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Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.

BackgroundSocial innovations in health are inclusive solutions to address the healthcare delivery gap that meet the needs of end users through a multi-stakeholder, community-engaged process. While social innovations for health have shown promise in closing the healthcare delivery gap, more research is needed to evaluate, scale up, and sustain social innovation. Research checklists can standardize and improve reporting of research findings, promote transparency, and increase replicability of study results and findings.Methods and findingsThe research checklist was developed through a 3-step community-engaged process, including a global open call for ideas, a scoping review, and a 3-round modified Delphi process. The call for entries solicited checklists and related items and was open between November 27, 2019 and February 1, 2020. In addition to the open call submissions and scoping review findings, a 17-item Social Innovation For Health Research (SIFHR) Checklist was developed based on the Template for Intervention Description and Replication (TIDieR) Checklist. The checklist was then refined during 3 rounds of Delphi surveys conducted between May and June 2020. The resulting checklist will facilitate more complete and transparent reporting, increase end-user engagement, and help assess social innovation projects. A limitation of the open call was requiring internet access, which likely discouraged participation of some subgroups.ConclusionsThe SIFHR Checklist will strengthen the reporting of social innovation for health research studies. More research is needed on social innovation for health.

The dynamin GTPase is known to bundle actin filaments, but the underlying molecular mechanism and physiological relevance remain unclear. Our genetic analyses revealed a function of dynamin in propelling invasive membrane protrusions during myoblast fusion in vivo. Using biochemistry, total internal reflection fluorescence microscopy, electron microscopy and cryo-electron tomography, we show that dynamin bundles actin while forming a helical structure. At its full capacity, each dynamin helix captures 12-16 actin filaments on the outer rim of the helix. GTP hydrolysis by dynamin triggers disassembly of fully assembled dynamin helices, releasing free dynamin dimers/tetramers and facilitating Arp2/3-mediated branched actin polymerization. The assembly/disassembly cycles of dynamin promote continuous actin bundling to generate mechanically stiff actin super-bundles. Super-resolution and immunogold platinum replica electron microscopy revealed dynamin along actin bundles at the fusogenic synapse. These findings implicate dynamin as a unique multifilament actin-bundling protein that regulates the dynamics and mechanical strength of the actin cytoskeletal network.

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in Drosophila melanogaster, but it is substantially larger (>18.7 Mb) in D. ananassae To identify the major contributors to the expansion of the F element and to assess their impact, we improved the genome sequence and annotated the genes in a 1.4-Mb region of the D. ananassae F element, and a 1.7-Mb region from the D element for comparison. We find that transposons (particularly LTR and LINE retrotransposons) are major contributors to this expansion (78.6%), while Wolbachia sequences integrated into the D. ananassae genome are minor contributors (0.02%). Both D. melanogaster and D. ananassae F-element genes exhibit distinct characteristics compared to D-element genes (e.g., larger coding spans, larger introns, more coding exons, and lower codon bias), but these differences are exaggerated in D. ananassae Compared to D. melanogaster, the codon bias observed in D. ananassae F-element genes can primarily be attributed to mutational biases instead of selection. The 5' ends of F-element genes in both species are enriched in dimethylation of lysine 4 on histone 3 (H3K4me2), while the coding spans are enriched in H3K9me2. Despite differences in repeat density and gene characteristics, D. ananassae F-element genes show a similar range of expression levels compared to genes in euchromatic domains. This study improves our understanding of how transposons can affect genome size and how genes can function within highly repetitive domains.

Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. In the mammary gland, the identity and characteristics of quiescent epithelial stem cells are not clear. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. Bcl11bhigh cells are enriched for cells that can regenerate mammary glands in secondary transplants. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. Gain- and loss-of-function studies show that Bcl11b induces cells to enter the G0 phase of the cell cycle and become quiescent. Taken together, these results suggest that Bcl11b acts as a central intrinsic regulator of mammary epithelial stem cell quiescence and exhaustion and is necessary for long-term maintenance of the mammary gland.

The current study evaluates the psychometric properties of the Behavior Rating Inventory of Executive Function (BRIEF) with children with Down syndrome. Caregivers of 84 children with Down syndrome rated their child's behavior with the BRIEF. Teacher ratings were obtained for 57 children. About 40% of children with Down syndrome were reported by parents, and 70% by teachers, to exhibit clinically significant challenges with executive functioning. Distribution of scores was normal, internal consistency for subscales was questionable to primarily excellent, and inter-rater reliability was poor to good. Normative data conversions controlled for age, IQ, and gender differences, with some exceptions. The study findings suggest that the BRIEF and its subscales generally performed in a psychometrically sound manner among children with Down syndrome.

Overview: Innovation has become increasingly urgent for companies to maintain competitive advantage, yet deep uncertainty persists regarding the end results of their innovation efforts. Early-stage experimentation offers a risk management approach that can dramatically accelerate cost-effective innovation. Experimentation relies on the scientific method to craft and test hypotheses. Insufficient guidance exists regarding how to help managers harness experimentation in early-stage innovation projects. Based on our observations of experienced experimenters engaged in early-stage innovation projects in four distinct settings, we developed a process model that offers practitioners a structured and scalable approach to foster early-stage experimentation. Managers in all parts of the organization can apply the process model and operationalize experimentation. The article's contribution is twofold: we articulate specific practices associated with choices around what is being tested, how it is being tested, and what is learned, and we offer a model designed to help build managerial literacy in early-stage experimentation. Conducting fast, simple experiments at the early stages of the innovation process offers a valuable way to better manage innovation costs and risks. Experimentation can be codified into a simplified and scalable process, using a 5-step process model proposed here, that can be practiced across organizational levels and functions. An organizational strategic capability for experimentation, developed in a systematic and scalable way, can enhance a firm's ability to adapt to change and exploit opportunities in an uncertain world. [ABSTRACT FROM AUTHOR]

Background: Conversion of laparoscopic cholecystectomy to open is uncommon, but is associated with longer hospital stay and recovery. Prognosticating conversion may aid service planning and provision. We therefore aimed to assess the external validity of the largest risk score for operative conversion. Methods: CHOLENZ was a multicentre, prospective, national cohort study of cholecystectomy for benign biliary disease conducted by STRATA, a trainee‐led collaborative network. Data were collected from patients undergoing cholecystectomy in New Zealand hospitals between 1 August and 30 October 2021 with 30‐day follow‐up. The Conversion from Laparoscopic to Open Cholecystectomy (CLOC) score from the CholeS study was assessed for external validity by interrogating its accuracy and calibration in the CHOLENZ dataset. Results: Of 1162 cholecystectomies started laparoscopically, 20 (1.7%) were converted to open in the CHOLENZ dataset. The CLOC score predicted 2.9% (IQR 1.3%–8.1%) would be converted. Area under the curve was 0.65 (95% 0.51–0.79) and calibration was acceptable with a Hosmer‐Lemeshow p value of 0.45; with evidence of tendency to overestimate with interrogation of calibration across a continuous risk profile (intercept 1.27, slope 0.4). Sensitivity analysis with imputed data improved accuracy. Recalibration with the addition of body mass index, and preoperative bilirubin also improved accuracy to 0.86 (95% CI 0.78–0.95). Conclusions: The CLOC score in its original form is not generalisable to the Aotearoa New Zealand setting and is therefore not suitable for clinical use in our local setting. [ABSTRACT FROM AUTHOR]