Evaluation of a Combinatorial Immunotherapy Regimen That Can Cure Mice Bearing MYCN-Driven High-Risk Neuroblastoma That Resists Current Clinical Therapy.

Background: Incorporating GD2-targeting monoclonal antibody into post-consolidation maintenance therapy has improved survival for children with high-risk neuroblastoma. However, ~50% of patients do not respond to, or relapse following, initial treatment. Here, we evaluated additional anti-GD2-based immunotherapy to better treat high-risk neuroblastoma in mice to develop a regimen for patients with therapy-resistant neuroblastoma. Methods: We determined the components of a combined regimen needed to cure mice of established MYCN-amplified, GD2-expressing, murine 9464D-GD2 neuroblastomas. Results: First, we demonstrate that 9464D-GD2 is nonresponsive to a preferred salvage regimen: anti-GD2 with temozolomide and irinotecan. Second, we have previously shown that adding agonist anti-CD40 mAb and CpG to a regimen of radiotherapy, anti-GD2/IL2 immunocytokine and anti-CTLA-4, cured a substantial fraction of mice bearing small 9464D-GD2 tumors; here, we further characterize this regimen by showing that radiotherapy and hu14.18-IL2 are necessary components, while anti-CTLA-4, anti-CD40, or CpG can individually be removed, and CpG and anti-CTLA-4 can be removed together, while maintaining efficacy. Conclusions: We have developed and characterized a regimen that can cure mice of a high-risk neuroblastoma that is refractory to the current clinical regimen for relapsed/refractory disease. Ongoing preclinical work is directed towards ways to potentially translate these findings to a regimen appropriate for clinical testing.

Impact of prior coronary artery bypass grafting and coronary lesion complexity on outcomes of transcatheter aortic valve replacement for severe aortic stenosis.

OBJECTIVE: To investigate the impact of prior coronary artery bypass grafting (CABG) and coronary lesion complexity on transcatheter aortic valve replacement (TAVR) outcomes for aortic stenosis. METHODS: Clinical outcomes of TAVR were retrospectively compared between patients with and without prior CABG, and between patients with prior CABG and without coronary artery disease (CAD). The impact of the CABG SYNTAX score was also evaluated in patients with prior CABG. RESULTS: The study included 1042 patients with a median age and follow-up of 82 years and 25 (range: 0-72) months, respectively. Of these, 175 patients had a history of CABG, while 401 were free of CAD. Patients with prior CABG were more likely to be male and had higher rates of diabetes, peripheral artery disease and atrial fibrillation compared with patients without prior CABG. After 2 : 1 propensity score matching, all-cause mortality (P = 0.17) and the composite of all-cause mortality, stroke and coronary intervention (P = 0.16) were similar between patients with (n = 166) and without (n = 304) prior CABG. A 1 : 1 propensity score-matched analysis, however, showed lower rates of all-cause mortality (P = 0.04) and the composite outcome (P = 0.04) in patients with prior CABG (n = 134) compared with patients without CAD (n = 134). The median CABG SYNTAX score was 16 (interquartile range: 9.0-23), which was not associated with better/worse clinical outcomes in patients with prior CABG. CONCLUSION: Prior CABG may positively affect mid-term TAVR outcomes for aortic stenosis compared with no CAD when adjusted for other comorbidities. The CABG SYNTAX score did not influence the prognosis after TAVR.

Microstructural Mapping of Neural Pathways in Alzheimer's Disease using Macrostructure-Informed Normative Tractometry.

Introduction: Diffusion MRI is sensitive to the microstructural properties of brain tissues, and shows great promise in detecting the effects of degenerative diseases. However, many approaches analyze single measures averaged over regions of interest, without considering the underlying fiber geometry. Methods: Here, we propose a novel Macrostructure-Informed Normative Tractometry (MINT) framework, to investigate how white matter microstructure and macrostructure are jointly altered in mild cognitive impairment (MCI) and dementia. We compare MINT-derived metrics with univariate metrics from diffusion tensor imaging (DTI), to examine how fiber geometry may impact interpretation of microstructure. Results: In two multi-site cohorts from North America and India, we find consistent patterns of microstructural and macrostructural anomalies implicated in MCI and dementia; we also rank diffusion metrics' sensitivity to dementia. Discussion: We show that MINT, by jointly modeling tract shape and microstructure, has potential to disentangle and better interpret the effects of degenerative disease on the brain's neural pathways.

Where do we intervene to optimize sports systems? Leverage Points the way.

Sport and sports research are inherently complex systems. This appears to be somewhat at odds with the current research paradigm in sport in which interventions are aimed are fixing or solving singular broken components within the system. In any complex system, such as sport, there are places where we can intervene to change behaviour and, ideally, system outcomes. Meadows influential work describes 12 different points with which to intervene in complex systems (termed "Leverage Points"), which are ordered from shallow to deeper based on their potential effectiveness to influence transformational change. Whether research in sport is aimed at shallow or deeper Leverage Points is unknown. This study aimed to assess highly impactful research in sports science, sports nutrition/metabolism, sports medicine, sport and exercise psychology, sports management, motor control, sports biomechanics and sports policy/law through a Leverage Points lens. The 10 most highly cited original-research manuscripts from each journal representing these fields were analysed for the Leverage Point with which the intervention described in the manuscript was focused. The results indicate that highly impactful research in sports science, sports nutrition/metabolism, sports biomechanics and sports medicine is predominantly focused at the shallow end of the Leverage Points hierarchy. Conversely, the interventions drawn from journals representing sports management and sports policy/law were focused on the deeper end. Other journals analysed had a mixed profile. Explanations for these findings include the dual practitioner/academic needing to "think fast" to solve immediate questions in sports science/medicine/nutrition, limited engagement with "working slow" systems and method experts and differences in incremental vs. non-incremental research strategies.

Synbiotic Bacillus megaterium DSM 32963 and n-3 PUFA Salt Composition Elevates Pro-Resolving Lipid Mediator Levels in Healthy Subjects: A Randomized Controlled Study.

Beneficial health effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) are partly attributed to specialized pro-resolving mediators (SPMs), which promote inflammation resolution. Strategies to improve n-3 PUFA conversion to SPMs may, therefore, be useful to treat or prevent chronic inflammatory disorders. Here, we explored a synbiotic strategy to increase circulating SPM precursor levels. Healthy participants (n = 72) received either SynΩ3 (250 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) lysine salts; two billion CFU Bacillus megaterium; n = 23), placebo (n = 24), or fish oil (300 mg EPA plus DHA; N = 25) capsules daily for 28 days in a randomized, double-blind placebo-controlled parallel 3-group design. Biomarkers were assessed at baseline and after 2 and 28 days of intervention. The primary analysis involved the comparison between SynΩ3 and placebo. In addition, SynΩ3 was compared to fish oil. The synbiotic SynΩ3 comprising Bacillus megaterium DSM 32963 and n-3 PUFA salts significantly increased circulating SPM precursor levels, including 18-hydroxy-eicosapentaenoic acid (18-HEPE) plus 5-HEPE, which was not achieved to this extent by fish oil with a similar n-3 PUFA content. Omega-3 indices were increased slightly by both SynΩ3 and fish oil. These findings suggest reconsidering conventional n-3 PUFA supplementation and testing the effectiveness of SynΩ3 particularly in conditions related to inflammation.

Implementation of kidney palliative care-lessons learned from the US Department of Veterans Affairs.

Advanced kidney disease is a progressive life-limiting illness associated with high symptom burden, disability, and highly intensive care near the end of life. There is growing interest in integrating palliative care principles into the care of patients with advanced kidney disease to improve care and outcomes for these patients. The United States (US) Department of Veterans Affairs (VA) has been a leader in advancing palliative care initiatives across its health system and whose experience and approach may be instructive to other health systems seeking to develop kidney palliative care (KPC) services. Herein, we review current KPC programs in the VA and highlight the different models of care that programs have been adopted and how key components of goals of care conversations and advance care planning, symptom management, multidisciplinary care, patient selection, and quality improvement have been implemented across programs. VA KPC programs have adopted "parallel", "merged", and "embedded" models of KPC that reflect the different configurations of partnerships between nephrology and palliative care providers to deliver KPC. A primary service of VA KPC programs is providing goals of care conversations and advance care planning to referred patients and systematically documenting the outcomes of these discussions in standardized note templates in the electronic medical record. Symptom management is delivered by KPC providers through regular shared or sequential visits with patients' nephrology providers and is guided by patient responses to validated symptom surveys. Programs are staffed by allied health professionals, such as chaplains, pharmacists, social workers, and dieticians, to provide whole-person care and regularly huddle with nephrology staff to reach a shared understanding of each patient's care needs and plan. KPC programs implement champions who select patients in greatest need of KPC using a combination of clinical events that trigger referral for KPC and validated mortality risk prediction scores that are automatically generated in each patient's medical record. KPC programs also routinely collect clinical, patient-reported, process, and care quality measures to assess its services. The experiences of the VA highlight novel approaches that strive to close the care gaps in meeting the KPC needs of patients with advanced kidney disease.

Reliability of beat-to-beat blood pressure variability in older adults.

Blood pressure variability (BPV) is emerging as an important risk factor across numerous disease states, including cerebrovascular and neurodegenerative disease in older adults. However, there is no current consensus regarding specific use cases for the numerous available BPV metrics. There is also little published data supporting the ability to reliably measure BPV across metrics in older adults. BPV metrics were derived from continuous beat-to-beat blood pressure monitoring data. Two sequential 7-minute waveforms were analyzed. Absolute and relative reliability testing was performed. Differences between antihypertensive medication users and non-users on BPV metric reliability was also assessed. All sequence and dispersion based BPV metrics displayed good test-retest reliability. A measure of BP instability displayed only moderate reliability. Systolic and diastolic average real variability displayed the highest levels of reliability at ICC= .87 and .82 respectively. Additionally, systolic average real variability was the most reliable metric in both the antihypertensive use group, and the no antihypertensive use group. Beat-to-beat dispersion and sequence-based metrics of BPV can be reliably obtained from older adults using noninvasive continuous blood pressure monitoring. Average real variability may be the most reliable and specific beat-to-beat blood pressure variability metric due to its decreased susceptibility to outliers and low frequency blood pressure oscillations.

A population health approach to workplace mental health: rationale, implementation and engagement.

Objectives: To describe a population health-based program to support employee and dependent mental health and learn from engagement trends. Methods: Retrospective analysis of a program utilizing an assessment of mental health risk. For scoring "at risk," a Care Concierge is offered to connect users with resources. Results: Participation was offered to 56,442 employees and dependents. Eight thousand seven hundred thirty-one completed the assessment (15%). Of those, 4,644 (53%) scored moderate or higher. A total of 418 (9%) engaged the Care Concierge. Factors that negatively influenced the decision to engage care included bodily pain, financial concerns. Positive influences were younger age, high stress, anxiety, PTSD and low social support. Conclusion: Proactive assessment plus access to a Care Concierge facilitates mental healthcare utilization. Several factors influence likelihood to engage in care. A better understanding of these factors may allow for more targeted outreach and improved engagement.

Estimating Tiotropium Wasted Doses After Adding Revefenacin to an Inpatient Formulary: A Single-Center Cross-Sectional Study.

Introduction: Revefenacin is a once-daily nebulized long-acting muscarinic antagonist (LAMA). Revefenacin is supplied as single-use nebulized vials, which may be preferable and less costly for hospital and health-system pharmacies to dispense versus multidose tiotropium inhalers. Estimates of LAMA multidose inhaler wasted doses remains unknown. Methods: This was a single-center descriptive cross-sectional study conducted between January 1 2021 and December 31 2021. Adult patients 18 years and older admitted to a 500-bed academic medical center in the southern United States and were ordered multidose tiotropium packages or single-use revefenacin vials during the study period were included. Results: Among 602 inpatients, there were 705 LAMA orders: 541 tiotropium (76.7%) and 164 revefenacin (23.3%). Four hundred ninety-five tiotropium orders (91.5%) wasted between 20% and 90% of multidose packages. Approximately $24,000 tiotropium doses were wasted versus single-use revefenacin vials. Conclusion: Multidose inhalers of tiotropium dispensed to hospitalized patients contributed to wasted doses compared to nebulized single-use revefenacin vials. Opportunities exist to minimize wasted doses of multidose long-acting inhalers dispensed to hospitalized patients.

Administration of intratumoral GD2-directed interleukin-2 immunocytokine and local radiation therapy to activate immune rejection of spontaneous canine melanoma.

Canine malignant melanoma provides a clinically relevant, large animal parallel patient population to study the GD2-reactive hu14.18-IL-2 immunocytokine as it is similar to human melanoma and expresses GD2. The objectives of this study were to evaluate safety, radiation fractionation, and identify informative biomarkers of an in-situ tumor vaccine involving local radiation therapy plus intratumoral-immunocytokine in melanoma tumor-bearing dogs. Twelve dogs (six dogs/arm) with locally advanced or metastatic melanoma were randomized to receive a single 8 Gy fraction (arm A) or three 8 Gy fractions over 1 week (arm B) to the primary site and regional lymph nodes (when clinically involved) with the single or last fraction 5 days before intratumoral-immunocytokine at 12 mg/m2 on 3 consecutive days. Serial tumor biopsies were obtained. All 12 dogs completed protocol treatment, and none experienced significant or unexpected adverse events. Evidence of antitumor activity includes one dog with a complete response at day 60, one dog with a partial response at day 60, and four dogs with mixed responses. Histology of serial biopsies shows a variably timed increase in intratumoral lymphocytic inflammation in some dogs. Canine NanoString analyses of serial biopsies identified changes in gene signatures of innate and adaptive cell types versus baseline. There were no significant differences in NanoString results between arm A and arm B. We conclude that intratumoral-immunocytokine in combination with local radiation therapy in canine melanoma is well tolerated and has antitumor activity with the potential to inform clinical development in melanoma patients.

Single-year change in views of democracy and society and support for political violence in the USA: findings from a 2023 nationally representative survey.

BACKGROUND: A 2022 survey in the USA found concerningly high prevalences of support for and personal willingness to engage in political violence, of beliefs associated with such violence, and of belief that civil war was likely in the near future. It is important to determine the durability of those findings. METHODS: Wave 2 of a nationally representative cohort survey was conducted May 18-June 8, 2023; the sample comprised all respondents to 2022's Wave 1. Outcomes are expressed as weighted proportions; changes from 2022 to 2023 are for respondents who participated in both surveys, based on aggregated individual change scores. RESULTS: The completion rate was 84.2%; there were 9385 respondents. After weighting, 50.7% (95% confidence interval (CI) 49.4%, 52.1%) were female; weighted mean (SD) age was 48.5 (25.9) years. About 1 in 20 respondents (5.7%, 95% CI 5.1%, 6.4%) agreed strongly/very strongly that "in the next few years, there will be civil war in the United States," a 7.7% decrease. In 2023, fewer respondents considered violence to be usually/always justified to advance at least 1 of 17 specific political objectives [25.3% (95% CI 24.7%, 26.5%), a 6.8% decrease]. However, more respondents thought it very/extremely likely that within the next few years, in a situation where they consider political violence justified, "I will be armed with a gun" [9.0% (95% CI 8.3%, 9.8%), a 2.2% increase] and "I will shoot someone with a gun" [1.8% (95% CI 1.4%, 2.2%), a 0.6% increase]. Among respondents who considered violence usually/always justified to advance at least 1 political objective, about 1 in 20 also thought it very/extremely likely that they would threaten someone with a gun (5.4%, 95% CI 4.0%, 7.0%) or shoot someone (5.7%, 95% CI 4.3%, 7.1%) to advance such an objective. CONCLUSIONS: In this cohort, support for political violence declined from 2022 to 2023, but predictions of firearm use in political violence increased. These findings can help guide prevention efforts, which are urgently needed.

The mitochondrial multi-omic response to exercise training across rat tissues.

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase.

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.

Higher dietary polyphenol intake is associated with lower blood inflammatory markers.

BACKGROUND: Evidence suggests a link between polyphenol intake and reduced incidence of several chronic diseases. This could arise through associations between polyphenol intake and reduced systemic oxidative stress and subsequent inflammation. However, confirming this association is difficult, as few large cohorts allow for comprehensive assessments of both polyphenol intake and markers of systemic inflammation. OBJECTIVE: To address this, polyphenol intake was assessed in the UK-based Airwave cohort using 7-day diet diaries and data from Phenol-Explorer to test for associations between polyphenol intake and blood biomarkers of inflammation. DESIGN: Participants included 9008 males and females aged 17-74 (median age 42) whose data was included in a cross-sectional analysis. Phenol-Explorer was used to estimate individuals' polyphenol intake from diet data describing the consumption of 4104 unique food items. C-reactive protein (CRP) and fibrinogen were used as blood biomarkers of inflammation. RESULTS: There were 448 polyphenols found in reported diet items. Median total polyphenol intake was 1536 (1058-2092) mg/d. Phenolic acids and flavonoids were the main types of polyphenols, and non-alcoholic beverages, vegetables, and fruit were the primary sources. Variation in energy-adjusted polyphenol intake was explained by age, sex, salary, BMI, education level, smoking, and alcohol consumption. Linear regressions showed inverse associations between total daily intake and both CRP (ß = -0.00702, P <0.001) and fibrinogen (ß = -0.00221, P = 0.038). Associations with specific polyphenol compound groups also were found. Logistic regressions using total polyphenol intake quartiles showed stepwise reductions in the odds of elevated CRP with higher intake (6%, 23% and 24% versus quartile 1; P = 0.003), alongside 3% and 7% lower odds per unit of polyphenol consumption equivalent to 1 cup of tea or coffee per day. CONCLUSIONS: This study describes polyphenol intake in a large, contemporary UK cohort. We observed associations between higher intake and lower CRP and fibrinogen. This contributes to evidence supporting the health benefits of dietary polyphenols.

Molecular breeding of flower load related traits in dioecious autotetraploid Actinidia arguta.

Flowering plants exhibit a wide range of sexual reproduction systems, with the majority being hermaphroditic. However, some plants, such as Actinidia arguta (kiwiberry), have evolved into dioecious species with distinct female and male vines. In this study, we investigated the flower load and growth habits of female kiwiberry genotypes to identify the genetic basis of high yield with low maintenance requirements. Owing to the different selection approaches between female and male genotypes, we further extended our study to male kiwiberry genotypes. By combining both investigations, we present a novel breeding tool for dioecious crops. A population of A. arguta seedlings was phenotyped for flower load traits, in particular the proportion of non-floral shoots, proportion of floral shoots, and average number of flowers per floral shoot. Quantitative trait locus (QTL) mapping was used to analyse the genetic basis of these traits. We identified putative QTLs on chromosome 3 associated with flower-load traits. A pleiotropic effect of the male-specific region of the Y chromosome (MSY) on chromosome 3 affecting flower load-related traits between female and male vines was observed in an A. arguta breeding population. Furthermore, we utilized Genomic Best Linear Unbiased Prediction (GBLUP) to predict breeding values for the quantitative traits by leveraging genomic data. This approach allowed us to identify and select superior genotypes. Our findings contribute to the understanding of flowering and fruiting dynamics in Actinidia species, providing insights for kiwiberry breeding programs aiming to improve yield through the utilization of genomic methods and trait mapping. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01476-7.

The CTLH Ubiquitin Ligase Substrates ZMYND19 and MKLN1 Negatively Regulate mTORC1 at the Lysosomal Membrane.

Most Epstein-Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic signaling. To gain insights into PI3K/mTOR pathway dysregulation in this context, we performed a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib. Multiple subunits of carboxy terminal to LisH (CTLH) E3 ligase, including the catalytic MAEA subunit, were among top screen hits. CTLH negatively regulates gluconeogenesis in yeast, but not in higher organisms. Instead, we identified that the CTLH substrates MKLN1 and ZMYND19, which highly accumulated upon MAEA knockout, associated with one another and with lysosomes to inhibit mTORC1. ZMYND19/MKLN1 bound Raptor and RagA/C, but rather than perturbing mTORC1 lysosomal recruitment, instead blocked a late stage of its activation, independently of the tuberous sclerosis complex. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.

Genetic Complexities of Cerebral Small Vessel Disease, Blood Pressure, and Dementia.

Importance: Vascular disease is a treatable contributor to dementia risk, but the role of specific markers remains unclear, making prevention strategies uncertain. Objective: To investigate the causal association between white matter hyperintensity (WMH) burden, clinical stroke, blood pressure (BP), and dementia risk, while accounting for potential epidemiologic biases. Design, Setting, and Participants: This study first examined the association of genetically determined WMH burden, stroke, and BP levels with Alzheimer disease (AD) in a 2-sample mendelian randomization (2SMR) framework. Second, using population-based studies (1979-2018) with prospective dementia surveillance, the genetic association of WMH, stroke, and BP with incident all-cause dementia was examined. Data analysis was performed from July 26, 2020, through July 24, 2022. Exposures: Genetically determined WMH burden and BP levels, as well as genetic liability to stroke derived from genome-wide association studies (GWASs) in European ancestry populations. Main Outcomes and Measures: The association of genetic instruments for WMH, stroke, and BP with dementia was studied using GWASs of AD (defined clinically and additionally meta-analyzed including both clinically diagnosed AD and AD defined based on parental history [AD-meta]) for 2SMR and incident all-cause dementia for longitudinal analyses. Results: In 2SMR (summary statistics-based) analyses using AD GWASs with up to 75 024 AD cases (mean [SD] age at AD onset, 75.5 [4.4] years; 56.9% women), larger WMH burden showed evidence for a causal association with increased risk of AD (odds ratio [OR], 1.43; 95% CI, 1.10-1.86; P = .007, per unit increase in WMH risk alleles) and AD-meta (OR, 1.19; 95% CI, 1.06-1.34; P = .008), after accounting for pulse pressure for the former. Blood pressure traits showed evidence for a protective association with AD, with evidence for confounding by shared genetic instruments. In the longitudinal (individual-level data) analyses involving 10 699 incident all-cause dementia cases (mean [SD] age at dementia diagnosis, 74.4 [9.1] years; 55.4% women), no significant association was observed between larger WMH burden and incident all-cause dementia (hazard ratio [HR], 1.02; 95% CI, 1.00-1.04; P = .07). Although all exposures were associated with mortality, with the strongest association observed for systolic BP (HR, 1.04; 95% CI, 1.03-1.06; P = 1.9 × 10-14), there was no evidence for selective survival bias during follow-up using illness-death models. In secondary analyses using polygenic scores, the association of genetic liability to stroke, but not genetically determined WMH, with dementia outcomes was attenuated after adjusting for interim stroke. Conclusions: These findings suggest that WMH is a primary vascular factor associated with dementia risk, emphasizing its significance in preventive strategies for dementia. Future studies are warranted to examine whether this finding can be generalized to non-European populations.

On the fate of protonated chloroformates in the gas phase: a competition between forming HCl and chloroformic acid.

Chloroformates are prevalent in the atmosphere due to their utilization as fuel additives and industrial solvents. These species may undergo interactions with atmospheric water resulting in protonated chloroformates. This study delves into the gas-phase dissociation of these protonated species. Tandem mass spectrometry was employed to scrutinize the unimolecular dissociation of protonated methyl (1), ethyl (2), neopentyl (3), and phenyl chloroformate (4). Notably, 1 and 4 exhibited HCl loss, yielding CH3OCO+ and C6H5OCO+, respectively, with 1 additionally generating neutral methanol and ClCO+. 4 additionally loses CO and CO2. In contrast, 2 and 3 each only exhibit a single fragmentation channel, with 2 losing C2H4 to generate protonated chloroformic acid and 3 generating protonated 2-methylbutene by losing neutral chloroformic acid. Density functional theory at the B3LYP/6-311+G(d,p) level of theory was employed to explore minimum energy reaction pathways for each ion, and CBS-QB3 single-point energy calculations were added to provide reliable energetics. The Rice-Ramsperger-Kassel-Marcus (RRKM) calculations of the rate constants for selected competing processes were carried out to link theory and experiment. One common unimolecular process observed was the 1,3-H shift of the proton from the carbonyl oxygen to the ester oxygen before dissociation.

Computational design of non-porous pH-responsive antibody nanoparticles.

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and is important for targeted delivery of biologics. Here we describe the design of octahedral non-porous nanoparticles with a targeting antibody on the two-fold symmetry axis, a designed trimer programmed to disassemble below a tunable pH transition point on the three-fold axis, and a designed tetramer on the four-fold symmetry axis. Designed non-covalent interfaces guide cooperative nanoparticle assembly from independently purified components, and a cryo-EM density map closely matches the computational design model. The designed nanoparticles can package protein and nucleic acid payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between 5.9 and 6.7. The ability to incorporate almost any antibody into a non-porous pH-dependent nanoparticle opens up new routes to antibody-directed targeted delivery.