effective and safe treatment for opioid use disorder, but the requirement for moderate opioid withdrawal symptoms to emerge prior to initiation is a significant treatment barrier. Case Presentation We report on two cases of hospitalized patients with severe, active opioid use disorder, in which we initiated treatment with transdermal buprenorphine over 48 h, followed by the administration of a single dose of sublingual buprenorphine/naloxone and then extended-release subcutaneous buprenorphine. The patients did not experience precipitated withdrawal and only had mild withdrawal symptoms. Conclusions This provides preliminary evidence for a rapid induction strategy that may improve tolerability, caregiver burden, and treatment retention as compared to previous induction strategies.

IntroductionHuman milk contains human milk oligosaccharides (HMOs) and microRNAs (miRNAs), which are key bioactive components. HMOs are indigestible carbohydrates that impact infant growth and development. miRNAs are small, non-coding RNAs that regulate post-transcriptional gene expression. miRNAs are abundant in human milk and can be contained in extracellular vesicles (EVs). There is evidence that miRNAs are synthesized in the mammary epithelium and may influence mammary gland development and milk synthesis. However, the relationships between miRNAs and HMOs have yet to be fully characterized.MethodsThis study examined the associations between 210 human milk EV-miRNAs and 19 HMOs in a cohort of 98 Latina mothers. HMO measures included summary measures and concentrations of 19 HMOs. Relationships between EV-miRNAs and HMOs were examined using principal components analysis and associations between individual EV-miRNAs and HMOs were assessed.ResultsOverall patterns of EV-miRNA levels, summarized using principal components, were associated with HMO summary measures and concentrations. Levels of individual EV-miRNAs were associated with HMO summary measures and individual concentrations of 2’FL, 3FL, 3’SL, 6’SL, FLNH, LNFP I, and LNH.DiscussionResults from this study suggest that human milk EV-miRNAs are associated with the concentration of HMOs, which may have important effects on infant growth and development.

Objectives: To evaluate the prevalence of weight discrimination (the perception of being treated unfairly based on weight) and its sociodemographic associations among early adolescents aged 10 to 13 in the United States. Methods: We analyzed cross-sectional data from the Adolescent Brain Cognitive Development (ABCD) Study in Year Two (2018–2020). Multivariable logistic regression analyses were conducted, with perceived weight discrimination as the dependent variable and age, sex, sexual orientation, race and ethnicity, body mass index (BMI) category, household income, and highest parental education level as adjusted independent variables. Interaction with BMI category and weight discrimination by sex, sexual orientation, race and ethnicity, and household income was tested for. Results: In our analytical sample (N = 7129), we found that 5.46 % of early adolescents reported experiencing weight discrimination. Adolescents with BMI percentile ≥95th (adjusted odds ratio [AOR], 6.41; 95 % confidence interval [CI], 4.71–8.70),

Food allergy represents an increasing global health issue, significantly impacting society on a personal and on a systems-wide level. The gold standard for diagnosing food allergy, the oral food challenge, is time-consuming, expensive, and carries risks of allergic reactions, with unpredictable severity. There is, therefore, an urgent need for more accurate, scalable, predictive diagnostic techniques. In this review, we discuss possible future directions in the world of food allergy diagnosis. We start by describing the current clinical approach to food allergy diagnosis, highlighting novel diagnostic methods recommended for use in clinical practice, such as the basophil activation test and molecular allergology, and go on to discuss tests that require more research before they can be applied to routine clinical use, including the mast cell activation test and bead-based epitope assay. Finally, we consider exploratory approaches, such as IgE glycosylation, IgG4, T and B cell assays, microbiome analysis, and plasma cytokines. Artificial intelligence is assessed for potential integrated interpretation of panels of diagnostic tests. Overall, a framework is proposed suggesting how combining established and emerging technologies can effectively enhance the accuracy of food allergy diagnosis in the future.

IntroductionThe maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn’s disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses.Results and discussionHowever, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2) or dendritic cells (Atg16l1ΔCd11c) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7.ConclusionIn conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants.

Abstract The full data set of the Daya Bay reactor neutrino experiment is used to probe the effect of the charged current non-standard interactions (CC-NSI) on neutrino oscillation experiments. Two different approaches are applied and constraints on the corresponding CC-NSI parameters are obtained with the neutrino flux taken from the Huber-Mueller model with a 5% uncertainty. For the quantum mechanics-based approach (QM-NSI), the constraints on the CC-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ are extracted with and without the assumption that the effects of the new physics are the same in the production and detection processes, respectively. The approach based on the weak effective field theory (WEFT-NSI) deals with four types of CC-NSI represented by the parameters [ε X ] eα . For both approaches, the results for the CC-NSI parameters are shown for cases with various fixed values of the CC-NSI and the Dirac CP-violating phases, and when they are allowed to vary freely. We find that constraints on the QM-NSI parameters ϵ eα and ϵ eα s $$ {\epsilon}_{e\alpha}^s $$ from the Daya Bay experiment alone can reach the order O $$ \mathcal{O} $$ (0.01) for the former and O $$ \mathcal{O} $$ (0.1) for the latter, while for WEFT-NSI parameters [ε X ] eα , we obtain O $$ \mathcal{O} $$ (0.1) for both cases.

Abstract Electric dipoles and magnetic dipoles are the most fundamental particles in electromagnetic theory. Huygens and Janus sources, formed by the orthogonal combination of electric and magnetic dipoles, both show good directionality in the near field. Although the Huygens source has been widely used in antennas and metasurfaces, the applications of Janus source are heretofore limited. In this paper we report the physical construction of an active Janus source. Through full-wave simulations within the parallel plate waveguide (PPW) environment, we show that our source achieves the directional electromagnetic near-field and quasi-isotropic far-field requisite of the Janus source. Using this fact, we demonstrate that two active Janus and Huygens sources in close proximity (about 0.10 to 0.25 wavelengths) achieve a near 1000-fold reduced mutual coupling compared to electric dipole sources. Particularly, the simultaneous achievement of strong mutual coupling suppression and quasi-isotropic radiation make the Janus source an ideal candidate for consideration in future compact multi-input multi-output (MIMO) communication systems.

Abstract Global crop protection and food security have become critical issues to achieve the ‘Zero Hunger’ goal in recent years, as significant crop damage is primarily caused by biotic factors. Applying nanoparticles in agriculture could enhance crop yield. Nano-silver, or AgNPs, have colossal importance in many fields like biomedical, agriculture, and the environment due to their antimicrobial potential. In this context, nano-silver was fabricated by Citrus medica L. (Cm) fruit juice, detected visually and by UV–Vis spectrophotometric analysis. Further, AgNPs were characterized by advanced techniques. UV–Vis spectroscopic analysis revealed absorbance spectra at around 487 nm. The zeta potential measurement value was noted as -23.7 mV. Spectral analysis by FT-IR proved the capping of the acidic groups. In contrast, the XRD analysis showed the Miller indices like the face-centered cubic (fcc) crystalline structure. NTA revealed a mean size of 35 nm for nano-silver with a 2.4 × 108 particles mL−1 concentration. TEM analysis demonstrated spherical Cm-AgNPs with 20–30 nm sizes. The focus of this research was to evaluate the antifungal activity of biogenic AgNPs against post-harvest pathogenic fungi, including Aspergillus niger, A. flavus, and Alternaria alternata. The Cm-AgNPs showed significant antifungal activity in the order of A. niger > A. flavus > A. alternata. The biogenic Cm-AgNPs can be used for the inhibition of toxigenic fungi.

Abstract Persistently high, worldwide mortality from cancer highlights the unresolved challenges of disease surveillance and detection that impact survival. Development of a non-invasive, blood-based biomarker would transform survival from cancer. We demonstrate the functionality of ultra-high content analyses of a newly identified population of tumor cells that are hybrids between neoplastic and immune cells in patient matched tumor and peripheral blood specimens. Using oligonucleotide conjugated antibodies (Ab-oligo) permitting cyclic immunofluorescence (cyCIF), we present analyses of phenotypes among tumor and peripheral blood hybrid cells. Interestingly, the majority of circulating hybrid cell (CHC) subpopulations were not identified in tumor-associated hybrids. These results highlight the efficacy of ultra-high content phenotypic analyses using Ab-oligo based cyCIF applied to both tumor and peripheral blood specimens. The combination of a multiplex phenotypic profiling platform that is gentle enough to analyze blood to detect and evaluate disseminated tumor cells represents a novel approach to exploring novel tumor biology and potential utility for developing the population as a blood-based biomarker in cancer.