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The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson's disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson's disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson's disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go-No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go-No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson's disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions. [ABSTRACT FROM AUTHOR]

Summary: Admixture is a fundamental process that has shaped levels and patterns of genetic variation in human populations. RFMIX version 2 (RFMIX2) utilizes a robust modeling approach to identify the genetic ancestries in admixed populations. However, this software does not have a built-in method to visually summarize the results of analyses. Here, we introduce the AncestryGrapher toolkit, which converts the numerical output of RFMIX2 into graphical representations of global and local ancestry (i.e., the per-individual ancestry components and the genetic ancestry along chromosomes, respectively)., Results: To demonstrate the utility of our methods, we applied the AncestryGrapher toolkit to visualize the global and local ancestry of individuals in the North African Mozabite Berber population from the Human Genome Diversity Panel (HGDP). Our results showed that the Mozabite Berbers derived their ancestry from the Middle East, Europe, and sub-Saharan Africa (global ancestry). We also found that the population origin of ancestry varied considerably along chromosomes (local ancestry). For example, we observed variance in local ancestry in the genomic region on chromosome 2 containing the regulatory sequence in the MCM6 gene associated with lactase persistence (LP), a human adaptive trait tied to the cultural development of adult milk consumption. Overall, the AncestryGrapher toolkit facilitates the exploration, interpretation, and reporting of ancestry patterns in human populations., Availability and Implementation: The AncestryGrapher toolkit is free and open source on https://github.com/alisi1989/RFmix2-Pipeline-to-plot., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2024. Published by Oxford University Press.)

Objective: To explore patient experiences with the diagnosis process for uterine cancer and the perceived barriers that may affect early diagnosis and racial disparities in stage at diagnosis., Methods: We conducted semi-structured interviews to ascertain the diagnostic journey of 11 non-Hispanic Black ("Black") and 11 non-Hispanic White ("White") patients who were diagnosed with uterine cancer in the past six months. All interviews were audio-recorded, professionally transcribed, and analyzed using thematic analysis. Findings were presented to patients and community advocates for critical review and feedback before being finalized., Results: Respondents had a median age of 64 years. Thirteen (59.1 %) had stage I tumor, whereas nine (40.9 %) had stage II-IV disease. Respondents were attentive to their symptoms but unaware that they could indicate uterine cancer. This was compounded by women's conditioned acceptance of discomfort and disconnection from gynecological care after reproductive age. Respondents often viewed racial disparities in diagnosis through other social determinants of health, including gender, age, and healthcare access. These overlapping social experiences, coupled with respondents' concentration on recovery, may mask their perceptions about systemic racism. Although few respondents noted negative experiences in their own evaluations leading to the diagnosis of uterine cancer, Black respondents often described how previous discriminatory experiences informed a wariness of healthcare systems., Conclusion: Lack of public awareness of uterine cancer, gendered expectations for discomfort, and disconnection from gynecologic care all interfered with early diagnosis of uterine cancer. Discriminatory experiences in prior healthcare further complicate Black patients' engagement with the healthcare system., Competing Interests: Declaration of competing interest Jason D. Wright has received royalties from UpToDate and honoraria from the American College of Obstetricians and Gynecologists and received research funding from Merck. Xiao Xu has received honoraria from the American Association of Gynecologic Laparoscopists. The other authors have no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We present a new integrated experimental and modeling effort that assesses the intrinsic sensitivity of energetic materials based on their reaction rates. The High Explosive Initiation Time (HEIT) experiment has been developed to provide a rapid assessment of the high-temperature reaction kinetics for the chemical decomposition of explosive materials. This effort is supported theoretically by quantum molecular dynamics (QMD) simulations that depict how different explosives can have vastly different adiabatic induction times at the same temperature. In this work, the ranking of explosive initiation properties between the HEIT experiment and QMD simulations is identical for six different energetic materials, even though they contain a variety of functional groups. We have also determined that the Arrhenius kinetics obtained by QMD simulations for homogeneous explosions connect remarkably well with those obtained from much longer duration one-dimensional time-to-explosion (ODTX) measurements. Kinetic Monte Carlo simulations have been developed to model the coupled heat transport and chemistry of the HEIT experiment to explicitly connect the experimental results with the Arrhenius rates for homogeneous explosions. These results confirm that ignition in the HEIT experiment is heterogeneous, where reactions start at the needle wall and propagate inward at a rate controlled by the thermal diffusivity and energy release. Overall, this work provides the first cohesive experimental and first-principles modeling effort to assess reaction kinetics of explosive chemical decomposition in the subshock regime and will be useful in predictive models needed for safety assessments.

(1) Background: Pulmonary hypertension (PH) increases pulmonary vascular resistance and right ventricular (RV) afterload. Assessment of RV systolic function in PH using RV fractional area change (RV FAC) as a marker directly correlates with mortality and the need for extracorporeal membrane oxygenation (ECMO). However, few studies have assessed neurodevelopmental outcomes. We hypothesize that cardiac RV systolic dysfunction with lower RV FAC is associated with worse neurodevelopmental impairment (NI). (2) Methods: Retrospective study of 42 subjects with PH to evaluate neurodevelopmental outcomes in the first two years of life based on (i) subjective assessment of RV systolic function and (ii) RV FAC, a specific echocardiographic marker for RV function. (3) Results: Subjects from the initial study cohort ( n = 135) with PH who had long-term follow-up were divided into RV dysfunction (study, n = 20) and non-RV dysfunction (control, n = 22) groups. RV FAC in the study vs. control group (0.18 vs. 0.25) was lower ( p = 0.00017). There was no statistically significant difference in NI either with RV dysfunction or lower RV FAC. Although not significant, RV dysfunction was associated with longer mean duration of mechanical ventilation, time on ECMO, and length of stay. In the initial cohort (135), mortality was 16.3% and the percentage of NI was 62%. (4) Conclusions: Neonatal pulmonary hypertension is associated with a high degree of neurodevelopment impairment. Early RV systolic dysfunction, as identified by RV FAC, was not an optimal predictive biomarker for infants with PH and neurodevelopmental impairment.

Pentaerythritol tetranitrate (PETN) has been used extensively in commercial detonators and other explosive applications for many decades. Here, we show the results of a comprehensive 1.5 year aging study of PETN in commercial detonators, addressing batch-to-batch variations, surface area changes, and comparisons of aged loose powders side-by-side with identically aged detonators. Function time analysis of the aged detonators has also been provided and discussed in the context of powder aging. This large-scale, statistically relevant study addresses long-standing questions on PETN aging without the complications from making comparisons between multiple batches of material. We have evaluated the aging time required to reach the maximum measured amount of PETN coarsening and estimated an activation barrier of ∼123 kJ mol -1 , which is higher than literature values reported by Gee et al. It is possible that this discrepancy is due to the fact that that this study cannot quantify the relative contributions of surface diffusion versus sublimation processes. At the lower temperatures of 50 and 60 °C, we assume that surface diffusion dominates over sublimation processes, even at longer aging times. At the higher temperature of 75 °C, we assume that both surface diffusion and sublimation contribute at the early time points, which are included in the Arrhenius analysis for coarsening., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

There are few techniques available for chemists to obtain time-to-explosion data with known temperature inputs at the early stages of the design and synthesis of new explosives. In the 1960s, a technique was developed to rapidly heat milligram-quantities of confined explosives to ∼1000 K on microsecond timescales. Wenograd [Trans. Faraday Soc. 57, 1612 (1961)] loaded explosives inside stainless steel hypodermic needles, connected them to a fireset and rapidly discharged a capacitor through the steel. He obtained the temperature by measuring the needle resistance in a Wheatstone bridge arrangement and the time to explosion from a needle rupture. However, owing to the narrow-gauge needles used in the original research, the experiment was only possible with melt-castable explosives; it was never replicated, and modern diagnostics are now available with advances beyond the 1960s. Here, we report the development of the High Explosives Initiation Time (HEIT) test, which utilizes a 250 J pulsed power system to heat the needles. This work extends the Wenograd approach by using optical diagnostics, computational modeling, and advanced techniques to measure needle resistance and needle rupture. Preliminary rate information for pentaerythritol tetranitrate (PETN) will be presented., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Background: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits)., Objective: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes., Methods: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification., Results: First, LCA supported the three-class solution - Motor Only, Psychiatric & Motor, and Cognitive & Motor- in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively., Conclusions: These results support the reproducibility and reliability of the Parkinson's disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Therese Cash received support from NIH (NS097437, NS075321, NS097799, NS124738, NS118146, AT011015). Christina N. Lessov-Schlaggar received support from NINDS NS097437. Erin R. Foster is funded by the National Institutes of Health (NIA R21AG063974, NIA R01AG065214, NIDDK R01DK126826, R01DK064832), the American Parkinson Disease Association (APDA) (ID# 971,949), and the APDA Advanced Parkinson Disease Research Center at Washington University in St Louis, and the Missouri Chapter of the APDA. Peter S. Myers received support from NINDS NS097437. Joshua J. Jackson received support from NINDS NS097437, NIMH AG061162-01, NIDCD DC017522-02S1. Baijayanta Maiti received funding from NINDS K23 NS125107, National Center for Advancing Translational Sciences of the National Institute of Health KL2 TR002346, American Academy of Neurology and American Brain Foundation Clinical Research Training Fellowship in Parkinson's disease, Parkinson Study Group/Parkinson's Disease Foundation Mentored Clinical Research Award, Missouri Chapter of American Parkinson Disease Association, and the Jo Oertli fund and has received honoraria for reviewing grants as a member of the Parkinson Study Group mentoring committee and from the American Academy of Neurology for authorship. Paul T. Kotzbauer received funding from National Institutes of Health NS110436, NS097799, NS075321, NS110456, AG071754, NS123860, NS097437, and from Biogen and has received previous funding and honoraria from AbbVie. Joel S. Perlmutter has received research funding from National Institutes of Health NS075321, NS103957, NS107281, NS092865, U10NS077384, NS097437, U54NS116025, U19 NS110456, AG050263, AG-64937, NS097799, NS075527, ES029524, NS109487, R61 AT010753, (NCATS, NINDS, NIA), R01NS118146, R01AG065214, Department of Defense (DOD W81XWH-217-1-0393), Michael J FoxFoundation, Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Missouri Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, Huntington Disease Society of America, Murphy Fund, N. Grant Williams Fund and CHDI. He co-directs the Dystonia Coalition, which received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke, TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). Dr. Perlmutter has provided medical legal consultation to Wood, Cooper and Peterson, LLC and to Simmons and Simmons LLP. He serves as Director of Medical and Scientific Advisory Committee of the Dystonia Medical Research Foundation, Chair of the Scientific Advisory Committee of the Parkinson Study Group, Chair of the Standards Committee of the Huntington Study Group (honoraria for this one), member of the Scientific Advisory Board of the APDA, Chair of the Scientific and Publication Committee for ENROLL-HD (honoraria from this one), and member of the Education Committee of the Huntington Study Group (honoraria from this one). Dr. Perlmutter has received honoraria from CHDI, Huntington Disease Study Group, Parkinson Study Group, Beth Israel Hospital (Harvard group), U Pennsylvania, Stanford U. Boston University. Meghan C. Campbell receives research support from NIH (NS097437, NS075321, NS097799, NS124378, AG063974, AT010753, AT010753-S1), the McDonnell Center for Systems Neuroscience, the Mallinckrodt Institute of Radiology at WUSTL, the Neurimaging Labs Innovation Award and has received honoraria from the Parkinson Foundation., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Molecular imaging of brain vesicular acetylcholine transporter provides a biomarker to explore cholinergic systems in humans. We aimed to characterize the distribution of, and optimize methods to quantify, the vesicular acetylcholine transporter-specific tracer (-)-(1-(8-(2-[ 18 F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([ 18 F]VAT) in the brain using PET. Methods: Fifty-two healthy participants aged 21-97 y had brain PET with [ 18 F]VAT. [ 3 H]VAT autoradiography identified brain areas devoid of specific binding in cortical white matter. PET image-based white matter reference region size, model start time, and duration were optimized for calculations of Logan nondisplaceable binding potential (BP ND ). Ten participants had 2 scans to determine test-retest variability. Finally, we analyzed age-dependent differences in participants. Results: [ 18 F]VAT was widely distributed in the brain, with high striatal, thalamic, amygdala, hippocampal, cerebellar vermis, and regionally specific uptake in the cerebral cortex. [ 3 H]VAT autoradiography-specific binding and PET [ 18 F]VAT uptake were low in white matter. [ 18 F]VAT SUVs in the white matter reference region correlated with age, requiring stringent erosion parameters. Logan BP ND estimates stabilized using at least 40 min of data starting 25 min after injection. Test-retest variability had excellent reproducibility and reliability in repeat BP ND calculations for 10 participants (putamen, 6.8%; r > 0.93). We observed age-dependent decreases in the caudate and putamen (multiple comparisons corrected) and in numerous cortical regions. Finally, we provide power tables to indicate potential mean differences that can be detected between 2 groups of participants. Conclusion: These results validate a reference region for BP ND calculations and demonstrate the viability, reproducibility, and utility of using the [ 18 F]VAT tracer in humans to quantify cholinergic pathways., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

A qualitative descriptive approach examined African American nurse scientists' (AANSs') experiences with African American research participants despite obstacles of structural racism. Fourteen nurse scientists participated in semistructured interviews that provided data for the thematic analysis. Major themes included barriers to overcome as doctoral students, cultural experiences with structural racism, designers of culturally sensitive research, and humanitarian respect and relationship depth. This is the first research study to illuminate the contributions of AANSs who lead research in health disparities. Therefore, nursing leadership needs to illuminate AANSs' contributions, increase nurse diversification, and dismantle structural racism that creates obstacles that ultimately impact population health., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Among patients with triple-negative breast cancer (TNBC), several studies have suggested that deregulated microRNA (miRNA) expression may be associated with a more aggressive phenotype. Although tumor molecular signatures may be race- and/or ethnicity-specific, there is limited information on the molecular profiles in women with TNBC of Hispanic and Latin American ancestry. We simultaneously profiled TNBC biopsies for the genome-wide copy number and miRNA global expression from 28 Latina women and identified a panel of 28 miRNAs associated with copy number alterations (CNAs). Four selected miRNAs (miR-141-3p, miR-150-5p, miR-182-5p, and miR-661) were validated in a subset of tumor and adjacent non-tumor tissue samples, with miR-182-5p being the most discriminatory among tissue groups (AUC value > 0.8). MiR-141-3p up-regulation was associated with increased cancer recurrence; miR-661 down-regulation with larger tumor size; and down-regulation of miR-150-5p with larger tumor size, high p53 expression, increased cancer recurrence, presence of distant metastasis, and deceased status. This study reinforces the importance of integration analysis of CNAs and miRNAs in TNBC, allowing for the identification of interactions among molecular mechanisms. Additionally, this study emphasizes the significance of considering the patients ancestral background when examining TNBC, as it can influence the relationship between intrinsic tumor molecular characteristics and clinical manifestations of the disease.

Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the pathology of various immune-mediated disorders, including asthma and corneal graft rejection. In contrast to monoclonal antibodies (mAbs) targeting ALCAM's T cell expressed binding partner CD6, no ALCAM-targeting mAbs have thus far entered clinical development. This is likely linked with the broad expression of ALCAM on many different cell types, which increases the risk of eliciting unwanted treatment-induced side effects upon systemic mAb application. Targeting ALCAM in surface-exposed tissues, such as the lungs or the cornea, by a topical application could circumvent this issue. Here, we report the development of various stability- and affinity-improved anti-ALCAM mAb fragments with cross-species reactivity towards mouse, rat, monkey, and human ALCAM. Fragments generated in either mono- or bivalent formats potently blocked ALCAM-CD6 interactions in a competition ELISA, but only bivalent fragments efficiently inhibited ALCAM-ALCAM interactions in a leukocyte transmigration assay. The different fragments displayed a clear size-dependence in their ability to penetrate the human corneal epithelium. Furthermore, intranasal delivery of anti-ALCAM fragments reduced leukocyte infiltration in a mouse model of asthma, confirming ALCAM as a target for topical application in the lungs., Competing Interests: Noria Segueni is a study director at Artimmune (https://www.artimmune.com/, accessed on 20 June 2023), the contract research company that performed the mouse asthma study. Yulia Kaluzhny is a principal scientist at MatTek (https://www.mattek.com/, accessed on 20 June 2023), a company providing 3D corneal tissue models. The authors have no additional relevant affiliations or conflicting financial interests. All other co-authors declare no conflict of interests.

Background: Individuals released from carceral facilities have high rates of hospitalization and death, especially in the weeks immediately after their return to community settings. During this transitional process, individuals leaving incarceration are expected to engage with multiple providers working in separate, complex systems, including health care clinics, social service agencies, community-based organizations, and probation and parole services. This navigation is often complicated by individuals' physical and mental health, literacy and fluency, and socioeconomic status. Personal health information technology, which can help people access and organize their health information, could improve the transition from carceral systems to the community and mitigate health risks upon release. Yet, personal health information technologies have not been designed to meet the needs and preferences of this population nor tested for acceptability or use., Objective: The objective of our study is to develop a mobile app to create personal health libraries for individuals returning from incarceration to help bridge the transition from carceral settings to community living., Methods: Participants were recruited through Transitions Clinic Network clinic encounters and professional networking with justice-involved organizations. We used qualitative research methods to assess the facilitators and barriers to developing and using personal health information technology for individuals returning from incarceration. We conducted individual interviews with people just released from carceral facilities (n=~20) and providers (n=~10) from the local community and carceral facilities involved with the transition for returning community members. We used rigorous rapid qualitative analysis to generate thematic output characterizing the unique circumstances impacting the development and use of personal health information technology for individuals returning from incarceration and to identify content and features for the mobile app based on the preferences and needs of our participants., Results: As of February 2023, we have completed 27 qualitative interviews with individuals recently released from carceral systems (n=20) and stakeholders (n=7) who support justice-involved individuals from various organizations in the community., Conclusions: We anticipate that the study will characterize the experiences of people transitioning from prison and jails to community settings; describe the information, technology resources, and needs upon reentry to the community; and create potential pathways for fostering engagement with personal health information technology., International Registered Report Identifier (irrid): DERR1-10.2196/44748., (©Marisol Foumakoye, Meredith Campbell Britton, Emile Ansari, Monya Saunders, Terika McCall, Emily A Wang, Lisa B Puglisi, T Elizabeth Workman, Qing Zeng-Treitler, Yin Ying, Shira Shavit, Cynthia A Brandt, Karen H Wang. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 03.05.2023.)

Background: Twice weekly lateral flow tests (LFTs) for secondary school children was UK Government policy from 8 March 2021. We evaluate use of LFTs (both supervised at test centres, and home test kits) in school-aged children in Cheshire and Merseyside., Methods: We report (i) number of LFT positives (ii) proportion of LFT positive with confirmatory reverse transcription polymerase chain reaction (PCR) test within 2 days, and (iii) agreement between LFT-positive and confirmatory PCR, and dependence of (i-iii) on COVID-19 prevalence., Findings: 1 248 468 LFTs were taken by 211 255 12-18 years old, and 163 914 by 52 116 5-11 years old between 6 November 2020 and 31 July 2021. Five thousand three hundred and fourteen (2.5%) 12-18 years old and 1996 (3.8%) 5-11 years old returned LFT positives, with 3829 (72.1%) and 1535 (76.9%) confirmatory PCRs, and 3357 (87.7%) and 1383 (90.1%) confirmatory PCR-positives, respectively.Monthly proportions of LFT positive with PCR negative varied between 4.7% and 35.3% in 12-18 years old (corresponding proportion of all tests positive: 9.7% and 0.3%).Deprivation and non-White ethnicity were associated with reduced uptake of confirmatory PCR., Interpretation: Substantial inequalities in confirmatory testing need more attention to avoid further disadvantage through education loss. When prevalence is low additional measures, including confirmatory testing, are needed. Local Directors of Public Health taking more control over schools testing may be needed., Funding: DHSC, MRC, NIHR, EPSRC., (© The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health.)

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD., Methods: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia., Results: A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer's disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies., Interpretation: Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2023;93:184-195., (© 2022 American Neurological Association.)

A qualitative descriptive approach examined perspectives of African Americans (AA) on their participation in health research despite historical research mistreatment. Nineteen AAs participated in semistructured interviews that provided data that were analyzed using thematic analysis. Salient themes included race concordance, being respected and valued by the researcher, research participation motivators, and cultural experiences of racism in health care. This study challenges dominant ideology that AAs are unwilling to participate in research and offers solutions to promote research inclusive of their perceptions. Therefore, researchers need to design research with inclusiveness and transparency that openly displays how research will impact future generations., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Studies have reported elevated rates of dissociative symptoms and comorbid dissociative disorders in functional neurological disorder (FND); however, a comprehensive review is lacking., Aims: To systematically review the severity of dissociative symptoms and prevalence of comorbid dissociative disorders in FND and summarise their biological and clinical associations., Method: We searched Embase, PsycInfo and MEDLINE up to June 2021, combining terms for FND and dissociation. Studies were eligible if reporting dissociative symptom scores or rates of comorbid dissociative disorder in FND samples. Risk of bias was appraised using modified Newcastle-Ottawa criteria. The findings were synthesised qualitatively and dissociative symptom scores were included in a meta-analysis (PROSPERO CRD42020173263)., Results: Seventy-five studies were eligible (FND n = 3940; control n = 3073), most commonly prospective case-control studies ( k = 54). Dissociative disorders were frequently comorbid in FND. Psychoform dissociation was elevated in FND compared with healthy ( g = 0.90, 95% CI 0.66-1.14, I 2 = 70%) and neurological controls ( g = 0.56, 95% CI 0.19-0.92, I 2 = 67%). Greater psychoform dissociation was observed in FND samples with seizure symptoms versus healthy controls ( g = 0.94, 95% CI 0.65-1.22, I 2 = 42%) and FND samples with motor symptoms ( g = 0.40, 95% CI -0.18 to 1.00, I 2 = 54%). Somatoform dissociation was elevated in FND versus healthy controls ( g = 1.80, 95% CI 1.25-2.34, I 2 = 75%). Dissociation in FND was associated with more severe functional symptoms, worse quality of life and brain alterations., Conclusions: Our findings highlight the potential clinical utility of assessing patients with FND for dissociative symptomatology. However, fewer studies investigated FND samples with motor symptoms and heterogeneity between studies and risk of bias were high. Rigorous investigation of the prevalence, features and mechanistic relevance of dissociation in FND is needed.

Background: Tracheostomy management and care is multifaceted and costly, commonly involving complex patients with prolonged hospitalisation. Currently, there are no agreed definitions of short and prolonged length of tracheostomy cannulation (LOC) and no consensus regarding the key factors that may be associated with time to decannulation., Objectives: The aims of this study were to identify the factors associated with short and prolonged LOC and to examine the number of tracheostomy-related adverse events of patients who had short LOC versus prolonged LOC., Methods: A retrospective observational study was undertaken at a large metropolitan tertiary hospital. Factors known at the time of tracheostomy insertion, including patient, acuity, medical, airway, and tracheostomy factors, were analysed using Cox proportional hazards model and Kaplan-Meier survival curves, with statistically significant factors then analysed using univariate logistic regression to determine a relationship to short or prolonged LOC as defined by the lowest and highest quartiles of the study cohort. The number of tracheostomy-related adverse events was analysed using the Kaplan-Meier survival curve., Results: One hundred twenty patients met the inclusion criteria. Patients who had their tracheostomy performed for loss of upper airway were associated with short LOC (odds ratio [OR]: 2.30 (95% confidence interval [CI]: 1.01-5.25) p = 0.049). Three factors were associated with prolonged LOC: an abdominal/gastrointestinal tract diagnosis (OR: 5.00 [95% CI: 1.40-17.87] p = 0.013), major surgery (OR: 2.51 [95% CI: 1.05-6.01] p = 0.038), and intubation for >12 days (OR: 0.30 [95% CI: 0.09-0.97] p = 0.044). Patients who had one or ≥2 tracheostomy-related adverse events had a high likelihood of prolonged LOC (OR: 5.21 [95% CI: 1.95-13.94] p = ≤0.001 and OR: 12.17 [95% CI: 2.68-55.32] p ≤ 0.001, respectively)., Conclusion: Some factors that are known at the time of tracheostomy insertion are associated with duration of tracheostomy cannulation. Tracheostomy-related adverse events are related to a high risk of prolonged LOC., (Copyright © 2021 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m 2 ) and fourteen obese (40.6 ± 1.4 kg/m 2 ) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, p < 0.05) and associated with insulin resistance (r = 0.37, p < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], p < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, p < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner ( p < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maschari, Saxena, Law, Walsh, Campbell and Consitt.)

Background and Objectives: People with Parkinson disease (PD) commonly experience cognitive decline, which may relate to increased α-synuclein, tau, and β-amyloid accumulation. This study examines whether the different proteins predict longitudinal cognitive decline in PD., Methods: All participants (PD n = 152, controls n = 52) were part of a longitudinal study and completed a lumbar puncture for CSF protein analysis (α-synuclein, total tau [tau], and β-amyloid 42 [β-amyloid]), a β-amyloid PET scan, and/or provided a blood sample for APOE genotype (ε4+, ε4-), which is a risk factor for β-amyloid accumulation. Participants also had comprehensive, longitudinal clinical assessments of overall cognitive function and dementia status, as well as cognitive testing of attention, language, memory, and visuospatial and executive function. We used hierarchical linear growth models to examine whether the different protein metrics predict cognitive change and multivariate Cox proportional hazard models to predict time to dementia conversion. Akaike information criterion was used to compare models for best fit., Results: Baseline measures of CSF β-amyloid predicted decline for memory ( p = 0.04) and overall cognitive function ( p = 0.01). APOE genotypes showed a significant group (ε4+, ε4-) effect such that ε4+ individuals declined faster than ε4- individuals in visuospatial function ( p = 0.03). Baseline β-amyloid PET significantly predicted decline in all cognitive measures (all p ≤ 0.004). Neither baseline CSF α-synuclein nor tau predicted cognitive decline. All 3 β-amyloid--related metrics (CSF, PET, APOE ) also predicted time to dementia. Models with β-amyloid PET as a predictor fit the data the best., Discussion: Presence or risk of β-amyloid accumulation consistently predicted cognitive decline and time to dementia in PD. This suggests that β-amyloid has high potential as a prognostic indicator and biomarker for cognitive changes in PD., (© 2022 American Academy of Neurology.)

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

Objective: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions., Methods: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aβ, and tau with recently developed sandwich ELISAs., Results: We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α-syn accumulation. Tau accumulation accompanied Aβ in only one LBD case., Interpretation: LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α-syn accumulation suggests a pathophysiologic relationship between these two processes., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Study Design: Cross-sectional study design., Objective: There are multiple accepted treatment options for internal fixation of mandibular angle fractures. The purpose of this study was to determine if there is a safe zone for lateral border fixation of mandibular angle fractures., Methods: One hundred coronal images of facial computed tomography (CT) scans were reviewed on patients between the ages of 18 to 48. Measurements were taken in the area of the second and third molar region related to the inferior border to the superior extent of the inferior alveolar canal and apex of the second molar root, along with buccal cortical measurements to the inferior alveolar canal and apical third of the second molar root., Results: The average measurement of the inferior border in the second molar area to the inferior alveolar canal and apex of the root was 1.12 cm (0.70-1.77) and 1.39 cm (0.91-2.30), respectively. The average measurement of the inferior border of the third molar to the inferior alveolar canal was 1.26 cm (0.78-1.83). The average measurement of the buccal cortex of the second molar to the inferior alveolar canal and apical one-third of the root was 0.64 cm (0.34-1.25) and 0.59 cm (0.33-0.98), respectively. The average measurement of the third molar buccal cortex to the inferior alveolar canal was 0.45 cm (0.18-0.98)., Conclusion: In the area of the second molar region, there is no ubiquitous safe zone for screw placement, cortical bone thickness is more critical than vertical placement of the fixation plate and screws. In the third molar region, cortical bone thickness and vertical orientation may provide a safe zone for screw placement., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Dysfunction of cerebellar vermis contributes to gait abnormalities in multiple conditions and may play a key role in gait impairment in Parkinson's disease (PD)., Objective: The purpose of this study was to investigate whether altered resting-state functional connectivity of the vermis relates to subsequent impairment of specific domains of gait in PD., Methods: We conducted morphometric and resting-state functional connectivity MRI analyses contrasting 45 PD and 32 age-matched healthy participants. Quantitative gait measures were acquired with a GAITRite walkway at varying intervals after functional connectivity data acquisition., Results: At baseline, PD participants had significantly altered functional connectivity between vermis and sensorimotor cortex compared with controls. Altered vermal functional connectivity with bilateral paracentral lobules correlated with subsequent measures of variability in stride length, step time, and single support time after controlling for confounding variables including the interval between imaging and gait measures. Similarly, altered functional connectivity between vermis and left sensorimotor cortex correlated with mean stride length and its variability. Vermis volume did not relate to any gait measure. PD participants did not differ from controls in vermis volume or cortical thickness at the site of significant regional clusters. Only altered lobule V:sensorimotor cortex functional connectivity correlated with subsequent gait measures in exploratory analyses involving all the other cerebellar lobules., Conclusions: These results demonstrate that abnormal vermal functional connectivity with sensorimotor cortex, in the absence of relevant vermal or cortical atrophy, correlates with subsequent gait impairment in PD. Our data reflect the potential of vermal functional connectivity as a novel imaging biomarker of gait impairment in PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Redondoviridae is a newly established family of circular Rep-encoding single-stranded (CRESS) DNA viruses found in the human ororespiratory tract. Redondoviruses were previously found in ∼15% of respiratory specimens from U.S. urban subjects; levels were elevated in individuals with periodontitis or critical illness. Here, we report higher redondovirus prevalence in saliva samples: four rural African populations showed 61 to 82% prevalence, and an urban U.S. population showed 32% prevalence. Longitudinal, limiting-dilution single-genome sequencing revealed diverse strains of both redondovirus species ( Brisavirus and Vientovirus ) in single individuals, persistence over time, and evidence of intergenomic recombination. Computational analysis of viral genomes identified a recombination hot spot associated with a conserved potential DNA stem-loop structure. To assess the possible role of this site in recombination, we carried out in vitro studies which showed that this potential stem-loop was cleaved by the virus-encoded Rep protein. In addition, in reconstructed reactions, a Rep-DNA covalent intermediate was shown to mediate DNA strand transfer at this site. Thus, redondoviruses are highly prevalent in humans, found in individuals on multiple continents, heterogeneous even within individuals and encode a Rep protein implicated in facilitating recombination. IMPORTANCE Redondoviridae is a recently established family of DNA viruses predominantly found in the human respiratory tract and associated with multiple clinical conditions. In this study, we found high redondovirus prevalence in saliva from urban North American individuals and nonindustrialized African populations in Botswana, Cameroon, Ethiopia, and Tanzania. Individuals on both continents harbored both known redondovirus species. Global prevalence of both species suggests that redondoviruses have long been associated with humans but have remained undetected until recently due to their divergent genomes. By sequencing single redondovirus genomes in longitudinally sampled humans, we found that redondoviruses persisted over time within subjects and likely evolve by recombination. The Rep protein encoded by redondoviruses catalyzes multiple reactions in vitro , consistent with a role in mediating DNA replication and recombination. In summary, we identify high redondovirus prevalence in humans across multiple continents, longitudinal heterogeneity and persistence, and potential mechanisms of redondovirus evolution by recombination.

Thirty-nine years ago, scrub typhus (ST), a disease, was not among the China's notifiable diseases. However, ST has reemerged to become a growing public health issue in the southwest part of China. The major factors contributing to an increased incidence and prevalence of this disease include rapid globalization, urbanization, expansion of humans into previously uninhabited areas, and climate change. The clinical manifestation of ST also consists of high fever, headache, weakness, myalgia, rash, and an eschar. In severe cases, complications (e.g. multi-organ failure, jaundice, acute renal failure, pneumonitis, myocarditis, and even death) can occur. The diagnosis of ST is mainly based on serological identification by indirect immunofluorescence assay and other molecular methods. Furthermore, several groups of antibiotics (e.g. tetracycline, chloramphenicol, macrolides, and rifampicin) are currently effective in treating this disease. This fact suggests the need for robust early diagnostic techniques, increased surveillance, and prompt treatment, and develop future vaccine.

Introduction: Parkinson's disease (PD) is a movement disorder caused by dysfunction in the basal ganglia (BG). Clinically relevant gait deficits, such as decreased velocity and increased variability, may be caused by underlying neural dysfunction. Reductions in resting-state functional connectivity (rs-FC) between networks have been identified in PD compared to controls; however, the association between gait characteristics and rs-FC of brain networks in people with PD has not yet been explored. The present study aimed to investigate these associations., Methods: Gait characteristics and rs-FC MRI data were collected for participants with PD (N = 50). Brain networks were identified from a set of seeds representing cortical, subcortical, and cerebellar regions. Gait outcomes were correlated with the strength of rs-FC within and between networks of interest. A stepwise regression analysis was also conducted to determine whether the rs-FC strength of brain networks, along with clinical motor scores, were predictive of gait characteristics., Results: Gait velocity was associated with rs-FC within the visual network and between motor and cognitive networks, most notably BG-thalamus internetwork rs-FC. The stepwise regression analysis showed strength of BG-thalamus internetwork rs-FC and clinical motor scores were predictive of gait velocity., Conclusion: The results of the present study demonstrate gait characteristics are associated with functional organization of the brain at the network level, providing insight into the neural mechanisms of clinically relevant gait characteristics. This knowledge could be used to optimize the design of gait rehabilitation interventions for people with neurological conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes., Methods: We recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, "Motor Only," "Psychiatric & Motor," and "Cognitive & Motor," which differed in dementia and mortality rates. Parkinson disease participants ("Motor Only": n = 61, "Psychiatric & Motor": n = 17, "Cognitive & Motor": n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow-up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three-way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages., Results: All three subtypes increased in motor dysfunction compared to controls. The "Motor Only" subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The "Cognitive & Motor" subtype's cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The "Psychiatric & Motor" subtype's elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages., Interpretation: Parkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: To investigate the global expression profile of miRNAs, their impact on cellular signaling pathways, and their association with poor prognostic parameters in African-American (AA) patients with triple negative breast cancer (TNBC)., Methods: Twenty-five samples of AA TNBC patients were profiled for global miRNA expression and stratified considering three clinical-pathological parameters: tumor size, lymph node (LN), and recurrence (REC) status. Differential miRNA expression analysis was performed for each parameter, and their discriminatory power was determined by Receiver Operating Characteristic (ROC) curve analysis. KMplotter was assessed to determine the association of the miRNAs with survival, and functional enrichment analysis to determine the main affected pathways and miRNA/mRNA target interactions., Results: A panel of eight, 23 and 27 miRNAs were associated with tumor size, LN, and REC status, respectively. Combined ROC analysis of two (miR-2117, and miR-378c), seven (let-7f-5p, miR-1255b-5p, miR-1268b, miR-200c-3p, miR-520d, miR-527, and miR-518a-5p), and three (miR-1200, miR-1249-3p, and miR-1271-3p) miRNAs showed a robust discriminatory power based on tumor size (AUC = 0.917), LN (AUC = 0.945) and REC (AUC = 0.981) status, respectively. Enrichment pathway analysis revealed their involvement in proteoglycans and glycan and cancer-associated pathways. Eight miRNAs with deregulated expressions in patients with large tumor size, positive LN metastasis, and recurrence were significantly associated with lower survival rates. Finally, the construction of miRNA/mRNA networks based in experimentally validated mRNA targets, revealed nodes of critical cancer genes, such as AKT1, BCL2, CDKN1A, EZR and PTEN., Conclusions: Altogether, our data indicate that miRNA deregulated expression is a relevant biological factor that can be associated with the poor prognosis in TNBC of AA patients, by conferring to their TNBC cells aggressive phenotypes that are reflected in the clinical characteristics evaluated in this study., (© 2021. The Author(s).)

Dendritic cell (DC) migration to draining lymph nodes (dLNs) is a slow process that is believed to begin with DCs approaching and entering into afferent lymphatic capillaries. From capillaries, DCs slowly crawl into lymphatic collectors, where lymph flow induced by collector contraction supports DC detachment and thereafter rapid, passive transport to dLNs. Performing a transcriptomics analysis of dermal endothelial cells, we found that inflammation induces the degradation of the basement membrane (BM) surrounding lymphatic collectors and preferential up-regulation of the DC trafficking molecule VCAM-1 in collectors. In crawl-in experiments performed in ear skin explants, DCs entered collectors in a CCR7- and β1 integrin-dependent manner. In vivo, loss of β1-integrins in DCs or of VCAM-1 in lymphatic collectors had the greatest impact on DC migration to dLNs at early time points when migration kinetics favor the accumulation of rapidly migrating collector DCs rather than slower capillary DCs. Taken together, our findings identify collector entry as a critical mechanism enabling rapid DC migration to dLNs in inflammation., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Arasa et al.)

Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamins are found in many cancers and its expression is correlated with better clinical outcomes. The nucleus is the largest organelle in the cell with a diameter between 10 and 20 μm. Nuclear size significantly impacts cell migration. Nuclear structural changes are predicted to impact cancer metastasis by regulating cancer cell migration. Here we show emerin regulates nuclear structure in invasive breast cancer cells to impact cancer metastasis. Invasive breast cancer cells had 40% to 50% less emerin than control cells, which resulted in decreased nuclear size. Overexpression of GFP-emerin in invasive breast cancer cells rescued nuclear size and inhibited migration through 3.0 and 8.0 μm pores. Mutational analysis showed emerin binding to nucleoskeletal proteins was important for its regulation of nuclear structure, migration, and invasion. Importantly, emerin expression inhibited lung metastasis by 91% in orthotopic mouse models of breast cancer. Emerin nucleoskeleton-binding mutants failed to inhibit metastasis. These results support a model whereby emerin binding to the nucleoskeleton regulates nuclear structure to impact metastasis. In this model, emerin plays a central role in metastatic transformation, because decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. IMPLICATIONS: Modulating emerin expression and function represents new targets for therapeutic interventions of metastasis, because increased emerin expression rescued cancer metastasis., (©2021 American Association for Cancer Research.)

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10 -11 ), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10 -8 ) and WWOX (HR = 2.12, P = 2.37 × 10 -8 ) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.

Lactase persistence (LP) is a genetically-determined trait that is prevalent in African, European and Arab populations with a tradition of animal herding and milk consumption. To date, genetic analyses have identified several common variants that are associated with LP. Furthermore, data have indicated that these functional alleles likely have been maintained in pastoralist populations due to the action of recent selection, exemplifying the ongoing evolution of anatomically modern humans. Additionally, demographic history has also played a role in the geographic distribution of LP and associated alleles in Africa. In particular, the migration of ancestral herders and their subsequent admixture with local populations were integral to the spread of LP alleles and the culture of pastoralism across the continent. The timing of these demographic events was often correlated with known major environmental changes and/or the ability of domesticated cattle to resist/avoid infectious diseases. This review summarizes recent advances in our understanding of the genetic basis and evolutionary history of LP, as well as the factors that influenced the origin and spread of pastoralism in Africa., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus., Methods: We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H 2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes., Results: Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates., Discussion: Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Junctional adhesion proteins play important roles in controlling angiogenesis, vascular permeability and leukocyte trafficking. CD112 (nectin-2) belongs to the immunoglobulin superfamily and was shown to engage in homophilic and heterophilic interactions with a variety of binding partners expressed on endothelial cells and on leukocytes. Recent in vitro studies suggested that CD112 regulates human endothelial cell migration and proliferation as well as transendothelial migration of leukocytes. However, so far, the role of CD112 in endothelial cell biology and in leukocyte trafficking has not been elucidated in vivo. We found CD112 to be expressed by lymphatic and blood endothelial cells in different murine tissues. In CD112-deficient mice, the blood vessel coverage in the retina and spleen was significantly enhanced. In functional in vitro studies, a blockade of CD112 modulated endothelial cell migration and significantly enhanced endothelial tube formation. An antibody-based blockade of CD112 also significantly reduced T cell transmigration across endothelial monolayers in vitro. Moreover, T cell homing to the spleen was significantly reduced in CD112-deficient mice. Overall, our results identify CD112 as a regulator of angiogenic processes in vivo and demonstrate a novel role for CD112 in T cell entry into the spleen.