Jag1 insufficiency alters liver fibrosis via T cell and hepatocyte differentiation defects.

Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.

Integrating the Memory Support Intervention into the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C): can improving memory for treatment in midlife and older adults improve patient outcomes? Study protocol for a randomized controlled trial.

BACKGROUND: Poor memory for treatment is associated with poorer treatment adherence and poorer patient outcomes. The memory support intervention (MSI) was developed to improve patient memory for treatment with the goal of improving patient outcomes. The aim of this study protocol is to conduct a confirmatory efficacy trial to test whether a new, streamlined, and potent version of the MSI improves outcomes for midlife and older adults. This streamlined MSI is comprised of constructive memory supports that will be applied to a broader range of treatment content. The platform for this study is the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C). We will focus on midlife and older adults who are low income and experiencing mobility impairments. METHODS: Participants (N = 178) will be randomly allocated to TranS-C + MSI or TranS-C alone. Both intervention arms include eight 50-min weekly sessions. Assessments will be conducted at pre-treatment, post-treatment, 6-, and 12-month follow-up (6FU and 12FU). Aim 1 will compare the effects of TranS-C + MSI versus TranS-C alone on sleep and circadian functioning, daytime functioning, well-being, and patient memory. Aim 2 will test whether patient memory for treatment mediates the relationship between treatment condition and patient outcomes. Aim 3 will evaluate if previously reported poor treatment response subgroups will moderate the relationship between treatment condition and (a) patient memory for treatment and (b) treatment outcome. Exploratory analyses will compare treatment condition on (a) patient adherence, patient-rated treatment credibility, and patient utilization of treatment contents, and (b) provider-rated acceptability, appropriateness, and feasibility. DISCUSSION: This study has the potential to provide evidence for (a) the efficacy of a new simplified version of the MSI for maintaining health, well-being, and functioning, (b) the wider application of the MSI for midlife and older adults and to the treatment of sleep and circadian problems, and (c) the efficacy of the MSI for sub-groups who are likely to benefit from the intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT05986604. Registered on 2 August 2023.

Interleukin 11 therapy causes acute left ventricular dysfunction.

AIMS: Interleukin 11 (IL11) was initially thought important for platelet production, which led to recombinant IL11 being developed as a drug to treat thrombocytopenia. IL11 was later found to be redundant for haematopoiesis and its use in patients is associated with unexplained and severe cardiac side effects. Here we aim to identify, for the first time, direct cardiomyocyte toxicities associated with IL11, which was previously believed cardioprotective. METHODS AND RESULTS: We injected recombinant mouse lL11 (rmIL11) into mice and studied its molecular effects in the heart using immunoblotting, qRT-PCR, bulk RNA-seq, single nuclei RNA-seq (snRNA-seq) and ATAC-seq. The physiological impact of IL11 was assessed by echocardiography in vivo and using cardiomyocyte contractility assays in vitro. To determine the activity of IL11 specifically in cardiomyocytes we made two cardiomyocyte-specific Il11ra1 knockout (CMKO) mouse models using either AAV9-mediated and Tnnt2-restricted (vCMKO) or Myh6 (m6CMKO) Cre expression and an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition on rmIL11-induced cardiac toxicities. Injection of rmIL11 caused acute and dose-dependent impairment of left ventricular ejection fraction (saline: 62.4% ± 1.9; rmIL11: 32.6% ± 2.9, p<0.001, n=5). Following rmIL11 injection, myocardial STAT3 and JNK phosphorylation were increased and bulk RNA-seq revealed upregulation of pro-inflammatory pathways (TNFα, NFκB and JAK/STAT) and perturbed calcium handling. snRNA-seq showed rmIL11-induced expression of stress factors (Ankrd1, Ankrd23, Xirp2), activator protein-1 (AP-1) transcription factor genes and Nppb in the cardiomyocyte compartment. Following rmIL11 injection, ATAC-seq identified the Ankrd1 and Nppb genes and loci enriched for stress-responsive, AP-1 transcription factor binding sites. Cardiomyocyte-specific effects were examined in vCMKO and m6CMKO mice, which were both protected from rmIL11-induced left ventricular impairment and molecular pathobiologies. In mechanistic studies, inhibition of JAK/STAT signalling with either ruxolitinib or tofacitinib prevented rmIL11-induced cardiac dysfunction. CONCLUSIONS: Injection of IL11 directly activates IL11RA/JAK/STAT3 in cardiomyocytes to cause acute heart failure. Our data overturn the earlier assumption that IL11 is cardioprotective and explain the serious cardiac side effects associated with IL11 therapy.

AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse intracellular and extracellular growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling established through biochemical and cell biological studies function under physiological states in specific mammalian tissues are unknown. Here, we characterize a genetic mouse model lacking the 5 phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can active mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as brain and skeletal muscle, associated with cell intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mouse model demonstrates that TSC2 phosphorylation is a primary mechanism of mTORC1 activation in some, but not all, tissues and provides a genetic tool to facilitate studies on the physiological regulation of mTORC1.

Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial cochlea.

Notch signaling patterns the cochlear organ of Corti, and patients with the JAG1/NOTCH2-related genetic disorder Alagille syndrome can thus experience hearing loss. We investigated the function of Jag1 in cochlear patterning and signaling using Jag1Ndr/Ndr mice, a model of Alagille syndrome. Jag1Ndr/Ndr mice exhibited expected vestibular and auditory deficits, a dose-dependent increase in ectopic inner hair cells, and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types further revealed that Jag1 represses Notch activation in lateral supporting cells and demonstrated a function for Jag1 in gene regulation and development of outer hair cells. Surprisingly, ectopic "outer hair cell-like" cells were present in the medial compartment and pillar cell region of Jag1Ndr/Ndr cochleae, yet they exhibited location-dependent expression of the inner hair cell fate-determinant Tbx2, suggesting Jag1 is required for Tbx2 to drive inner hair cell commitment. This study thus identifies new roles for Jag1 in supporting cells, and in outer hair cell specification and positioning.

Variation in air sac morphology and postcranial skeletal pneumatization patterns in the African grey parrot.

The anatomy of the avian lower respiratory system includes a complex interaction between air-filled pulmonary tissues, pulmonary air sacs, and much of the postcranial skeleton. Hypotheses related to the function and phylogenetic provenance of these respiratory structures have been posed based on extensive interspecific descriptions for an array of taxa. By contrast, intraspecific descriptions of anatomical variation for these features are much more limited, particularly for skeletal pneumatization, and are essential to establish a baseline for evaluating interspecific variation. To address this issue, we collected micro-computed tomography (µCT) scans of live and deceased African grey parrots (Psittacus erithacus) to assess variation in the arrangement of the lungs, the air sacs, and their respective invasion of the postcranial skeleton via pneumatic foramina. Analysis reveals that the two pairs of caudalmost air sacs vary in size and arrangement, often exhibiting an asymmetric morphology. Further, locations of the pneumatic foramina are more variable for midline, non-costal skeletal elements when compared to other pneumatized bones. These findings indicate a need to better understand contributing factors to variation in avian postcranial respiratory anatomy that can inform future intraspecific and interspecific comparisons.

The Psychosocial Consequences of Sexual Violence Stigma: A Scoping Review.

Over the past decade, scholars have explored whether the stigma associated with sexual violence (SV) represents a risk factor for psychopathology and related comorbidities following SV. We conducted a scoping review to summarize and evaluate the state of this burgeoning literature. We included studies from Pubmed, APA PsychInfo, Embase, CINAHL Plus, Social Science Premium, and Web of Science that quantified stigma related to SV. Studies were screened and abstracted in accordance with the PRISMA-SCR guidelines for scoping reviews. Our final sample contained 62 studies. We address two key questions about SV stigma. First, is SV a stigmatized status? Articles (n = 14) provided evidence for SV stigma among potential stigmatizers (e.g., individuals who may perpetuate stigma) across a range of methods (e.g., vignettes) and outcomes (e.g., desire for social distance). Additional work (n = 20) corroborates perceptions of SV stigma among targets (i.e., SV survivors). Second, what are the psychosocial consequences of SV stigma? We reviewed studies (n = 28) demonstrating that SV stigma is correlated with a range of adverse psychosocial outcomes-including anxiety, depression, posttraumatic stress disorder, problematic drinking, and somatic symptoms-among individuals experiencing multiple types of SV (e.g., childhood sexual abuse and sexual assault). Thus, emerging evidence suggests that SV stigma may be a critical determinant of risk and recovery following SV exposure. However, a number of limitations were observed, including that SV stigma has not been consistently measured and that the literature has not fully incorporated stigma constructs, such as concealment and structural stigma. We offer several recommendations to advance this line of work.

Trans-obliquus inferior capitis course of the greater occipital nerve: A potential cause of occipital neuralgia?

Occipital neuralgia can be due to multiple etiologies. One of these is potential compression of the greater occipital nerve (GON). In this regard, one relationship of the GON, its course through the obliquus inferior capitis muscle (OIC), has yet to be well studied. Therefore, the current anatomical study was performed to elucidate this relationship better. In the prone position, the suboccipital triangle was exposed, and the relationship between the GON and OIC was documented in 72 adult cadavers (144 sides). The GON was found to pierce the OIC on four sides (2.8%), unilaterally in two cadavers and bilaterally in one cadaver. Two cadavers were male, and one was female. Histological samples were taken from GONs with a normal course around the OIC, and nerves were found to pierce the OIC. The GON of all four sides identified histological changes consistent with nerve potential compression (e.g., epineurial and perineurial thickening). This is also the first histological analysis of the trans-OIC course of the GON, demonstrating signs of chronic nerve potential compression. Although uncommon, entrapment of the GON by the OIC may be an underrecognized etiology of occipital neuralgia.

Twelve-month outcomes of a community-based, father-daughter physical activity program delivered by trained facilitators.

BACKGROUND: Dads and Daughters Exercising and Empowered (DADEE) is a program targeting fathers/father-figures to improve their daughters' physical activity and well-being. Previous randomised controlled efficacy and effectiveness trials of DADEE demonstrated meaningful improvements in a range of holistic outcomes for both fathers and daughters in the short-term. This study aims to assess the long-term impact (12-months) of the program when delivered in the community by trained facilitators. METHODS: Fathers/father-figures and their primary school-aged daughters were recruited from Newcastle, Australia into a single-arm, non-randomised, pre-post study with assessments at baseline, 10-weeks (post-intervention) and 12-months. The 9-session program included weekly 90-min educational and practical sessions, plus home-based tasks. The primary outcome was fathers' and daughters' days per week meeting national physical activity recommendations (≥ 30 min/day of MVPA for fathers, ≥ 60 min/day MVPA for daughters). Secondary outcomes included physical activity, screen time, self-esteem, father-daughter relationship, social-emotional well-being, parenting measures, and process outcomes (including recruitment, attendance, retention and program acceptability). RESULTS: Twelve programs were delivered with 257 fathers (40.0 ± 9.2 years) and 285 daughters (7.7 ± 1.9 years). Mixed effects regression models revealed significant intervention effects for the primary outcome, with fathers increasing the days/week meeting physical activity recommendations by 27% at 10-weeks (p < 0.001) and by 19% at 12-months (p < 0.001) compared with baseline. Likewise, for daughters there was a significant increase by 25% at 10-weeks (p < 0.001) and by 14% at 12-months (p = 0.02) when compared to baseline. After conducting a sensitivity analysis with participants unaffected by COVID-19 lockdowns (n = 175 fathers, n = 192 daughters), the primary outcome results strengthened at both time-points for fathers and at 12-months for daughters. Additionally, the sensitivity analysis revealed significant intervention effects at post-program and 12-months for all secondary outcomes in both fathers and daughters. Furthermore, the process outcomes for recruitment capability, attendance, retention and satisfaction levels were high. CONCLUSIONS: Findings provide support for a sustained effect of the DADEE program while delivered in a community setting by trained facilitators. Further investigation is required to identify optimised implementation processes and contextual factors to deliver the program at scale. TRIAL REGISTRATION: ACTRN12617001450303 . Date registered: 12/10/2017.

Predominant approaches to measuring pregnancy-related anxiety in Sub-saharan Africa: a scoping review.

BACKGROUND: Pregnancy-related anxiety significantly impacts maternal and fetal health in low- and middle-income countries (LMICs), including those within Sub-Saharan Africa (SSA). Most studies conducted to evaluate pregnancy-related anxiety in LMICs have utilized scales developed in high-income countries, despite significant variations in pregnancy-related anxiety due to socioeconomic and cultural contexts. This review surveyed existing literature in order to identify which scales have been used to measure pregnancy-related anxiety in SSA. METHODS: A systematic search was conducted in PubMed, Health and Psychosocial Instruments, and APA PsycNet for relevant studies published in the English language up to March 22, 2023. Eligible studies focused on anxiety in pregnant populations within SSA, using validated scales or tools. Screening followed PRIMSA guidelines, with blinded review at the abstract/title level and subsequent full-text review. Data was extracted and analyzed to identify trends and characteristics of the screening tools used. RESULTS: From 271 articles, 37 met inclusion criteria, identifying 24 different tools used to measure anxiety in pregnant women in SSA. The most common tools were the Generalized Anxiety Disorder 7-item scale (seven uses), State-Trait Anxiety Inventory (five uses), and the Self-Reporting Questionnaire 20 (five uses). Seven tools were pregnancy-specific, with only two designed specifically for SSA: the Risk Factor Assessment (RFA), and the 4-Item Screening Tool. Studies were most frequently conducted in South Africa, followed by Tanzania, Ethiopia, Nigeria, and Ghana. CONCLUSIONS: This scoping review illustrates that only two tools (the RFA and 4-item Screening Tool) were created to assess pregnancy-related anxiety specifically in SSA. This highlights the need for more culturally sensitive tools tailored to the specific contexts of pregnant populations in SSA.

Exome Sequencing of a Blastomycosis Case-Control Cohort From Manitoba and Northwestern Ontario, Canada.

BACKGROUND: Blastomycosis is a pulmonary disease caused by Blastomyces spp., a group of pathogenic dimorphic fungi endemic to a number of geographic regions, specifically Manitoba and northwestern Ontario, Canada. Immunosuppression is a major risk factor affecting disease susceptibility, yet host immunity is not well understood. Genetic immunodeficiencies can also influence disease, with variants in IL6, GATA2 and VDBP shown to influence susceptibility. Additional genetic factors in disease susceptibility and severity remain undetected. Our study seeks to identify potential genetic risk factors in a blastomycosis case-control cohort from Manitoba and northwestern Ontario, Canada. METHODS: Exomes from 18 blastomycosis cases and 9 controls were sequenced, variants were identified and filtered for accuracy and quality. We performed candidate gene prioritisation and variant aggregation to identify genetic associations and explored the full exome dataset. RESULTS: Ninety-nine genetic variants in 42 candidate genes were identified in the exome dataset. No variants associated with susceptibility were identified in a single-variant analysis although two non-synonymous variants in TYK2 were enriched among cases suggesting a possible role in susceptibility. Gene-based association analysis found variants in TLR1 enriched in controls (p = 0.024) suggesting a possible protective effect. Gene cluster analysis identified genetic variants in genes of chromatin remodelling, proteasome and intraflagellar transport significantly enriched in cases (false discovery rates < 14%). CONCLUSIONS: The findings in this study show novel associations with blastomycosis susceptibility. A better understanding of host immunity and genetic predisposition to Blastomyces infection can help to inform clinical practice for improved outcomes.

A survey of US and Caribbean veterinary schools reveals strengths and opportunities in antimicrobial stewardship and infection prevention and control activities.

OBJECTIVE: To understand antimicrobial stewardship (AS) and infection prevention and control (IPC) activities in veterinary schools. METHODS: An online survey was completed by representatives from American Association of Veterinary Medical Colleges-accredited veterinary schools in the US and Caribbean prior to attending the Inaugural Small Animal Antimicrobial Stewardship Workshop for US Veterinary Schools. Responses were examined to identify patterns among AS and IPC activities and adherence to the AVMA core principles. RESULTS: Half (12 of 24) of the surveyed schools had an AS committee and most (79% [19 of 24]) had an IPC committee. Lack of dedicated staff time was a common barrier to AS (88% [21 of 24]) and IPC (75% [18 of 24]) reported by schools both with and without AS and IPC committees. Eleven of 24 schools (46%) reported performing at least 1 activity focused on each of the AVMA's 5 core principles of AS. Although 79% (19 of 24) of schools incorporate AS into preclinical curricula, training of clinical faculty (17% [4 of 24]), veterinary technicians and support staff (21% [5 of 24]), and house officers (42% [10 of 24]) is less common, despite these individuals engaging in teaching clinical-year veterinary students. CONCLUSIONS: Veterinary schools varied in established AS education and AS and IPC practices, though financial and human resources were a common barrier. CLINICAL RELEVANCE: A collaborative and cohesive approach to AS and IPC among schools to create sustainable frameworks for practice improvement will help combat the global threat of antimicrobial resistance. This is a critical action for settings where future veterinarians are trained.

"So Many Other Things Improve" with Transdiagnostic Treatment for Sleep and Circadian Problems: Interviews with Community Providers on Treating Clients with Serious Mental Illness.

Community mental health centers (CMHCs) offer invaluable, publicly-funded treatment for serious mental illness (SMI). Unfortunately, evidence-based psychological treatments are often not delivered at CMHCs, in part due to implementation barriers, such as limited time, high caseloads, and complex clinical presentations. Transdiagnostic treatments may help address these barriers, because they allow providers to treat symptoms across multiple disorders concurrently. However, little research has investigated CMHC providers' experiences of delivering transdiagnostic treatments "on the ground," particularly for adults with SMI. Thus, the aim of the present study was to assess CMHC providers' perspectives on delivering a transdiagnostic treatment - the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) - to adults diagnosed with SMI. In the context of a larger parent trial, providers were randomized to deliver a standard version of TranS-C (Standard TranS-C) or a version adapted to the CMHC context (Adapted TranS-C). Twenty-five providers from the parent trial participated in a semi-structured interview (n = 10 Standard TranS-C; n = 15 from Adapted TranS-C). Responses were deductively and inductively coded to identify themes related to Proctor's taxonomy of implementation outcomes. Four novel "transdiagnostic take homes" were identified: (1) transdiagnostic targets, such as sleep, can be perceived as motivating and appropriate when treating SMI, (2) strategies to bolster client motivation/adherence and address a wider range of symptom severity may improve transdiagnostic treatments, (3) balancing feasibility with offering in-depth resources is an important challenge for transdiagnostic treatment development, and (4) adapting transdiagnostic treatments to the CMHC context may improve provider perceptions of implementation outcomes.

Microbial interactions impact stress tolerance in a model oral community.

Understanding the molecular mechanisms governing microbial interactions is crucial for unraveling the complexities of microbial communities and their ecological impacts. Here, we employed a two-species model system comprising the oral bacteria Aggregatibacter actinomycetemcomitans and Streptococcus gordonii to investigate how synergistic and antagonistic interactions between microbes impact their resilience to environmental change and invasion by other microbes. We used an in vitro colony biofilm model and focused on two S. gordonii-produced extracellular molecules, L-lactate and H2O2, which are known to impact fitness of this dual-species community. While the ability of A. actinomycetemcomitans to cross-feed on S. gordonii-produced L-lactate enhanced its fitness during co-culture, this function showed little impact on the ability of co-cultures to resist environmental change. In fact, the ability of A. actinomycetemcomitans to catabolize L-lactate may be detrimental in the presence of tetracycline, highlighting the complexity of interactions under antimicrobial stress. Furthermore, H2O2, known for its antimicrobial properties, had negative impacts on both species in our model system. However, H2O2 production by S. gordonii enhanced A. actinomycetemcomitans tolerance to tetracycline, suggesting a protective role under antibiotic pressure. Finally, S. gordonii significantly inhibited the bacterium Serratia marcescens from invading in vitro biofilms, but this inhibition was lost during co-culture with A. actinomycetemcomitans and in a murine abscess model, where S. gordonii actually promoted S. marcescens invasion. These data indicate that microbial interactions can impact fitness of a bacterial community upon exposure to stresses, but these impacts are highly environment dependent. IMPORTANCE: Microbial interactions are critical modulators of the emergence of microbial communities and their functions. However, how these interactions impact the fitness of microbes in established communities upon exposure to environmental stresses is poorly understood. Here, we utilized a two-species community consisting of Aggregatibacter actinomycetemcomitans and Streptococcus gordonii to examine the impact of synergistic and antagonistic interactions on microbial resilience to environmental fluctuations and susceptibility to microbial invasion. We focused on the S. gordonii-produced extracellular molecules, L-lactate and H2O2, which have been shown to mediate interactions between these two microbes. We discovered that seemingly beneficial functions, such as A. actinomycetemcomitans cross-feeding on S. gordonii-produced L-Lactate, can paradoxically exacerbate vulnerabilities, such as susceptibility to antibiotics. Moreover, our data highlight the context-dependent nature of microbial interactions, emphasizing that a seemingly potent antimicrobial, such as H2O2, can have both synergistic and antagonistic effects on a microbial community dependent on the environment.

Key roles of C2/GAP domains in SYNGAP1-related pathophysiology.

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency. However, some affected individuals carry missense mutations in its calcium/lipid binding (C2) and GAP domains, suggesting that many clinical features result from loss of functions carried out by these domains. To test this hypothesis, we targeted the exons encoding the C2 and GAP domains of SYNGAP. Rats heterozygous for this deletion exhibit reduced exploration and fear extinction, altered social investigation, and spontaneous seizures-key phenotypes shared with Syngap heterozygous null rats. Together, these findings indicate that the reduction of SYNGAP C2/GAP domain function is a main feature of SYNGAP haploinsufficiency. This rat model provides an important system for the study of ID, autism, and epilepsy.

Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies.

Neurofibromatosis type 1 (NF1), Noonan syndrome and related syndromes, grouped as the RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together the RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared to the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the last decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multi-disciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 AACR Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other healthcare professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.

Age-dependent changes in phagocytic activity: in vivo response of mouse pulmonary antigen presenting cells to direct lung delivery of charged PEGDA nanoparticles.

BACKGROUND: Current needle-based vaccination for respiratory viruses is ineffective at producing sufficient, long-lasting local immunity in the elderly. Direct pulmonary delivery to the resident local pulmonary immune cells can create long-term mucosal responses. However, criteria for drug vehicle design rules that can overcome age-specific changes in immune cell functions have yet to be established. RESULTS: Here, in vivo charge-based nanoparticle (NP) uptake was compared in mice of two age groups (2- and 16-months) within the four notable pulmonary antigen presenting cell (APC) populations: alveolar macrophages (AM), interstitial macrophages (IM), CD103+ dendritic cells (DCs), and CD11b+ DCs. Both macrophage populations exhibited preferential uptake of anionic nanoparticles but showed inverse rates of phagocytosis between the AM and IM populations across age. DC populations demonstrated preferential uptake of cationic nanoparticles, which remarkably did not significantly change in the aged group. Further characterization of cell phenotypes post-NP internalization demonstrated unique surface marker expression and activation levels for each APC population, showcasing heightened DC inflammatory response to NP delivery in the aged group. CONCLUSION: The age of mice demonstrated significant preferences in the charge-based NP uptake in APCs that differed greatly between macrophages and DCs. Carefully balance of the targeting and activation of specific types of pulmonary APCs will be critical to produce efficient, age-based vaccines for the growing elderly population.

Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination.

Schwann cells are critical for the proper development and function of the peripheral nervous system (PNS), where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long-term myelin maintenance and axon health, they may also be present at the Schwann cell-axon interface during development. Here, we expand on this, showing that drug-mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell-specific ablation of prohibitin 2 (Phb2) in vivo results in severe defects in radial sorting and myelination. We show in vivo that Phb2-null Schwann cells cannot effectively proliferate and the transcription factors EGR2 (KROX20), POU3F1 (OCT6), and POU3F2 (BRN2), necessary for proper Schwann cell maturation, are dysregulated. Schwann cell-specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the developmental defect seen in mice lacking Schwann cell Phb2. Finally, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on neuronal signals, and thus are potential mediators of PHB2-associated developmental defects. This work develops our understanding of Schwann cell biology, revealing that Phb2 may modulate the timely expression of transcription factors necessary for proper PNS development, and proposing candidates that may play a role in PHB2-mediated integration of axon signals in the Schwann cell.