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Grapevine is an economically-important culture worldwide but is currently the target of decline, especially caused by grapevine trunk diseases (GTD). One of the major grapevine trunk disease is Botryosphaeria dieback, which is associated with Botryosphaeriaceae fungi. Among the different methods that could contribute to increase grapevine fitness under stresses, viticulture could take advantage of symbiosis with arbuscular mycorrhizal fungi. Within this context, we investigated the effect of V. vinifera cv. Gewurztraminer colonization with the arbuscular mycorrhizal fungus Rhizophagus irregularis on plant tolerance to wood inoculation with Neofusicoccum parvum Bt67, one of the most aggressive fungus associated with Botryosphaeria dieback. We showed that grapevine mycorrhization resulted in a small but significant reduction of wood necrosis size and less intense necrosis symptoms on the leaves. We further characterized the response of grapevine leaves and roots to both arbuscular mycorrhizal fungus (AMF) symbiosis and GTD fungus inoculation, especially the interaction between these two conditions, with a non-targeted metabolomic approach. In the roots, both mycorrhization and N. parvum infection triggered metabolite reprogramming, especially sugars and stilbenes, which were downregulated by both AMF symbiosis and pathogen infection. Furthermore, N. parvum infection triggered a significant decrease in fatty acids and oxylipins in leaves of non-mycorrhized plants, whereas contents were maintained or increased in Rhizophagus irregularis-colonized plants. In conclusion, AMF symbiosis may be an interesting tool to improve health of young grapevines and help sustaining infection by trunk disease fungi, by harnessing lipid metabolism.

Purpose: To investigate the impact of smartphone viewing distance and angle on reaction times. Design: A prospective, self-controlled, single-center study. Methods: Participants engaged in a driving simulation facing a large screen with a simulated brake pedal. They were tasked to stop the simulation once recognizing the deceleration of upcoming traffic. Tests were conducted without distraction and with a standardized distraction simulating texting while driving (TWD). Smartphone positions varied at distances of 30 cm and 60 cm, and at angles parallel to and 30° below the road plane. Reaction times were measured from the onset of simulated closure to detection. Stopping distances were extrapolated using data from the National Highway Traffic Safety Administration. Results: Ninety-four participants were included with a mean age of 24 ± 2.7 years. The control reaction time was 11.5 ± 4.1 s. Reaction times significantly decreased with smartphone placement at a closer distance of 30 cm parallel (17.0 ± 3.3 s) vs 60 cm parallel (15.4 ± 3.8 s), P

The presented data relates to the investigation of the adsorption properties of carbon dioxide (CO2), methane (CH4), and dihydrogen (H2) within pristine and functionalized carbophene pores. The carbophenes were functionalized with one of the groups carboxyl (COOH), amine (NH2), nitro (NO2), hydroxyl (OH), or an amide (CONH2, NHCOOH, and N(COOH)2) groups. The systems were optimized using the density functional tight-binding theory code DFTB+ (pre-compiled Version 19.1) with the matsci Slater-Koster files on the Mana high performance computing cluster at the University of Hawaiʻi at Mānoa. The dataset consists of the molecular geometries, lattice vectors, and the total energies for each specific system. One possible use of the data is for training or validating force fields for running molecular dynamics simulations.

Silicon is a promising material for anodes in future generations of LIBs. However, its volume changes during the lithiation/delithiation process that degrades battery performance, making it an impractical alternative. To mitigate this issue, we have found a viable alternate solution, which is the preparation of adamantane-polyacrylic acid (AdEN-AA) and β-cyclodextrin-polyacrylic acid (βCD6A-AA) polymers as supramolecular binders. The advantage of these binders is that polymers leverage host-guest interactions. To carry out this research, we prepared the anode materials in water and in NMP, and then we studied their capacity to crosslink and gel. Additionally, we examined the extent of the supramolecular interaction vs. hydrogen bond. Thermogravimetric analysis showed that the thermal stability of the mixture of complementary polymer increased in the following order: AdEN-AA/βCD6A-AA in NMP

Purpose: To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development. Design: Prospective study of individuals with NOP. Participants: Three hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic. Methods: The Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of P 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 (MMP19) (P = 1.12 × 10−5), zinc finger RNA-binding motif and serine/arginine rich-1 (ZRSR1) (P = 1.48 × 10−4), CTC-487M23.8 (P = 1.79 × 10−4), receptor expression-enhancing protein-5 (REEP5) (P = 2.36 × 10−4), and signal recognition particle-19 (SRP19) (P = 2.56 × 10−4). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 × 10−3) and olfactory signaling (false discovery rate = 1.63 × 10−2) pathways were enriched with the most significant genes. Conclusions: Our GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better understanding of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Summary: Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNA methyltransferase 3A (DNMT3A), a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a Dnmt3aP900L/+ mouse mimicking a mutation with mild to moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes that may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease.

GM1 gangliosidosis is a rare, inherited neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes the lysosomal hydrolase acid β-galactosidase (β-gal). β-gal deficiency leads to toxic accumulation of GM1 ganglioside, predominantly in the central nervous system (CNS), resulting in progressive neurodegeneration. LYS-GM101 is an AAVrh.10-based gene therapy vector carrying the human GLB1 cDNA. The efficacy of intra-cerebrospinal fluid injection of LYS-GM101 analogs was demonstrated in GM1 mouse and cat models with widespread diffusion of β-gal and correction of GM1 ganglioside accumulation in the CNS without observable adverse effects. Clinical dose selection was performed, based on a good-laboratory-practice study, in nonhuman primates (NHPs) using the clinical LYS-GM101 vector. A broadly distributed increase of β-gal activity was observed in NHP brain 3 months after intra-cisterna magna injection of LYS-GM101 at 1.0 × 1012 vg/mL CSF and 4.0 × 1012 vg/mL CSF, with 20% and 60% increases compared with vehicle-treated animals, respectively. Histopathologic examination revealed asymptomatic adverse changes in the sensory pathways of the spinal cord and dorsal root ganglia in both sexes and at both doses. Taken as a whole, these pre-clinical data support the initiation of a clinical study with LYS-GM101 for the treatment of GM1 gangliosidosis.

Summary: Polygenic risk scores (PRSs) developed from multi-ancestry genome-wide association studies (GWASs), PRSmulti, hold promise for improving PRS accuracy and generalizability across populations. To establish best practices for leveraging the increasing diversity of genomic studies, we investigated how various factors affect the performance of PRSmulti compared with PRSs constructed from single-ancestry GWASs (PRSsingle). Through extensive simulations and empirical analyses, we showed that PRSmulti overall outperformed PRSsingle in understudied populations, except when the understudied population represented a small proportion of the multi-ancestry GWAS. Furthermore, integrating PRSs based on local ancestry-informed GWASs and large-scale, European-based PRSs improved predictive performance in understudied African populations, especially for less polygenic traits with large-effect ancestry-enriched variants. Our work highlights the importance of diversifying genomic studies to achieve equitable PRS performance across ancestral populations and provides guidance for developing PRSs from multiple studies.

The Hispanic, Latino, or Spanish (hereafter, “Hispanic”) populations in the U.S. bear a disproportionate burden of COVID-19-related outcomes, including disease incidence and mortality. Developing culturally appropriate national public health services for Hispanic persons remains a challenge. This study examined the association of heritage and language preference with COVID-19 testing (tested vs. not tested) and vaccination (vaccinated vs. not vaccinated) outcomes among Hispanic participants from 18 Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) projects (n = 3308; mean age = 44.1 years [SD = 14.9], 60% women; 83% spoke other than English at home). Generalized estimating equation models adjusted for age, gender, education level, income, insurance coverage, geographic region, comorbidities, and prior infection. Relative to Mexican heritage, individuals identifying as Puerto Rican or Dominican were more likely to test for COVID-19, and South American heritage was associated with higher testing and vaccination rates. Speaking Spanish or another language at home was associated with increased testing compared with speaking English at home for individuals who preferred not to report their heritage, and increased vaccination for those with Mexican, Cuban, or Central American heritage. This study highlights heterogeneity in testing and vaccination behaviors among Hispanic populations based on heritage and language preference, underscoring the diversity within the U.S. Hispanic community. In contrast to other studies on linguistic acculturation and health care utilization, our study found that a language other than English spoken at home was associated with greater vaccine uptake. That is, enculturation – the retention of Spanish language and presumably of Hispanic cultural norms – was linked with being vaccinated.

Background: The doctor-patient relationship has always been at the core of health care, and this relationship remains of paramount importance, regardless of treatment location or the patient's condition. The hospital emergency department (ED) plays a major role in this relationship by providing access to board-certified, residency-trained emergency physicians capable of rapid diagnosis and treatment of urgent, emergent, and life-threatening conditions. U.S. EDs also serve as the nation's safety net for the care of uninsured and underinsured patients. Discussion: As the ED has become a major profit center in the multi-trillion-dollar health care industry, business-centric pressures on ED care pose major threats to the doctor-patient relationship. This article describes and evaluates business-imposed practices that can undermine this relationship in the ED. Conclusions: Health systems should strive to enhance relationships between emergency physicians and their patients and to avoid business practices that undermine them.

Background: Laminectomy with fusion (LF) and laminoplasty (LP) are common posterior decompression procedures used to treat multilevel degenerative cervical myelopathy (DCM). There is debate on their relative efficacy and safety for treatment of DCM. The goal of this study is to examine outcomes and costs of LF and LP procedures for DCM. Methods: This is a retrospective review of adult patients (.05). Patients were successfully weaned off opioids at similar rates (LF: 88%, LP: 86%). Fixed and variable costs respectively with LF cases hospital were higher, 15.7% and 25.7% compared to LP cases (p=.03 and p

Summary: Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target. Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (

Summary: Background: GM1 gangliosidosis is a rare, fatal, neurodegenerative disease caused by mutations in the GLB1 gene and deficiency in β-galactosidase. Delay of symptom onset and increase in lifespan in a GM1 gangliosidosis cat model after adeno-associated viral (AAV) gene therapy treatment provide the basis for AAV gene therapy trials. The availability of validated biomarkers would greatly improve assessment of therapeutic efficacy. Methods: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to screen oligosaccharides as potential biomarkers for GM1 gangliosidosis. The structures of pentasaccharide biomarkers were determined with mass spectrometry, as well as chemical and enzymatic degradations. Comparison of LC-MS/MS data of endogenous and synthetic compounds confirmed the identification. The study samples were analyzed with fully validated LC-MS/MS methods. Findings: We identified two pentasaccharide biomarkers, H3N2a and H3N2b, that were elevated more than 18-fold in patient plasma, cerebrospinal fluid (CSF), and urine. Only H3N2b was detectable in the cat model, and it was negatively correlated with β-galactosidase activity. Following intravenous (IV) AAV9 gene therapy treatment, reduction of H3N2b was observed in central nervous system, urine, plasma, and CSF samples from the cat model and in urine, plasma, and CSF samples from a patient. Reduction of H3N2b accurately reflected normalization of neuropathology in the cat model and improvement of clinical outcomes in the patient. Interpretations: These results demonstrate that H3N2b is a useful pharmacodynamic biomarker to evaluate the efficacy of gene therapy for GM1 gangliosidosis. H3N2b will facilitate the translation of gene therapy from animal models to patients. Funding: This work was supported by grants U01NS114156, R01HD060576, ZIAHG200409, and P30 DK020579 from the National Institutes of Health (NIH) and a grant from National Tay-Sachs and Allied Diseases Association Inc.

Early in vertebrate evolution, a single homeobox (Hox) cluster in basal chordates was quadrupled to generate the Hox gene clusters present in extant vertebrates. Here we ask how this expanded gene pool may have influenced the evolution of the visual system. We suggest that a single neurosensory cell type split into ciliated sensory cells (photoreceptors, which transduce light) and retinal ganglion cells (RGC, which project to the brain). In vertebrates, development of photoreceptors is regulated by the basic helix-loop-helix (bHLH) transcription factor Neurod1 whereas RGC development depends on Atoh7 and related bHLH genes. Lancelet (a basal chordate) does not express Neurod or Atoh7 and possesses a few neurosensory cells with cilia that reach out of the opening of the neural tube. Sea-squirts (Ascidians) do not express Neurod and express a different bHLH gene, Atoh8, that is likely expressed in the anterior vesicle. Recent data indicate the neurosensory cells in lancelets may correspond to three distinct eye fields in ascidians, which in turn may be the basis of the vertebrate retina, pineal and parapineal. In this review we contrast the genetic control of visual structure development in these chordates with that of basal vertebrates such as lampreys and hagfish, and jawed vertebrates. We propose an evolutionary sequence linking whole-genome duplications, initially to a split between photoreceptor and projection neurons (RGC) and subsequently between pineal and lateral eye structures.

Summary: Background: An urgent need exists to rapidly screen potential therapeutics for severe COVID-19 or other emerging pathogens associated with high morbidity and mortality. Methods: Using an adaptive platform design created to rapidly evaluate investigational agents, hospitalised patients with severe COVID-19 requiring ≥6 L/min oxygen were randomised to either a backbone regimen of dexamethasone and remdesivir alone (controls) or backbone plus one open-label investigational agent. Patients were enrolled to the arms described between July 30, 2020 and June 11, 2021 in 20 medical centres in the United States. The platform contained up to four potentially available investigational agents and controls available for randomisation during a single time-period. The two primary endpoints were time-to-recovery (

Summary: African populations are vastly underrepresented in genetic studies but have the most genetic variation and face wide-ranging environmental exposures globally. Because systematic evaluations of genetic prediction had not yet been conducted in ancestries that span African diversity, we calculated polygenic risk scores (PRSs) in simulations across Africa and in empirical data from South Africa, Uganda, and the United Kingdom to better understand the generalizability of genetic studies. PRS accuracy improves with ancestry-matched discovery cohorts more than from ancestry-mismatched studies. Within ancestrally and ethnically diverse South African individuals, we find that PRS accuracy is low for all traits but varies across groups. Differences in African ancestries contribute more to variability in PRS accuracy than other large cohort differences considered between individuals in the United Kingdom versus Uganda. We computed PRS in African ancestry populations using existing European-only versus ancestrally diverse genetic studies; the increased diversity produced the largest accuracy gains for hemoglobin concentration and white blood cell count, reflecting large-effect ancestry-enriched variants in genes known to influence sickle cell anemia and the allergic response, respectively. Differences in PRS accuracy across African ancestries originating from diverse regions are as large as across out-of-Africa continental ancestries, requiring commensurate nuance.

Throughout their evolution seabirds have not had to contend with the collision risk posed by discrete objects that extend into their flight space above the water surface. However, the recent introduction of offshore wind turbines has significantly increased the potential for collisions. Bird collision risk with Offshore Wind Farm (OWF) turbines is now a major consenting consideration for OWF projects due to potential local population impacts on birds, especially those associated with protected sites. Therefore, the possibility of reducing those risks through a simple mitigation is highly desirable. Key elements for the design of vision-based mitigation measures aimed at reducing the collision of marine birds with wind turbines should be based upon knowledge of the vision of birds, not the vision of humans. May et al. (2020) tested a vision-based wind turbine mitigation measure and reported a modelled 70% reduction in annual turbine-blade collision mortality rate at a terrestrial location in a suite of 19 bird species. The aim of the present proposals is to extend this vision-based mitigation approach and increase its applicability to a broad suite of bird species considered vulnerable to collisions with wind turbines at sea. Key aspects of the vision, behaviour and ecology of marine birds which contribute to their collision risk under a range of natural viewing conditions are reviewed. The same information is then employed to give insights into the requirements of vision-based mitigation measures. We argue that the internal visual contrast of wind turbines should be increased using achromatic patterns applied to blades and pylons. These patterns should reduce the collision vulnerability of marine birds in general and should be effective under a range of visibility conditions determined by natural light levels and weather conditions. The measures should allow birds with different flight speeds and visual acuities to detect turbines sufficiently early to allow alteration of flight direction and avoid collision. The proposed mitigation requires changes to the appearance of wind turbines that can be implemented at the time of manufacture. They do not interfere with statutory requirements already required for the marking of turbines for the benefit of shipping and aircraft.

Transformative results of adeno-associated virus (AAV) gene therapy in patients with spinal muscular atrophy and Leber’s congenital amaurosis led to approval of the first two AAV products in the United States to treat these diseases. These extraordinary results led to a dramatic increase in the number and type of AAV gene-therapy programs. However, the field lacks non-invasive means to assess levels and duration of therapeutic protein function in patients. Here, we describe a new magnetic resonance imaging (MRI) technology for real-time reporting of gene-therapy products in the living animal in the form of an MRI probe that is activated in the presence of therapeutic protein expression. For the first time, we show reliable tracking of enzyme expression after a now in-human clinical trial AAV gene therapy (ClinicalTrials.gov: NTC03952637) encoding lysosomal acid beta-galactosidase (βgal) using a self-immolative βgal-responsive MRI probe. MRI enhancement in AAV-treated enzyme-deficient mice (GLB-1−/−) correlates with βgal activity in central nervous system and peripheral organs after intracranial or intravenous AAV gene therapy, respectively. With >1,800 gene therapies in phase I/II clinical trials (ClinicalTrials.gov), development of a non-invasive method to track gene expression over time in patients is crucial to the future of the gene-therapy field.

Summary: Polygenic risk scores (PRSs) have been widely explored in precision medicine. However, few studies have thoroughly investigated their best practices in global populations across different diseases. We here utilized data from Global Biobank Meta-analysis Initiative (GBMI) to explore methodological considerations and PRS performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRSs using pruning and thresholding (P + T) and PRS-continuous shrinkage (CS). For both methods, using a European-based linkage disequilibrium (LD) reference panel resulted in comparable or higher prediction accuracy compared with several other non-European-based panels. PRS-CS overall outperformed the classic P + T method, especially for endpoints with higher SNP-based heritability. Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma, which has known variation in disease prevalence across populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using GBMI resources and highlight the importance of best practices for PRS in the biobank-scale genomics era.

Breast cancer is one of the most diagnosed cancer in women worldwide and lymphedema is one of the most common late and chronic adverse effects of breast cancer treatment. Lymphedema symptoms are essential signs of early-stage of lymphedema as they often precede changes in limb size or girth or a lymphedema diagnosis. Therefore, to achieve early detection and prevent lymphedema progression, it is important to promote patient selfcare in terms of the awareness symptoms identification. To this purpose Breast Cancer and Lymphedema Symptom Experience Index (BCLE SEI Esp) scale was used.Between October 2018 and June 2020, we collected data from 286 lymphedema and non-lymphedema patients post-breast cancer treatment on sociodemographic information, lymphedema symptoms, daily living-function and psychosocial distress, women and the data comparison between lymphedema and non-lymphedema patients were provided in this publication.This dataset can be used as a reference in clinical settings or in clinical studies or as an instructional tool to teach breast cancer patients and clinicians to be aware of lymphedema symptoms and to help clinicians and patients to achieve early identification of lymphedema symptoms and the impacts of lymphedema symptoms in women´s life and to develop future research, for example, to develop predictive algorithms.

A transceiver volume coil for High Field Magnetic Resonance Imaging was developed based on Temnikov’s NMR probe coil. The critical advantage of this design is that requires only one trimmer capacitor for both tuning and matching. Electromagnetic simulations of our coil were compared to a four-rung birdcage coil to evaluate their performances. A transceiver coil prototype, called the double-cross coil and a birdcage coil were built to compare and contrast their feasibility. Both coil prototypes were operated in the linear mode. Experimental quality factors were Qu/Ql=101/45 for the double-cross coil and Qu/Ql=105/43 for the birdcage coil. Phantom images were acquired to test the viability of each coil for high field magnetic resonance imaging applications. The signal-to-noise ratios, noise factors and uniformity values were also calculated: 85.26/0.74/44.48 for the double-cross coil and 76.54/1.9/65.65 for the birdcage coil. These volume coils showed similar performance, but the double-cross coil has better uniformity and a slightly lower noise figure than the birdcage coil. A remarkable agreement of experimental and simulated B1 was obtained for the double-cross coil. These experimental and numerical results demonstrate the feasibility of the double-cross volume coil with better uniformity for rodent magnetic resonance imaging at 7 T.

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of ~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline β-galactosidase (β-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where β-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and β-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.

Summary: Polygenic risk scores (PRS) measure genetic disease susceptibility by combining risk effects across the genome. For coronary artery disease (CAD), type 2 diabetes (T2D), and breast and prostate cancer, we performed cross-ancestry evaluation of genome-wide PRSs in six biobanks in Europe, the United States, and Asia. We studied transferability of these highly polygenic, genome-wide PRSs across global ancestries, within European populations with different health-care systems, and local population substructures in a population isolate. All four PRSs had similar accuracy across European and Asian populations, with poorer transferability in the smaller group of individuals of African ancestry. The PRSs had highly similar effect sizes in different populations of European ancestry, and in early- and late-settlement regions with different recent population bottlenecks in Finland. Comparing genome-wide PRSs to PRSs containing a smaller number of variants, the highly polygenic, genome-wide PRSs generally displayed higher effect sizes and better transferability across global ancestries. Our findings indicate that in the populations investigated, the current genome-wide polygenic scores for common diseases have potential for clinical utility within different health-care settings for individuals of European ancestry, but that the utility in individuals of African ancestry is currently much lower.

Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer’s disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/β based on presence/absence of intermediate-high likelihood AD: AD-TDP type-β (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-β. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. Additionally, brain atrophy regional rates also vary by non-FTLD TDP-43 type.

Quantitative susceptibility mapping (QSM) can detect iron distribution in the brain by estimating local tissue magnetic susceptibility properties at every voxel. Iron deposition patterns are well studied in typical Alzheimer’s disease (tAD), but little is known about these patterns in atypical clinical presentations of AD such as logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA). Seventeen PCA patients and eight LPA patients were recruited by the Neurodegenerative Research Group at Mayo Clinic, Rochester, MN, and underwent MRI that included a five-echo gradient echo sequence for calculation of QSM. Mean QSM signal was extracted from gray and white matter for regions-of-interest across the brain using the Mayo Clinic Adult Lifespan Template. Bayesian hierarchical models were fit per-region and per-hemisphere to compare PCA, LPA, 63 healthy controls, and 20 tAD patients. Strong evidence (posterior probability > 0.99) was observed for greater susceptibility in the middle occipital gyrus and amygdala in both LPA and PCA, and in the right inferior parietal, inferior temporal, and angular gyri in PCA and the caudate and substantia nigra in LPA compared to controls. Moderate evidence for greater susceptibility (posterior probability > 0.90) was also observed in the inferior occipital gyrus, precuneus, putamen and entorhinal cortex in both LPA and PCA, along with superior frontal gyrus in PCA and inferior temporal gyri, insula and basal ganglia in LPA, when compared to controls. Between phenotypic comparisons, LPA had greater susceptibility in the caudate, hippocampus, and posterior cingulate compared to PCA, while PCA showed greater susceptibility in the right superior frontal and middle temporal gyri compared to LPA. Both LPA and PCA showed moderate and strong evidence for greater susceptibility than tAD, particularly in medial and lateral parietal regions, while tAD showed greater susceptibility in the hippocampus and basal ganglia. This study proposes the possibility of unique iron profiles existing between LPA and PCA within cortical and subcortical structures. These changes match well with the disease-related changes of the clinical phenotypes, suggesting that QSM could be an informative candidate marker to study iron deposition in these patients.

Background: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy with neurodegeneration typically observed in the superior cerebellar peduncle (SCP) and dentatorubrothalamic tracts (DRTT). However, it is unclear how these tracts are differentially affected in different clinical variants of PSP. Objectives: To determine whether diffusion tractography of the SCP and DRTT can differentiate autopsy-confirmed PSP with Richardson’s syndrome (PSP-RS) and PSP with predominant speech/language disorder (PSP-SL). Methods: We studied 22 autopsy-confirmed PSP patients that included 12 with PSP-RS and 10 with PSP-SL. We compared these two groups to 11 patients with autopsy-confirmed Alzheimer’s disease with SL problems, i.e., logopenic progressive aphasia (AD-LPA) (disease controls) and 10 healthy controls. Whole brain tractography was performed to identify the SCP and DRTT, as well as the frontal aslant tract and superior longitudinal fasciculus. We assessed fractional anisotropy and mean diffusivity for each tract. Hierarchical linear modeling was used for statistical comparisons, and correlations were assessed with clinical disease severity, ocular motor impairment, and parkinsonism. DRTT connectomics matrix analysis was also performed across groups. Results: The SCP showed decreased fractional anisotropy for PSP-RS and PSP-SL and increased mean diffusivity in PSP-RS, compared to controls and AD-LPA. Right DRTT fibers showed lower fractional anisotropy in PSP-RS and PSP-SL compared to controls and AD-LPA, with PSP-RS also showing lower values compared to PSP-SL. Reductions in connectivity were observed in infratentorial DRTT regions in PSP-RS vs cortical regions in PSP-SL. PSP-SL showed greater abnormalities in the frontal aslant tract and superior longitudinal fasciculus compared to controls, PSP-RS, and AD-LPA. Significant correlations were observed between ocular motor impairment and SCP in PSP-RS (p = 0.042), and DRTT in PSP-SL (p = 0.022). In PSP-SL, the PSP Rating Scale correlated with the SCP (p = 0.045) and DRTT (p = 0.008), and the Unified Parkinson’s Disease Rating Scale correlated with the DRTT (p = 0.014). Conclusions: Degeneration of the SCP and DRTT are diagnostic features of both PSP-RS and PSP-SL and associations with clinical metrics validate the role of these tracts in PSP-related clinical features, particularly in PSP-SL.

Firefighting is a mentally and physically demanding profession which is compounded by poor sleep due to shift schedules commonly used by fire departments. Compared to other professions, firefighters are at high risk for musculoskeletal injuries, mental illnesses, and cardiovascular diseases. The purpose of this study was to systemically review the effects of sleep on firefighter occupational performance and health. A search was conducted for studies that conducted a quantitative analysis involving sleep and occupational performance in firefighters. Relevant data were extracted and study quality evaluated with Newcastle-Ottawa Scale. There were 15 articles meeting the inclusion criteria with a total sample of 1591 (1539 male, 52 female) firefighters. We found that firefighters with poor sleep measures had worse cognitive performance and overall health, but physical capabilities were not impacted by acute sleep restriction. However, chronic poor sleep would likely negatively impact physical performance due to being associated with a decline in numerous health measures. To avoid sleep-related declines in occupational performance fire departments should consider the consequences of shift schedules on the performance and health of firefighters. Furthermore, sleep education interventions, the use of wearables to monitor, recovery and sleep health screening appear beneficial based on prior research.

In the present study, following a one-pot two-step protocol, we have synthesized novel sulfonamides-isoxazolines hybrids (3a-r) via a highly regioselective 1,3-dipolar cycloaddition. The present methodology capitalized on trichloroisocyanuric acid (TCCA) as a safe and ecological oxidant and chlorinating agent for the in-situ conversion of aldehydes to nitrile oxides in the presence of hydroxylamine hydrochloride, under ultrasound activation. These nitrile oxides could be engaged in 1,3-dipolar cycloaddition reactions with various alkene to afford the targeted sulfonamides-isoxazolines hybrids (3a-r). The latter were assessed for their antineoplastic activity against model leukemia cell lines (Chronic Myeloid Leukemia, K562 and Promyelocytic Leukemia, HL-60).

Summary: In cancer, autophagy is upregulated to promote cell survival and tumor growth during times of nutrient stress and can confer resistance to drug treatments. Several major signaling networks control autophagy induction, including the p53 tumor suppressor pathway. In response to DNA damage and other cellular stresses, p53 is stabilized and activated, while HDM2 binds to and ubiquitinates p53 for proteasome degradation. Thus blocking the HDM2-p53 interaction is a promising therapeutic strategy in cancer; however, the potential survival advantage conferred by autophagy induction may limit therapeutic efficacy. In this study, we leveraged an HDM2 inhibitor to identify kinases required for p53-dependent autophagy. Interestingly, we discovered that p53-dependent autophagy requires several kinases, including the myotonic dystrophy protein kinase-like alpha (MRCKα). MRCKα is a CDC42 effector reported to activate actin-myosin cytoskeletal reorganization. Overall, this study provides evidence linking MRCKα to autophagy and reveals additional insights into the role of kinases in p53-dependent autophagy. : Biological Sciences; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Biological Sciences, Cell Biology, Functional Aspects of Cell Biology

Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.

Background: α4β7 is a gut-homing integrin heterodimer that can act as a non-essential binding molecule for HIV. A previous study in heterosexual African women found that individuals with higher proportions of α4β7 expressing CD4+ T cells were more likely to become infected with HIV, as well as present with faster disease progression. It is unknown if this phenomenon is also observed in men who have sex with men (MSM) or people who inject drugs (PWID). Methods: MSM and transgender women who seroconverted as part of the HVTN 505 HIV vaccine trial and PWID who seroconverted during the ALIVE cohort study were selected as cases and matched to HIV-uninfected controls from the same studies (1:1 and 1:3, respectively). Pre-seroconversion PBMC samples from cases and controls in both studies were examined by flow cytometry to measure levels of α4β7 expression on CD4+ T cells. Multivariable conditional logistic regression was used to compare α4β7 expression levels between cases and controls. A Kaplan-Meier curve was used to examine the association of α4β7 expression pre-seroconversion with HIV disease progression. Findings: In MSM and transgender women (n = 103 cases, 103 controls), there was no statistically significant difference in the levels of α4β7 expression on CD4+ T cells between cases and controls (adjusted odds ratio [adjOR] =1.10, 95% confidence interval [CI]=0.94,1.29; p = 0.246). Interestingly, in PWID (n = 49 cases, 143 controls), cases had significantly lower levels of α4β7 expression compared to their matched controls (adjOR = 0.80, 95% CI = 0.68, 0.93; p = 0.004). Among HIV-positive PWID (n = 47), there was no significant association in HIV disease progression in individuals above or below the median level of α4β7 expression (log-rank p = 0.84). Interpretation: In contrast to findings in heterosexual women, higher α4β7 expression does not predict HIV acquisition or disease progression in PWID or MSM. Funding: This study was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. The study was also supported by extramural grants from NIAID T32AI102623 (E.U.P.), and UM1AI069470.

Gillnet bycatch accounts for over 400,000 bird mortalities worldwide every year, affecting a wide variety of species, especially those birds that dive when foraging. Technological solutions to improve gillnet visibility or deter birds from approaching nets, such as LED lights, are essential for aiding diving birds to perceive nets as a hazard. Designing such solutions requires obtaining visual and behavioural ecology information from species to assess their ability to see the warning devices, and to examine their behavioural responses to them. Seaducks, particularly Long-tailed Ducks Clangula hyemalis, have high bycatch mortality rates. We examined the visual fields of four Long-tailed Ducks to understand their three-dimensional view around the head. The visual field characteristics of this species indicate a reliance on visual guidance for foraging associated with their capture of varied, mobile prey in their generalist diet. We subsequently conducted dive tank trials to test the effectiveness of 12 different LED treatments as visual deterrents to the underwater foraging behaviour of 8 Long-tailed Ducks. During each trial, ducks were offered food rewards from a specific underwater location in a dive tank, having the choice of whether to take the food or not. At the same time, they were exposed to either one LED light or the control (no light) to determine whether the presence of each light affected the foraging success rate of dives compared to the control. Exposure of ducks to all 13 treatment combinations was randomised over the trial period. White lights with an increasing flash rate were shown to have a significant positive effect on foraging success, and likely acted as a visual attractant, rather than as a deterrent. No light treatment significantly reduced the foraging success of ducks. LED lights did not inhibit the feeding of Long-tailed Ducks. Such lights may be ineffective as underwater visual deterrents when deployed on gillnets, while white flashing lights may make foraging sites more attractive to Long-tailed Ducks.

The SARS-CoV-2 pandemic has produced an unprecedented rush to develop new therapies, ranging from immunizations and antivirals to host-directed therapies to dampen potentially deleterious host inflammatory responses. With a sense of urgency, many groups have proposed repurposing approved drugs for other indications that might be deployed rapidly to control the viral infection or improve host responses. However, many of these therapies are based on drug availability rather than on a rational understanding of important steps in pathogenesis, particularly in the lungs, that lead to critical illness and life-threatening acute respiratory failure. Here we propose that the viral infection initially triggers a profound activation of innate immunity in the lungs that generates a self-perpetuating cytokine storm affecting the entire body. Inhibiting key proximal points in innate immunity pathways is feasible and offers a science-based approach to improving outcomes in moderate to severe COVID-19 illness.

Summary: In response to stress, cancer cells generate nutrients and energy through a cellular recycling process called autophagy, which can promote survival and tumor progression. Accordingly, autophagy inhibition has emerged as a potential cancer treatment strategy. Inhibitors targeting ULK1, an essential and early autophagy regulator, have provided proof of concept for targeting this kinase to inhibit autophagy; however, these are limited individually in their potency, selectivity, or cellular activity. In this study, we report two small molecule ULK1 inhibitors, ULK-100 and ULK-101, and establish superior potency and selectivity over a noteworthy published inhibitor. Moreover, we show that ULK-101 suppresses autophagy induction and autophagic flux in response to different stimuli. Finally, we use ULK-101 to demonstrate that ULK1 inhibition sensitizes KRAS mutant lung cancer cells to nutrient stress. ULK-101 represents a powerful molecular tool to study the role of autophagy in cancer cells and to evaluate the therapeutic potential of autophagy inhibition. : Therapeutics; Functional Aspects of Cell Biology; Cancer Subject Areas: Therapeutics, Functional Aspects of Cell Biology, Cancer

Abstract Background Double inversion recovery (DIR) fast spin-echo (FSE) cardiovascular magnetic resonance (CMR) sequences are used clinically for black-blood T2-weighted imaging. However, these sequences suffer from slice inefficiency due to the non-selective inversion pulses. We propose a multi-band (MB) encoded DIR radial FSE (MB-DIR-RADFSE) technique to simultaneously excite two slices. This sequence has improved signal-to-noise ratio per unit time compared to a single slice excitation. It is also motion robust and enables the reconstruction of high-resolution black-blood T2-weighted images and T2 maps for the excited slices. Methods Hadamard encoded MB pulses were used in MB-DIR-RADFSE to simultaneously excite two slices. A principal component based iterative reconstruction was used to jointly reconstruct black-blood T2-weighted images and T2 maps. Phantom and in vivo experiments were performed to evaluate T2 mapping performance and results were compared to a T2-prepared balanced steady state free precession (bSSFP) method. The inter-segment variability of the T2 maps were assessed using data acquired on healthy subjects. A reproducibility study was performed to evaluate reproducibility of the proposed technique. Results Phantom experiments show that the T2 values estimated from MB-DIR-RADFSE are comparable to the spin-echo based reference, while T2-prepared bSSFP over-estimated T2 values. The relative contrast of the black-blood images from the multi-band scheme was comparable to those from a single slice acquisition. The myocardial segment analysis on 8 healthy subjects indicated a significant difference (p-value

Preclinical and clinical studies have shown bidirectional interactions within the brain-gut-microbiome axis. Gut microbes communicate to the central nervous system through at least 3 parallel and interacting channels involving nervous, endocrine, and immune signaling mechanisms. The brain can affect the community structure and function of the gut microbiota through the autonomic nervous system, by modulating regional gut motility, intestinal transit and secretion, and gut permeability, and potentially through the luminal secretion of hormones that directly modulate microbial gene expression. A systems biological model is proposed that posits circular communication loops amid the brain, gut, and gut microbiome, and in which perturbation at any level can propagate dysregulation throughout the circuit. A series of largely preclinical observations implicates alterations in brain-gut-microbiome communication in the pathogenesis and pathophysiology of irritable bowel syndrome, obesity, and several psychiatric and neurologic disorders. Continued research holds the promise of identifying novel therapeutic targets and developing treatment strategies to address some of the most debilitating, costly, and poorly understood diseases. Keywords: Serotonin, Stress, Irritable Bowel Syndrome, Intestinal Permeability