Artificial intelligence and machine learning have demonstrated their potential role in predictive chemistry and synthetic planning of small molecules; there are at least a few reports of companies ...employing in silico synthetic planning into their overall approach to accessing target molecules. A data-driven synthesis planning program is one component being developed and evaluated by the Machine Learning for Pharmaceutical Discovery and Synthesis (MLPDS) consortium, comprising MIT and 13 chemical and pharmaceutical company members. Together, we wrote this perspective to share how we think predictive models can be integrated into medicinal chemistry synthesis workflows, how they are currently used within MLPDS member companies, and the outlook for this field.
On the 400th anniversary of Harvey's Lumleian lectures, this review focuses on "hemodynamic" forces associated with the movement of blood through arteries in humans and the functional and structural ...adaptations that result from repeated episodic exposure to such stimuli. The late 20th century discovery that endothelial cells modify arterial tone via paracrine transduction provoked studies exploring the direct mechanical effects of blood flow and pressure on vascular function and adaptation in vivo. In this review, we address the impact of distinct hemodynamic signals that occur in response to exercise, the interrelationships between these signals, the nature of the adaptive responses that manifest under different physiological conditions, and the implications for human health. Exercise modifies blood flow, luminal shear stress, arterial pressure, and tangential wall stress, all of which can transduce changes in arterial function, diameter, and wall thickness. There are important clinical implications of the adaptation that occurs as a consequence of repeated hemodynamic stimulation associated with exercise training in humans, including impacts on atherosclerotic risk in conduit arteries, the control of blood pressure in resistance vessels, oxygen delivery and diffusion, and microvascular health. Exercise training studies have demonstrated that direct hemodynamic impacts on the health of the artery wall contribute to the well-established decrease in cardiovascular risk attributed to physical activity.
Physical activity has profound impacts on the vasculature in humans. Acute exercise induces immediate changes in artery function, whereas repeated episodic bouts of exercise induce chronic functional ...adaptation and, ultimately, structural arterial remodeling. The nature of these changes in function and structure are dependent on the characteristics of the training load and may be modulated by other factors such as exercise-induced inflammation and oxidative stress. The clinical implications of these physiological adaptations are profound. Exercise impacts on the development of atherosclerosis and on the incidence of primary and secondary cardiovascular events, including myocardial infarction and stroke. Exercise also plays a role in the amelioration of other chronic diseases that possess a vascular etiology, including diabetes and dementia. The mechanisms responsible for these effects of exercise on the vasculature are both primary and secondary in nature, in that the benefits conferred by changes in cardiovascular risk factors such as lipid profiles and blood pressure occur in concert with direct effects of arterial shear stress and mechanotransduction. From an evolutionary perspective, exercise is an essential stimulus for the maintenance of vascular health:
.
In humans, exercise training and moderate to high levels of physical activity are protective against cardiovascular disease.
In fact they are â¼40% more protective than predicted based on the ...changes in traditional risk factors (blood lipids, hypertension,
diabetes etc.) that they cause. In this review, we highlight the positive effects of exercise on endothelial function and
the autonomic nervous system. We also ask if these effects alone, or in combination, might explain the protective effects
of exercise against cardiovascular disease that appear to be independent of traditional risk factor modification. Our goal
is to use selected data from our own work and that of others to stimulate debate on the nature and cause of the ârisk factor
gap' associated with exercise and physical activity.
Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease ...(CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.
Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease (CVD). Endothelial dysfunction is an early manifestation of atherosclerosis and an important ...prognostic marker for future cardiovascular events. The aim of this study was twofold: to examine 1) the association between liver fat, visceral adipose tissue (VAT), and endothelial dysfunction in obese NAFLD patients and 2) the impact of supervised exercise training on this vascular defect. Brachial artery endothelial function was assessed by flow-mediated dilatation (FMD) in 34 obese NAFLD patients and 20 obese controls of similar age and cardiorespiratory fitness peak oxygen uptake (V̇o2 peak) (48 ± 2 vs. 47 ± 2 yr; 27 ± 1 vs. 26 ± 2 ml·kg−1·min−1−1). Magnetic resonance imaging and spectroscopy quantified abdominal and liver fat, respectively. Twenty-one NAFLD patients completed either 16 wk of supervised moderate-intensity exercise training (n = 13) or conventional care (n = 8). Differences between NAFLD and controls were compared using independent t-tests and effects of interventions by analysis of covariance. NAFLD patients had higher liver fat 11.6% (95% CI = 7.4, 18.1), P < 0.0005 and VAT 1.6 liters (95% CI = 1.2, 2.0), P < 0.0001 than controls and exhibited impaired FMD compared with controls −3.6% (95% CI = −4.9, −2.2), P < 0.0001. FMD was inversely correlated with VAT (r = −0.54, P = 0.001) in NAFLD, although the impairment in FMD remained following covariate adjustment for VAT 3.1% (95% CI = 1.8, 4.5), P < 0.001. Exercise training, but not conventional care, significantly improved V̇o2 peak 9.1 ml·kg−1·min−1 (95% CI = 4.1, 14.1); P = 0.001 and FMD 3.6% (95% CI = 1.6, 5.7), P = 0.002. Endothelial dysfunction in NAFLD cannot be fully explained by excess VAT but can be reversed with exercise training; this has potential implications for the primary prevention of CVD in NAFLD.
In 2007, the NASA Hyperspectral InfraRed Imager (HyspIRI) mission was recommended in Earth Science and Applications from Space: National Imperatives for the Next Decade and Beyond (Decadal Survey) to ...address critical science questions in multiple areas, in particular ecosystems and natural hazards. HyspIRI is comprised of two instruments, a visible to short-wavelength infrared (VSWIR) imaging spectrometer and a thermal infrared (TIR) multispectral imager, together with an Intelligent Payload Module (IPM) for onboard processing and rapid downlink of selected data. The VSWIR instrument will have 10nm contiguous bands and cover the 380–2500nm spectral range with 30m spatial resolution and a revisit of 16days. The TIR instrument will have 8 discrete bands in the 4–13μm range with 60m spatial resolution and a revisit of 5days. With these two instruments in low Earth orbit, HyspIRI will be able to address key science and applications questions in a wide array of fields, ranging from ecosystem function and diversity to human health and urbanization.
Display omitted
•The HyspIRI mission was recommended in the 2007 Earth Science Decadal Survey.•HyspIRI would have 2 instruments: a VSWIR imaging spectrometer and a multiband TIR.•Global coverage, frequent revisits (5–16days), good spatial resolution (30–60m)•HyspIRI addresses unique and urgent Earth science and applications objectives.
Two populations of Nkx2-1+ progenitors in the developing foregut endoderm give rise to the entire postnatal lung and thyroid epithelium, but little is known about these cells because they are ...difficult to isolate in a pure form. We demonstrate here the purification and directed differentiation of primordial lung and thyroid progenitors derived from mouse embryonic stem cells (ESCs). Inhibition of TGFβ and BMP signaling, followed by combinatorial stimulation of BMP and FGF signaling, can specify these cells efficiently from definitive endodermal precursors. When derived using Nkx2-1GFP knockin reporter ESCs, these progenitors can be purified for expansion in culture and have a transcriptome that overlaps with developing lung epithelium. Upon induction, they can express a broad repertoire of markers indicative of lung and thyroid lineages and can recellularize a 3D lung tissue scaffold. Thus, we have derived a pure population of progenitors able to recapitulate the developmental milestones of lung/thyroid development.
Display omitted
► ESCs differentiate to lung and thyroid lineages via Nkx2-1+ endodermal progenitors ► Combined BMP and FGF signaling are required to specify these Nkx2.1+ lineages ► Nkx2-1+ progenitors can be purified and expanded in culture ► The resulting cells can recellularize 3D lung scaffolds
Vascular endothelial function is essential for maintenance of health of the vessel wall and for vasomotor control in both
conduit and resistance vessels. These functions are due to the production of ...numerous autacoids, of which nitric oxide (NO)
has been the most widely studied. Exercise training has been shown, in many animal and human studies, to augment endothelial,
NO-dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle
mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training
can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated
in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions
may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated
exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential
for autacoid bioavailability. Recent human studies also indicate that exercise training may improve endothelial function by
up-regulating eNOS protein expression and phosphorylation. While improvement in NO vasodilator function has been less frequently
found in healthy subjects, a higher level of training may lead to improvement. Regarding time course, studies indicate that
short-term training increases NO bioactivity, which acts to homeostatically regulate the shear stress associated with exercise.
Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise
is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodelling
and structural normalization of shear. Given the strong prognostic links between vascular structure, function and cardiovascular
events, the implications of these findings are obvious, yet many unanswered questions remain, not only concerning the mechanisms
responsible for NO bioactivity, the nature of the cellular effect and relevance of other autacoids, but also such practical
questions as the optimal intensity, modality and volume of exercise training required in different populations.
Prior studies have suggested that patients with stage II/III colon cancer receive similar benefit from intravenous (IV) fluoropyrimidine adjuvant therapy regardless of age. Combination regimens and ...oral fluorouracil (FU) therapy are now standard. We examined the impact of age on colon cancer recurrence and mortality after adjuvant therapy with these newer options.
We analyzed 11,953 patients age < 70 and 2,575 age ≥ 70 years from seven adjuvant therapy trials comparing IV FU with oral fluoropyrimidines (capecitabine, uracil, or tegafur) or combinations of fluoropyrimidines with oxaliplatin or irinotecan in stage II/III colon cancer. End points were disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR).
In three studies comparing oxaliplatin-based chemotherapy with IV FU, statistically significant interactions were not observed between treatment arm and age (P interaction = .09 for DFS, .05 for OS, and .36 for TTR), although the stratified point estimates suggested limited benefit from the addition of oxaliplatin in elderly patients (DFS hazard ratio HR, 0.94; 95% CI, 0.78 to 1.13; OS HR, 1.04; 95% CI, 0.85 to 1.27). No significant interactions by age were detected with oral fluoropyrimidine therapy compared with IV FU; noninferiority was supported in both age populations.
Patients age ≥ 70 years seemed to experience reduced benefit from adding oxaliplatin to fluoropyrimidines in the adjuvant setting, although statistically, there was not a significant effect modification by age, whereas oral fluoropyrimidines retained their efficacy.
PDF
