Lower extremity amputation rates in patients with chronic kidney disease: A database study comparing patients with and without diabetes mellitus.

Lower extremity amputation (LEA) is one of the most feared consequences of diabetes mellitus (DM). The purpose of this study was to evaluate the impact of DM on LEA rates in patients at various stages of chronic kidney disease (CKD). A commercially available de-identified database was searched for patients undergoing LEA and for CKD patients, from 2010 to 2023. Patients with DM and patients without DM who were followed for at least 5 years were included. LEA rates were then compared for patients at all 5 CKD stages in patients with and without diabetes. Rates of all LEA were found to be significantly higher at all CKD stages for patients with diabetes (overall, minor and major LEA). Compared to patients without DM who have CKD stage 5 (end stage renal disease), patients with DM and CKD stage 5 have a 30 fold increased likelihood of undergoing overall LEA [OR 30.2 (24.48-37.19), p < 0.001], 29 fold increased likelihood of undergoing minor LEA [28.9i (22.91-36.35), p < 0.001] and 40 times fold increased likelihood of undergoing major LEA [40.1 (26.59-60.42), p < 0.001]. For all stages of CKD, independent of diabetes status, minor LEA were performed with greater frequency than major LEA. In patients with DM, LEA rates significantly increased with CKD progression between stages 2-5 with a substantial jump between stages 4 and 5 [OR 2.6 (CI 2.49-2.74), p < 0.001]. However, CKD progression between stages 1 and 2 was not significantly associated with increased LEA rates (OR 1.1 (CI 0.92-1.21), p = 0.24) in patients with diabetes. Patients with comorbid diabetes have elevated risk for LEA at all stages of CKD compared to those without diabetes.

The discovery and structural basis of two distinct state-dependent inhibitors of BamA.

BamA is the central component of the essential ß-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds ß-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders.

Enzymopathy disorders are the result of missing or defective enzymes. Amongst these enzymopathies, mucopolysaccharidosis type I, is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), ultimately causes toxic build-up of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T cells (Tm) migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS, though only minimal improved cognition was observed. Our study indicates that genetically engineered Tm holds great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.

Variant-to-function mapping of late-onset Alzheimer's disease GWAS signals in human microglial cell models implicates RTFDC1 at the CASS4 locus.

Late-onset Alzheimer's disease (LOAD) research has principally focused on neurons over the years due to their known role in the production of amyloid beta plaques and neurofibrillary tangles. In contrast, recent genomic studies of LOAD have implicated microglia as culprits of the prolonged inflammation exacerbating the neurodegeneration observed in patient brains. Indeed, recent LOAD genome-wide association studies (GWAS) have reported multiple loci near genes related to microglial function, including TREM2, ABI3, and CR1. However, GWAS alone cannot pinpoint underlying causal variants or effector genes at such loci, as most signals reside in non-coding regions of the genome and could presumably confer their influence frequently via long-range regulatory interactions. We elected to carry out a combination of ATAC-seq and high-resolution promoter-focused Capture-C in two human microglial cell models (iPSC-derived microglia and HMC3) in order to physically map interactions between LOAD GWAS-implicated candidate causal variants and their corresponding putative effector genes. Notably, we observed consistent evidence that rs6024870 at the GWAS CASS4 locus contacted the promoter of nearby gene, RTFDC1. We subsequently observed a directionallly consistent decrease in RTFDC1 expression with the the protective minor A allele of rs6024870 via both luciferase assays in HMC3 cells and expression studies in primary human microglia. Through CRISPR-Cas9-mediated deletion of the putative regulatory region harboring rs6024870 in HMC3 cells, we observed increased pro-inflammatory cytokine secretion and decreased DNA double strand break repair related, at least in part, to RTFDC1 expression levels. Our variant-to-function approach therefore reveals that the rs6024870-harboring regulatory element at the LOAD 'CASS4' GWAS locus influences both microglial inflammatory capacity and DNA damage resolution, along with cumulative evidence implicating RTFDC1 as a novel candidate effector gene.

Post-operative outcomes of talus fracture open reduction internal fixation in patients with diabetes mellitus.

Little is known regarding outcomes of talus fracture management among patients with diabetes mellitus. This study aimed to compare post-operative outcomes after open reduction and internal fixation for talus fracture in patients with complicated diabetes, uncomplicated diabetes, and patients without diabetes. We used the PearlDiver database to identify patients who underwent operative repair of talus fractures from 2009 to 2021. Complications were evaluated at 30-days, 90-days, and 1 year of surgery. As we performed multiple separate analyses, to minimize the risk of type 1 error we employed the Bonferroni correction for statistical significance (p< 0.017). The PearlDiver identified 5,232 patients with talus fracture that underwent open reduction internal fixation. Stratified by diabetes status, the "complicated diabetes," "uncomplicated diabetes," and "no diabetes" groups contained 223, 418, and 4591 patients, respectively. Reoperation, acute kidney injury, and myocardial infarction were increased among diabetes patients compared to non-diabetes patients, irrespective of diabetes severity within 3 months of surgery. Furthermore, patients with complicated diabetes were more likely to develop sepsis and wound disruption compared to their non-diabetes counterparts within 3 months. While not statistically significant, complicated diabetes patients were diagnosed with talar non-union at higher rates compared with non-diabetes patients. Further analysis may reveal a clinically significant discrepancy in non-union between these groups. Complicated diabetes is associated with significantly higher risk of multiple adverse events following talus fracture repair. LEVEL OF CLINICAL EVIDENCE: 3.

Association of COVID-19 Vaccination With Risk of Medically Attended Postacute Sequelae of COVID-19 During the Ancestral, Alpha, Delta, and Omicron Variant Eras.

Background: Uncertainty exists regarding the effectiveness of COVID-19 vaccine to prevent postacute sequelae of COVID-19 (PASC) following a breakthrough infection. While most studies based on symptom surveys found an association between preinfection vaccination status and PASC symptoms, studies of medically attended PASC are less common and have reported conflicting findings. Methods: In this retrospective cohort of patients with an initial SARS-CoV-2 infection who were continually empaneled for primary care in a large US health system, the electronic health record was queried for preinfection vaccination status, demographics, comorbidity index, and diagnosed conditions. Multivariable logistic regression was used to model the outcome of a medically attended PASC diagnosis within 6 months of SARS-CoV-2 infection. Likelihood ratio tests were used to assess the interaction between vaccination status and prevalent variant at the time of infection and between vaccination status and hospitalization for SARS-CoV-2 infection. Results: During the observation period, 6.9% of patients experienced medically attended and diagnosed PASC. A diagnosis of PASC was associated with older age, female sex, hospitalization for the initial infection, and an increased severity-weighted comorbidity index and was inversely associated with infection during the Omicron period. No difference in the development of diagnosed PASC was observed between unvaccinated patients and those vaccinated with either 2 doses of an mRNA vaccine or >2 doses. Conclusions: We found no association between vaccination status at the time of infection and development of medically diagnosed PASC. Vaccine remains an important measure to prevent SARS-CoV-2 infection and severity. Further research is needed to identify effective measures to prevent and treat PASC.

Catalytic Heaters at Oil and Gas Sites May be a Significant yet Overlooked Seasonal Source of Methane Emissions.

Successful reduction of oil and gas sector methane emissions to meet near-zero intensity targets requires the identification and mitigation of all possible sources. One potentially important source is catalytic heaters, which have largely escaped attention in regulatory and mitigation efforts despite being ubiquitous at upstream production sites in cold climate regions. This study reports direct in situ measurements of the exhaust streams of 38 natural gas-fired catalytic heaters at upstream production sites in British Columbia, Canada. All heaters in the sample showed consistently poor methane conversion with mean destruction efficiencies of 61 ± 5% while releasing 235 [+31/-28] g of methane per cubic meter of fuel. Although individual units are generally small methane sources (mean of 0.28 ± 0.04 kg/h), their prevalence means they could represent 6% of the total provincial upstream methane inventory and as an aggregate methane source could be 5× more significant than abandoned wells. Notably, these heaters are seasonal sources whose emissions would be missed in measurement campaigns occurring solely in summer months. However, additional measurements from a small number of heat medium burners demonstrate that, where feasible, methane emissions can be reduced by approximately 425× by replacing catalytic heaters with centralized heat systems.

Family shapes child development: The role of codevelopmental trajectories of interparental conflict and emotional warmth for children's longitudinal development of internalizing and externalizing problems.

This study aimed (1) to identify distinct family trajectory profiles of destructive interparental conflict and parent-child emotional warmth reported by one parent, and (2) to examine whether these codevelopmental profiles were associated with the longitudinal development of children and adolescents' self-reported internalizing and externalizing problems. Six longitudinal data waves from the German Family Panel (pairfam) study (Waves 2-7) from 722 parent-child dyads were used (age of children and adolescents in years: M = 10.03, SD = 1.90, range = 8-15; 48.3% girls; 73.3% of parents were native Germans). Data were analyzed using growth mixture and latent growth curve modeling. Two classes, harmonious and conflictual-warm families, were found based on codevelopmental trajectories of interparental conflict and emotional warmth. These family profiles were linked with the development of externalizing problems in children and adolescents but not their internalizing problems. Family dynamics are entangled in complex ways and constantly changing, which appears relevant to children's behavior problems.

Countermovement Jump Peak Power Changes with Age in Masters Weightlifters.

Aging is associated with decreased muscle strength and power. Power is particularly important for maintaining the independence of older adults when performing activities of daily living. The countermovement jump has been identified as a reliable and safe method to assess lower extremity power across the lifespan. The purpose of this investigation was to study sex differences and age-related changes in countermovement jump peak power among masters weightlifters with the secondary purpose of comparing results to previous reports of community and masters athletes. Female (n = 63, 39 to 70 yrs, med (56 yrs)) and male (n = 39, 35 to 86 yrs, med (59 yrs)) participants of the 2022 World Masters Championships completed three maximal effort countermovement jump repetitions following a dynamic warm-up. Vertical ground reaction forces were recorded, and peak power normalized to body mass was calculated. Results indicated significant age-related peak power among weightlifters, with the decline being significantly more pronounced in males than females. Female weightlifters exhibited less age-related decline compared to normative data as well as the other Master athlete comparison cohorts (short and long-distance runners), whereas the males demonstrated similar age-related declines as the comparison cohorts. While the female weightlifters in the current study generally demonstrated the least age-related declines in CMJ peak power of the comparative literature, the male weightlifters showed similar age-related decline rates.

Exploring the diversity of anti-defense systems across prokaryotes, phages, and mobile genetic elements.

The co-evolution of prokaryotes, phages, and mobile genetic elements (MGEs) over the past billions of years has driven the emergence and diversification of defense and anti-defense systems alike. Anti-defense proteins have diverse functional domains, sequences, and are typically small, creating a challenge to detect anti-defense homologs across the prokaryotic genomes. To date, no tools comprehensively annotate anti-defense proteins within a desired genome or MGE. Here, we developed "AntiDefenseFinder" - a free open-source tool and web service that detects 156 anti-defense systems (of one or more proteins) in any genomic sequence. Using this dataset, we identified 47,981 anti-defense systems distributed across prokaryotes, phage, and MGEs. We found that some genes co-localize in "anti-defense islands", including E. coli T4 and Lambda phages, although many are standalone. Out of the 112 systems detected in bacteria, 100 systems localize only or preferentially in prophages, plasmids, phage satellites, integrons, and integrative and conjugative elements. However, over 80% of anti-Pycsar protein 1 (Apyc1) resides in non-mobile regions of bacteria. Evolutionary and functional analyses revealed that Apyc1 likely originated in bacteria to regulate cNMP signaling, but was co-opted multiple times by phages to overcome cNMP-utilizing defenses. With the AntiDefenseFinder tool, we hope to facilitate the identification of the full repertoire of anti-defense systems in MGEs, the discovery of new protein functions, and a deeper understanding of host-pathogen arms race.

A Reduced Resistance, Concentric-Gated Artificial Membrane Lung for Pediatric End-Stage Lung Failure.

The goal of the low-resistance pediatric artificial lung (PAL-LR) is to serve as a pumpless bridge-to-transplant device for children with end-stage lung failure. The PAL-LR doubles the exposed fiber length of the previous PAL design. In vitro and in vivo studies tested hemocompatibility, device flow, gas exchange and pressure drop performance. For in vitro tests, average rated blood flow (outlet SO2 of 95%) was 2.56 ± 0.93 L/min with a pressure drop of 25.88 ± 0.90 mm Hg. At the targeted pediatric flow rate of 1 L/min, the pressure drop was 8.6 mm Hg compared with 25 mm Hg of the PAL. At rated flow, the average O2 and CO2 transfer rates were 101.75 ± 10.81 and 77.93 ± 8.40 mL/min, respectively. The average maximum O2 and CO2 exchange efficiencies were 215.75 ± 22.93 and 176.99 ± 8.40 mL/(min m2), respectively. In vivo tests revealed an average outlet SO2 of 100%, and average pressure drop of 2 ± 0 mm Hg for a blood flow of 1.07 ± 0.02 L/min. Having a lower resistance, the PAL-LR is a promising step closer to a pumpless artificial membrane lung that alleviates right ventricular strain associated with idiopathic pulmonary hypertension.

Diverse viral cas genes antagonize CRISPR immunity.

Prokaryotic CRISPR-Cas immunity is subverted by anti-CRISPRs (Acrs), which inhibit Cas protein activities when expressed during the phage lytic cycle or from resident prophages or plasmids1. Acrs often bind to specific cognate Cas proteins, and hence inhibition is typically limited to a single CRISPR-Cas subtype2. Furthermore, although acr genes are frequently organized together in phage-associated gene clusters3, how such inhibitors initially evolve has remained unclear. Here we investigated the Acr content and inhibition specificity of diverse Listeria isolates, which naturally harbour four CRISPR-Cas systems (types I-B, II-A, II-C and VI-A). We observed widespread antagonism of CRISPR, which we traced to 11 previously unknown and 4 known acr gene families encoded by endogenous mobile elements. Among these were two Acrs that possess sequence homology to type I-B Cas proteins, one of which assembles into a defective interference complex. Surprisingly, an additional type I-B Cas homologue did not affect type I immunity, but instead inhibited the RNA-targeting type VI CRISPR system by means of CRISPR RNA (crRNA) degradation. By probing viral sequence databases, we detected abundant orphan cas genes located within putative anti-defence gene clusters. Among them, we verified the activity of a particularly broad-spectrum cas3 homologue that inhibits type I-B, II-A and VI-A CRISPR immunity. Our observations provide direct evidence of Acr evolution by cas gene co-option, and new genes with potential for broad-spectrum control of genome editing technologies.

Genome-wide assessment of population structure and association mapping for agronomic and grain nutritional traits in proso millet (Panicum miliaceum L.).

Proso millet is an important but under-researched and underutilized crop with the potential to become a future smart crop because of its climate-resilient features and high nutrient content. Assessing diversity and marker-trait associations are essential to support the genomics-assisted improvement of proso millet. This study aimed to assess the population structure and diversity of a proso millet diversity panel and identify marker-trait associations for agronomic and grain nutrient traits. In this study, genome-wide single nucleotide polymorphisms (SNPs) were identified by mapping raw genotyping-by-sequencing (GBS) data onto the proso millet genome, resulting in 5621 quality-filtered SNPs in 160 diverse accessions. The modified Roger's Distance assessment indicated an average distance of 0.268 among accessions, with the race miliaceum exhibiting the highest diversity and ovatum the lowest. Proso millet germplasm diversity was structured according to geographic centers of origin and domestication. Genome-wide association mapping identified 40 marker-trait associations (MTAs), including 34 MTAs for agronomic traits and 6 for grain nutrients; 20 of these MTAs were located within genes. Favourable alleles and phenotypic values were estimated for all MTAs. This study provides valuable insights into the population structure and diversity of proso millet, identified marker-trait associations, and reported favourable alleles and their phenotypic values for supporting genomics-assisted improvement efforts in proso millet.

Successful Resuscitation of Porcine Hearts After 12 and 24 h of Static Cold Storage With Normothermic Ex Situ Perfusion.

Background: Heart transplantation is always an emergency because the transplant needs to occur within 6 h after procurement to prevent primary graft dysfunction. Static cold storage (SCS) is the gold-standard preservation method. This study describes the outcomes of hearts preserved after prolonged SCS (12 and 24 h); those are then resuscitated with a novel normothermic ex situ heart perfusion (NEHP) system. Methods: Anesthetized piglets (n = 10) were used as heart donors. Hearts were procured and stored at 5 °C CoStorSol following standard SCS protocols. Two groups were studied: SCS-12 h and SCS-24 h. After SCS, 8 h of NEHP (37 °C blood-based perfusate) was performed at 0.7-1.0 mL/min/g of cardiac tissue. NEHP parameters were monitored continuously. Results were corroborated with 3 additional hearts transplanted orthotopically in healthy recipients (n = 3) after SCS (24 h) + NEHP (5 h). Recipients were observed for 90 min after weaning off cardiopulmonary bypass support. Results: All hearts (after 12 and 24 h of SCS) regained normal function and metabolism within 10 min and retained it throughout 8 h of NEHP. No differences were observed in NEHP parameters and histopathology between groups. Three hearts were successfully transplanted after a total ~30 h of preservation (24 h of SCS + 5 h of NEHP + 1 h of second cold ischemia time). The 3 recipients were weaned off cardiopulmonary bypass with mild vasopressor support. Conclusions: NEHP has the potential to routinely resuscitate porcine hearts that have undergone SCS for up to 24 h, restoring them to viable function. By objectively assessing heart function before transplant, NEHP may enhance the success rate of transplants. If these resuscitated hearts can be successfully transplanted, it would support the effectiveness of NEHP in ensuring heart viability.

Greenwashed Cigarette Ad Text and Imagery Produce Inaccurate Harm, Addictiveness, and Nicotine Content Perceptions: Results from a Randomized Online Experiment.

INTRODUCTION: The tobacco industry has a long history of circumventing regulations to present their products, inaccurately, as less harmful. Greenwashing (portraying a product as natural/eco-friendly) is increasingly used by tobacco companies and may mislead consumers to believe that certain cigarettes are less harmful than others. This study assesses the effect of some common greenwashing tactics on consumer product perceptions. METHODS: We conducted an online experiment with 1,504 participants ages 18-29, randomized to view a cigarette ad manipulated for presence/absence of a combination of 4 different greenwashing techniques: greenwashed ad text, greenwashed ad imagery, recycled paper ad background, and image of greenwashed cigarette pack. Participants rated perceived absolute harm, relative harm to other cigarettes, absolute addictiveness, relative addictiveness, and relative nicotine content. RESULTS: Participants who viewed ads containing greenwashed text were more likely to have inaccurate perceptions about absolute harm (AOR=1.72), relative harm (AOR=3.92), relative addictiveness (AOR=2.93) and nicotine content (AOR=2.08). Participants who viewed ads containing greenwashed imagery were more likely to have inaccurate perceptions of relative harm (AOR=1.55), absolute addictiveness (AOR=1.72), relative addictiveness (AOR=1.60) and nicotine content (AOR=1.48). Forty-two percent of those who saw an ad with all greenwashed features believed the product was less harmful than other cigarettes vs. 2% of those who saw an ad without greenwashed features. CONCLUSIONS: We found greenwashed text and imagery produced inaccurate risk perceptions. More active U.S. Food & Drug Administration (FDA) enforcement against such greenwashing and new FDA rulemaking to prohibit unnecessary imagery in tobacco advertising and establish plain packaging requirements would help protect consumers and public health. IMPLICATIONS: These findings provide evidence that greenwashing tactics used by the tobacco industry increase inaccurate product risk perceptions. These tactics could be a way for the industry to make implicit modified risk claims, despite applicable U.S. Family Smoking Prevention and Tobacco Control Act prohibitions. Findings from this study support the need for prohibitions on these tactics, and the potential for such prohibitions to help protect public health.

Associations Between the Superwoman Schema, Stress, and Cardiovascular Health Among African-American Women.

BACKGROUND: African-American (AA) women are less likely to achieve ideal cardiovascular (CV) health compared with women of other racial/ethnic subgroups, primarily due to structural and psychosocial barriers. A potential psychosocial construct relevant to ideal CV health is the superwoman schema (SWS). PURPOSE: We explored whether the SWS was associated with perceived stress, CV risk factors, and overall CV health among AA women. METHODS: This cross-sectional analysis of the FAITH! Heart Health+ Study was conducted among AA women with high cardiometabolic risk. Pearson correlation evaluated associations between SWS and CV risk factors (e.g., stress, hypertension, diabetes, etc.). The 35-item SWS questionnaire includes five domains. Stress was measured by the 8-item Global Perceived Stress Scale (GPSS). CV health was assessed using the American Heart Association Life's Simple 7 (LS7) rubric of health behaviors/biometrics. Data acquisition spanned from February to August 2022. RESULTS: The 38 women included in the analysis (mean age 54.3 [SD 11.5] years) had a high CV risk factor burden (71.1% hypertension, 76.3% overweight/obesity, 28.9% diabetes, 39.5% hyperlipidemia). Mean GPSS level was 7.7 (SD 5.2), CV health score 6.7 (SD 1.8), and SWS score 60.3 (SD 18.0). Feeling an "obligation to help others" and "obligation to present an image of strength" had strongest correlations with GPSS score among all SWS domains (r = 0.51; p = .002 and r = 0.39; p = .02, respectively). Correlation among the SWS domains and traditional CV risk factors was not statistically significant. CONCLUSION: Our findings suggest that an obligation to help others and to project an image of strength could be contributing to stress among AA women.

Compared with women of other racial groups, African-American (AA) women in the USA have a higher cardiovascular (CV) disease burden and are at higher risk of maternal mortality from preventable CV health outcomes. The Giscombe Superwoman Schema (SWS) is a framework designed to characterize various aspects of the superwoman role that AA women may adopt to preserve themselves, their families, and their communities amidst the myriad of inequities that can compromise their ability to achieve ideal CV health. In this Brief Report, our team explored whether the SWS was associated with perceived stress, CV risk factors, and overall CV health among AA women. The study participants were AA women with high cardiometabolic risk residing in the Rochester and Minneapolis, St. Paul, Minnesota areas, recruited from the FAITH! Heart Health+ Study. We observed a positive association between the SWS and perceived stress levels, suggesting that the obligation to help others and to project an image of strength could be contributing to overall stress levels among AA women.

Induction of homologous recombination by site-specific replication stress.

DNA replication stress is one of the primary causes of genome instability. In response to replication stress, cells can employ replication restart mechanisms that rely on homologous recombination to resume replication fork progression and preserve genome integrity. In this review, we provide an overview of various methods that have been developed to induce site-specific replication fork stalling or collapse in eukaryotic cells. In particular, we highlight recent studies of mechanisms of replication-associated recombination resulting from site-specific protein-DNA barriers and single-strand breaks, and we discuss the contributions of these findings to our understanding of the consequences of these forms of stress on genome stability.

Neural pathways associated with reduced rigidity during pallidal deep brain stimulation for Parkinson's disease.

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) can markedly reduce muscle rigidity in people with Parkinson's disease (PD); however, the mechanisms mediating this effect are poorly understood. Computational modeling of DBS provides a method to estimate the relative contributions of neural pathway activations to changes in outcomes. In this study, we generated subject-specific biophysical models of GPi DBS (derived from individual 7-T MRI), including pallidal efferent, putamenal efferent, and internal capsule pathways, to investigate how activation of neural pathways contributed to changes in forearm rigidity in PD. Ten individuals (17 arms) were tested off medication under four conditions: off stimulation, on clinically optimized stimulation, and on stimulation specifically targeting the dorsal GPi or ventral GPi. Quantitative measures of forearm rigidity, with and without a contralateral activation maneuver, were obtained with a robotic manipulandum. Clinically optimized GPi DBS settings significantly reduced forearm rigidity (P < 0.001), which aligned with GPi efferent fiber activation. The model demonstrated that GPi efferent axons could be activated at any location along the GPi dorsal-ventral axis. These results provide evidence that rigidity reduction produced by GPi DBS is mediated by preferential activation of GPi efferents to the thalamus, likely leading to a reduction in excitability of the muscle stretch reflex via overdriving pallidofugal output.NEW & NOTEWORTHY Subject-specific computational models of pallidal deep brain stimulation, in conjunction with quantitative measures of forearm rigidity, were used to examine the neural pathways mediating stimulation-induced changes in rigidity in people with Parkinson's disease. The model uniquely included internal, efferent and adjacent pathways of the basal ganglia. The results demonstrate that reductions in rigidity evoked by deep brain stimulation were principally mediated by the activation of globus pallidus internus efferent pathways.

Prospective Health Impacts of a Universal Basic Income: Evidence from Community Engagement in South Tyneside, United Kingdom.

Studies have suggested that universal basic income (UBI) has the capacity to have substantial health benefits across the population at national level. Multiple impact pathways have recently been theorized and there are calls for trials to explore these pathways empirically. However, very limited research has taken place at local levels to explore potential context-specific effects, or how these effects could play out in economic, social, and behavioral changes. In order to examine these effects and to think through potential issues and unintended consequences, we brought together citizen engagement groups in Jarrow, South Tyneside, in the northeast of England to explore local people's expectations and positions on the development of UBI policies and pilots prior to their implementation. We found that people's expectations regarding the potential beneficial health impacts of UBI on their communities mapped strongly onto academically theorized impact pathways. They also extended understanding of these pathways in meaningful ways. Our findings add to the literature about UBI and health and provide important insights for the future development of empirical, health focused, UBI research.

Large attachment organelle mediates interaction between Nanobdellota archaeon YN1 and its host.

DPANN archaea are an enigmatic superphylum that are difficult to isolate and culture in the laboratory due to their specific culture conditions and apparent ectosymbiotic lifestyle. Here, we successfully isolated and cultivated a coculture system of a novel Nanobdellota archaeon YN1 and its host Sulfurisphaera ohwakuensis YN1HA. We characterized the coculture system by complementary methods, including metagenomics and metabolic pathway analysis, fluorescence microscopy, and high-resolution electron cryo-tomography (cryoET). We show that YN1 is deficient in essential metabolic processes and requires host resources to proliferate. CryoET imaging revealed an enormous attachment organelle present in the YN1 envelope that forms a direct interaction with the host cytoplasm, bridging the two cells. Together, our results unravel the molecular and structural basis of ectosymbiotic relationship between YN1 and YN1HA. This research broadens our understanding of DPANN biology and the versatile nature of their ectosymbiotic relationships.