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Hatfield Lamm posted an update 6 months ago
Tools for tuning transcription in mammalian cells have broad applications, from basic biological discovery to human gene therapy. While precise control over target gene transcription via dosing with small molecules (drugs) is highly sought, the design of such inducible systems that meets required performance metrics poses a great challenge in mammalian cell synthetic biology. Important characteristics include tight and tunable gene expression with a low background, minimal drug toxicity, and orthogonality. Here, we review small-molecule-inducible transcriptional control devices that have demonstrated success in mammalian cells and mouse models. Most of these systems employ natural or designed ligand-binding protein domains to directly or indirectly communicate with transcription machinery at a target sequence, via carefully constructed fusions. Example fusions include those to transcription activator-like effectors (TALEs), DNA-targeting proteins (e.g. dCas systems) fused to transactivating domains, and recombinases. Similar to the architecture of Type I nuclear receptors, many of the systems are designed such that the transcriptional controller is excluded from the nucleus in the absence of an inducer. Techniques that use ligand-induced proteolysis and antibody-based chemically induced dimerizers are also described. Collectively, these transcriptional control devices take advantage of a variety of recently developed molecular biology tools and cell biology insights and represent both proof of concept (e.g. targeting reporter gene expression) and disease-targeting studies.Uncontrolled hypertension is a leading contributor to cardiovascular disease. A cluster-randomized trial in 16 primary care clinics showed that 12 months of home blood pressure telemonitoring and pharmacist management lowered blood pressure more than usual care (UC) for 24 months. We report cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, hospitalized heart failure, coronary revascularization, and cardiovascular death) and costs over 5 years of follow-up. In the telemonitoring intervention (TI group, n=228), there were 15 cardiovascular events (5 myocardial infarction, 4 stroke, 5 heart failure, 1 cardiovascular death) among 10 patients. In UC group (n=222), there were 26 events (11 myocardial infarction, 12 stroke, 3 heart failure) among 19 patients. The cardiovascular composite end point incidence was 4.4% in the TI group versus 8.6% in the UC group (odds ratio, 0.49 , P=0.09). Including 2 coronary revascularizations in the TI group and 10 in the UC group, the secondary cardiovascular composite end point incidence was 5.3% in the TI group versus 10.4% in the UC group (odds ratio, 0.48 , P=0.08). Microsimulation modeling showed the difference in events far exceeded predictions based on observed blood pressure. Intervention costs (in 2017 US dollars) were $1511 per patient. Over 5 years, estimated event costs were $758 000 in the TI group and $1 538 000 in the UC group for a return on investment of 126% and a net cost savings of about $1900 per patient. Telemonitoring with pharmacist management lowered blood pressure and may have reduced costs by avoiding cardiovascular events over 5 years. Registration- URL https//www.clinicaltrials.gov; Unique identifier NCT00781365.Kidney diseases secondary to several pathogeneses affect millions of people worldwide and have become increasingly recognized as a global public health problem. Recent evidence suggests that cellular senescence plays an important role in the pathogenesis of different forms of renal damage, including acute and chronic kidney disease, and renal transplantation. Renal senescence involves cell cycle arrest and affects several cellular pathways, manifesting in downregulation of klotho, elevated expression of cyclin-dependent kinase inhibitors, cellular telomere shortening, and oxidative stress. Furthermore, senescent cells might induce kidney injury by paracrine release of inflammatory factors. Yet, cellular senescence may be renoprotective during development and in some models of renal diseases, reflecting the yin/yang duality of cellular senescence. This review provides an overview of the role of this emerging player in renal injury, with emphasis on new findings of cellular senescence.The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. BI-4020 ic50 Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while recording fetal cardiovascular function as the hypoxic pregnancy is occurring. We use novel technology in sheep pregnancy that combines induction of controlled chronic hypoxia with simultaneous, wireless recording of blood pressure and blood flow signals from the fetus. Here, we investigated the cardiovascular defense of the hypoxic fetus to superimposed acute hypotension. Pregnant ewes carrying singleton fetuses surgically prepared with catheters and flow probes were randomly exposed to normoxia or chronic hypoxia from 121±1 days of gestation (term ≈145 days). After 10 days of exposure, fetuses were subjected to acute hypotension via fetal nitroprusside intravenous infusion. Underlying in vivo mechanisms were explored by (1) analyzing fetal cardiac and peripheral vasomotor baroreflex function; (2) measuring the fetal plasma catecholamines; and (3) establishing fetal femoral vasoconstrictor responses to the α1-adrenergic agonist phenylephrine. Relative to controls, chronically hypoxic fetal sheep had reversed cardiac and impaired vasomotor baroreflex function, despite similar noradrenaline and greater adrenaline increments in plasma during hypotension. Chronic hypoxia markedly diminished the fetal vasopressor responses to phenylephrine. Therefore, we show that the chronically hypoxic fetus displays markedly different cardiovascular responses to acute hypotension, providing in vivo evidence of mechanisms linking its greater susceptibility to superimposed stress.
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