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Background: Current protein biomarkers are only moderately predictive at identifying individuals with mild traumatic brain injury or concussion. Therefore, more accurate diagnostic markers are needed for sport-related concussion. Methods: This was a multicenter, prospective, case-control study of athletes who provided blood samples and were diagnosed with a concussion or were a matched non-concussed control within the National Collegiate Athletic Association–Department of Defense Concussion Assessment, Research, and Education Consortium conducted between 2015 and 2019. The blood was collected within 48 h of injury to identify protein abnormalities at the acute and subacute timepoints. Athletes with concussion were divided into 6 h post-injury (0–6 h post-injury) and after 6 h post-injury (7–48 h post-injury) groups. We applied a highly multiplexed proteomic technique that used a DNA aptamers assay to target 1305 proteins in plasma samples from athletes with and without sport-related concussion. Results: A total of 140 athletes with concussion (79.3% males; aged 18.71 ± 1.10 years, mean ± SD) and 21 non-concussed athletes (76.2% males; 19.14 ± 1.10 years) were included in this study. We identified 338 plasma proteins that significantly differed in abundance (319 upregulated and 19 downregulated) in concussed athletes compared to non-concussed athletes. The top 20 most differentially abundant proteins discriminated concussed athletes from non-concussed athletes with an area under the curve (AUC) of 0.954 (95% confidence interval: 0.922‒0.986). Specifically, after 6 h of injury, the individual AUC of plasma erythrocyte membrane protein band 4.1 (EPB41) and alpha-synuclein (SNCA) were 0.956 and 0.875, respectively. The combination of EPB41 and SNCA provided the best AUC (1.000), which suggests this combination of candidate plasma biomarkers is the best for diagnosing concussion in athletes after 6 h of injury. Conclusion: Our data suggest that proteomic profiling may provide novel diagnostic protein markers and that a combination of EPB41 and SNCA is the most predictive biomarker of concussion after 6 h of injury.

The heart is formed from several spatiotemporally distinct progenitor pools during development. Here they show that modulation of retinoic acid signaling can instruct human pluripotent stems cells into heart progenitors that are useful for studying human development and disease.

ObjectiveThe aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes.MethodsThis pilot study comprised two independent cohorts. The first cohort—part of a Traumatic Head Injury Neuroimaging Classification (THINC) study—with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort—with a mean age of 19 years—comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay.ResultsConcentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690–0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT−/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT−/MRI−, n = 111) findings and UIC (P-values < 0.05).ConclusionThese findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.

Photovoltaics (PVs) are a critical technology for curbing growing levels of anthropogenic greenhouse gas emissions, and meeting increases in future demand for low-carbon electricity. In order to fulfill ambitions for net-zero carbon dioxide equivalent (CO _2 eq) emissions worldwide, the global cumulative capacity of solar PVs must increase by an order of magnitude from 0.9 TW _p in 2021 to 8.5 TW _p by 2050 according to the International Renewable Energy Agency, which is considered to be a highly conservative estimate. In 2020, the Henry Royce Institute brought together the UK PV community to discuss the critical technological and infrastructure challenges that need to be overcome to address the vast challenges in accelerating PV deployment. Herein, we examine the key developments in the global community, especially the progress made in the field since this earlier roadmap, bringing together experts primarily from the UK across the breadth of the PVs community. The focus is both on the challenges in improving the efficiency, stability and levelized cost of electricity of current technologies for utility-scale PVs, as well as the fundamental questions in novel technologies that can have a significant impact on emerging markets, such as indoor PVs, space PVs, and agrivoltaics. We discuss challenges in advanced metrology and computational tools, as well as the growing synergies between PVs and solar fuels, and offer a perspective on the environmental sustainability of the PV industry. Through this roadmap, we emphasize promising pathways forward in both the short- and long-term, and for communities working on technologies across a range of maturity levels to learn from each other.

As-printed Laser-Powder Bed Fusion (LPBF) surfaces can provide anchoring spots for the infiltration of polymer printed by Fused Filament Fabrication (FFF), enhancing metal-polymer joint strength. This work evaluates the influence of the as-printed LPBF surface roughness and FFF parameters on the strength of Ti-6Al-4V/PA-CF joints produced by this process combination. A three-point bending testing method based on ISO 14679:1997 was deployed, whereby the energy dissipated by the joint interface was measured. Roughness was varied by 3D-printing the substrate with different inclination angles; Height and printing speed of the coating layer (the polymer layer in direct contact with the metal) were also varied. Data was interpreted using a combination between Decision Tree and Gradient Boosting Regression, ultimately suggesting that printing speed is the prominent parameter followed by inclination angle for joint strength. Additionally, the combined effect of low printing speed and inclination angle resulted in the highest energy absorption at the interface (>200 J).

Sport-related concussion (SRC) is a major concern among athletes and clinicians around the world. Research into fluid biomarkers of SRC has made significant progress in understanding the complex underlying pathophysiology of concussion. However, little headway has been made toward clinically validating any biomarkers to improve the clinical management of SRC. A major obstacle toward clinical translation of any fluid biomarker is the heterogeneity of SRC overlapping with multiple physiological systems involved in pathology and recovery. Neuroinflammation post-SRC is one such system that may confound fluid biomarker data on many fronts. Neuroinflammatory processes consist of cell mediators, both within the central nervous system and the periphery, that play vital roles in regulating the response to brain injury. Further, neuroinflammation is influenced by many biopsychosocial variables present in most athletic populations. In this commentary, we propose that future fluid biomarker research should take a systems biology approach in the context of the neuroinflammatory response to SRC. We highlight how biological variables, such as age, sex, immune challenges, and hypothalamic-pituitary-adrenal (HPA)-axis responses to stress, may alter neuroinflammation. Further, we underscore the importance of accounting for health and lifestyle variables, such as diet, exercise, sleep, and pre-morbid medical factors, when measuring inflammatory markers of SRC. To successfully move toward clinical translation, fluid biomarker research should take a more holistic approach in study design and data interpretation, collecting information on hidden variables that may be influencing the neuroinflammatory response to SRC.

Soot particles are potential candidates for ice-nucleating particles in cirrus cloud formation, which is known to exert a net-warming effect on climate. Bare soot particles, generally hydrophobic and fractal ones, mainly exist near emission sources. Coated or internally mixed soot particles are more abundant in the atmosphere and have a higher probability of impacting cloud formation and climate. However, the ice nucleation ability of coated soot particles is not as well understood as that of freshly produced soot particles. In this laboratory study, two samples, a propane flame soot and a commercial carbon black, were used as atmospheric soot surrogates and coated with varying wt % of sulfuric acid (H2SO4). The ratio of coating material mass to the mass of bare soot particles was controlled and progressively increased from less than 5 wt % to over 100 wt %. Both bare and coated soot particle ice nucleation activities were investigated with a continuous-flow diffusion chamber operated at mixed-phase and cirrus cloud conditions. The mobility diameter and mass distribution of size-selected soot particles with/without H2SO4 coating were measured by a scanning mobility particle sizer and a centrifugal particle mass analyser running in parallel. The mixing state and morphology of soot particles were characterized by scanning electron microscopy and transmission electron microscopy. In addition, the evidence of the presence of H2SO4 on a coated soot particle surface is shown by energy-dispersive X-ray spectroscopy. Our study demonstrates that H2SO4 coatings suppress the ice nucleation activity of soot particles to varying degrees depending on the coating thickness, but in a non-linear fashion. Thin coatings causing pore filling in the soot aggregate inhibits pore condensation and freezing. Thick coatings promote particle ice activation via droplet homogeneous freezing. Overall, our findings reveal that H2SO4 coatings will suppress soot particle ice nucleation abilities in the cirrus cloud regime, having implications for the fate of soot particles with respect to cloud formation in the upper troposphere.

In dissolution-dynamic nuclear polarization, a hyperpolarized solid is dissolved with a jet of hot solvent. The solution is then transferred to a secondary magnet, where spectra can be recorded with improved sensitivity. In bullet-dynamic nuclear polarization this order is reversed. Pressurized gas is used to rapidly transfer the hyperpolarized solid to the secondary magnet, and the hyperpolarized solid is dissolved only upon arrival. A potential advantage of this approach is that it may avoid excessive dilution and the associated signal loss, in particular for small sample quantities. Previously, we have shown that liquid-state NMR spectra with polarization levels of up to 30 % may be recorded within less than 1 s after the departure of the hyperpolarized solid from the polarizing magnet. The resolution of the recorded spectra however was limited. The system consumed significant amounts of liquid helium, and substantial manual work was required in between experiments to prepare for the next shot. Here, we present a new bullet-DNP (dynamic nuclear polarization) system that addresses these limitations.

Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) represent an excellent in vitro model in cardiovascular research. Changes in their action potential (AP) dynamics convey information that is essential for disease modeling, drug screening and toxicity evaluation. High-throughput optical AP recordings utilizing intramolecular Förster resonance energy transfer (FRET) of the voltage-sensitive fluorescent protein (VSFP) have emerged as a substitute or complement to the resource-intensive patch clamp technique. Here, we functionally validated our recently generated voltage indicator hiPSC lines stably expressing CAG-promoter-driven VSFP in the AAVS1 safe harbor locus. By combining subtype-specific cardiomyocyte differentiation protocols, we established optical AP recordings in ventricular, atrial, and nodal CMs in 2D monolayers using fluorescence microscopy. Moreover, we achieved high-throughput optical AP measurements in single hiPSC-derived CMs in a 3D context. Overall, this system greatly expands the spectrum of possibilities for high-throughput, non-invasive and long-term AP analyses in cardiovascular research and drug discovery.

Abstract Conventional neuropsychological assessments for Alzheimer’s disease are burdensome and inaccurate at detecting mild cognitive impairment and predicting Alzheimer’s disease risk. Altoida’s Digital Neuro Signature (DNS), a longitudinal cognitive test consisting of two active digital biomarker metrics, alleviates these limitations. By comparison to conventional neuropsychological assessments, DNS results in faster evaluations (10 min vs 45–120 min), and generates higher test-retest in intraindividual assessment, as well as higher accuracy at detecting abnormal cognition. This study comparatively evaluates the performance of Altoida’s DNS and conventional neuropsychological assessments in intraindividual assessments of cognition and function by means of two semi-naturalistic observational experiments with 525 participants in laboratory and clinical settings. The results show that DNS is consistently more sensitive than conventional neuropsychological assessments at capturing longitudinal individual-level change, both with respect to intraindividual variability and dispersion (intraindividual variability across multiple tests), across three participant groups: healthy controls, mild cognitive impairment, and Alzheimer’s disease. Dispersion differences between DNS and conventional neuropsychological assessments were more pronounced with more advanced disease stages, and DNS-intraindividual variability was able to predict conversion from mild cognitive impairment to Alzheimer’s disease. These findings are instrumental for patient monitoring and management, remote clinical trial assessment, and timely interventions, and will hopefully contribute to a better understanding of Alzheimer’s disease.

The importance of acetogens for H2 turnover and overall anaerobic degradation in peatlands remains elusive. In the well-studied minerotrophic peatland fen Schlöppnerbrunnen, H2-consuming acetogens are conceptualized to be largely outcompeted by iron reducers, sulfate reducers, and hydrogenotrophic methanogens in bulk peat soil. However, in root zones of graminoids, fermenters thriving on rhizodeposits and root litter might temporarily provide sufficient H2 for acetogens. In the present study, root-free peat soils from around the roots of Molinia caerulea and Carex rostrata (i.e., two graminoids common in fen Schlöpnnerbrunnen) were anoxically incubated with or without supplemental H2 to simulate conditions of high and low H2 availability in the fen. In unsupplemented soil treatments, H2 concentrations were largely below the detection limit (∼10 ppmV) and possibly too low for acetogens and methanogens, an assumption supported by the finding that neither acetate nor methane substantially accumulated. In the presence of supplemental H2, acetate accumulation exceeded CH4 accumulation in Molinia soil whereas acetate and methane accumulated equally in Carex soil. However, reductant recoveries indicated that initially, additional unknown processes were involved either in H2 consumption or the consumption of acetate produced by H2-consuming acetogens. 16S rRNA and 16S rRNA gene analyses revealed that potential acetogens (Clostridium, Holophagaceae), methanogens (Methanocellales, Methanobacterium), iron reducers (Geobacter), and physiologically uncharacterized phylotypes (Acidobacteria, Actinobacteria, Bacteroidetes) were stimulated by supplemental H2 in soil treatments. Phylotypes closely related to clostridial acetogens were also active in soil-free Molinia and Carex root treatments with or without supplemental H2. Due to pronounced fermentation activities, H2 consumption was less obvious in root treatments, and acetogens likely thrived on root organic carbon and fermentation products (e.g., ethanol) in addition to H2. Collectively, the data highlighted that in fen Schlöppnerbrunnen, acetogens are associated to graminoid roots and inhabit the peat soil around the roots, where they have to compete for H2 with methanogens and iron reducers. Furthermore, the study underscored that the metabolically flexible acetogens do not rely on H2, potentially a key advantage over other H2 consumers under the highly dynamic conditions characteristic for the root-zones of graminoids in peatlands.

ObjectiveTo investigate the plasma proteomic profiling in identifying biomarkers related to return to sport (RTS) following a sport-related concussion (SRC).MethodsThis multicenter, prospective, case-control study was part of a larger cohort study conducted by the NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium, athletes (n = 140) with blood collected within 48 h of injury and reported day to asymptomatic were included in this study, divided into two groups: (1) recovery

Abstract Cerebral microbleeds, observed as small, spherical hypointense regions on gradient echo (GRE) or susceptibility weighted (SWI) magnetic resonance imaging (MRI) sequences, reflect small hemorrhagic infarcts, and are associated with conditions such as vascular dementia, small vessel disease, cerebral amyloid angiopathy, and Alzheimer’s disease. The current gold standard for detecting and rating cerebral microbleeds in a research context is visual inspection by trained raters, a process that is both time consuming and subject to poor reliability. We present here a novel method to automate microbleed detection on GRE and SWI images. We demonstrate in a community-based cohort of older adults that the method is highly sensitive (greater than 92% of all microbleeds accurately detected) across both modalities, with reasonable precision (fewer than 20 and 10 false positives per scan on GRE and SWI, respectively). We also demonstrate that the algorithm can be used to identify microbleeds over longitudinal scans with a higher level of sensitivity than visual ratings (50% of longitudinal microbleeds correctly labeled by the algorithm, while manual ratings was 30% or lower). Further, the algorithm identifies the anatomical localization of microbleeds based on brain atlases, and greatly reduces time spent completing visual ratings (43% reduction in visual rating time). Our automatic microbleed detection instrument is ideal for implementation in large-scale studies that include cross-sectional and longitudinal scanning, as well as being capable of performing well across multiple commonly used MRI modalities.

Assessment of the electrophysiological properties of cardiomyocytes is necessary for phenotyping cardiac disorders and for drug screening. Optical action potential imaging using a genetically encoded voltage-sensing fluorescent protein (VSFP) allows for high-throughput functional characterization of cardiomyocytes, which offers an advantage over the traditional patch-clamp technique. Here, we knocked VSFP into the AAVS1 safe harbor locus of human iPSCs, generating two stable voltage indicator lines - one heterozygous (MRIi003-A-5) and the other homozygous (MRI003-A-6). Both lines can be used for optical membrane potential recordings and provide a powerful platform for a wide range of applications in cardiovascular biomedicine.

TRPM4 is a Ca2+-activated channel mediating the transport of monovalent cations across the cell membrane. Mutations in the TRPM4 gene have been associated with cardiac arrhythmias in humans. Using CRISPR/Cas9 gene editing technology, we established two TRPM4 knockout human iPSC lines – one heterozygous (MRli003-A-3) and one homozygous (MRli003-A-4) – by inserting a frameshift mutation in exon 2 of the TRPM4 gene. Both lines maintained pluripotency, a normal karyotype, parental cell morphology, and the ability to differentiate into the three germ layers.

Summary: Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.

Myosin-10, also known as non-muscle myosin IIB, is a cytoskeletal protein implicated in cardiac development and disease. In humans, it is encoded by the MYH10 gene. Using CRISPR/Cas9 gene editing technology, we generated two MYH10 knockout human iPSC lines – one heterozygous (MRli003-A-1) and one homozygous (MRli003-A-2) – by introducing a frameshift deletion in exon 2. We then verified that both lines had maintained pluripotency, parental cell morphology, trilineage differentiation potential and a normal karyotype.

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD.Methods: Older adults (ages 55–90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (MRI). Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, and Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes.Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden [β = 1.0 × 105, 95% CI (0.2, 1.9), p = 0.019], after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex [β = 0.001, 95% CI (0.000, 0.001), p = 0.048].Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in SVD.

Acceleration parameters have been utilized for the last six decades to investigate pathology in both human and animal models of traumatic brain injury (TBI), design safety equipment, and develop injury thresholds. Previous large animal models have quantified acceleration from impulsive loading forces (i.e., machine/object kinematics) rather than directly measuring head kinematics. No study has evaluated the reproducibility of head kinematics in large animal models. Nine (five males) sexually mature Yucatan swine were exposed to head rotation at a targeted peak angular velocity of 250 rad/s in the coronal plane. The results indicated that the measured peak angular velocity of the skull was 51% of the impulsive load, was experienced over 91% longer duration, and was multi- rather than uni-planar. These findings were replicated in a second experiment with a smaller cohort (N = 4). The reproducibility of skull kinematics data was mostly within acceptable ranges based on published industry standards, although the coefficients of variation (8.9% for peak angular velocity or 12.3% for duration) were higher than the impulsive loading parameters produced by the machine (1.1 vs. 2.5%, respectively). Immunohistochemical markers of diffuse axonal injury and blood–brain barrier breach were not associated with variation in either skull or machine kinematics, suggesting that the observed levels of variance in skull kinematics may not be biologically meaningful with the current sample sizes. The findings highlight the reproducibility of a large animal acceleration model of TBI and the importance of direct measurements of skull kinematics to determine the magnitude of angular velocity, refine injury criteria, and determine critical thresholds.

Abstract Backgrounds Folate Hydrolase‐1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo‐vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb‐based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591‐brachytherapy. Materials & Methods Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium‐177. Kaplan–Meier survival curves were calculated based on patient outcome data and FOLH1 expression. Results Eighty‐one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo‐vessel. 42% (34/81) of patients with FOLH1+/− MCC had available survival data for analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (− and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC‐specific survival or recurrence free survival, respectively. Conclusions We report the first evidence of prevalent FOLH1 expression within MCC‐associated neo‐vessels, in 60‐77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy of FOLH1‐targeted brachytherapy for MCC. What's already known about this topic? We report the first evidence of prevalent folate hydrolase‐1 (FOLH1; also known as prostate‐specific membrane antigen) expression within MCC‐associated neovessels. What does this study add? Herein, FOLH1 expression in Merkel cell carcinoma neovasculature is validated, and the therapeutic mechanism of specific, systemic targeting of disseminated disease with antibody‐based brachytherapy, is defined.

Background: Colony-stimulating factor 3 (CSF3), more commonly known as granulocyte colony-stimulating factor (G-CSF), acts via a specific cell surface receptor CSF3R (or G-CSFR) to regulate hematopoiesis, with a particularly key role in the myeloid cell lineage where it impacts the development and function of neutrophilic granulocytes. Zebrafish possess a conserved CSF3R homologue, Csf3r, which is involved in both steady-state and emergency myelopoiesis, as well as regulating early myeloid cell migration. Two CSF3 proteins have been identified in zebrafish, Csf3a and Csf3b. Methods: This study investigated the roles of the Csf3a and Csf3b ligands as well as the downstream Janus kinase (JAK) and phosphatidylinositol 3-kinase (PI3K) pathways in mediating the effects of Csf3r in early myeloid cell development and function using gene knockdown and pharmacologic approaches. Results: This study revealed that both Csf3a and Csf3b contribute to the developmental and emergency production of early myeloid cells, but Csf3a is responsible for the developmental migration of early neutrophils whereas Csf3b plays the major role in their wounding-induced migration, differentially participated in these responses, as did several downstream signaling pathways. Both JAK and PI3K signaling were required for developmental production and migration of early myeloid cells, but PI3K signaling was required for emergency production and initial migration in response to wounding, while JAK signaling mediated retention at the site of wounding. Conclusions: This study has revealed both distinct and overlapping functions for Csf3a and Csf3b and the downstream JAK and PI3K signaling pathways in early myeloid cell production and function.

Prior studies have reported long-term differences in brain structure (brain morphometry) as being associated with cumulative concussion and contact sport participation. There is emerging evidence to suggest that similar effects of prior concussion and contact sport participation on brain morphometry may be present in younger cohorts of active athletes. We investigated the relationship between prior concussion and primary sport participation with subcortical and cortical structures in active collegiate contact sport and non-contact sport athletes. Contact sport athletes (CS; N = 190) and matched non-contact sport athletes (NCS; N = 95) completed baseline clinical testing and participated in up to four serial neuroimaging sessions across a 6-months period. Subcortical and cortical structural metrics were derived using FreeSurfer. Linear mixed-effects (LME) models examined the effects of years of primary sport participation and prior concussion (0, 1+) on brain structure and baseline clinical variables. Athletes with prior concussion across both groups reported significantly more baseline concussion and psychological symptoms (all ps < 0.05). The relationship between years of primary sport participation and thalamic volume differed between CS and NCS (p = 0.015), driven by a significant inverse association between primary years of participation and thalamic volume in CS (p = 0.007). Additional analyses limited to CS alone showed that the relationship between years of primary sport participation and dorsal striatal volume was moderated by concussion history (p = 0.042). Finally, CS with prior concussion had larger hippocampal volumes than CS without prior concussion (p = 0.015). Years of contact sport exposure and prior concussion(s) are associated with differences in subcortical volumes in young-adult, active collegiate athletes, consistent with prior literature in retired, primarily symptomatic contact sport athletes. Longitudinal follow-up studies in these athletes are needed to determine clinical significance of current findings.

Background: The amyloid cascade hypothesis characterizes the stereotyped progression of pathological changes in Alzheimer's disease (AD) beginning with beta amyloid deposition, but does not address the reasons for amyloid deposition. Brain areas with relatively higher neuronal activity, metabolic demand, and production of reactive oxygen species in earlier life may have higher beta amyloid deposition in later life. The aim of this study was to investigate early life patterns of perfusion and late life patterns of amyloid deposition to determine the extent to which normative cerebral perfusion predisposes specific regions to future beta amyloid deposition. Materials and Methods: One hundred twenty-eight healthy, older human subjects (age: 56–87 years old; 44% women) underwent positron emission tomography (PET) imaging with [11C]PiB for measures of amyloid burden. Cerebral perfusion maps derived from 47 healthy younger adults (age: 22–49; 47%) who had undergone single photon emission computed tomography (SPECT) imaging, were averaged to create a normative template, representative of young, healthy adults. Perfusion and amyloid measures were investigated in 31 cortical regions from the Hammers atlas. We examined the spatial relationship between normative perfusion patterns and amyloid pathophysiology. Results: The pattern of increasing perfusion (temporal lobe

Abstract The SARS‐CoV‐2 global pandemic will disproportionately impact countries with weak economies and vulnerable populations including people with dementia. Latin American and Caribbean countries (LACs) are burdened with unstable economic development, fragile health systems, massive economic disparities, and a high prevalence of dementia. Here, we underscore the selective impact of SARS‐CoV‐2 on dementia among LACs, the specific strain on health systems devoted to dementia, and the subsequent effect of increasing inequalities among those with dementia in the region. Implementation of best practices for mitigation and containment faces particularly steep challenges in LACs. Based upon our consideration of these issues, we urgently call for a coordinated action plan, including the development of inexpensive mass testing and multilevel regional coordination for dementia care and related actions. Brain health diplomacy should lead to a shared and escalated response across the region, coordinating leadership, and triangulation between governments and international multilateral networks.

Abstract Background Research investigating treatments and interventions for cognitive decline fail due to difficulties in accurately recognizing behavioral signatures in the presymptomatic stages of the disease. For this validation study, we took our previously constructed digital biomarker‐based prognostic models and focused on generalizability and robustness of the models. Method We validated prognostic models characterizing subjects using digital biomarkers in a longitudinal, multi‐site, 40‐month prospective study collecting data in memory clinics, general practitioner offices, and home environments. Results Our models were able to accurately discriminate between healthy subjects and individuals at risk to progress to dementia within 3 years. The model was also able to differentiate between people with or without amyloid neuropathology and classify fast and slow cognitive decliners with a very good diagnostic performance. Conclusion Digital biomarker prognostic models can be a useful tool to assist large‐scale population screening for the early detection of cognitive impairment and patient monitoring over time.

Objective: A recent systematic review determined that the physiological effects of concussion may persist beyond clinical recovery. Preclinical models suggest that ongoing physiological effects are accompanied by increased cerebral vulnerability that is associated with risk for subsequent, more severe injury. This study examined the association between signal alterations on diffusion tensor imaging following clinical recovery of sport-related concussion in athletes with and without a subsequent second concussion.Methods: Average mean diffusivity (MD) was calculated in a region of interest (ROI) in which concussed athletes (n = 82) showed significantly elevated MD acutely after injury (

Approximately 30% of adolescents with concussion develop persistent post-concussion symptoms (PPCS) that include emotional symptoms. Elevated amygdalae reactivity to emotional faces has been reported in a variety of psychopathologies characterized by emotional symptoms overlapping with those in PPCS. We tested the hypothesis that amygdalae reactivity to emotional faces in adolescents with PPCS+ is elevated compared to concussed adolescents without PPCS and healthy controls. Concussed adolescents (ages 14–18) with (PPCS+; n = 23) and without PPCS (PPCS-; n = 13) participated in visits at least 4 weeks post-injury. Adolescents without prior concussion served as controls (HC; n = 15). All participants completed a detailed clinical battery and a common emotional face processing task that involved matching of emotional faces or shapes. Compared to HC and PPCS-, adolescents with PPCS+ had elevated depression symptoms, anhedonia, general psychological symptoms, and anxiety symptoms. Contrary to our hypothesis, PPCS+ had lower amygdalae activity to the emotional faces versus shapes condition relative to HC and a trend for lower activity relative to PPCS-. There was a non-significant inverse association between anhedonia amygdalae activity in adolescents with PPCS. Results suggest that adolescents with PPCS have altered amygdalae activity during the processing of emotional face stimuli.

Acute mood disturbance following sport-related concussion is common and is known to adversely affect post-concussion symptoms and recovery. The physiological underpinnings of depressive symptoms following concussion, however, are relatively understudied. We hypothesized that functional connectivity of the emotional processing network would be altered in concussed athletes and associated with the severity of depressive symptoms following concussion. Forty-three concussed collegiate athletes were assessed at approximately one day (N = 34), one week (N = 34), and one month post-concussion (N = 30). Fifty-one healthy contact-sport athletes served as controls and completed a single visit. The Hamilton Rating Scale for Depression (HAM-D) was used to measure depressive symptoms. Resting state fMRI data was collected on a 3 T scanner (TR = 2 s) and functional connectivity was calculated in a meta-analytically derived network of regions associated with emotional processing. Concussed athletes had elevated depressive symptoms across the first month post-concussion relative to control athletes, but showed partial recovery by one month relative to more acute visits (ps

Abstract Background The incidence of Alzheimer’s disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Aβ), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk. Methods Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Aβ was measured by 11C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-ε4 carrier status). Results A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p