The rockefeller university

BackgroundRed mullet (Mullus barbatus) is a key species in Mediterranean fisheries, yet its stock structure and population dynamics remain poorly understood due to a lack of comprehensive genomic resources. This study provides the first high-quality reference genome for M. barbatus and a comprehensive set of SNP markers to investigate its population structure and adaptive potential across the Mediterranean.ResultsUsing the newly generated chromosome-level reference genome, we re-analyzed a Mediterranean-wide reduced-representation genomic dataset. Our analysis reveals a panmictic population structure with strong genetic connectivity across the species' range, likely driven by extensive larval dispersal and multigenerational gene flow. Despite minimal genome-wide differentiation, outlier analysis identified candidate loci under directional selection, linked to key biological processes such as ontogeny and environmental adaptation.ConclusionsThis study presents the first genomic resource for M. barbatus, providing valuable insights into its genetic structure and adaptive mechanisms. While the identification of loci under selection offers promising leads, these findings are preliminary due to the limited genomic coverage of the dataset. Nonetheless, they pave the way for future genomic studies to explore how M. barbatus adapts to environmental and anthropogenic pressures. These results hold significant implications for the sustainable management of Mediterranean fisheries, especially in the context of climate change and conservation.

Juvenile hormones (JH) regulate insect development, reproduction, and behavior. The JH analog Methoprene, widely used in pest control, disrupts these processes by inhibiting maturation rather than causing mortality. Beyond its physiological effects, Methoprene influences insect behavior, including mate choice, social organization, and foraging, by altering neuronal sensitivity and gene expression via the Methoprene-tolerant receptor. These behavioral disruptions may negatively impact insect populations, including pollinators like honeybees. While laboratory studies highlight Methoprene's behavioral consequences, field research is needed to assess its ecological effects. Understanding these broader impacts is crucial for evaluating the risks associated with JH-based pest control strategies.

Biallelic pathogenic variants in the essential DNA repair gene BRCA2 cause Fanconi anemia complementation group D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under Sonic Hedgehog (SHH) activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 Delta ex3-4;Trp53-/- animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping putative G-quadruplexes (G4s). Brca2-deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary medulloblastoma tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2-deficient medulloblastomas.

BackgroundWe sought to determine the comparative effectiveness of two strategies for assigning care coordinators to people living with dementia (PLWD) and their caregivers.MethodsWe conducted a pragmatic randomized clinical trial embedded in a Medicare accountable care organization (ACO) in New York, NY in 2022-2024. We included community-dwelling PLWD >= 65 years who were attributed to the ACO and had highly fragmented ambulatory care in the previous year (reversed Bice-Boxerman Index >= 0.86). The trial compared usual care (assigning care coordinators to PLWD after hospital discharge) to usual care plus proactive outreach, which assigned care coordinators to PLWD if they or their caregivers reported difficulty with care coordination on a telephone survey. Participants were followed for the combined outcome of emergency department (ED) visit or hospitalization.ResultsAmong the 385 PLWD in the trial, the mean age was 82.6 years (SD 6.9), and 56.4% were female. Overall, participants had had a mean of 14.9 ambulatory visits to 8.9 different providers the previous year. The acceptance rate of care management was higher in the control group (73.7%) than in the intervention group (38.0%). Care coordinators were ultimately assigned to 14 of 192 PLWD in the control group (7.3%) and 19 of 193 PLWD in the intervention group (9.8%). The intention-to-treat analysis (N = 385) found a trend toward fewer ED visits in the intervention group (0.14 ED visits per 100 person-days alive vs. 0.18 ED visits per 100 person-days alive, p = 0.07) but no difference in the combined outcome of ED visit or hospitalization (p = 0.71).ConclusionAlthough the particular intervention we tested was not more effective than usual care, this trial is novel in that it used highly fragmented care as an inclusion criterion and shows that more work is needed to address fragmented care among PLWD.

Background/Objectives: While single variants may have only small effects on common heritable traits like schizophrenia, methods for combining such effects over multiple variants have been proposed for more than 30 years. The currently favored approaches are polygenic risk scores. Their main aim is the genetic prediction of phenotypes. Methods: To accommodate the inherent genetic heterogeneity between males and females, we separated them into two independent datasets and in each developed allelic polygenic risk scores. We focused on variants with high predictability rather than high statistical significance and derived a statistical test to assess the significance of results obtained in one sex and replicated in the other sex. Results: As few as 5000 highly predictive variants achieved accuracy exceeding 95% in each of males and females, and only 2.8% and 3.3% of cases and controls were misclassified in females and males, respectively. Conclusions: Our allelic polygenic risk scores are based on individual genotypes rather than summary statistics and produce highly accurate, cross-validated phenotype predictions. Although variants were originally selected as being highly predictive rather than statistically significant, 544 disease-associated variants were shown to be significantly shared between males and females, which represents a replication in an independent dataset.

Like the sensory organs of the human inner ear, the lateral-line neuromasts (NMs) of fish such as the zebrafish (Danio rerio) contain mechanosensory hair cells (HCs) that are surrounded by supporting cells (SCs). A damaged NM can quickly regenerate new HCs by expressing genes such as atoh1a, the master regulator of HC fate, in the SCs at the NM's center. We used the supervised learning algorithm DELAY to infer the early gene-regulatory network for regenerating central SCs and HCs and identified adaptations that promote the rapid regeneration of lateral-line HCs in larval zebrafish. The top hub in the network, Y-box binding protein 1 (ybx1), is highly expressed in HC progenitors and young HCs and its protein can recognize DNA-binding motifs in cyprinids' candidate regeneration-responsive promoter element for atoh1a. We showed that NMs from ybx1 mutant zebrafish larvae display consistent, regeneration-specific deficits in HC number and initiate both HC regeneration and atoh1a expression 20% slower than in wild-type siblings. By demonstrating that ybx1 promotes rapid HC regeneration through early atoh1a upregulation, the results support DELAY's ability to identify key temporal regulators of gene expression.

Background Inborn errors of immunity (IEI) are inherited defects of innate or adaptive immune system. Thrombocytopenia is a significant multifactorial complication in IEI patients leading to severe clinical consequences including coagulative disorders and vasculopathies. Methods In the present study, we assessed frequency of thrombocytopenia in the most common IEI including combined immunodeficiency (CID), common variable immunodeficiency (CVID), selective immunoglobulin A deficiency (SIgAD), agammaglobulinemia (AGA), hyper immunoglobulin M (HIGM) syndrome, chronic granulomatous disease (CGD) and congenital neutropenia (CN). Also, we compared demographic, clinical and laboratory data between IEI patients with and without thrombocytopenia. Results A total of 890 patients (37% female) were included in this study. The frequency of thrombocytopenia in total IEI was 26.6%. Patients with CID and SIgAD had the highest and lowest frequency of thrombocytopenia (50.9% and 8.7%), respectively. Although rare, thrombocytopenia was more severe (< 50000/ul) among patients with AGA compared to other IEI entities. Notably hepatosplenomegaly and autoimmunity were significantly associated with thrombocytopenia and higher mortality in patients with humoral immunodeficiencies. Conclusion The significant association between thrombocytopenia with lymphoproliferation and autoimmunity emphasizes the importance of paying attention to these clinical features for suspecting IEI disorders. Understanding the pathophysiology of thrombocytopenia in various genetic defects associated with IEI is required for the development of proper diagnostic and therapeutic techniques as well as improved quality of life of these patients.

Replication of cellular chromosomes requires a primase to generate short RNA primers to initiate genomic replication. While bacterial and archaeal primase generate short RNA primers, the eukaryotic primase, Polc-primase, contains both RNA primase and DNA polymerase (Pol) subunits that function together to form a >20 base hybrid RNA-DNA primer. Interestingly, the DNA Pol1 subunit of Polc lacks a 3'- 5' proofreading exonuclease, contrary to the high-fidelity normally associated with DNA replication. However, Polo and Pol epsilon synthesize the majority of the eukaryotic genome, and both contain 3'- 5' exonuclease activity for high fidelity. Nonetheless, even the small amount of DNA produced by Pol1 in each of the many RNA/DNA primers during chromosome replication adds up to tens of millions of nucleotides in a human genome. Thus, it has been a longstanding question why Pol1 lacks a proofreading exonuclease. We show here that Polc is uniquely capable of traversing common oxidized or hydrolyzed template nucleotides and propose that Polc evolved to bypass these common template lesions when they are encountered during chromosome replication. Additionally, we show a unique ability of replication factor C (RFC) to stimulate Polo lesion bypass, independent of its sliding clamp. This suggests that there may be a coordination between Polo and RFC that does not involve RFC loading of PCNA.