3 research outputs found
Long term stability and infectivity of herpesviruses in water
For viruses to utilize environmental vectors (hard surfaces, soil, water) for
transmission, physical and chemical stability is a prerequisite. There are
many factors including pH, salinity, temperature, and turbidity that are known
to contribute to the ability of viruses to persist in water. Equine
herpesvirus type-1 (EHV-1) is a pathogenic alphaherpesvirus associated with
domestic horses and wild equids. EHV-1 and recombinants of EHV-1 and EHV-9 are
able to cause infections in non-equid animal species, particularly in captive
settings. Many of the captive non-equid mammals are not naturally sympatric
with equids and do not share enclosures, however, in many cases water sources
may overlap. Similarly, in the wild, equids encounter many species at
waterholes in times of seasonal drought. Therefore, we hypothesized that EHV-1
is stable in water and that water may act as a vector for EHV-1. In order to
establish the conditions promoting or hindering EHV-1 longevity, infectivity
and genomic stability in water; we exposed EHV-1 to varied water environments
(pH, salinity, temperature, and turbidity) in controlled experiments over 21
days. The presence and infectivity of the virus was confirmed by both qPCR and
cell culture experiments. Our results show that EHV-1 remains stable and
infectious under many conditions in water for up to three weeks
mTORC1 Inhibition Corrects Neurodevelopmental and Synaptic Alterations in a Human Stem Cell Model of Tuberous Sclerosis
Hyperfunction of the mTORC1 pathway has been associated with idiopathic and syndromic forms of autism spectrum disorder (ASD), including tuberous sclerosis, caused by loss of either TSC1 or TSC2. It remains largely unknown how developmental processes and biochemical signaling affected by mTORC1 dysregulation contribute to human neuronal dysfunction. Here, we have characterized multiple stages of neurogenesis and synapse formation in human neurons derived from TSC2-deleted pluripotent stem cells. Homozygous TSC2 deletion causes severe developmental abnormalities that recapitulate pathological hallmarks of cortical malformations in patients. Both TSC2+/â and TSC2â/â neurons display altered synaptic transmission paralleled by molecular changes in pathways associated with autism, suggesting the convergence of pathological mechanisms in ASD. Pharmacological inhibition of mTORC1 corrects developmental abnormalities and synaptic dysfunction during independent developmental stages. Our results uncouple stage-specific roles of mTORC1 in human neuronal development and contribute to a better understanding of the onset of neuronal pathophysiology in tuberous sclerosis
Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors
© 2020 The Authors Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC. In the pursuit of hormone receptor modulators in prostate cancer, a potent, ultraselective CDK9 inhibitor is discovered. This study describes the most selective inhibitors of CDK9 known to date and provides compelling preclinical in vitro and in vivo support for CDK9 as a therapeutic target