Case Western Reserve University

Tau and α-synuclein (α-syn) are prone-to-aggregate proteins that can be responsible for pathological lesions found in the brains of Alzheimer’s disease (AD), Lewy body dementia (LBD), and Parkinson’s disease (PD) patients. The early-stage oligomers and protofibrils of tau are believed to be strongly linked to human cognitive impairment while the toxic α-syn oligomers are associated with behavioral motor deficits. Therefore, concurrent targeting of both proteinaceous aggregates and oligomers are very challenging. Herein, rhodanine-based compounds were designed and synthesized to target the fibrils and oligomers of tau and α-syn proteins. In particular, the indole-containing rhodanines 5l and 5r displayed significantly high anti-aggregation activity towards α-syn fibrils by reducing of the thioflavin-T (ThT) fluorescence to less than 5 %. Moreover, 5r showed a remarkable decrease in the fluorescence of thioflavin-S (ThS) when incubated with the non-phosphorylated tau 0N4R and 2N4R, as well as the hyperphosphorylated tau isoform 1N4R. Transmission electron microscopy (TEM) analyses validated the powerful anti-fibrillar activity of 5l and 5r towards both protein aggregates. In addition, both 5l and 5r highly suppressed 0N4R tau and α-syn oligomer formation using the photo-induced cross-linking of unmodified protein (PICUP) assay. The fluorescence emission intensity of 5l was quenched to almost half in the presence of both protein fibrils at 510 nm. 5r showed a similar fluorescence response upon binding to 2N4R fibrils while no quenching effect was observed with α-syn aggregates. Ex vivo disaggregation assay using extracted human Aβ plaques was employed to confirm the ability of 5l and 5r to disaggregate the dense fibrils. Both inhibitors reduced the Aβ fibrils isolated from AD brains. 5l and 5r failed to show activity toward the cell-based α-syn inclusion formation. However, another indolyl derivative 5j prevented the α-syn inclusion at 5 µM. Collectively, the indolyl-rhodanine scaffold could act as a building block for further structural optimization to obtain dual targeting disease-modifying candidates for AD, LBD, and PD.

Aqueous zinc‐sulfur batteries (Zn−S) are promising alternatives to conventional lithium‐ion technology due to their high energy density, low cost, and enhanced safety. However, challenges such as slow redox kinetics of sulfur cathode conversion and inadequate anode stability persist. This study demonstrates that by tuning the electrolyte structure with the introduction of propylene glycol methyl ether (PM) as a co‐solvent and ZnI2 as an electrolyte additive, and significant improvements at both electrodes could be achieved. Experimental and theoretical calculations reveal that the larger polar −OH and C−O−C electron‐donating groups in the PM molecule can donate electrons for the redox reaction of I⁻/I3⁻. Its role as a redox mediator improves the reversibility of the sulfur cathodic transformation. Additionally, the dipole moment induced by the hydroxyl groups in PM enhances electron transfer from the zinc anode to the electrolyte and promote the decomposition of anions (OTF⁻), improving the interfacial stability of the zinc anode. The synergistic effect of PM and the I⁻/I3⁻ redox mediator pair enables the zinc‐sulfur battery to deliver an impressive capacity of 1456 mAh g⁻¹ and a high energy density of 471.8 Wh kg⁻¹ at a current density of 0.2 A g⁻¹.

Detection and monitoring of environmental contaminants such as antibiotic residues in aquatic environments is challenging. To address this, a variety of detection methods has been developed; out of which optical sensing using fluorescence is found as one of the most robust methods. However, most of the reported sensors are made from metal ions using tedious synthetic processes, on the other hand, optical sensors using biosourced polymers are rarely reported. Herein, an anionic glycogen functionalized aggregation induced emission (AIE) active system; NCMCTPN was prepared using a simple Schiff base condensation reaction of tetraphenylethene amine (TPENH2) and carboxymethyl cellulose dialdehyde (NCMCA) and its self‐assembled polymeric nanoaggregates were explored for sensitive and selective turn‐off fluorescence detection of a broad‐spectrum tetracycline antibiotic, in an aqueous medium with a limit of detection of 127.5 ppb. The combination of factors such as inner filter effect and photoinduced electron transfer from the polymeric nanoaggregates to tetracycline through activation of a non‐radiative decay process is possibly responsible for the high sensitivity of the fluorescent nanoprobe towards the antibiotic.

Objective Among patients with large vessel occlusion (LVO) and large ischemic cores, critical decisions often need to be made about decompressive hemicraniectomy (DHC) or early withdrawal of life‐sustaining therapy (WLST). In this study, we aimed to evaluate utilization of DHC and early WLST and factors associated with them in patients with large strokes from the SELECT2 trial. Methods We analyzed the entire SELECT2 trial population, which randomized 352 patients with stroke due to LVO and large ischemic cores to endovascular thrombectomy (EVT) or medical management. We used the as‐treated principle to compare the use of DHC and early WLST within 7 days after randomization. We further assessed functional outcomes (modified Rankin Score) after these decisions. Results Of 352 patients enrolled in this study, 55 received DHC and 81 transitioned to early WLST. Patients treated with EVT were as likely to undergo DHC (16% vs 15%, adjusted relative risk [aRR] = 1.19, 95% CI:0.75–1.88, p = 0.46) or WLST (22% vs 24%, aRR = 0.94, 95% CI: 0.66–1.34, p = 0.72) as those given medical management. DHC was used more frequently in younger patients and WLST more in older patients. EVT efficacy was maintained after adjusting for DHC (adjusted generalized odds ratio [aGenOR] = 1.68, 95% CI: 1.24–2.11, p < 0.001), with no interaction between DHC and treatment (p‐interaction = 0.93). At 1 year, 21% of DHC‐treated patients were ambulatory; the outcomes were universally poor after early WLST. Interpretation In the SELECT2 trial of patients with large ischemic core, DHC was performed in ~1 of 6 patients and early WLST in ~1 of 5 patients, without differences based on treatment with EVT or medical management, nor successful reperfusion. DHC or WLST did not detract from thrombectomy treatment benefit. Additionally, ~20% of patients achieved independent ambulation despite receiving DHC by the 1‐year follow‐up. The similar distribution of these critical care decisions provides reassurance that the overall trial outcomes were not biased by open‐label treatment allocation. ANN NEUROL 2024

Purpose This report compares device use in a cohort of Spanish–English bilingual and English monolingual children who are deaf and hard of hearing, including children fitted with traditional hearing aids, cochlear implants (CIs), and/or bone-conduction hearing devices. Method Participants were 84 Spanish–English bilingual children and 85 English monolingual children from clinical sites across the United States. The data represent a subset obtained in a larger clinical trial. Device use obtained via data logging was modeled as a function of language group, device type, child age, sex, and parental education. Results Among children with traditional hearing aids, bilingual children wore their devices significantly fewer hours per day than monolingual children, but this group difference was not observed for children with CIs or bone-conduction hearing devices. In the monolingual group, older children wore their devices significantly more hours than younger children, but this effect of age was not present in the bilingual group. Parent report was consistent with data logging for bilingual and monolingual children. Conclusions Spanish–English bilingual hearing aid users wore their devices less than their English monolingual peers, particularly among older children. This group effect was not observed for children with CIs or bone-conduction hearing devices. Additional studies are needed to identify factors that contribute to device use among bilingual children with hearing aids.

This review examines the relationship between long-term antipsychotic use and individual functioning, emphasizing clinical implications and the need for personalized care. The initial impression that antipsychotic medications may worsen long-term outcomes is critically assessed, highlighting the confounding effects of illness trajectory and individual patient characteristics. Moving beyond a focus on methodological limitations, the discussion centers on how these findings can inform clinical practice, keeping in consideration that a subset of patients with psychotic disorders are on a trajectory of long-term remission and that for a subset of patient the adverse effects of antipsychotics outweigh potential benefits. Key studies such as the OPUS study, Chicago Follow-up study, Mesifos trial, and RADAR trial are analyzed. While antipsychotics demonstrate efficacy in short-term symptom management, their long-term effects on functioning are less obvious and require careful interpretation. Research on long-term antipsychotic use and individual functioning isn't sufficient to favor antipsychotic discontinuation or dose reduction below standard doses for most patients, but it is sufficient to highlight the necessity of personalization of clinical treatment and the appropriateness of dose reduction/discontinuation in a considerable subset of patients.

Identifying communal rituals in the Paleolithic is of scientific importance, as it reflects the expression of collective identity and the maintenance of group cohesion. This study provides evidence indicating the practice of deep cave collective rituals in the Levant during the Early Upper Paleolithic (EUP) period. It is demonstrated that these gatherings occurred within a distinct ritual compound and were centered around an engraved object in the deepest part of Manot Cave, a pivotal EUP site in southwest Asia. The ritual compound, segregated from the living areas, encompasses a large gallery partitioned by a cluster of remarkable speleothems. Within this gallery, an engraved boulder stands out, displaying geometric signs suggesting a unique representation of a tortoise. Isotopic analysis of calcite crusts on the boulder’s grooves revealed alignment with values found in speleothems from the cave dated to ~37 to 35 ka BP. Additionally, meticulous shape analysis of the grooves’ cross-section and the discernible presence of microlinear scratches on the grooves’ walls confirmed their anthropogenic origin. Examination of stalagmite laminae (36 ka BP) near the engraved boulder revealed a significant presence of wood ash particles within. This finding provides evidence for using fire to illuminate the dark, deep part of the cave during rituals. Acoustic tests conducted in various cave areas indicate that the ritual compound was well suited for communal gatherings, facilitating conversations, speeches, and hearing. Our results underscore the critical role of collective practices centered around a symbolic object in fostering a functional social network within the regional EUP communities.

Objectives This paper demonstrates International Caries Detection and Assessment System (ICDAS) training procedures and inter/intra‐examiner reliability for lesion severity, activity, and filling criteria in an elementary school setting. Methods ICDAS training was conducted in December 2021 prior to a school‐based cluster‐randomized controlled trial. A total of 59 children (6–8 years old) in grades 1–2 from one school in Houston, Texas were recruited. Two licensed dentists received a 5‐day training from an ICDAS trainer at the participating school. Thirty‐eight children were evaluated at least once by each dental trainee, and 18 had repeat examinations. The ICDAS criteria were used to classify dental caries lesion severity (0–6), lesion activity (active/inactive), and filling material (0–9) of all visually available primary and permanent tooth surfaces. Inter and intra‐examiner reliability between each dental trainee and the “gold standard” trainer was evaluated using Kappa statistics. Results For lesion severity, the examination indicated an inter‐rater weighted Kappa of 0.77 (95% CI 0.71–0.82) and 0.82 (95% CI 0.77–0.87) for each trainee examiner compared to the gold standard examiner. The Kappas increased slightly from the first to second examinations (lesion‐weighted Kappa: 0.76 to 0.84 and 0.82 to 0.84). The intra‐rater reliability indicated excellent reliability for lesion and filling (0.83 to 0.94) and moderate for activity (0.58). Conclusions ICDAS training/calibration were essential to ensure accuracy and reliability of dental caries measurements. The study demonstrated that ICDAS training of dentists with no prior criteria experience is feasible in a community setting and can lead to high reliability and repeatability.

Millions of people worldwide die of acute myeloid leukaemia (AML) each year. Although N6-methyladenosine (m ⁶ A) modification has been reported to regulate the pathogenicity of AML, the mechanisms by which m ⁶ A induces dysfunctional hematopoietic differentiation in elderly AML patients remain elusive. This study elucidates the mechanisms of the m ⁶ A landscape and the specific roles of m ⁶ A regulators in hematopoietic cells of elderly AML patients. Notably, fat mass and obesity-associated protein ( FTO ) was found to be upregulated in hematopoietic stem cells (HSCs), myeloid cells, and T-cells, where it inhibits their differentiation via the WNT signaling pathway. Additionally, elevated YT521-B homology domain family proteins 2 ( YTHDF2 ) expression in erythrocytes was observed to negatively regulate differentiation through oxidative phosphorylation, resulting in leukocyte activation. Moreover, IGF2BP2 was significantly upregulated in myeloid cells, contributing to an aberrant chromosomal region and disrupted oxidative phosphorylation. m ⁶ A regulators were shown to induce abnormal cell-cell communication within hematopoietic cells, mediating ligand-receptor interactions across various cell types through the HMGB1-mediated pathway, thereby promoting AML progression. External validation was conducted using an independent single-cell RNA sequencing (scRNA-Seq) dataset. The THP-1 and MV411 cell lines were utilized to corroborate the m ⁶ A regulator profile; in vitro experiments involving short hairpin RNA (shRNA) targeting FTO demonstrated inhibition of cell proliferation, migration, and oxidative phosphorylation, alongside induction of cell cycle arrest and apoptosis. In summary, these findings suggest that the upregulation of m ⁶ A regulators in HSCs, erythrocytes, myeloid cells, and T-cells may contribute to the malignant differentiation observed in AML patients. This research provides novel insights into the pathogenesis of AML in elderly patients and identifies potential therapeutic targets.

Tactile feedback from brain-controlled bionic hands can be partially restored via intracortical microstimulation (ICMS) of the primary somatosensory cortex. In ICMS, the location of percepts depends on the electrode’s location and the percept intensity depends on the stimulation frequency and amplitude. Sensors on a bionic hand can thus be linked to somatotopically appropriate electrodes, and the contact force of each sensor can be used to determine the amplitude of a stimulus. Here we report a systematic investigation of the localization and intensity of ICMS-evoked percepts in three participants with cervical spinal cord injury. A retrospective analysis of projected fields showed that they were typically composed of a focal hotspot with diffuse borders, arrayed somatotopically in keeping with their underlying receptive fields and stable throughout the duration of the study. When testing the participants’ ability to rapidly localize a single ICMS presentation, individual electrodes typically evoked only weak sensations, making object localization and discrimination difficult. However, overlapping projected fields from multiple electrodes produced more localizable and intense sensations and allowed for a more precise use of a bionic hand.

INTRODUCTION High microglial heterogeneities hinder the development of microglia‐targeted treatment for Alzheimer's disease (AD). METHODS We integrated 0.7 million single‐nuclei RNA‐sequencing transcriptomes from human brains using a variational autoencoder. We predicted AD‐relevant microglial subtype‐specific transition networks for disease‐associated microglia (DAM), tau microglia, and neuroinflammation‐like microglia (NIM). We prioritized drugs by specifically targeting microglia‐specific transition networks and validated drugs using two independent real‐world patient databases. RESULTS We identified putative AD molecular drivers (e.g., SYK, CTSB, and INPP5D) in transition networks of DAM and NIM. Via specifically targeting NIM, we identified that usage of ketorolac was associated with reduced AD incidence in both MarketScan (hazard ratio [HR] = 0.89) and INSIGHT (HR = 0.83) Clinical Research Network databases, mechanistically supported by ketorolac‐treated transcriptomic data from AD patient induced pluripotent stem cell–derived microglia. DISCUSSION This study offers insights into the pathobiology of AD‐relevant microglial subtypes and identifies ketorolac as a potential anti‐inflammatory treatment for AD. Highlights An integrative analysis of ≈ 0.7 million single‐nuclei RNA‐sequencing transcriptomes from human brains identified Alzheimer's disease (AD)–relevant microglia subtypes. Network‐based analysis identified putative molecular drivers (e.g., SYK, CTSB, INPP5D) of transition networks between disease‐associated microglia (DAM) and neuroinflammation‐like microglia (NIM). Via network‐based prediction and population‐based validation, we identified that usage of ketorolac (a US Food and Drug Administration–approved anti‐inflammatory medicine) was associated with reduced AD incidence in two independent patient databases. Mechanistic observation showed that ketorolac treatment downregulated the Type‐I interferon signaling in patient induced pluripotent stem cell–derived microglia, mechanistically supporting its protective effects in real‐world patient databases.

BACKGROUND Persistent immune activation is linked to elevated cardiovascular diseases in people with HIV on antiretroviral therapy. The fat attenuation index (FAI) is a measure of peri-coronary inflammation that independently predicts cardiovascular disease risk in people without HIV. Whether FAI is associated with immune activation is unknown. METHODS Peripheral blood T-cell activation and homing phenotypes were measured in people with HIV (n=58) and people without HIV (n=16) without known cardiovascular disease who underwent coronary computed tomography angiography and had FAI measurements. A cross-sectional analysis of an observational cohort was performed. The primary aim was to evaluate associations of T-cell activation and phenotypes with the outcome variables, FAI values of the right coronary artery and left anterior descending artery, which were assessed using multivariable regression models adjusted for age, natal sex, race, low-density lipoprotein cholesterol, body mass index, and use of lipid-lowering medication. RESULTS T cells from people with HIV showed greater activation, as measured by cluster of differentiation (CD) 38/human leukocyte antigen – DR isotype coexpression on CD4 central memory and terminally-differentiated effector memory subsets and on CD8 effector memory (TEM), than did cells from people without HIV. Expression of the chemokine receptor C-C Chemokine Receptor 2 was reduced on CD4 central memory and TEM and CD8 TEM and terminally-differentiated effector memory subsets in people with HIV. Among all participants, PD-1 (programmed cell death 1) in CD8 central memory was associated with worsened peri-coronary inflammation of the right coronary artery, whereas perforin/granzyme B on CD8 TEM was associated with improved peri-coronary inflammation of the right coronary artery and left anterior descending artery in adjusted analyses. When accounting for HIV serostatus, CD38/human leukocyte antigen – DR isotype coexpression on CD8 central memory, TEM, and terminally-differentiated effector memory cells was associated with more peri-coronary inflammation of the left anterior descending artery. CONCLUSIONS The associations between T-cell activation with FAI are novel and suggest that T-cell activation may be an important driver of peri-coronary inflammation, occurring at an early stage of atherosclerosis, even before the development of clinical disease.

Background To evaluate the one-year safety and effectiveness of bio-interventional cyclodialysis and scleral reinforcement in open-angle glaucoma (OAG) patients undergoing cataract surgery. Methods An ab-interno approach was used to create a sectoral cyclodialysis in OAG patients who were prospectively followed in a consecutive case series. Subsequent visco-cycloplasty with scleral reinforcement using homologous minimally modified allograft scaffold was completed to maintain patency of the cyclodialysis reservoir and increase uveoscleral outflow. Outcomes were mean medicated IOP and mean number of IOP-lowering medications. Safety outcomes were adverse events (AEs) and best-corrected visual acuity (BCVA) changes. Results Successful cyclodialysis and allograft bio-scaffold reinforcement was achieved in 117 eyes. There was minimal intraoperatie bleeding and few post-operative adverse events. At baseline, mean BCVA was 0.48 (95% CI: 0.42‒0.54; 20/40 Snellen) and mean ± SD medicated IOP was 20.2 ± 6.0 mmHg on 1.4 ± 1.3 IOP-lowering medications. At 12 months, there was a 27.1% reduction from baseline mean medicated IOP. In eyes with medicated baseline IOP > 21 mmHg (n = 45), there was a 39.7% paired IOP reduction at 12 months with a concurrent reduction in the mean number of IOP lowering medications to 0.8 ± 0.9 which were statistically significant (p < 0.01). For all eyes, 81.9% achieved a medicated IOP ≤ 18 mmHg with no increase in medications at 12 months. To achieve target IOP control, secondary glaucoma surgery was performed in 3.2% of the cases. Conclusion IOP lowering through uveoscleral outflow enhancement can be achieved by means of a bio-interventional cyclodialysis procedure with allograft scleral reinforcement.

Collagen type II fibril formation is affected by network moduli.

Background Registered Dietitian Nutritionists (RDNs) have long been part of the interdisciplinary team recommended for obesity treatment. Obesity education for RDNs is important not only for ensuring adequate knowledge but also for reducing weight stigma. The objective of this study was to benchmark the inclusion of obesity-related competencies in dietetic supervised practice programs, as self-reported by supervised practice directors, to begin to understand the training that U.S. RDNs receive. Methods This was an exploratory, cross-sectional, online survey of U.S. dietetic supervised practice directors distributed in July of 2022. The directors were asked about the importance and extent of inclusion of 31 obesity-related competencies, as well as barriers for inclusion. The competencies were derived from the 2017 Provider Competencies on the Prevention and Management of Obesity. Results We received 36 survey responses, representing 10.4% of supervised practice directors in the U.S. Very few programs reported ‘not at all incorporated’ for any competencies; the most frequent were ‘potential role of genetics/epigenetics’ (15%, n = 5) and ‘physiology/pathophysiology of obesity’ (12%, n = 4). The competencies most frequently reported as ‘very important’ were ‘perform effectively in an interprofessional team’ and ‘discuss obesity in a non-judgmental manner’. Lack of time in the curriculum was the most frequently reported barrier. Conclusions For programs hoping to both expand obesity education and decrease weight stigma in a limited amount of time, improving coverage of competencies related to non-modifiable causes of obesity may be an area to prioritize.

How do social support and the use of social media contribute to mental health and resilience among those who are pursuing a new path of identity and life? Those who exit ultra-Orthodox Judaism often struggle with loss of social support while simultaneously increasing their use of social media. We conducted a cross-cultural survey among 1146 individuals who left ultra-Orthodox Judaism. Our findings show that escapist and avoidant coping through social media correlated with more negative mental health outcomes, while using social media to problem solve and perceiving oneself as giving and receiving social support correlated with more positive outcomes. Resilience negatively associated with escapist and avoidant styles of coping through social media. Some aspects of perceived social support had positive associations with resilience. These findings shed light on potentially helpful mechanisms for using social media among marginalized communities, specifically those who exit high-cost religious communities.