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While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.

Background & aimsBreast regression protein 39 (BRP39) (Chi3L1) and its human homolog YKL-40, is an established biomarker of liver fibrosis in nonalcoholic steatohepatitis (NASH) patients, but its role in NASH pathogenesis remains unclear. We recently identified Chi3L1 as one of the top up-regulated genes in mice with inducible gain-of-function NOD-like receptor protein 3 (NLRP3) activation that mimics several liver features of NASH. This study aimed to investigate the effects of BRP39 deficiency on NLRP3-induced liver inflammation using tamoxifen-inducible Nlrp3 knockin mice sufficient (Nlrp3A350V CRT) and deficient for BRP39 (Nlrp3A350V/BRP-/- CRT).MethodsUsing Nlrp3A350V CRT mice and Nlrp3A350V BRP-/- CRT, we investigated the consequences of BRP39 deficiency influencing NLRP3-induced liver inflammation.ResultsOur results showed that BRP39 deficiency in NLRP3-induced inflammation improved body weight and liver weight. Moreover, liver inflammation, fibrosis, and hepatic stellate cell activation were reduced significantly, corresponding to significantly decreased Ly6C+ infiltrating macrophages, CD68+ osteopontin-positive hepatic lipid-associated macrophages, and activated Lymphocyte antigen 6 complex locus G6D positive (Ly6G+) and citrullinated histone H3 postivie (H3Cit+) neutrophil accumulation in the liver. Further investigation showed that circulatory neutrophils from NLRP3-induced BRP39-deficient mice have impaired chemotaxis and migration ability, and this was confirmed by RNA bulk sequencing showing reduced immune activation, migration, and signaling responses in neutrophils.ConclusionsThese data showcase the importance of BRP39 in regulating the NLRP3 inflammasome during liver inflammation and fibrotic NASH by altering cellular activation, recruitment, and infiltration during disease progression, and revealing BRP39 to be a potential therapeutic target for future treatment of inflammatory NASH and its associated diseases.

Planning inclusive research should center meaningful engagement of co-researchers with intellectual and/or developmental disabilities to address issues that are important to their communities. There are a variety of approaches to planning research projects consistent with the guiding principles of inclusive research. We describe components of planning inclusive research by comparing two inclusive dissertation research projects. We organize our comparison into five sections: (1) initiating the projects, (2) team member characteristics and roles, (3) building and sustaining relationships, (4) accessibility in the research process, and (5) outcomes. We then discuss how contextual and team-level factors influence the process of planning inclusive research.

Graphical Abstract Highlight Research • The results of this research showed that allometric growth in males and females had negative allometric growth characteristics. • The growth condition index in male and female fish is dominated by thin and fat body shapes.The maximum length growth (L∞) and growth speed of males is higher than that of females. • Total mortality and fishing mortality for males is higher than for females, but natural mortality for females is higher than for males. • The exploitation rate of males and females is in the Under-exploitation category because the E value is

Chitinase-3-like 1 protein (CHI3L1) is a secreted glycoprotein, strongly correlated with fibrosis severity in chronic liver diseases including non-alcoholic steatohepatitis (NASH). However, the mechanisms by which CHI3L1 contributes to fibrogenesis remain undefined. Here, we showed that infiltrating monocyte-derived liver macrophages represent the main source of CHI3L1 in murine NASH. We developed a floxed CHI3L1 knock-out (KO) mouse to further study the cell-specific role of CHI3L1 ablation. Wildtype (WT) and myeloid cell-specific CHI3L1 KO mice (CreLyz) were challenged with a highly inflammatory and fibrotic dietary model of NASH by administering choline-deficient high-fat diet for 10 weeks. Macrophage accumulation and inflammatory cell recruitment were significantly ameliorated in the CreLyz group compared to WT (F4/80 IHC p

Background:. We evaluate the performance of plastic surgeons in converting National Institutes of Health K grants in early career to R grants intended for established investigators. We also investigate characteristics that may positively predict successful transition from K to R grants. Methods:. K08, K23, and R01 (or equivalent) grants awarded to plastic surgeons and physicians within the departments of ophthalmology, dermatology, and neurosurgery were collected. Analyses of successful conversion rates from a K to an R grant between plastic surgeons and physicians within the selected departments were performed. Cross-sectional analysis of characteristics among identified plastic surgeons was completed via logistic regression to elucidate possible predictors of successful conversion. Results:. Comparison of pathway initiation rates demonstrate that plastic surgeons receive significantly fewer K grants relative to the size of their field when compared with other specialties (all P < 0.01). Of the analyzed plastic surgeons, 52.9% successfully converted to an R-series grant within 5.4 years of beginning their K-series grant. Conversion rates were not significantly different between plastic surgeons and physicians within the selected departments. Logistic regression analyses revealed that the time-adjusted mean relative citation ratio of K series–associated publications is a positive predictor of successful conversion (P = 0.047). Conclusions:. With regard to increasing National Institutes of Health funding via the K-to-R pathway, we believe the field of plastic surgery could benefit from an increased effort to pursue a pathway of K-to-R conversion with a focus on quality over quantity when publishing articles associated with a K-series grant.

Background and aimsNucleotide-binding oligomerization domain-like receptor-family pyrin domain-containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL-18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis.Approach and resultsWe observed significantly increased serum levels of IL-18 (128.4 pg/ml vs. 74.9 pg/ml) and IL-18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1 . Treatment of cultured primary murine HSC with recombinant mouse IL-18 accelerated their transdifferentiation into myofibroblasts. In vivo , IL-18 receptor-deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC-specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH-induced fibrosis by feeding a choline-deficient, L-amino acid-defined, high fat diet showed that genes related to IL-18 and its downstream signaling were significantly upregulated, and Il18-/- mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin-positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL-18 signaling was blocked by its naturally occurring antagonist IL-18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell-specific NLRP3 gain-of-function was rescued by IL-18BP.ConclusionsOur study highlights the role of IL-18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL-18 as a target to treat liver fibrosis.

Background: Peer-provided services are a common model for addressing mental health concerns. Peer providers report a range of benefits and challenges associated with their role. However, there is little information about the experiences of peer providers with intellectual/developmental disabilities. Aim: To explore the experiences of young adult peer-providers with intellectual/developmental disabilities in the context of a mental health intervention. Methods: We conducted interviews with four young adults with intellectual/developmental disabilities and their parents and teachers to understand their experiences providing a peer mentoring mental health intervention. Results: Young adult peer mentors perceived themselves as responsible for maintaining the mentoring relationship, delivering the intervention and acting as helpers and independent professionals. The experiences of young adult peer mentors were driven by the temporal, institutional and social contexts of their work. Peer mentoring was an enjoyable, social activity. Mentors, parents and teachers emphasised how taking on the peer mentoring role during the transition to adulthood and within the capital-rich university context led to a sense of pride and professional development. Further, these contexts may have led mentors to emphasise their intervention-delivery, helper and professional roles over relationship maintenance. Discussion & conclusion: Context may shape the perceived roles and benefits for young adult peer mentors with intellectual/developmental disabilities.

Demographic factors are fundamental in shaping infectious disease dynamics. Aspects of populations that create structure, like age and sex, can affect patterns of transmission, infection intensity and population outcomes. However, studies rarely link these processes from individual to population-scale effects. Moreover, the mechanisms underlying demographic differences in disease are frequently unclear. Here, we explore sex-biased infections for a multi-host fungal disease of bats, white-nose syndrome, and link disease-associated mortality between sexes, the distortion of sex ratios and the potential mechanisms underlying sex differences in infection. We collected data on host traits, infection intensity and survival of five bat species at 42 sites across seven years. We found females were more infected than males for all five species. Females also had lower apparent survival over winter and accounted for a smaller proportion of populations over time. Notably, female-biased infections were evident by early hibernation and likely driven by sex-based differences in autumn mating behaviour. Male bats were more active during autumn which likely reduced replication of the cool-growing fungus. Higher disease impacts in female bats may have cascading effects on bat populations beyond the hibernation season by limiting recruitment and increasing the risk of Allee effects.

Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference.

Retention policy is an important guiding principle implemented by academic institution to promote students' development, yet evidence is unable to disentangle how the effect of retention policy varies by the outcome in student's intellect and morality. This study gathered the views and perspectives of students in relation to the retention policy of the college. This study used the qualitative-phenomenological method. Seven participants who gained the lowest general percentage average were purposively selected. In-depth interviews were conducted to obtain the pertinent information. Results revealed that retention policy was a source of encouragement for students to perform well and it was a necessity to develop and enhance students' cognition. However, few students mentioned that the retention policy was a source of stress because they needed to comply with the standard requirements imposed by the college. They reiterated that the policy discriminated against slow-learners. The findings implicate that concrete actions may be done to address the misconception on the retention policy. Strong academic support and resources may be offered to address students' needs especially to those who were at-risk. Retention policy will remain a challenge to all students if the academic institution is not fully equipped to respond to the needs of the students.

Background:. Although long-term benefits of reduction mammaplasty have been proven, the appropriate age for adolescent reduction mammaplasty has been highly debated due to possible need for revision surgery. Practitioners often delay offering breast reduction to adolescents below age 18 based on presumed insurance denial. We reviewed trends in insurance denial at a single children’s hospital to analyze whether age and/or insurance carriers have a significant impact on coverage of breast reduction. Methods:. A retrospective chart review from 2012 to 2022 of cisgender female patients with macromastia aged 12–20 years at the time of diagnosis was analyzed for differences in breast reduction insurance coverage based on age and body mass index at the time of diagnosis, referral to plastic surgery, and surgery. Results:. A total of 121 cisgender women were included. There were no significant differences in the mean ages of patients who underwent breast reduction versus those who did not (16.46 years versus 16.96 years, respectively; P = 0.089), or in the mean body mass index for patients who did versus those who did not receive breast reduction (28.58 kg/m² versus 29.05kg/m², P = 0.382). Furthermore, there were no significant differences in the proportion of patients undergoing breast reduction by age (P = 0.200) or by insurance class (P = 0.403). Conclusion:. Although insurance varies with carrier, the present findings suggest that surgeons need not delay in facilitating preauthorization for breast reduction in symptomatic patients presenting anytime during their teenage years.

Abstract The shared functions of the skull are thought to result in common evolutionary patterns in mammalian cranial shape. Craniofacial evolutionary allometry (CREA) is a particularly prominent pattern where larger species display proportionally elongate facial skeletons and smaller braincases. It was recently proposed that CREA arises from biomechanical effects of cranial scaling when diets are similar. Thus, deviations from CREA should occur with changes in cranial biomechanics, for example due to dietary change. Here, we test this using 3D geometric morphometric analysis in a dataset of Australian murine crania, which are highly allometric. We contrast allometric and non‐allometric variation in the cranium by comparing evolutionary mode, allometry, ordinations, as well as allometry, integration, and modularity in functional modules. We found evidence of stabilising selection in allometry‐containing and size‐free shape, and substantial non‐allometric variation aligned with dietary specialisation in parallel with CREA. Integration among cranial modules was higher, and modularity lower, with size included, but integration between rostrum and cranial vault, which are involved in the CREA pattern, dropped dramatically after size removal. Our results thus support the hypothesis that CREA is a composite arising from selection on cranial function, with substantial non‐allometric shape variation occurring alongside CREA where dietary specialisation impacts selection on gnawing function. This emphasises the need to research mammalian cranial evolution in the context of allometric and non‐allometric selection on biomechanical function.

Academic departments have been highlighted as key targets to sustainably transform the learning environments of postsecondary science, technology, engineering, and mathematics (STEM) courses in the United States. Despite STEM department chairs playing a critical role in shaping their unit, few studies have characterized how chairs view the teaching culture within their department and how cultural features influence instructional change. This study addressed this gap by applying the four-frames model for organizational change to analyze interviews conducted with 14 STEM department chairs at one research-intensive institution in the United States. The department chairs identified several challenges to supporting and advancing teaching culture. These challenges were mostly related to the structures and symbols frames and included an institutional emphasis on research over teaching, inadequate methods to evaluate effective teaching, and weak teaching feedback mechanisms available to faculty. The chairs also described how they leverage their power to affect people and thereby influence the teaching culture. For example, they strategically position teaching as an important aspect of the departmental culture during hiring processes and elevate certain groups of faculty who have demonstrated interest and efficacy in teaching. This study contributes to the literature by providing a rich description of the teaching culture in STEM departments at a research-intensive institution from the perspective of department chairs. This unique focus on department chairs helps identify opportunities for instructional reforms that are grounded in the reality of the departmental environment and provides a framework for considering how change might occur in STEM departments at research-intensive institutions. The opportunities identified emphasize the importance for department chairs to consider and leverage all four frames to enact instructional change.

Abstract Introduction Typically, oncology is not a structured part of the curriculum in Brazilian medical schools. Furthermore, sarcomas, which are uncommon tumors, are seldom covered in depth. A lack of comprehensive education on sarcomas might result in medical professionals being ill-equipped to care for patients with this condition. Objectives To assess medical students' understanding and awareness of sarcomas and the specific principles related to these tumors. Materials and methods A quantitative, cross-sectional study was conducted using a questionnaire, applied to medical students, focusing on the epidemiology, pathophysiology, and treatments of bone and soft tissue sarcomas. In all tests, the significance level adopted was 5%. The SPSS version 25.0 software was used. Results Of the 825 questionnaires distributed, 325 were returned. Educational sessions on sarcomas did not appear to significantly improve the student's knowledge. Only 29.5% of students identified the lack of pain as an indicator of potential malignancy in soft tissue sarcomas, while 73.8% correctly recognized pain as a symptom of bone sarcomas. Limb amputation as the optimal surgical method for patient recovery was incorrectly reported by 39.1% of the sample. Conclusion A great part of the surveyed population does not have adequate knowledge about the basic concepts associated with limb sarcomas. The minority of them are satisfied with the knowledge gained during their medical education about these tumors. Inadequate medical academic training may initially lead to the wrong clinical management of patients with bone and soft tissue tumor lesions. An educational effort is needed to enhance oncology education for medical students, especially concerning sarcomas.

Background & Aims: Breast regression protein 39 (BRP39) (Chi3L1) and its human homolog YKL-40, is an established biomarker of liver fibrosis in nonalcoholic steatohepatitis (NASH) patients, but its role in NASH pathogenesis remains unclear. We recently identified Chi3L1 as one of the top up-regulated genes in mice with inducible gain-of-function NOD-like receptor protein 3 (NLRP3) activation that mimics several liver features of NASH. This study aimed to investigate the effects of BRP39 deficiency on NLRP3-induced liver inflammation using tamoxifen-inducible Nlrp3 knockin mice sufficient (Nlrp3A350V CRT) and deficient for BRP39 (Nlrp3A350V/BRP-/- CRT). Methods: Using Nlrp3A350V CRT mice and Nlrp3A350V BRP-/- CRT, we investigated the consequences of BRP39 deficiency influencing NLRP3-induced liver inflammation. Results: Our results showed that BRP39 deficiency in NLRP3-induced inflammation improved body weight and liver weight. Moreover, liver inflammation, fibrosis, and hepatic stellate cell activation were reduced significantly, corresponding to significantly decreased Ly6C+ infiltrating macrophages, CD68+ osteopontin-positive hepatic lipid-associated macrophages, and activated Lymphocyte antigen 6 complex locus G6D positive (Ly6G+) and citrullinated histone H3 postivie (H3Cit+) neutrophil accumulation in the liver. Further investigation showed that circulatory neutrophils from NLRP3-induced BRP39-deficient mice have impaired chemotaxis and migration ability, and this was confirmed by RNA bulk sequencing showing reduced immune activation, migration, and signaling responses in neutrophils. Conclusions: These data showcase the importance of BRP39 in regulating the NLRP3 inflammasome during liver inflammation and fibrotic NASH by altering cellular activation, recruitment, and infiltration during disease progression, and revealing BRP39 to be a potential therapeutic target for future treatment of inflammatory NASH and its associated diseases.

Provoked by decades of grassroots activism, anti-ableist work is underway to advance disability rights. Intellectual disability (ID) researchers can integrate these social changes into their work by interrogating and transforming the beliefs and practices that underpin ID research. We share actionable ideas to foster anti-ableism and allyship in ID research. These include: (1) Learn from and nurture long-term, mutual relationships with people with ID; (2) Amplify the voices of people with ID in institutional structures that influence research; (3) Infuse anti-ableist frameworks into our own research; and (4) Embody a career-long commitment to disability rights, reflexive practice, and growth.

Abstract COVID-19 vaccines were originally designed based on the ancestral Spike protein, but immune escape of emergent Variants of Concern (VOC) jeopardized their efficacy, warranting variant-proof vaccines. Here, we used preclinical rodent models to establish the cross-protective and cross-neutralizing capacity of adenoviral-vectored vaccines expressing VOC-matched Spike. CoroVaxG.3-D.FR, matched to Delta Plus Spike, displayed the highest levels of nAb to the matched VOC and mismatched variants. Cross-protection against viral infection in aged K18-hACE2 mice showed dramatic differences among the different vaccines. While Delta-targeted vaccines fully protected mice from a challenge with Gamma, a Gamma-based vaccine offered only partial protection to Delta challenge. Administration of CorovaxG.3-D.FR in a prime/boost regimen showed that a booster was able to increase the neutralizing capacity of the sera against all variants and fully protect aged K18-hACE2 mice against Omicron BA.1, as a BA.1-targeted vaccine did. The neutralizing capacity of the sera diminished in all cases against Omicron BA.2 and BA.5. Altogether, the data demonstrate that a booster with a vaccine based on an antigenically distant variant, such as Delta or BA.1, has the potential to protect from a wider range of SARS-CoV-2 lineages, although careful surveillance of breakthrough infections will help to evaluate combination vaccines targeting antigenically divergent variants yet to emerge.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. The NLRP3 inflammasome, a platform for caspase-1 activation and release of interleukin 1β, is increasingly recognized in the induction of inflammation and liver fibrosis during NAFLD. However, the cell-specific contribution of NLRP3 inflammasome activation in NAFLD remains unknown.MethodsTo investigate the role of NLRP3 inflammasome activation in hepatocytes, hepatic stellate cells (HSCs) and myeloid cells, a conditional Nlrp3 knock-out mouse was generated and bred to cell-specific Cre mice. Both acute and chronic liver injury models were used: lipopolysaccharide/adenosine-triphosphate to induce in vivo NLRP3 activation, choline-deficient, L-amino acid-defined high-fat diet, and Western-type diet to induce fibrotic nonalcoholic steatohepatitis (NASH). In vitro co-culture studies were performed to dissect the crosstalk between myeloid cells and HSCs.ResultsMyeloid-specific deletion of Nlrp3 blunted the systemic and hepatic increase in interleukin 1β induced by lipopolysaccharide/adenosine-triphosphate injection. In the choline-deficient, L-amino acid-defined high-fat diet model of fibrotic NASH, myeloid-specific Nlrp3 knock-out but not hepatocyte- or HSC-specific knock-out mice showed significant reduction in inflammation independent of steatosis development. Moreover, myeloid-specific Nlrp3 knock-out mice showed ameliorated liver fibrosis and decreased HSC activation. These results were validated in the Western-type diet model. In vitro co-cultured studies with human cell lines demonstrated that HSC can be activated by inflammasome stimulation in monocytes, and this effect was significantly reduced if NLRP3 was downregulated in monocytes.ConclusionsThe study provides new insights in the cell-specific role of NLRP3 in liver inflammation and fibrosis. NLRP3 inflammasome activation in myeloid cells was identified as crucial for the progression of NAFLD to fibrotic NASH. These results may have implications for the development of cell-specific strategies for modulation of NLRP3 activation for treatment of fibrotic NASH.