Beyond CREA: Evolutionary patterns of non-allometric shape variation and divergence in a highly allometric clade of murine rodents.

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.

Responsible inclusion: A systematic review of consent to social-behavioral research with adults with intellectual disability in the US.

BACKGROUND: In recognition of their status as a health disparities population, there is growing emphasis on conducting research inclusive of adults with intellectual disability to generate new knowledge and opportunities to improve health and equity. Yet they are often excluded from research, and human research participant protection experts and researchers lack agreement on effective consent protocols for their inclusion. OBJECTIVE: We sought to identify approaches to consent in US-based social-behavioral research with adults with intellectual disability. METHODS: We conducted a systematic review on approaches to self-consent with adults with intellectual disability published between 2009 and 2023, identified via searching eight databases and reference list hand searches. We identified 13 manuscripts and conducted a thematic analysis. RESULTS: Our analysis identified themes related to guiding principles, strategies to enhance informed and voluntary consent, approaches to consent capacity, involving individuals subject to guardianship, and strategies for expressing decisions and enhancing ongoing decisions. CONCLUSIONS: Manuscripts largely reflected an emphasis on identifying approaches to consent that reflect disability rights principles to promote the right to be included and make one's own decisions based on assessment of relevant information, risks and benefits, and to employ reasonable modifications to achieve inclusion. To avoid the risks of exclusion and advance the responsible inclusion of adults with intellectual disability, we make recommendations to align consent approaches anchored in contemporary thinking about human research participant protections, including through integration with disability rights.

Disparities and Biases in Food Insecurity Screening Among Admitted Children.

BACKGROUND AND OBJECTIVES: Food insecurity (FI) has increasingly become a focus for hospitalized patients. The best methods for screening practices, particularly in hospitalized children, are unknown. The purpose of the study was to evaluate results of an electronic medical record (EMR) embedded, brief screening tool for FI among inpatients. METHODS: This was a cross-sectional study from August 2020 to September 2022 for all children admitted to a quaternary children's hospital. Primary outcomes were proportion of those screened for FI and those identified to have a positive screen. FI was evaluated by The Hunger Vital Sign, a validated 2-question screen verbally obtained in the nursing intake form in the EMR. Covariates include demographic variables of age, sex, race, ethnicity, primary language, and insurance. Statistical analyses including all univariate outcome and bivariate comparisons were performed with SAS 9.4. RESULTS: There were 31 553 patient encounters with 81.7% screened for FI. Patients had a median age of 6.3 years, were mostly male (54.2%), White (60.6%), non-Hispanic (92.7%), English-speaking (94.3%), and had government insurance (79.8%). Younger (0-2 years), non-White, and noninsured patients were all screened significantly less often for FI (all P < .001). A total of 3.4% were identified as having FI. Patients who were older, non-White, Hispanic, non-English speaking, and had nonprivate insurance had higher FI (all P < .001). CONCLUSIONS: Despite the use of an EMR screening tool intended to be universal, we found variation in how we screen for FI. At times, we missed those who would benefit the most from intervention, and thus it may be subject to implementation bias.

Correlating neighborhood-level deprivation and pediatric metabolic dysfunction-associated steatotic liver disease.

OBJECTIVES: The primary objective of this study is to further explore associations between social influencers of health and markers of disease severity at the time of presentation of patients with pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) using neighborhood-level Area Deprivation Index (ADI) scores. METHODS: A retrospective cross-sectional study was conducted among 344 pediatric MASLD patients. Each patient received an ADI score based on their 9-digit zip code. Groups were defined as low (≤5) and high (6≥) ADI. Associations between ADI and symptomatology and laboratory values at presentation, as well as initial liver biopsy pathology were tested via analyses of covariance, χ2 testing, and logistic regressions. RESULTS: The mean ADI was 6.54 (standard deviation = 2.09). ADI groups did not significantly differ in age of presentation, type of presentation, or associated conditions, except for the higher ADI group having on average lower vitamin D levels (26.70 vs. 29.91, p = 0.02) and being two times more likely to also be diagnosed with low high-density lipoprotein (HDL) levels (p = 0.04, 95% CI 1.04-3.89). Mean transaminases and histopathologic nonalcoholic fatty liver disease (NAFLD) Activity Scores did not significantly differ between ADI groups. CONCLUSIONS: Pediatric patients with MASLD in this study span the entire spectrum of neighborhood deprivation. There were no differences in presentation characteristics or severity of MASLD, aside from lower HDL-cholesterol and vitamin D values in the high ADI group. Area deprivation was not predictive of more severe disease as assessed by serum transaminases and liver biopsy NAFLD activity scores.

Advancing Dermatology Education and Care in Rwanda: The Impact of a New Academic Partnership.

It is the realization of a long-dreamed aspiration to create a university that would advance global health delivery by training a new generation of global health leaders who are equipped to not just build, but sustain effective and equitable health systems.

Shifting forward: Urban ecology in perspective.

The world has become urban; cities increasingly shape our worldviews, relation to other species, and the large-scale, long-term decisions we make. Cities are nature, but they need to align better with other ecosystems to avoid accelerating climate change and loss of biodiversity. We need a science to guide urban development across the diverse realities of global cities. This need can be met, in part, by shifts in urban ecology and its linkages to related sciences. This perspective is a "synthesis of syntheses", consolidating ideas from the other articles in the Special Section. It re-examines the role of urban ecology, and explores its integration with other disciplines that study cities. We conclude by summarizing the next steps in the ongoing shift in urban ecology, which is fast becoming an integral part of urban studies.

A transformative shift in urban ecology toward a more active and relevant future for the field and for cities.

This paper builds on the expansion of urban ecology from a biologically based discipline-ecology in the city-to an increasingly interdisciplinary field-ecology of the city-to a transdisciplinary, knowledge to action endeavor-an ecology for and with the city. We build on this "prepositional journey" by proposing a transformative shift in urban ecology, and we present a framework for how the field may continue this shift. We conceptualize that urban ecology is in a state of flux, and that this shift is needed to transform urban ecology into a more engaged and action based field, and one that includes a diversity of actors willing to participate in the future of their cities. In this transformative shift, these actors will engage, collaborate, and participate in a continuous spiral of knowledge → action → knowledge spiral and back to knowledge loop, with the goal of co producing sustainable and resilient solutions to myriad urban challenges. Our framework for this transformative shift includes three pathways: (1) a repeating knowledge → action → knowledge spiral of ideas, information, and solutions produced by a diverse community of agents of urban change working together in an "urban sandbox"; (2) incorporation of a social-ecological-technological systems framework in this spiral and expanding the spiral temporally to include the "deep future," where future scenarios are based on a visioning of seemingly unimaginable or plausible future states of cities that are sustainable and resilient; and (3) the expansion of the spiral in space, to include rural areas and places that are not yet cities. The three interrelated pathways that define the transformative shift demonstrate the power of an urban ecology that has moved beyond urban systems science and into a realm where collaborations among diverse knowledges and voices are working together to understand cities and what is urban while producing sustainable solutions to contemporary challenges and envisioning futures of socially, ecologically, and technologically resilient cities. We present case study examples of each of the three pathways that make up this transformative shift in urban ecology and discuss both limitations and opportunities for future research and action with this transdisciplinary broadening of the field.

Forging just ecologies: 25 years of urban long-term ecological research collaboration.

We ask how environmental justice and urban ecology have influenced one another over the past 25 years in the context of the US Long-Term Ecological Research (LTER) program and Baltimore Ecosystem Study (BES) project. BES began after environmental justice emerged through activism and scholarship in the 1980s but spans a period of increasing awareness among ecologists and environmental practitioners. The work in Baltimore provides a detailed example of how ecological research has been affected by a growing understanding of environmental justice. The shift shows how unjust environmental outcomes emerge and are reinforced over time by systemic discrimination and exclusion. We do not comprehensively review the literature on environmental justice in urban ecology but do present four brief cases from the Caribbean, Africa, and Asia, to illustrate the global relevance of the topic. The example cases demonstrate the necessity for continuous engagement with communities in addressing environmental problem solving.

Cell Death in Liver Disease and Liver Surgery.

Cell death is crucial for maintaining tissue balance and responding to diseases. However, under pathological conditions, the surge in dying cells results in an overwhelming presence of cell debris and the release of danger signals. In the liver, this gives rise to hepatic inflammation and hepatocellular cell death, which are key factors in various liver diseases caused by viruses, toxins, metabolic issues, or autoimmune factors. Both clinical and in vivo studies strongly affirm that hepatocyte death serves as a catalyst in the progression of liver disease. This advancement is characterized by successive stages of inflammation, fibrosis, and cirrhosis, culminating in a higher risk of tumor development. In this review, we explore pivotal forms of cell death, including apoptosis, pyroptosis, and necroptosis, examining their roles in both acute and chronic liver conditions, including liver cancer. Furthermore, we discuss the significance of cell death in liver surgery and ischemia-reperfusion injury. Our objective is to illuminate the molecular mechanisms governing cell death in liver diseases, as this understanding is crucial for identifying therapeutic opportunities aimed at modulating cell death pathways.

Alpha 1-acid glycoprotein is upregulated in severe COVID-19 patients and decreases neutrophil NETs in SARS-CoV-2 infection.

Orosomucoid, or alpha-1 acid glycoprotein (AGP), is a major acute-phase protein expressed in response to systemic injury and inflammation. AGP has been described as an inhibitor of neutrophil migration on sepsis, particularly its immunomodulation effects. AGP's biological functions in coronavirus disease 2019 (COVID-19) are not understood. We sought to investigate the role of AGP in severe COVID-19 infection patients and neutrophils infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Epidemiological data, AGP levels, and other laboratory parameters were measured in blood samples from 56 subjects hospitalized in the ICU with SARS-CoV-2 infection. To evaluate the role of AGP in NETosis in neutrophils, blood samples from health patients were collected, and neutrophils were separated and infected with SARS-CoV-2. Those neutrophils were treated with AGP or vehicle, and NETosis was analyzed by flow cytometry. AGP was upregulated in severe COVID-19 patients (p<0.05). AGP level was positively correlated with IL-6 and C-reactive protein (respectively, p=0.005, p=0.002) and negatively correlated with lactate (p=0.004). AGP treatment downregulated early and late NETosis (respectively, 35.7% and 43.5%) in neutrophils infected with SARS-CoV-2 and up-regulated IL-6 supernatant culture expression (p<0.0001). Our data showed increased AGP in COVID-19 infection and contributed to NETosis regulation and increased IL-6 production, possibly related to the Cytokine storm in COVID-19.

Synaptotagmin 7 C2 domains induce membrane curvature stress via electrostatic interactions and the wedge mechanism.

Synaptotagmin 7 (Syt-7) is part of the synaptotagmin protein family that regulates exocytotic lipid membrane fusion. Among the family, Syt-7 stands out by its membrane binding strength and stabilization of long-lived membrane fusion pores. Given that Syt-7 vesicles form long-lived fusion pores, we hypothesize that its interactions with the membrane stabilize the specific curvatures, thicknesses, and lipid compositions that support a metastable fusion pore. Using all-atom molecular dynamics simulations and FRET-based assays of Syt-7's membrane-binding C2 domains (C2A and C2B), we found that Syt-7 C2 domains sequester anionic lipids, are sensitive to cholesterol, thin membranes, and generate lipid membrane curvature by two competing, but related mechanisms. First, Syt-7 forms strong electrostatic contacts with the membrane, generating negative curvature stress. Second, Syt-7's calcium binding loops embed in the membrane surface, acting as a wedge to thin the membrane and induce positive curvature stress. These curvature mechanisms are linked by the protein insertion depth as well as the resulting protein tilt. Simplified quantitative models of the curvature-generating mechanisms link simulation observables to their membrane-reshaping effectiveness.

Assessment of medical students' knowledge of primary limb sarcomas.

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.

The Next Chapter in Immunotherapy and Radiation Combination Therapy: Cancer-Specific Perspectives.

Immunotherapeutic agents have revolutionized cancer treatment over the past decade. However, most patients fail to respond to immunotherapy alone. A growing body of preclinical studies highlights the potential for synergy between radiation therapy and immunotherapy, but the outcomes of clinical studies have been mixed. This review summarizes the current state of immunotherapy and radiation combination therapy across cancers, highlighting existing challenges and promising areas for future investigation.

BRP39 Regulates Neutrophil Recruitment in NLRP3 Inflammasome-Induced Liver Inflammation.

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.

Depression and Anxiety Among English- and Spanish-Speaking Patients With Breast Cancer Receiving Radiation Therapy.

PURPOSE: An estimated 30% and 40% of patients with breast cancer experience depression and anxiety, respectively. However, distress experienced by patients with breast cancer receiving radiation therapy may vary among patients and vary at different time points. This study sought to describe the changes in levels of depression and anxiety experienced by English- and Spanish-speaking patients throughout a course of radiation therapy for breast cancer, along with the effect of different variables to better understand potential gaps. METHODS AND MATERIALS: Eligibility criteria included English- and Spanish-speaking females, aged 18 or older, undergoing radiation therapy treatment for breast cancer at 2 institutions. Pre- and posttreatment surveys were completed before and after delivery of radiation therapy. Sociodemographic characteristics collected included race, ethnicity, marital status, education level, longest residency location, religion, housing, and food insecurity. The survey ended with the standardized PHQ-4 questionnaire to assess anxiety and depression. Results were analyzed using the analysis of covariance procedure. RESULTS: A total of 160 participants completed pre- and posttreatment surveys, with an initial response rate of 100% (169 patients), though 9 were lost to follow-up. Most of the participants were nonwhite (50%), primarily married (42.5%), and had a high school or associate's level education (46.9%). The total baseline distress mean (BDM) was 2.96 and the final distress mean was 2.78. English-speaking patients comprised 82.5% (n = 132) of the sample and had a BDM of 2.91 with an adjusted change mean decrease of 0.45. Spanish-speaking patients comprised 17.5% (n = 28) of the sample, with a baseline distress mean of 3.21 and an adjusted change mean increase of 1.03 (P = .002). Housing (P = .017) and food insecurity (P = .0002) also showed increasing distress with increased insecurity at baseline. CONCLUSIONS: Patients who speak Spanish, identify as Hispanic, or are experiencing food and housing insecurity are at an increased risk for depression and anxiety, and could benefit from more support during their course of radiation therapy to minimize distress.

TLR4 antagonism provides short-term but not long-term clinical benefit in a full-depth cartilage defect mouse model.

PURPOSE/AIM: Cartilage injury and subsequent osteoarthritis (OA) are debilitating conditions affecting millions worldwide. As there are no cures for these ailments, novel therapies are needed to suppress disease pathogenesis. Given that joint injuries are known to produce damage-associated molecular patterns (DAMPs), our central premise is that the Toll-like receptor 4 (TLR4) pathway is a principal driver in the early response to cartilage damage and subsequent pathology. We postulate that TLR4 activation is initiated/perpetuated by DAMPs released following joint damage. Thus, antagonism of the TLR4 pathway immediately after injury may suppress the development of joint surface defects. MATERIALS AND METHODS: Two groups were utilized: (1) 8-week-old, male C57BL6 mice treated systemically with a known TLR4 antagonist and (2) mice injected with vehicle control. A full-depth cartilage lesion on the midline of the patellofemoral groove was created in the right knee of each mouse. The left knee was used as a sham surgery control. Gait changes were evaluated over 4 weeks using a quantitative gait analysis system. At harvest, knee joints were processed for pathologic assessment, Nanostring® transcript expression, and immunohistochemistry (IHC). RESULTS: Short-term treatment with a TLR4 antagonist at 14-days significantly improved relevant gait parameters; improved cartilage metrics and modified Mankin scores were also seen. Additionally, mRNA expression and IHC showed reduced expression of inflammatory mediators in animals treated with the TLR4 antagonist. CONCLUSIONS: Collectively, this work demonstrates that systemic treatment with a TLR4 antagonist is protective to further cartilage damage 14-days post-injury in a murine model of induced disease.

Structural and enzymatic evidence for the methylation of the ACK1 tyrosine kinase by the histone lysine methyltransferase SETD2.

SETD2 (SET-domain containing protein 2) is a histone methyltransferase (HMT) of the SET family responsible for the trimethylation of K36 of histone H3, thus producing the epigenetic mark H3K36me3. Recent studies have shown that certain SET family HMTs, such as SMYD2, SMYD3 or SETDB1 can also methylate protein kinases and therefore be involved in signaling pathways. Here we provide structural and enzymatic evidence showing that SETD2 methylates the protein tyrosine kinase ACK1 in vitro. ACK1 is recognized as a major integrator of signaling from various receptor tyrosine kinases. Using ACK1 peptides and recombinant proteins, we show that SETD2 methylates the K514 residue of ACK1 generating K514 mono, di or tri-methylation. Interestingly, K514 is found in a "H3K36-like" motif of ACK1 which is known to be post-translationally modified and to be involved in protein-protein interaction. The crystal structure of SETD2 catalytic domain in complex with an ACK1 peptide further provides the structural basis for the methylation of ACK1 K514 by SETD2. Our work therefore strongly suggests that ACK1 could be a novel non-histone substrate of SETD2 and further supports that SET HMTs, such as SETD2, could be involved in both epigenetic regulations and cell signaling.