Cross-coupling of CO and an isocyanide mediated by a tetrameric magnesium hydride cluster.

Sequential addition of CNXyl (Xyl = 2,6-dimethylphenyl) and CO to a tetrametallic magnesium hydride cluster results in stepwise reduction and cross-coupling of these substrates. Cross-coupling results in the formation of an ethene amidolate ligand [OC1(H1)[double bond, length as m-dash]C2(H2)NAr]2- a previously unknown entity which contains a 1,2-difunctionalised carbon chain reminiscent of those found in aminoalcohols and amino acids. To the best of our knowledge, this is the first example of such reactivity with metal hydride precursors. DFT calculations support a mechanism that parallels that established for coupling of CO to form ethenediolate ligands, with the key carbon-carbon bond step occurring by nucleophilic attack of a putative azamethylene intermediate on CO. The cluster plays a key role in templating the synthesis, providing kinetic control over each of the steps. The ethene amidolate ligand can be transferred to other metals (Al) and semi-metals (B) through onwards metathesis reactions.

Crowdsourced Feedback to Improve Resident Physician Error Disclosure Skills: A Randomized Clinical Trial.

Importance: Residents must prepare for effective communication with patients after medical errors. The video-based communication assessment (VCA) is software that plays video of a patient scenario, asks the physician to record what they would say, engages crowdsourced laypeople to rate audio recordings of physician responses, and presents feedback to physicians. Objective: To evaluate the effectiveness of VCA feedback in resident error disclosure skill training. Design, Setting, and Participants: This single-blinded, randomized clinical trial was conducted from July 2022 to May 2023 at 7 US internal medicine and family medicine residencies (10 total sites). Participants were second-year residents attending required teaching conferences. Data analysis was performed from July to December 2023. Intervention: Residents completed 2 VCA cases at time 1 and were randomized to the intervention, an individual feedback report provided in the VCA application after 2 weeks, or to control, in which feedback was not provided until after time 2. Residents completed 2 additional VCA cases after 4 weeks (time 2). Main Outcomes and Measures: Panels of crowdsourced laypeople rated recordings of residents disclosing simulated medical errors to create scores on a 5-point scale. Reports included learning points derived from layperson comments. Mean time 2 ratings were compared to test the hypothesis that residents who had access to feedback on their time 1 performance would score higher at time 2 than those without feedback access. Residents were surveyed about demographic characteristics, disclosure experience, and feedback use. The intervention's effect was examined using analysis of covariance. Results: A total of 146 residents (87 [60.0%] aged 25-29 years; 60 female [41.0%]) completed the time 1 VCA, and 103 (70.5%) completed the time 2 VCA (53 randomized to intervention and 50 randomized to control); of those, 28 (54.9%) reported reviewing their feedback. Analysis of covariance found a significant main effect of feedback between intervention and control groups at time 2 (mean [SD] score, 3.26 [0.45] vs 3.14 [0.39]; difference, 0.12; 95% CI, 0.08-0.48; P = .01). In post hoc comparisons restricted to residents without prior disclosure experience, intervention residents scored higher than those in the control group at time 2 (mean [SD] score, 3.33 [0.43] vs 3.09 [0.44]; difference, 0.24; 95% CI, 0.01-0.48; P = .007). Worse performance at time 1 was associated with increased likelihood of dropping out before time 2 (odds ratio, 2.89; 95% CI, 1.06-7.84; P = .04). Conclusions and Relevance: In this randomized clinical trial, self-directed review of crowdsourced feedback was associated with higher ratings of internal medicine and family medicine residents' error disclosure skill, particularly for those without real-life error disclosure experience, suggesting that such feedback may be an effective way for residency programs to address their requirement to prepare trainees for communicating with patients after medical harm. Trial Registration: ClinicalTrials.gov Identifier: NCT06234085.

A Novel, Low-Cost Alternative to Traditional Glaucoma Surgeries.

Purpose: To investigate the real-world efficacy of a novel, low-cost glaucoma drainage device in canine and human patients. Methods: A retrospective case series of 17 eyes in 14 canines and one eye of a human patient who each underwent novel drainage device implantation is described. This device was constructed by insertion and advancement of a 24-gauge cannula (canine) or 23-gauge cannula (human) perpendicularly through five adjacent tubes of a 25-mm Yeates surgical drain. Results: Of the canine patients, the average follow-up period was 362 days (range, 27-863). The mean preoperative intraocular pressure (IOP) was 50.9 ± 17.9 mm Hg. Following tube surgery, IOP was maintained at <20 mm Hg in 81.3%, 100%, 100%, 85.7%, 100%, and 75.0% of eyes at 1, 2, 3, 6, 9, and 12 months, respectively. Bleb needling and/or revisions were required in five eyes. Enucleations and/or device explantations were performed in five eyes at mean day 140. In the human case, the device was implanted in the right eye of a 64-year-old male with refractory raised IOP (55 mm Hg) despite maximum medical therapy. IOP was well controlled until day 818, when eventual tissue breakdown necessitated device removal. Conclusions: This design represents a novel, low-cost, effective alternative to traditional glaucoma tube devices. Translational Relevance: This device has great potential for use in regions where the needs for glaucoma drainage devices and surgical alternatives to trabeculectomy have not been met. Further development may include tube crimping or fenestration and preoperative loading of slow-release antibiotics and/or anti-metabolite medications within the non-draining lumens.

EDS-FLU efficacy in patients with chronic rhinosinusitis with or without prior sinus surgery in ReOpen1 and ReOpen2 randomized controlled trials.

BACKGROUND: The inability of topical medications to reach sinus cavities is a potential reason for lack of efficacy in chronic rhinosinusitis (CRS). One purpose of endoscopic sinus surgery (ESS) is to enable delivery of medications into the sinus cavities. The exhalation delivery system with fluticasone (EDS-FLU; XHANCE) creates unique biomechanics that enable deposition of intranasal corticosteroid into sinuses and sinus drainage pathways but may have differing efficacy in operated versus unoperated sinuses. Two 24-week randomized trials (ReOpen1/2) evaluated EDS-FLU versus EDS-placebo in patients with CRS, stratified by surgical status. METHODS: Surgery-naive (n = 332) and prior-surgery (n = 215) patient groups were analyzed as pooled data from ReOpen1/2. Outcome measures (least-squares mean change from baseline) included combined symptom score (CSS) and congestion score at weeks 4, 8, and 12 and average of percentages of opacified volume (APOV) of ethmoid/maxillary sinuses on CT and Sinonasal Outcome Test 22 (SNOT-22) total score at week 24. RESULTS: Baseline scores suggested moderate-severe disease: mean CSS = 5.8; APOV = 67.2%. EDS-FLU produced significant improvement versus placebo (p < 0.05): CSS (surgery-naive, -0.68 vs. -1.42; prior ESS, -0.70 vs. -1.87); congestion (surgery-naive, -0.24 vs. -0.59; prior ESS, -0.24 vs. -0.69); and SNOT-22 (surgery-naive, -7.56 vs. -18.30; prior ESS, -10.72 vs. -18.74). Similar results were observed for APOV (p < 0.05). No statistically significant difference was observed between surgery subgroups with either EDS-FLU dose. CONCLUSION: EDS-FLU improved symptoms, sinus opacification, and quality of life in patients with CRS with or without prior ESS, suggesting a role for EDS-FLU in both populations.

Immune cell population dynamics following neonatal BCG vaccination and aerosol BCG revaccination in rhesus macaques.

The BCG vaccine is given to millions of children globally but efficacy wanes over time and differences in the immune systems between infants and adults can influence vaccine efficacy. To this end, 34 rhesus macaques were vaccinated with BCG within seven days of birth and blood samples were collected over 88 weeks for quantification of blood cell populations. Overall, the composition of cell populations did not change significantly between BCG vaccinated and unvaccinated groups, and that BCG vaccination did not perturb normal development. In comparison to adult macaques, higher numbers of CD4+ T-cells, Tregs and NK cells were measured in the infant age group, suggesting a potential bias towards immunosuppressive and innate immune populations. Antigen-specific IFNγ secreting cell frequencies in infant BCG vaccinated animals were detectable in peripheral blood samples for 36 weeks after vaccination but declined following this. To evaluate the long-term impact of infant BCG vaccination on subsequent revaccination with BCG, a pilot study of three adult macaques received an aerosol BCG revaccination approximately 3 years after their initial BCG vaccination as infants. This induced an increase in PPD-specific IFNγ secreting cells, and increased secretion of the cytokines IFNγ and IL-1ß, following stimulation with other microorganisms, which are signals associated with trained innate immunity.

Updates on the Natural History and Clinical Characteristics of NSAID-ERD.

Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) is a distinct clinical syndrome characterized by nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity, asthma, and nasal polyposis. Its diagnosis is challenging owing to variable presentations and a lack of simple tests, leading to diagnostic delays. Recent research has revealed its genetic predispositions, environmental triggers, and associations with atopy and second-hand tobacco smoke exposure or smoking cessation. Despite its severity, diagnostic awareness remains low, leading to the delay in effective management. Therapeutically, NSAID-ERD necessitates multidisciplinary approaches, often combining surgical interventions with medical management, including aspirin desensitization and biologic agents. However, predictive biomarkers for treatment response remain elusive. Understanding the underlying mechanisms driving NSAID-ERD pathogenesis and identifying reliable biomarkers are crucial for enhancing diagnostic accuracy and refining targeted therapeutic strategies for this debilitating condition. This review aims to provide a thorough understanding of NSAID-ERD, covering its history, clinical features, epidemiology, diagnosis, systemic and molecular biomarkers, available treatment options, and avenues for future research.

Bioactive sucralfate-based microneedles promote wound healing through reprogramming macrophages and protecting endogenous growth factors.

Impaired wound healing due to insufficient cell proliferation and angiogenesis is a significant physical and psychological burden to patients worldwide. Therapeutic delivery of exogenous growth factors (GFs) at high doses for wound repair is non-ideal as GFs have poor stability in proteolytic wound environments. Here, we present a two-stage strategy using bioactive sucralfate-based microneedle (SUC-MN) for delivering interleukin-4 (IL-4) to accelerate wound healing. In the first stage, SUC-MN synergistically enhanced the effect of IL-4 through more potent reprogramming of pro-regenerative M2-like macrophages via the JAK-STAT pathway to increase endogenous GF production. In the second stage, sucralfate binds to GFs and sterically disfavors protease degradation to increase bioavailability of GFs. The IL-4/SUC-MN technology accelerated wound healing by 56.6 % and 46.5 % in diabetic mice wounds and porcine wounds compared to their respective untreated controls. Overall, our findings highlight the innovative use of molecular simulations to identify bioactive ingredients and their incorporation into microneedles for promoting wound healing through multiple synergistic mechanisms.

Outcomes and Baseline Predictors of Failure in Primary Standalone Xen45 Gel Stent versus Trabeculectomy for Glaucoma.

PURPOSE: To compare safety, effectiveness, and baseline predictors of failure in standalone primary Xen45 gel stent (Xen) versus trabeculectomy (Trab) in glaucoma. DESIGN: Retrospective study. SUBJECTS: Subjects that underwent primary Xen or Trab augmented by mitomycin-C with at least 12 months follow-up. METHODS: Multinational observational study of eyes in the Fight Glaucoma Blindness international registry MAIN OUTCOME MEASURES: The primary outcome was success at 12 months defined by intraocular pressure (IOP) reduction ≥ 20% from baseline and ≤ threshold IOPs of 15, 18, and 21 mmHg with (qualified) or without (complete) medications and without secondary glaucoma surgery. Multivariable mixed effects Cox regression models were used to identify risk factors for failure in each cohort. RESULTS: A total of 701 eyes (Xen, 308; Trab, 393) of 596 subjects were included with baseline IOP being significantly higher (22.4 vs. 19.9 mmHg, P < 0.001) and baseline medications significantly lower in the Xen versus the Trab group (2.9 vs. 3.4, P < 0.001). Baseline visual field mean deviation was less severe in the Xen group (-9.47 vs. -13.04 dB, P < 0.001). The proportion of complete surgical success was significantly lower in the Xen versus Trab group across the 3 upper IOP limits at 12 months; 32% versus 52% at 15 mmHg, 37% versus 54% at 18 mmHg, and 39% versus 55% at 21 mmHg (P < 0.001). The incidence of postoperative numerical and symptomatic hypotony was lower in the Xen versus Trab group. In the Xen cohort, a higher failure rate was associated with Asian ethnicity (hazard ratio [HR], 1.97; 95% confidence interval (CI), 1.03-3.79) and use of oral acetazolamide at baseline (HR, 1.74; 95% CI, 1.13-2.70), whereas a lower failure rate was associated with diagnosis of ocular hypertension/open-angle glaucoma suspect (HR, 0.40; 95% CI, 0.20-0.82) and secondary open-angle glaucoma (HR, 0.46; 95% CI, 0.26-0.82). Exposure to prostaglandin analog was associated with greater failure in the Trab group (HR, 2.66; 95% CI, 1.18-6.01). CONCLUSIONS: There was significantly greater complete success at 12 months across all complete success definitions for Trab compared with Xen, whereas the rate of postoperative hypotony was significantly lower in the Xen group. Asian ethnicity and use of oral acetazolamide at baseline were associated with greater failure in Xen, whereas exposure to prostaglandin analog was associated with greater failure in Trab patients. Such baseline predictors of success and failure may help guide patient selection for subconjunctival minimally invasive glaucoma surgery in patients undergoing surgical intervention. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Total Synthesis of a Peptide Diatom Sex Pheromone Bearing a Sulfated Aspartic Acid.

The peptide sex-inducing pheromone SIP+ (1) bearing an unusual sulfated aspartic acid residue induces sexual reproduction in diatom populations. Herein, we report the first total synthesis of SIP+ using both a sulfated building block approach and a solid-phase peptide synthesis (SPPS)-compatible late-stage sulfation strategy to assemble the natural product. The modular approaches provide concise routes to useful quantities of the natural product for future structure activity relationship studies examining the role of SIP+ in diatom biology.

Mast cell activation syndrome: Current understanding and research needs.

Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers.

Chemical synthesis of grafted cyclotides using a "plug and play" approach.

Cyclotides are a diverse class of plant-derived cyclic, disulfide-rich peptides with a unique cyclic cystine knot topology. Their remarkable structural stability and resistance to proteolytic degradation can lead to improved pharmacokinetics and oral activity as well as selectivity and high enzymatic stability. Thus, cyclotides have emerged as powerful scaffold molecules for designing peptide-based therapeutics. The chemical engineering of cyclotides has generated novel peptide ligands of G protein-coupled receptors (GPCRs), today's most exploited drug targets. However key challenges potentially limit the widespread use of cyclotides in molecular grafting applications. Folding of cyclotides containing bioactive epitopes remains a major bottleneck in cyclotide synthesis. Here we present a modular 'plug and play' approach that effectively bypasses problems associated with the oxidative folding of cyclotides. By grafting onto a pre-formed acyclic cyclotide-like scaffold we show that difficult-to-graft sequences can be easily obtained and can target GPCRs with nanomolar affinities and potencies. We further show the suitability of this new method to graft other complex epitopes including structures with additional disulfide bonds that are not readily available via currently employed chemical methods, thus fully unlocking cyclotides to be used in drug design applications.

Augmenting large language models with chemistry tools.

Large language models (LLMs) have shown strong performance in tasks across domains but struggle with chemistry-related problems. These models also lack access to external knowledge sources, limiting their usefulness in scientific applications. We introduce ChemCrow, an LLM chemistry agent designed to accomplish tasks across organic synthesis, drug discovery and materials design. By integrating 18 expert-designed tools and using GPT-4 as the LLM, ChemCrow augments the LLM performance in chemistry, and new capabilities emerge. Our agent autonomously planned and executed the syntheses of an insect repellent and three organocatalysts and guided the discovery of a novel chromophore. Our evaluation, including both LLM and expert assessments, demonstrates ChemCrow's effectiveness in automating a diverse set of chemical tasks. Our work not only aids expert chemists and lowers barriers for non-experts but also fosters scientific advancement by bridging the gap between experimental and computational chemistry.

Low-dose M.tb infection but not BCG or MTBVAC vaccination enhances heterologous antibody titres in non-human primates.

Introduction: Mycobacteria are known to exert a range of heterologous effects on the immune system. The mycobacteria-based Freund's Complete Adjuvant is a potent non-specific stimulator of the immune response used in immunization protocols promoting antibody production, and Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccination has been linked with decreased morbidity and mortality beyond the specific protection it provides against tuberculosis (TB) in some populations and age groups. The role of heterologous antibodies in this phenomenon, if any, remains unclear and under-studied. Methods: We set out to evaluate antibody responses to a range of unrelated pathogens following infection with Mycobacterium tuberculosis (M.tb) and vaccination with BCG or a candidate TB vaccine, MTBVAC, in non-human primates. Results: We demonstrate a significant increase in the titer of antibodies against SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, tetanus toxoid, and respiratory syncytial virus antigens following low-dose aerosol infection with M.tb. The magnitude of some of these responses correlated with TB disease severity. However, vaccination with BCG administered by the intradermal, intravenous or aerosol routes, or intradermal delivery of MTBVAC, did not increase antibody responses against unrelated pathogens. Discussion: Our findings suggest that it is unlikely that heterologous antibodies contribute to the non-specific effects of these vaccines. The apparent dysregulation of B cell responses associated with TB disease warrants further investigation, with potential implications for risk of B cell cancers and novel therapeutic strategies.

Opportunities for targeted therapies: trametinib as a therapeutic approach to canine oral squamous cell carcinomas.

Oral tumors are relatively common in dogs, and canine oral squamous cell carcinoma (COSCC) is the most prevalent oral malignancy of epithelial origin. COSCC is locally aggressive with up to 20% of patients showing regional or distant metastasis at the time of diagnosis. The treatment of choice most typically involves wide surgical excision. Although long-term remission is possible, treatments are associated with significant morbidity and can negatively impact functionality and quality of life. OSCCs have significant upregulation of the RAS-RAF-MEK-MAPK signaling axis, and we had previously hypothesized that small-molecule inhibitors that target RAS signaling might effectively inhibit tumor growth and progression. Here, we demonstrate that the MEK inhibitor trametinib, an FDA-approved drug for human cancers, significantly blocks the growth of several COSCC cell lines established from current patient tumor samples. We further show clinical evidence that the drug is able to cause significant tumor regression in some patients with spontaneously occurring COSCC. Given the limited treatment options available and the high rate of owner rejection of these offered options, these findings provide new hope that more acceptable treatment options may soon enter the veterinary clinic.

Current Practice: Rationale for Screening Children with Hereditary Hemorrhagic Telangiectasia for Brain Vascular Malformations.

BACKGROUND: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular dysplasia characterized by mucocutaneous telangiectasias, recurrent epistaxis, and organ vascular malformations including in the brain, which occur in about 10% of patients. These brain vascular malformations include high-flow AVMs and AVFs as well as low-flow capillary malformations. High-flow lesions can rupture, causing neurologic morbidity and mortality. STATE OF PRACTICE: International guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia recommend screening children for brain vascular malformations with contrast enhanced MR imaging at hereditary hemorrhagic telangiectasia diagnosis. Screening has not been uniformly adopted by some practitioners who contend that screening is not justified. Arguments against screening include application of short-term data from the adult A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial of unruptured sporadic brain AVMs to children with hereditary hemorrhagic telangiectasia as well as concerns about administration of sedation or IV contrast and causing patients or families increased anxiety. ANALYSIS: In this article, a multidisciplinary group of experts on hereditary hemorrhagic telangiectasia reviewed data that support screening guidelines and counter arguments against screening. Children with hereditary hemorrhagic telangiectasia have a preponderance of high-flow lesions including AVFs, which have the highest rupture risk. The rupture risk among children is estimated at about 0.7% per lesion per year and is additive across lesions and during a lifetime. ARUBA, an adult clinical trial of expectant medical management versus treatment of unruptured brain AVMs, favored medical management at 5 years but is not applicable to pediatric patients with hereditary hemorrhagic telangiectasia given the life expectancy of a child. Additionally, interventional, radiosurgical, and surgical techniques have improved with time. Experienced neurovascular experts can prospectively determine the best treatment for each child on the basis of local resources. The "watch and wait" approach to imaging means that children with brain vascular malformations will not be identified until a potentially life-threatening and deficit-producing intracerebral hemorrhage occurs. This expert group does not deem this to be an acceptable trade-off.

Two-year outcomes of Xen 45 gel stent implantation in patients with open-angle glaucoma: real-world data from the Fight Glaucoma Blindness registry.

OBJECTIVE: To evaluate efficacy and safety outcomes of the Xen 45 gel stent implant over 24 months of follow-up. METHODS: A retrospective analysis of prospectively collected data from the Fight Glaucoma Blindness observational registry. Complete success (CS) was defined as intraocular pressure (IOP) reduction ≥20% from preoperative and an IOP ≤18 mm Hg and ≥6 mm Hg with no secondary procedure at 2 years and without IOP-lowering medications. Qualified success (QS) was defined similarly, allowing the use of IOP-lowering medications. RESULTS: The Xen 45 gel stent implant was implanted in 646 eyes of 515 patients. Preoperative IOP was 21.4±7.6 (mean±SD) mm Hg on 2.7±1.3 IOP-lowering medication and mean deviation was -10.2±8.4 dB. After 24-month follow-up, IOP was 16.8±7.3 mm Hg (mean reduction of 21.7%) on 1.2±1.4 IOP-lowering medications. CS and QS rates at 24 months were 26% and 48%, respectively. CS and QS were higher in the Xen stand-alone group (33% and 52%, respectively) than in the Xen+cataract group (16% and 42%, respectively). Bleb needling was performed in 28.4% of cases, and 18% underwent a secondary procedure. CONCLUSIONS: The Xen 45 gel stent implant offers acceptable long-term efficacy for the treatment of open-angle glaucoma. However, there is a significant rate of reoperation and needling, and outcomes are less effective if combined with cataract surgery.

Learning peptide properties with positive examples only.

Deep learning can create accurate predictive models by exploiting existing large-scale experimental data, and guide the design of molecules. However, a major barrier is the requirement of both positive and negative examples in the classical supervised learning frameworks. Notably, most peptide databases come with missing information and low number of observations on negative examples, as such sequences are hard to obtain using high-throughput screening methods. To address this challenge, we solely exploit the limited known positive examples in a semi-supervised setting, and discover peptide sequences that are likely to map to certain antimicrobial properties via positive-unlabeled learning (PU). In particular, we use the two learning strategies of adapting base classifier and reliable negative identification to build deep learning models for inferring solubility, hemolysis, binding against SHP-2, and non-fouling activity of peptides, given their sequence. We evaluate the predictive performance of our PU learning method and show that by only using the positive data, it can achieve competitive performance when compared with the classical positive-negative (PN) classification approach, where there is access to both positive and negative examples.

Correction: Predicting small molecules solubility on endpoint devices using deep ensemble neural networks.

[This corrects the article DOI: 10.1039/D3DD00217A.].

Highly Efficient and Scalable p-i-n Perovskite Solar Cells Enabled by Poly-metallocene Interfaces.

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

A stem cell-based assay platform demonstrates alpha-synuclein dependent synaptic dysfunction in patient-derived cortical neurons.

Alpha-synuclein (αS)-rich Lewy bodies and neurites in the cerebral cortex correlate with the presence of dementia in Parkinson disease (PD) and Dementia with Lewy bodies (DLB), but whether αS influences synaptic vesicle dynamics in human cortical neurons is unknown. Using a new iPSC-based assay platform for measuring synaptic vesicle cycling, we found that in human cortical glutamatergic neurons, increased αS from either transgenic expression or triplication of the endogenous locus in patient-derived neurons reduced synaptic vesicle cycling under both stimulated and spontaneous conditions. Thus, using a robust, easily adopted assay platform, we show for the first time αS-induced synaptic dysfunction in human cortical neurons, a key cellular substrate for PD dementia and DLB.