Biology subjects

Levin, B.

Publications and source records attributed to Levin, B..

8 recordsLinked to original sources

bioRxiv2024

Relationships of hematocrit concentration with dementia from a multiethnic population-based study

ObjectiveRed blood cell (RBC) concentration impacts cerebrovascular disease, yet it is unclear whether RBC concentrations relate to dementia risk, particularly in racially/ethnically diverse cohorts. We investigated whether RBC concentrations associate with incident dementia risk in a diverse population of stroke-free individuals and explored whether cerebral small vessel disease (CSVD) mediates this relationship. MethodsA longitudinal observational analysis was performed using a population-based cohort of stroke-free, older adult participants (>50 years) from the Northern Manhattan Study (NOMAS) enrolled between 2003-2008. Participants received baseline hematocrit testing, MRI neuroimaging, and cognitive assessments at baseline and long-term follow-up. Associations of baseline hematocrit as a categorical variable (low, normal [reference], and high based on laboratory reference levels) with incident dementia were assessed using Cox models adjusting for relevant covariates. Separate analyses investigated whether MRI CSVD mediated these relationships. ResultsWe studied 1207 NOMAS participants (mean age 71{+/-}9 years, 60% female, 66% Hispanic). Mean hematocrit was 41.2% ({+/-}3.8) with 16% of participants developing incident dementia. Lower hematocrit associated with increased dementia risk (adjusted hazard ratio 1.81 [1.01-3.23]) after adjusting for age, sex, race/ethnicity, education, APOE status, and comorbidities. High hematocrit was not associated with dementia risk. No interactions by sex or race/ethnicity were seen and baseline CSVD did not mediate relationships between hematocrit and dementia. ConclusionsLow hematocrit associated with dementia risk in our diverse population cohort. Further work is needed to assess mechanisms behind anemias relationship with dementia to assess whether this can serve as a trackable, preventable/treatable risk factor for dementia.

neuroscience↗

bioRxiv2024

Cyclin A/B RxL Macrocyclic Inhibitors to Treat Cancers with High E2F Activity

Cancer cell proliferation requires precise control of E2F1 activity; excess activity promotes apoptosis. Here, we developed cell-permeable and bioavailable macrocycles that selectively kill small cell lung cancer (SCLC) cells with inherent high E2F1 activity by blocking RxL-mediated interactions of cyclin A and cyclin B with select substrates. Genome-wide CRISPR/Cas9 knockout and random mutagenesis screens found that cyclin A/B RxL macrocyclic inhibitors (cyclin A/Bi) induced apoptosis paradoxically by cyclin B- and Cdk2-dependent spindle assembly checkpoint activation (SAC). Mechanistically, cyclin A/Bi hyperactivate E2F1 and cyclin B by blocking their RxL-interactions with cyclin A and Myt1, respectively, ultimately leading to SAC activation and mitotic cell death. Base editor screens identified cyclin B variants that confer cyclin A/Bi resistance including several variants that disrupted cyclin B:Cdk interactions. Unexpectedly but consistent with our base editor and knockout screens, cyclin A/Bi induced the formation of neo-morphic Cdk2-cyclin B complexes that promote SAC activation and apoptosis. Finally, orally-bioavailable cyclin A/Bi robustly inhibited tumor growth in chemotherapy-resistant patient-derived xenograft models of SCLC. This work uncovers gain-of-function mechanisms by which cyclin A/Bi induce apoptosis in cancers with high E2F activity, and suggests cyclin A/Bi as a therapeutic strategy for SCLC and other cancers driven by high E2F activity.

cancer biology↗

bioRxiv2024

Reconstructing the evolutionary history of freshwater fishes (Nemacheilidae) across Eurasia since early Eocene

Eurasia has undergone substantial tectonic, geological, and climatic changes throughout the Cenozoic era, primarily associated with tectonic plate collisions and a global cooling trend. The evolution of present-day biodiversity unfolded in this dynamic environment, characterised by intricate interactions of abiotic factors. However, comprehensive, large-scale reconstructions illustrating the extent of these influences are lacking. We reconstructed the evolutionary history of the freshwater fish family Nemacheilidae across Eurasia and spanning most of the Cenozoic era on the base of 471 specimens representing 279 species and 37 genera. Molecular phylogeny using 6 genes uncovered six major clades within the family, along with numerous unresolved taxonomic issues. Dating of cladogenetic events and ancestral range estimation traced the origin of Nemacheilidae to Indochina around 48 million years ago. Subsequently, one branch of Nemacheilidae colonised eastern, central, and northern Asia, as well as Europe, while another branch expanded into the Burmese region, the Indian subcontinent, the Near East, and northeast Africa. These expansions were facilitated by tectonic connections, favourable climatic conditions, and orogenic processes. Conversely, aridification emerged as the primary cause of extinction events. Our study marks the first comprehensive reconstruction of the evolution of Eurasian freshwater biodiversity on a continental scale and across deep geological time.

evolutionary biology↗

bioRxiv2023

Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility in Atrial Fibrillation

BackgroundAtrial fibrillation (AF), the most common sustained cardiac arrhythmia, increases thromboembolic stroke risk five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C, the PP1 regulatory subunit targeting atrial myosin light chain 2 (MLC2a), causes hypophosphorylation of MLC2a and results in atrial hypocontractility. MethodsRight atrial appendage tissues were isolated from human AF patients versus sinus rhythm (SR) controls. Western blots, co-immunoprecipitation, and phosphorylation studies were performed to examine how the PP1c-PPP1R12C interaction causes MLC2a de-phosphorylation. In vitro studies of pharmacologic MRCK inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with EP studies. ResultsIn human patients with AF, PPP1R12C expression was increased two-fold versus SR controls (P=2.0x10-2, n=12,12 in each group) with > 40% reduction in MLC2a phosphorylation (P=1.4x10-6, n=12,12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9x10-2 and 6.7x10-3 respectively, n=8,8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Lenti-12C mice demonstrated a 150% increase in LA size versus controls (P=5.0x10-6, n=12,8,12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in Lenti-12C mice was significantly higher than controls (P=1.8x10-2 and 4.1x10-2 respectively, n= 6,6,5). ConclusionsAF patients exhibit increased levels of PPP1R12C protein compared to controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

molecular biology↗

bioRxiv2021

Adaptive radiation and burst speciation of hillstream cyprinid fish in African river

Adaptive radiation of fishes was long thought to be possible only in lacustrine environments. Recently, several studies have shown that also riverine and stream environments provide the ecological opportunity for adaptive radiation. In this study, we report on a riverine adaptive radiation of six ecomorphs of cyprinid hillstream fishes of the genus Garra in a river located in the Ethiopian Highlands in East Africa. Garra are predominantly highly specialized algae-scrapers with a wide distribution ranging from Southeastern Asia to Western Africa. However, adaptive phenotypic diversification in mouth type, sucking disc morphology, gut length and body shape have been found among these new species in a single Ethiopian river. Moreover, we found two novel phenotypes of Garra ( thick-lipped and predatory) that were not described before in this species-rich genus (>160 species). Mitochondrial and genome-wide data suggest monophyletic, intra-basin evolution of Garra phenotypic diversity with signatures of gene flow from other local populations. Although sympatric ecomorphs are genetically distinct and can be considered to being young species as suggested by genome-wide SNP data, mtDNA was unable to identify any genetic structure suggesting a recent and rapid speciation event. Furthermore, we found evidence for a hybrid origin of the novel thick-lipped phenotype, as being the result of the hybridization of two other sympatrically occurring species. Here we highlight how, driven by ecological opportunity, an ancestral trophically highly specialized lineage is likely to have rapidly adaptively radiated in a riverine environment, and that this radiation was promoted by the evolution of novel feeding strategies.

evolutionary biology↗

bioRxiv2018

Adaptive radiation of barbs of the genus Labeobarbus (Cyprinidae) in the East African river

Large African barbs of the genus Labeobarbus are widely distributed in African freshwaters, and exhibit profound phenotypic plasticity that could be a prerequisite for adaptive radiation. Using morphological, molecular, and stable isotope analyses, we investigated whether an adaptive radiation has occurred in a riverine assemblage of the L. gananensis complex. This complex is composed of six phenotypically distinct sympatric forms inhabiting the Genale River (Ethiopian highlands, East Africa). Of the six forms, five were divergent in their mouth morphology, corresponding to generalized, lipped, scraping (two forms) and large-mouthed phenotypes. Stable isotope analysis revealed differences in 15N and 13C among these forms, representing different foraging strategies (omnivorous, scraping and piscivorous). Phylogenetic analysis of two mtDNA markers confirmed the monophyly of L. gananensis, suggesting an intra-riverine radiation. However, the Genale assemblage appears to have originated through a combination of allopatric and sympatric events. Some of the specialized forms within this drainage originated independently from the local generalized forms in three different river regions within local mini-flocks composed of two to three sympatric forms. Our study shows that adaptive radiation in rivers can be enhanced by a combination of sympatric speciation and temporal geographic isolation, leading to local sympatric speciation followed by migration.

evolutionary biology↗

bioRxiv2018

Short-term effectiveness of HIV care coordination among persons with recent HIV diagnosis or history of poor HIV outcomes

The New York City HIV Care Coordination Program (CCP) combines multiple evidence-based strategies to support persons living with HIV (PLWH) at risk for, or with a recent history of, poor HIV outcomes. We assessed the comparative effectiveness of the CCP by merging programmatic data on CCP clients with population-based surveillance data on all New York City PLWH. A non-CCP comparison group of similar PLWH who met CCP eligibility criteria was identified using surveillance data. The CCP and non-CCP groups were matched on propensity for CCP enrollment within four baseline treatment status groups (newly diagnosed or previously diagnosed and either consistently unsuppressed, inconsistently suppressed or consistently suppressed). We compared CCP to non-CCP proportions with viral load suppression at 12-month follow-up. Among the 13,624 persons included, 15{middle dot}3% were newly diagnosed; among the 84{middle dot}7% previously diagnosed, 14{middle dot}2% were consistently suppressed, 28{middle dot}9% were inconsistently suppressed, and 41 {middle dot}6% were consistently unsuppressed in the year prior to baseline. At 12-month follow-up, 59{middle dot}9% of CCP and 53{middle dot}9% of non-CCP participants had viral load suppression (Relative Risk=1.11, 95%CI:1.08-1.14). Among those newly diagnosed and those consistently unsuppressed at baseline, the relative risk of viral load suppression in the CCP versus non-CCP participants was 1.15 (95%CI:1.09-1.23) and 1.32 (95%CI:1.23-1.42), respectively. CCP exposure shows benefits over no CCP exposure for persons newly diagnosed or consistently unsuppressed, but not for persons suppressed in the year prior to baseline. We recommend more targeted case finding for CCP enrollment and increased attention to viral load suppression maintenance.

epidemiology↗

bioRxiv2017

Immune Loss as a Driver of Coexistence During Host-Phage Coevolution

Bacteria and their viral pathogens face constant pressure for augmented immune and infective capabilities, respectively. Under this reciprocally imposed selective regime, we expect to see a runaway evolutionary arms race, ultimately leading to the extinction of one species. Despite this prediction, in many systems host and pathogen coexist with minimal coevolution even when well-mixed. Previous work explained this puzzling phenomenon by invoking fitness tradeoffs, which can diminish an arms race dynamic. Here we propose that the regular loss of immunity by the bacterial host can also produce host-phage coexistence. We pair a general model of immunity with an experimental and theoretical case study of the CRISPR-Cas immune system to contrast the behavior of tradeoff and loss mechanisms in well-mixed systems. We find that, while both mechanisms can produce stable coexistence, only immune loss does so robustly within realistic parameter ranges.

ecology↗