Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated in Prostate Cancer and Chronic Fatigue Syndrome

Xenotropic murine leukemia-related retrovirus (XMRV) is a recently discovered retrovirus that has been linked to human prostate cancer and chronic fatigue syndrome (CFS). Both diseases affect a large fraction of the world population, with prostate cancer affecting one in six men, and CFS affecting an estimated 0.4 to 1% of the population.. We found that the retroviral integrase inhibitor, raltegravir, was potent and selective against XMRV at submicromolar concentrations, in MCF-7 and LNCaP cells, a breast cancer and prostate cancer cell line, respectively. Another integrase inhibitor, L-000870812, and two nucleoside reverse transcriptase inhibitors, zidovudine (ZDV), and tenofovir disoproxil fumarate (TDF) also inhibited XMRV replication. When combined, these drugs displayed mostly synergistic effects against this virus, suggesting that combination therapy may delay or prevent the selection of resistant viruses.If XMRV proves to be a causal factor in prostate cancer or CFS, these discoveries may allow for rational design of clinical trials

APOE loss-of-function variants: Compatible with longevity and associated with resistance to Alzheimers disease pathology.

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimers disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive supranuclear palsy, and one carrier was affected by AD with an unremarkable age at onset of 75 years. Two APOE ε3/ε4 controls carried a stop-gain affecting ε4: one was cognitively normal at 90 years and had no neuritic plaques at autopsy; the other was cognitively healthy at 79 years, and lumbar puncture at 76 years showed normal levels of amyloid. These results suggest that ε4 drives AD risk through the gain of abnormal function and support ε4 knockdown as a viable therapeutic option

Accelerated Identification of Disease-Causing Variants With Ultra-Rapid Nanopore Genome Sequencing

Whole-genome sequencing (WGS) can identify variants that cause genetic disease, but the time required for sequencing and analysis has been a barrier to its use in acutely ill patients. In the present study, we develop an approach for ultra-rapid nanopore WGS that combines an optimized sample preparation protocol, distributing sequencing over 48 flow cells, near real-time base calling and alignment, accelerated variant calling and fast variant filtration for efficient manual review. Application to two example clinical cases identified a candidate variant inprioritization, and accelerates diagnostic clinical genome sequencing twofold compared with previous approaches

Left ventricular trabeculation in Hominidae : divergence of the human cardiac phenotype

DATA AVAILABILITY : The data that support the findings of this study are available in Figshare repository with the identifiers: https://doi.org/10.6084/m9.figshare.24274852 and https://doi.org/10.6084/m9.figshare.24274855.Although the gross morphology of the heart is conserved across mammals, subtle interspecific variations exist in the cardiac phenotype, which may reflect evolutionary divergence among closely-related species. Here, we compare the left ventricle (LV) across all extant members of the Hominidae taxon, using 2D echocardiography, to gain insight into the evolution of the human heart. We present compelling evidence that the human LV has diverged away from a more trabeculated phenotype present in all other great apes, towards a ventricular wall with proportionally greater compact myocardium, which was corroborated by post-mortem chimpanzee (Pan troglodytes) hearts. Speckle-tracking echocardiographic analyses identified a negative curvilinear relationship between the degree of trabeculation and LV systolic twist, revealing lower rotational mechanics in the trabeculated non-human great ape LV. This divergent evolution of the human heart may have facilitated the augmentation of cardiac output to support the metabolic and thermoregulatory demands of the human ecological niche.The Natural Sciences and Engineering Research Council and the Canadian Foundation for Innovation.https://www.nature.com/commsbio/hj2024Centre for Veterinary Wildlife StudiesSDG-03:Good heatlh and well-bein

Rapid Sequencing Wet Lab v1

Aim: To prepare an ONT non-barcoded library using LSK109, to be distributed over 48 flow cells from 2ml of whole blood. </p