Identification and structural characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3.

Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that are targetable by adoptive T-cell therapy in metastatic diseases. To expand mutant KRAS-specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T-cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (7VVVGAVGVGK16) using a vaccination approach with transgenic mice expressing HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not WT KRAS peptides. To investigate the molecular basis for neoantigen recognition by this TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3ß and CDR1ß formed a hydrophobic pocket to interact with p6 Val of the G12V but not the WT KRAS peptide. To improve the tumor sensitivity of this TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding avidity to HLA-A3 (G12V) but did not sufficiently improve T-cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations.

Variations in Benefits of Intergenerational Tutoring in the "New Normal".

This study investigated the benefits and challenges of intergenerational tutoring in a post-pandemic context. We explored how the benefits of intergenerational tutoring vary among subgroups of volunteers-first-time tutors, male tutors, tutors who are caregivers, and tutors with moderate or severe loneliness. Older adult tutors (N = 319) were surveyed before and after the 2021-2022 school year, and the data were analyzed with structural equation multivariate regression and thematic analysis. Results indicated that while public health measures like mask-wearing posed challenges for some tutors, there were positive outcomes for tutors, especially first-time tutors, who experienced more health and well-being benefits, and tutors who are caregivers, who experienced improved civic attitudes towards public education. These results can help programs attract subgroups of volunteers who are likely to benefit the most, as well as attend to the unique challenges of pandemic-related policies.

Single-level laminoplasty approach to selective dorsal rhizotomy with conus localization by rapid spine MRI.

INTRODUCTION: While selective dorsal rhizotomy (SDR) was originally described as a multilevel approach, single-level approaches are now popularized. Conus localization is beneficial for operative planning in single-level selective dorsal rhizotomy. Our approach to SDR involves minimal exposure for a single-level laminoplasty, preserving one attached interspinous ligament. Pre-operative conus localization is required for this tailored approach to determine the laminoplasty level and dictate rostral or caudal division of the superior spinus ligament. While rapid MRI sequences have been popularized for pediatric cranial imaging, its utility for spinal imagining is less well-described, and specific application for conus localization has not been reported. OBJECTIVE: Illustrate that rapid MRI without sedation is sufficient to identify conus level for tailored single-level laminoplasty SDR. MATERIAL AND METHODS: Patients undergoing SDR from 2014 to 2022 at one institution were reviewed for type of pre-operative MRI (rapid vs full), conus level, procedural time for MRI, and radiology report. The typical rapid MRI has four sequences utilizing single-shot technique (scout, sagittal T2, axial T2, and axial T1) that typically take less than 1 min each of acquisition time, with non-single-shot sequences added periodically in cooperative patients. To include time for patient positioning, pre-scan shimming, procedural incidentals, and other patient-specific variations, MRI procedure length was recorded as documented in the electronic medical record. RESULTS: N = 100 patients had documentation of an MRI for pre-operative imaging. Seventy-nine of these had a rapid MRI, and 21 required a full MRI with anesthesia for their treatment plan. Mean total procedure time for rapid MRI was 21.5 min (median 17). Mean procedure time for MRI under general anesthesia was 91.2 min (median 94). Of patients with rapid MRI imaging, 2/79 had an ambiguous conus level (1 from motion artifact, 1 from spinal hardware) vs 1/21 with a full MRI under anesthesia (due to spinal hardware). CONCLUSION: Rapid spinal MRI without sedation can be used for conus localization in a pediatric population. This may be routinely used as pre-operative imaging for a single-level approach to selective dorsal rhizotomy, without sedation or intubation procedures.

Inhibition of HIV-1 release by ADAM metalloproteinase inhibitors.

HIV-1 gp120 glycan binding to C-type lectin adhesion receptor L-selectin/CD62L on CD4 T cells facilitates viral attachment and entry. Paradoxically, the adhesion receptor impedes HIV-1 budding from infected T cells and the viral release requires the shedding of CD62L. To systematically investigate CD62L-shedding mediated viral release and its potential inhibition, we screened compounds specific for serine-, cysteine-, aspartyl-, and Zn-dependent proteases for CD62L shedding inhibition and found that a subclass of Zn-metalloproteinase inhibitors, including BB-94, TAPI, prinomastat, GM6001, and GI25423X, suppressed CD62L shedding. Their inhibition of HIV-1 infections correlated with enzymatic suppression of both ADAM10 and 17 activities and expressions of these ADAMs were transiently induced during the viral infection. These metalloproteinase inhibitors are distinct from the current antiretroviral drug compounds. Using immunogold labeling of CD62L, we observed association between budding HIV-1 virions and CD62L by transmission electron microscope, and the extent of CD62L-tethering of budding virions increased when the receptor shedding is inhibited. Finally, these CD62L shedding inhibitors suppressed the release of HIV-1 virions by CD4 T cells of infected individuals and their virion release inhibitions correlated with their CD62L shedding inhibitions. Our finding reveals a new therapeutic approach targeted at HIV-1 viral release.

Rapid brain MRI for image-guided ventricular catheter placement in pediatric patients: protocol and preliminary clinical outcomes.

OBJECTIVE: Neuronavigation is a useful adjunct for catheter placement during neurosurgical procedures for hydrocephalus or ventricular access. MRI protocols for navigation are lengthy and require sedation for young children. CT involves ionizing radiation. In this study, the authors introduce the clinical application of a 1-minute rapid MRI sequence that does not require sedation in young children and report their preliminary clinical experience using this technique in their pediatric population. METHODS: All patients who underwent ventricular catheter placement at a children's hospital using a rapid noncontrast MRI protocol, standard MRI, or head CT from July 2021 to August 2023 were included. Type of procedure, etiology of hydrocephalus, ventricle configuration and size, morphology of ventricles, need for adjunctive intraoperative ultrasound, duration of procedure, accuracy of catheter placement, and need for proximal revision within 90 days were retrospectively recorded and compared across imaging modalities. RESULTS: Sixty-eight patients underwent 83 procedures: 21 underwent CT navigation, 29 standard MRI, and 33 rapid MRI. Patients who received standard MRI more often had tumor etiology, while those who underwent CT and rapid MRI had posthemorrhagic etiology (χ2 = 13.04, p = 0.042). Intraoperative ultrasound was required for 1 patient in the standard MRI group and 1 patient in the CT group. There was no difference in procedure time across groups (p = 0.831). On multivariable analysis, procedure time differed by procedure type, where external ventricular drain placement and proximal revision were faster (p < 0.001 and p < 0.028, respectively). Proximal revision due to obstruction within 90 days occurred in 3 cases (in the same patient with complex loculated hydrocephalus) in the rapid MRI group and 2 cases in the CT group. CONCLUSIONS: Although this study was not powered for statistical inference, the authors report on the clinical use of a 1-minute rapid MRI sequence for neuronavigation in hydrocephalus or ventricular access surgery. There were no instances in which intraoperative ultrasound was required as an adjunct for procedures navigated with rapid MRI, and intraoperative time did not differ from that of standard navigation protocols.

The Effect of Home- and Community-Based Services on Social Engagement.

Objectives: Home- and community-based services (HCBS) help older adults to remain active in community settings. However, it is not known if there is a causal relationship between HCBS and social engagement. Methods: We used data from the 2010 and 2012 Health and Retirement Study and measured the effect of HCBS on social engagement via nearest-neighbor Mahalanobis matching, optimal pair matching, genetic matching, and optimal full matching. Results: Genetic matching showed that the odds of social engagement for participants who received at least one HCBS (congregate meal, home-delivered meal, transportation service, case management, homemaker or housekeeping services, or caregiver services) in the prior two years was 1.07 times more likely than participants who have not received any HCBS (robust SE = .030, p = .040). Discussion: HCBS may remove barriers to social engagement through increasing older adults' personal resources and personal networks.

Pediatric neuroblastoma with intraspinal extension: the role of surgical management.

OBJECTIVE: Neuroblastoma with spinal involvement accounts for up to 30% of pediatric spinal tumors and can cause profound neurological deficits. Chemotherapy is the preferred treatment option, but in select patients resection may be indicated. The goal of this study was to identify preoperative factors that led to early surgical intervention, with a specific emphasis on identifying differences on long-term neurological function and spinal deformity in the recent treatment era. METHODS: A retrospective chart review was performed on all children diagnosed with neuroblastoma at a single institution from 2007 to 2020. Patient demographics, symptoms (motor deficit and sphincter dysfunction), and tumor characteristics (e.g., 123I metaiodobenzylguanidine [MIBG] avidity, MYCN amplification, chromosomal abnormality, pathology, catecholamine secretion, and stage) were recorded. Spine involvement included neural or vertebral extension, spinal cord compression, and/or T2 signal change on MRI. Survival, neurological status (motor deficit, sphincter dysfunction), and spine deformity at last follow-up were compared using univariate and multivariate analyses. The variables that contributed to neurological and deformity outcome were assessed with binomial logistic and linear regression models using R software. RESULTS: Seventy-seven of the 160 patients with neuroblastoma had spinal neuroblastoma, meaning either bone metastases alone (n = 43) or intraspinal extension with or without neurological deficit (n= 34). Most patients with spinal neuroblastoma were treated with chemotherapy and/or radiation therapy (97% and 57%, respectively). Resection of the spinal tumor was performed in 14 (18%) patients, all of whom also received chemotherapy. Between the surgical and nonsurgical patients, no baseline demographic differences were found. However, surgical patients were more likely to present with either motor deficits (50% vs 5%, p = 0.0011) or bladder/bowel dysfunction (14% vs 0%, p 0.035), and a shorter median time to onset of neurological symptoms (33 vs 80 days, p = 0.0096). Surgical patients also had a significantly shorter median overall survival (33.0 vs 54 months, p = 0.014). Of the 14 patients who underwent spine surgery, 2 patients underwent surgery at the time of diagnosis while the remaining 12 underwent initial chemotherapy followed later by resection. The 2 patients who underwent initial surgery had excellent outcomes, with neither long-term motor or bowel/bladder deficits nor spinal deformity. CONCLUSIONS: Surgical patients had shorter overall survival. However, the 2 patients with radiographic evidence of cord compression and acute neurological symptom onset who underwent initial, immediate surgery within 3 days of diagnosis had fewer long-term neurological deficits than surgical patients who underwent initial trials of chemotherapy. Thus, acute decompression may provide benefit in carefully selected patients with acute neurological deficits and cord compression on imaging.

SARS-CoV-2 infection of human lung epithelial cells induces TMPRSS-mediated acute fibrin deposition.

Severe COVID-associated lung injury is a major confounding factor of hospitalizations and death with no effective treatments. Here, we describe a non-classical fibrin clotting mechanism mediated by SARS-CoV-2 infected primary lung but not other susceptible epithelial cells. This infection-induced fibrin formation is observed in all variants of SARS-CoV-2 infections, and requires thrombin but is independent of tissue factor and other classical plasma coagulation factors. While prothrombin and fibrinogen levels are elevated in acute COVID BALF samples, fibrin clotting occurs only with the presence of viral infected but not uninfected lung epithelial cells. We suggest a viral-induced coagulation mechanism, in which prothrombin is activated by infection-induced transmembrane serine proteases, such as ST14 and TMPRSS11D, on NHBE cells. Our finding reveals the inefficiency of current plasma targeted anticoagulation therapy and suggests the need to develop a viral-induced ARDS animal model for treating respiratory airways with thrombin inhibitors.

Growing recyclable and healable piezoelectric composites in 3D printed bioinspired structure for protective wearable sensor.

Bionic multifunctional structural materials that are lightweight, strong, and perceptible have shown great promise in sports, medicine, and aerospace applications. However, smart monitoring devices with integrated mechanical protection and piezoelectric induction are limited. Herein, we report a strategy to grow the recyclable and healable piezoelectric Rochelle salt crystals in 3D-printed cuttlebone-inspired structures to form a new composite for reinforcement smart monitoring devices. In addition to its remarkable mechanical and piezoelectric performance, the growth mechanisms, the recyclability, the sensitivity, and repairability of the 3D-printed Rochelle salt cuttlebone composite were studied. Furthermore, the versatility of composite has been explored and applied as smart sensor armor for football players and fall alarm knee pads, focusing on incorporated mechanical reinforcement and electrical self-sensing capabilities with data collection of the magnitude and distribution of impact forces, which offers new ideas for the design of next-generation smart monitoring electronics in sports, military, aerospace, and biomedical engineering.

Innate receptors with high specificity for HLA class I-peptide complexes.

Genetic studies associate killer cell immunoglobulin-like receptors (KIRs) and their HLA class I ligands with a variety of human diseases. The basis for these associations and the relative contribution of inhibitory and activating KIR to NK cell responses are unclear. Because KIR binding to HLA-I is peptide dependent, we performed systematic screens, which totaled more than 3500 specific interactions, to determine the specificity of five KIR for peptides presented by four HLA-C ligands. Inhibitory KIR2DL1 was largely peptide sequence agnostic and could bind ~60% of hundreds of HLA-peptide complexes tested. Inhibitory KIR2DL2, KIR2DL3, and activating KIR2DS1 and KIR2DS4 bound only 10% and down to 1% of HLA-peptide complexes tested, respectively. Activating KIR2DS1, previously described as weak, had high binding affinity for HLA-C, with high peptide sequence specificity. Our data revealed MHC-restricted peptide recognition by germline-encoded NK receptors and suggest that NK cell responses can be shaped by HLA-I-bound immunopeptidomes in the context of disease or infection.

The solution structure of the unbound IgG Fc receptor CD64 resembles its crystal structure: Implications for function.

FcγRI (CD64) is the only high-affinity Fcγ receptor found on monocytes, macrophages, eosinophils, neutrophils and dendritic cells. It binds immunoglobulin G (IgG) antibody-antigen complexes at its Fc region to trigger key immune responses. CD64 contains three immunoglobulin-fold extracellular domains (D1, D2 and D3) and a membrane-spanning region. Despite the importance of CD64, no solution structure for this is known to date. To investigate this, we used analytical ultracentrifugation, small-angle X-ray scattering, and atomistic modelling. Analytical ultracentrifugation revealed that CD64 was monomeric with a sedimentation coefficient s020,w of 2.53 S, together with some dimer. Small-angle X-ray scattering showed that its radius of gyration RG was 3.3-3.4 nm and increased at higher concentrations to indicate low dimerization. Monte Carlo modelling implemented in the SASSIE-web package generated 279,162 physically-realistic trial CD64 structures. From these, the scattering best-fit models at the lowest measured concentrations that minimised dimers revealed that the D1, D2 and D3 domains were structurally similar to those seen in three CD64 crystal structures, but showed previously unreported flexibility between D1, D2 and D3. Despite the limitations of the scattering data, the superimposition of the CD64 solution structures onto crystal structures of the IgG Fc-CD64 complex showed that the CD64 domains do not sterically clash with the IgG Fc region, i.e. the solution structure of CD64 was sufficiently compact to allow IgG to bind to its high-affinity Fcγ receptor. This improved understanding may result in novel approaches to inhibit CD64 function, and opens the way for the solution study of the full-length CD64-IgG complex.

The Landau-Zener-Stückelberg-Majorana transition in the T2 ≪ T1 limit.

Landau-Zener-Stückelberg-Majorana (LZSM) transitions occur between quantum states when parameters in the system's Hamiltonian are varied continuously and rapidly. In magnetic resonance, losses in adiabatic rapid passage can be understood using the physics of LZSM transitions. Most treatments of LZSM transitions ignore the T2 dephasing of coherences, however. Motivated by ongoing work in magnetic resonance force microscopy, we employ the Bloch equations, coordinate transformation, and the Magnus expansion to derive expressions for the final magnetization following a rapid field sweep at fixed irradiation intensity that include T2 losses. Our derivation introduces an inversion-function, Fourier transform method for numerically evaluating highly oscillatory integrals. Expressions for the final magnetization are given for low and high irradiation intensity, valid in the T2≪T1 limit. Analytical results are compared to numerical simulations and nuclear magnetic resonance experiments. Our relatively straightforward calculation reproduces semiquantitatively the well known LZSM result in the T2→0 limit.

mmodel: A workflow framework to accelerate the development of experimental simulations.

Simulation has become an essential component of designing and developing scientific experiments. The conventional procedural approach to coding simulations of complex experiments is often error-prone, hard to interpret, and inflexible, making it hard to incorporate changes such as algorithm updates, experimental protocol modifications, and looping over experimental parameters. We present mmodel, a Python framework designed to accelerate the writing of experimental simulation packages. mmodel uses a graph-theory approach to represent the experiment steps and can rewrite its own code to implement modifications, such as adding a loop to vary simulation parameters systematically. The framework aims to avoid duplication of effort, increase code readability and testability, and decrease development time.

Update on Pediatric Mild Traumatic Brain Injury in Rural and Underserved Regions: A Global Perspective.

BACKGROUND: Mild traumatic brain injury (MTBI) causes morbidity and disability worldwide. Pediatric patients are uniquely vulnerable due to developmental and psychosocial factors. Reduced healthcare access in rural/underserved communities impair management and outcome. A knowledge update relevant to current gaps in care is critically needed to develop targeted solutions. METHODS: The National Library of Medicine PubMed database was queried using comprehensive search terms (("mild traumatic brain injury" or "concussion") and ("rural" or "low-income" or "underserved") and ("pediatric" or "child/children")) in the title, abstract, and Medical Subject Headings through December 2022. Fifteen articles on rural/underserved pediatric MTBI/concussion not covered in prior reviews were examined and organized into four topical categories: epidemiology, care practices, socioeconomic factors, and telehealth. RESULTS: Incidences are higher for Individuals in rural regions, minorities, and those aged 0-4 years compared to their counterparts, and are increasing over time. Rural healthcare utilization rates generally exceed urban rates, and favor emergency departments (vs. primary care) for initial injury assessment. Management guidelines require customization to resource-constrained settings for implementation and adoption. Decreased community recognition of the seriousness of injury is a consensus challenge to care provision by clinicians. Low parental education and income were correlated with decreased MTBI knowledge and worse outcome. Telehealth protocols for triage/consultation and rehabilitation were feasible in improving care delivery to rural and remote settings. CONCLUSIONS: Pediatric MTBI/concussion patients in rural/underserved regions experience increased risks of injury, geographic and financial healthcare barriers, and poorer outcomes. Globally, under-reporting of injury has hindered epidemiological understanding. Ongoing MTBI education should be implemented for rural caregivers, schools, and low-income populations to improve community awareness. Telehealth can improve care delivery across acuity settings, and warrants judicious inclusion in triage and treatment protocols.

FcγRI FG-loop functions as a pH sensitive switch for IgG binding and release.

Understanding the molecular mechanism underlying the hierarchic binding between FcγRs and IgG antibodies is critical for therapeutic antibody engineering and FcγR functions. The recent determination of crystal structures of FcγRI-Fc complexes, however, resulted in two controversial mechanisms for the high affinity receptor binding to IgG. Here, we describe high resolution structures of a bovine FG-loop variant of FcγRI in complex with the Fc fragment of IgG1 crystallized in three different conditions at neutral pH, confirming the characteristic FG loop-Fc interaction is critical to the high affinity immunoglobulin binding. We showed that the FcγRI D2-domain FG-loop functioned as a pH-sensing switch for IgG binding. Further live cell imaging of FcγRI-mediated internalization of immune complexes showed a pH sensitive temporal-spatial antibody-antigen uptake and release. Taken together, we demonstrate that the structures of FcγRI-Fc crystallized at neutral and acidic pH, respectively, represent the high and low affinity binding states of the receptor for IgG uptake and release. These results support a role for FcγRI in antigen delivery, highlight the importance of Fc glycan in antibody binding to the high affinity receptor and provide new insights to future antibody engineering.

HIV-1 release requires Nef-induced caspase activation.

HIV infection remains incurable to date and there are no compounds targeted at the viral release. We show here HIV viral release is not spontaneous, rather requires caspases activation and shedding of its adhesion receptor, CD62L. Blocking the caspases activation caused virion tethering by CD62L and the release of deficient viruses. Not only productive experimental HIV infections require caspases activation for viral release, HIV release from both viremic and aviremic patient-derived CD4 T cells also require caspase activation, suggesting HIV release from cellular viral reservoirs depends on apoptotic shedding of the adhesion receptor. Further transcriptomic analysis of HIV infected CD4 T cells showed a direct contribution of HIV accessory gene Nef to apoptotic caspases activation. Current HIV cure focuses on the elimination of latent cellular HIV reservoirs that are resistant to infection-induced cell death. This has led to therapeutic strategies to stimulate T cell apoptosis in a "kick and kill" approach. Our current work has shifted the paradigm on HIV-induced apoptosis and suggests such approach would risk to induce HIV release and thus be counter-productive. Instead, our study supports targeting of viral reservoir release by inhibiting of caspases activation.

A comparison of incidental and symptomatic unruptured brain arteriovenous malformations in children.

OBJECTIVE: Patients with unruptured brain arteriovenous malformations (AVMs) may present with headaches, seizures, and/or neurological deficits. A smaller number of cases may be discovered incidentally. These lesions remain incompletely understood due to their sparse reporting. Herein, the authors describe the largest series to date comparing the presentation, angioarchitecture, and management of incidental versus symptomatic unruptured AVMs in children. METHODS: The authors performed a retrospective analysis of patients who presented with brain AVMs from 1998 to 2022 at the University of California, San Francisco. Inclusion criteria were age ≤ 18 years at the time of presentation and an angiographically proven unruptured AVM that had been diagnosed postnatally. RESULTS: Of 76 children with unruptured AVMs, 66 (86.8%) presented with headaches, seizures, and/or neurological deficit. Ten AVMs (13.1%) were incidentally discovered through unrelated disease workup (50%), cranial trauma (40%), or research study participation (10%). Compared with patients with symptomatic unruptured AVMs, patients with incidental unruptured AVMs had a smaller mean ± SD maximum nidus diameter (2.82 ± 1.1 vs 3.98 ± 1.52 cm, p = 0.025) and fewer had deep venous drainage (20% of patients vs 61%, p = 0.036). They also presented at an earlier age (10 ± 5.2 vs 13.5 ± 4 years, p = 0.043) and with longer duration to first treatment (541 ± 922 vs 196 ± 448 days, p = 0.005). During the observation period, 1 patient developed recurring headaches and demonstrated AVM nidus growth. Four AVMs greater than 3 cm in size or in a deep location were treated with radiosurgery. Six other AVMs were treated with resection, with 2 receiving preoperative embolization. Eight AVMs (80%) were obliterated on last follow-up. Postprocedural complications included 2 transient neurological deficits after resection and 1 case of delayed seizure development after radiosurgery. The mean follow-up period was 5.7 ± 5.7 years without any hemorrhage episodes. CONCLUSIONS: A substantial proportion of pediatric patients with unruptured AVMs are discovered incidentally. With earlier presentation and more elementary angioarchitecture than symptomatic unruptured AVMs, these incidental lesions provide a snapshot into the natural history of AVM before symptom development or rupture.

A Non-Perturbative, Low-Noise Surface Coating for Sensitive Force-Gradient Detection of Electron Spin Resonance in Thin Films.

The sensitivity of magnetic resonance force microscopy (MRFM) is limited by surface noise. Coating a thin-film polymer sample with metal has been shown to decrease, by orders of magnitude, sample-related force noise and frequency noise in MRFM experiments. Using both MRFM and inductively detected measurements of electron-spin resonance, we show that thermally evaporating a 12 nm gold layer on a 40 nm nitroxide-doped polystyrene film inactivates the nitroxide spin labels to a depth of 20 nm, making single-spin measurements difficult or impossible. We introduce a "laminated sample" protocol in which the gold layer is first evaporated on a sacrificial polymer. The sample is deposited on the room-temperature gold layer, removed using solvent lift-off, and placed manually on a coplanar waveguide. Electron spin resonance (ESR) of such a laminated sample was detected via MRFM at cryogenic temperatures using a high-compliance cantilever with an integrated 100-nm-scale cobalt tip. A 20-fold increase of spin signal was observed relative to a thin-film sample prepared instead with an evaporated metal coating. The observed signal is still somewhat smaller than expected, and we discuss possible remaining sources of signal loss.

Deaths of Despair and Population Aging in Missouri.

Recent declines in life expectancy in the US, especially for middle-aged White persons, have called attention to mortality from deaths of despair - deaths due to alcohol, drugs, and suicide. Using data from the Centers for Disease Control and the U.S. Census Bureau, this paper examined deaths of despair by race/ethnicity, age, cause of death, birth cohort, and sex in Missouri. We focused on Area Agencies on Aging as geographic units of interest to increase usefulness of our findings to public administrators. Deaths of despair began trending up for all age groups beginning in 2007-2009, with the sharpest increases occurring for Black or African American non-Hispanics beginning in 2013-2015. The most dramatic increases occurred for the population age 50-59 in St. Louis City and Area Agency on Aging regions in southern Missouri. For older adults, considerable variation in rates, trends, and cause of deaths of despair is evident across the state.

Function of cell adhesion molecules in differentiation of ray sensory neurons in C. elegans.

For proper functioning of the nervous system, it is crucial that neurons find their appropriate partners and build the correct neural connection patterns. Although cell adhesion molecules (CAMs) have been studied for many years as essential players in neural connections, we have yet to unravel the code by which CAMs encode synaptic specificity. We analyzed the effects of mutations in CAM genes on the morphology and synapses of a set of sensory neurons in the Caenorhabditis elegans male tail. B-type ray sensory neurons express 10 genes encoding CAMs. We examined the effect on axon trajectory and localization of pre-synaptic components in viable mutants of nine of these. We found axon trajectory defects in mutants of UNC-40/DCC, SAX-3/ROBO, and FMI-1/Flamingo/Celsr1. None of the mutations caused loss of pre-synaptic components in axons, and in several the level even appeared to increase, suggesting possible accumulation of pre-synapses. B-type sensory neurons fasciculate with a second type of ray sensory neuron, the A-type, in axon commissures. We found a CAM expressed in A-type functions additively with a CAM expressed in B-type in axon guidance, and lack of a CAM expressed in B-type affected A-type axon guidance. Overall, single and multiple mutants of CAM genes had limited effects on ray neuron trajectories and accumulation of synaptic components.