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Evaluation of Cleavable Crosslinking for Characterization of Proteoform Structural Differences by Top-Down Mass Spectrometry
No full textCleavable crosslinking has traditionally been employed in bottom-up mass spectrometry to elucidate protein structure and protein-protein interactions through identification of peptides bearing characteristic mass adducts. Here, we demonstrate the application of cleavable crosslinking in top-down mass spectrometry to enhance fragmentation efficiency and enable precise localization of crosslink sites. We first validated this approach using cytochrome c, a well-characterized model protein. Subsequently, we extended top-down cleavable crosslinking to transthyretin, a natively homotetrameric protein exhibiting extensive proteoform heterogeneity, to investigate whether proteoform variations induce structural changes detectable by this method. Our results confirm that cleavable crosslinks can be detected and characterized by top-down mass spectrometry, with crosslinker cleavage under collisional activation significantly enhancing fragmentation. Application to transthyretin (intramolecular crosslinks) yielded complex crosslinking patterns that precluded complete identification of crosslinks. However, the crosslinking data provided valuable information on solvent-accessible residues, functioning effectively as a covalent labeling strategy. This work establishes cleavable crosslinking as a viable chemical crosslinking approach for top-down mass spectrometry applications
Tau Topography Subtypes in Early‐Onset Alzheimer's Disease: Explaining Clinical Heterogeneity and Propagation Patterns
No full textBackground:
The clinical heterogeneity of Early‐Onset Alzheimer's Disease (EOAD) is a key factor behind delayed diagnosis within this young(<65yo) group. However, most research has focused on late‐onset amnestic participants and largely underutilized tau‐PET, despite its ability to link neuropathology with clinical outcomes. We aimed to characterize tau‐based subtypes through a robust data‐driven approach in the Longitudinal Early‐onset Alzheimer's Disease Study.
Method:
Baseline [18F]Flortaucipir‐PET scans from 365 amyloid‐PET‐positive participants with sporadic EOAD were quantified in 10 regions: left and right medial temporal, lateral temporal, occipital, parietal, and frontal. Tau‐PET values were z‐scored against 85 amyloid‐PET‐negative cognitively normal age‐matched controls and fitted into Subtype and Stage Inference (SuStaIn), an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross‐sectional data.
Result:
Three tau‐PET‐based subtypes were identified (Figure 1): Subtype1 (n = 144, 39.5%) had a typical bilateral temporoparietal pattern, while Subtype2 (n = 111, 30.4%) showed predominant left temporal binding, and Subtype3 (n = 104, 28.5%) showed early occipital tau. Subtypes show no significant demographic differences (Figure 2a) but were associated with clinical presentations. Subtype1 was enriched in amnestic participants, while Subtype2 accounted for 61% participants with primary progressive aphasia, and Subtype3 included 79% participants with posterior cortical atrophy (Figure 2b). At baseline, higher SuStaIn stages were associated with higher CDR‐SB (Figure 2c). All subtypes showed longitudinal increase in CDR‐SB, but clinical decline was faster in Subtype1 (Figure 2d). When follow‐up Flortaucipir‐PET scans were fitted to SuStaIn trained on baseline data, 85.6% participants were clustered within the same subtype as their baseline scans; SustaIn stage increased by 0.56/year on average with no difference across subtypes (Figure 3a‐b). Modeling voxelwise tau‐PET over time revealed striking differences (Figure 3c), as each subtype showed significant accumulation in regions that were relatively spared at baseline: tau‐PET increase predominated in the occipital lobe for Subtype1, in bilateral frontal and right temporal areas for Subtype2, and bilateral frontotemporal lobes for Subtype3.
Conclusion:
SuStaIn was able to identify robust tau‐PET‐based subtypes that were associated, but not redundant with known clinical phenotypes in AD. Subtypes exhibited differences in prospective clinical decline and patterns of tau‐PET changes, highlighting their potential to refine prognosis and improve progression monitoring in clinical practice and trials
Indiana's 2024 Behavioral Health and Human Services Workforce Snapshot: All BHHS Professionals Excluding Associates
No full textThis document is a 2024 data snapshot of actively practicing licensed Behavioral Health and Human Services (BHHS) professionals in Indiana, excluding associate‑level licenses. It reports the total size of the licensed workforce (9,677 professionals) and identifies primary practice settings, with nearly half practicing in private practice, followed by community mental health centers and telehealth. The document highlights core services provided, particularly general counseling and mental health diagnosis, and identifies key populations served, with a strong emphasis on adults and individuals in recovery
Using Nuclear Magnetic Moments to Search for Axionic Dark Matter
No full textAmericium (241Am), with an unpaired proton in the F5/2 orbital, exhibits a significant magnetic dipole moment. It decays into an excited state of 237Np, leading to production of several detectable gamma emissions. The dipole moments of both 241Am and 237Np can be partially aligned at room temperature with the application of modest external magnetic fields (Bext), as little as 1-3G. When the magnetic field direction is rotated by 90°, the Bext-dipole interaction leads to a relative shifting of the energy spectrum for the emitted gammas, as measured by typical NaI or CeBr scintillating detectors, due to changes in the direction of the anisotropic emissions. This paper presents data taken as part of an experimental search for Axionic particles produced via a Primakoff coupling between photons and a magnetic field. The results show that the measured energy shifting, due to rotation of the magnetic field, was impacted by photons pass through the magnetic cavity upstream of the radioactive sample even though the photon beam was blocked from reaching the sample. Shining light through the magnetic field, while blocking the radioactive target, alters the value of the measured shifting. This experiment has been repeated several times with different detectors, sources and magnetic field configurations, yielding consistent results. Verification of these results will prove the production of Axions, Axion Like Particles (ALPs) or some beyond the Standard Model boson through the Primakoff mechanism for visible photons. As important, these results could establish the use of radioactive isotopes as detectors of Axionic, ALPs or other light bosons, candidates for future Dark Matter experimentation
Presenilin L166P Mutation, a Model of Familial Alzheimer's Disease, Leads to Early Onset Bone Loss
No full textAccelerated bone loss has been reported in the early stages of Alzheimer's disease (AD) as indicated by reduced bone mineral density and increased fracture risk in these patients, compared to healthy individuals. In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock-in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12-month PSEN1/hAPP Tg+ mice exhibited reduced whole-body bone mineral density and bone mineral content, compared to sex-matched controls. Consistent with PSEN1 L166P driving the phenotype, female PSEN1 KI mice lacking the hAPP transgene also displayed low bone mass with a reduction in bone microarchitecture observed as early as 1 month of age. Correspondingly, PSEN1 KI mice exhibit reduced cortical and trabecular bone mass compared to age- and sex-matched control mice. The loss of bone microarchitecture was largely attributed to a reduction in bone formation as indicated by decreases in serum P1NP levels and osteoblast ALP activity and mRNA expression in vitro. At the ages examined, PSEN1 KI mice exhibited increased follicle stimulating hormone (FSH) levels, which is known to cause a decrease in bone mass. Western blotting also identified both PSEN1 and amyloid-beta protein expression in bone and brain tissue. Taken together, the data indicate that female-specific bone loss in familial AD is potentially due to the direct actions of mutant PSEN1 in bone cells combined with systemic crosstalk caused by brain-expressed PSEN1 L116P
P-1501. Effectiveness of 2024–2025 seasonal influenza vaccines against influenza–associated hospitalizations among adults — VISION Network
No full textBackground:
CDC recommends annual influenza vaccination for all persons aged ≥ 6 months. We estimated 2024–2025 seasonal influenza vaccine effectiveness (VE) against influenza–associated hospitalizations among adults.
Methods:
Data from the VISION Network were used to estimate influenza VE using a test-negative, case-control design. The analysis included hospitalizations among adults aged ≥ 18 years with ≥ 1 acute respiratory illness (ARI)–associated ICD-10 discharge diagnosis code from October 1, 2024–March 7, 2025 in six US healthcare systems. Cases were ARI hospitalizations with a positive molecular influenza test within 10 days before to 72 hours after the admission date. Controls were ARI hospitalizations with a negative molecular influenza test during the same interval. VE was estimated using multivariable logistic regression comparing the odds of receipt of ≥ 1 2024–2025 influenza vaccine dose versus no dose among cases and controls. VE models were adjusted for age, sex, race and ethnicity, calendar day, and healthcare system.
Results:
A total of 31,338 ARI hospitalizations met inclusion criteria, including 4,969 cases and 26,369 controls (Figure). Overall VE against influenza–associated hospitalizations was 46% (95% CI=43–50%) with a median time since vaccination of 79 days (IQR=50–107). When stratified by time since vaccination, VE was 46% (95% CI=38–53%) at 14–59 days, 41% (95% CI=36–45%) at 60–119 days, and 9% (95% CI=-1 to 19%) at ≥ 120 days. VE was 46% (95% CI=42–50%) against influenza A and 65% (95% CI=41–80%) against influenza B. Among immunocompetent and immunocompromised adults, VE was 49% (95% CI=45–53%) and 33% (95% CI=23–42%), respectively. VE against influenza–associated intensive care unit (ICU) admission was 49% (95% CI=38–58%) and against in-hospital death was 48% (95% CI=31–62%).
Conclusion:
2024–2025 seasonal influenza vaccines provided protection against influenza–associated hospitalizations among adults with evidence of decreased VE ≥ 120 days after vaccination. VE point estimates were higher against influenza B than against influenza A and among immunocompetent versus immunocompromised adults. VE against influenza–associated ICU admission and in-hospital death were similar to that against hospitalization
Folate status markers are inversely associated with metabolic syndrome in the post-folic acid fortification period in US adults
No full textBackground: In the US, the mandatory fortification of cereal products with folic acid in 1998 has dramatically increased the folate status. It is not known if this increased folate status is associated with metabolic syndrome (MetSyn) in the post-folic acid fortification period.
Objective: The objective of this study was to investigate the association between folate status and MetSyn in US adults using nationally representative sample surveys.
Methods: Data from five cycles of National Health and Nutrition Examination Surveys, 2007-2008, 2011-2012, 2013-2014, 2015-2016, and 2017-2018 were combined into one master analytic database. After excluding data for missing variables, the final study sample consisted of 9458 adults. National Cholesterol Education Program ATP III criteria were used to define the MetSyn. The relation between folate status markers (serum total folate and 5-methyl tetrahydrofolate) and MetSyn was investigated using multivariable logistic regression.
Results: The likelihood of having MetSyn in the 4th quartile of serum total folate was significantly lower compared to the 1st quartile (odds ratio, 0.7; 95% CI, 0.57, 0.87 vs 1; P<0.001), Also, the likelihood of having MetSyn in the 4th quartile of 5-menthyl tetrahydrofolate was significantly lower compared to the 1st quartile (odds ratio, 0.71; 95% CI, 0.57, 0.88 vs. 1; P <0.001).
Conclusion: Serum total folate and 5-menthyl tetrahydrofolate concentrations are inversely associated with the prevalence of MetSyn in the adult US population. It is prudent that persons with MetSyn phenotypes, especially those who have suboptimal folate status, may benefit from consuming diets rich in folate and folic-acid-fortified foods
A pilot feasibility study of human-centered design for cirrhosis care: Development and pilot testing of SMARTLiver prototype, a FHIR-based clinical decision support system for hepatology
No full textManagement of cirrhosis suffers from poor guideline adherence due to fragmented electronic health record (EHR) systems that scatter critical patient data across multiple modules, creating cognitive burden for clinicians and impeding evidence-based care delivery. We developed SMARTLiver, a Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources (SMART-on-FHIR) clinical decision support application employing human-centered design principles to consolidate patient data, incorporate evidence-based guidelines, and enhance cirrhosis care workflows. Following literature reviews of cirrhosis management guidelines and clinical workflow analysis within our health system, we created a FHIR-based application integrating automated task management, prognostic scoring, patient-reported outcomes, and real-time clinical decision support features. Usability evaluation with five clinical staff members using Think-Aloud protocols and the validated Health-ITUES survey revealed high satisfaction scores for Clinical Utility (4.4-4.6/5.0) and User Interface design (4.2/5.0), with moderate scores for workflow integration (4.0/5.0) and decision support (3.8-4.0/5.0). Qualitative feedback aligned with quantitative results, identifying enhancement opportunities in customization controls and notification management. The SMARTLiver prototype demonstrated technical feasibility in aggregating fragmented clinical data into a unified interface, automating evidence-based task generation, and maintaining interoperability across healthcare systems. This pilot study provides initial evidence for the potential of SMART-on-FHIR technology to address EHR fragmentation in cirrhosis care, though clinical effectiveness remains to be demonstrated
Associations of Newborn Social Risk Factors With High Infant Weight-for-Length at Age 6 Months: Observational Clinical Cohort
No full textObjective: This study aimed to quantify associations between newborn social risk factors and high infant weight-for-length (WFL) at 6 months.
Methods: We conducted a longitudinal, observational study using electronic health record data among infants in New York City. We included newborns with a primary care screening questionnaire for social risk factors (food insecurity, housing instability, transportation problems, and utility hardship) measured using the Accountable Health Communities Screening Tool. We conducted regression analyses to assess associations between social risk factors and high WFL, or the 97.7th percentile at 6 months. Secondary analyses included additional single-time-point and longitudinal weight outcomes (continuous and dichotomous).
Results: Among 1876 newborns, 77.3% identified as Hispanic/Latino, almost all had Medicaid insurance (96.6%), 355 (23.3%) had food insecurity risk, 149 (7.9%) had housing instability, 132 (7.0%) had transportation problems, and 110 (5.9%) had utility hardship. Newborns with utility hardship had higher odds of high WFL in unadjusted (OR 3.0, 95% CI: 1.8-5.2) and adjusted models (aOR 3.1, 95% CI: 1.7-5.6) accounting for infant, parent, and social risk factors.
Conclusions: Newborn utility hardship was associated with obesity risk at age 6 months. Interventions to address newborn social risk factors should examine the effectiveness of utility shutoff protection to reduce excess infant weight gain
Müller Glial Kir4.1 Channel Dysfunction in APOE4‐KI Model of Alzheimer's Disease
No full textAlzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K+ channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD