A phenome-wide association and Mendelian randomisation study of alcohol use variants in a diverse cohort comprising over 3 million individuals.

Background: Alcohol consumption is associated with numerous negative social and health outcomes. These associations may be direct consequences of drinking, or they may reflect common genetic factors that influence both alcohol consumption and other outcomes.

Methods: We performed exploratory phenome-wide association studies (PheWAS) of three of the best studied protective single nucleotide polymorphisms (SNPs) in genes encoding ethanol metabolising enzymes (ADH1B: rs1229984-T, rs2066702-A; ADH1C: rs698-T) using up to 1109 health outcomes across 28 phenotypic categories (e.

Optimized Methodology for Reference Region and Image-Derived Input Function Kinetic Modeling in Preclinical PET.

PET imaging of small animals is often used for assessing biodistribution of a novel radioligand and pharmacology in small animal models of disease. PET acquisition and processing settings may affect reference region or image-derived input function (IDIF) kinetic modeling estimates. We examined four different factors in comparing quantitative results: 1) effect of reconstruction algorithm, 2) number of MAP iterations, 3) strength of the MAP prior, and 4) Attenuation and scatter.

Study design and implementation of the PRecision Medicine In MEntal health Care (PRIME Care) Trial.

Genomic testing has the potential to improve patient outcomes and reduce patient care costs by personalizing medication selection. Commercial pharmacogenetic (PGx) testing for psychotropic and other medications is widely available and promoted as a means to implement "precision medicine." Despite evidence that genetic variation affects the metabolism of psychotropic medications, the clinical utility of these test results has not been established.

Blood pressure reduction and outcome after endovascular therapy with successful reperfusion: a multicenter study.

Background: Elevated systolic blood pressure (SBP) after mechanical thrombectomy (MT) correlates with worse outcome. However, the association between SBP reduction (SBPr) and outcome after successful reperfusion with MT is not well established.

Objective: To investigate the association between SBPr in the first 24 hours after successful reperfusion and the functional and safety outcomes of MT.

Key factors in pincer ligand design.

Pincers, tridentate ligands that prefer a meridional geometry, are a rising class because of their distinctive combination of properties. They permit a good level of control on the nature of the coordination sphere by holding the donor groups in a predictable arrangement. Some groups, such as an aryl or a pyridine, that would normally be easily lost as monodentate ligands, become reliably coordinated, especially if they form the central donor unit of the three.

Reactive protoplasmic and fibrous astrocytes contain high levels of calpain-cleaved alpha 2 spectrin.

Calpain, a family of calcium-dependent neutral proteases, plays important roles in neurophysiology and pathology through the proteolytic modification of cytoskeletal proteins, receptors and kinases. Alpha 2 spectrin (αII spectrin) is a major substrate for this protease family, and the presence of the αII spectrin breakdown product (αΙΙ spectrin BDP) in a cell is evidence of calpain activity triggered by enhanced intracytoplasmic Ca(2+) concentrations. Astrocytes, the most dynamic CNS cells, respond to micro-environmental changes or noxious stimuli by elevating intracytoplasmic Ca(2+) concentration to become activated.

Genomic Characterization of Interspecific Hybrids and an Admixture Population Derived from Panicum amarum × P. virgatum.

Switchgrass (Panicum virgatum L.) and its relatives are regarded as top bioenergy crop candidates; however, one critical barrier is the introduction of useful genetic diversity and the development of new cultivars and hybrids. Combining genomes from related cultivars and species provides an opportunity to introduce new traits.

MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury.

Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed.

Macrophage migration inhibitory factor deficiency in chronic obstructive pulmonary disease.

The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD.

Let-7d microRNA affects mesenchymal phenotypic properties of lung fibroblasts.

MicroRNAs are small noncoding RNAs that inhibit protein expression. We have previously shown that the inhibition of the microRNA let-7d in epithelial cells caused changes consistent with epithelial-to-mesenchymal transition (EMT) both in vitro and in vivo. The aim of this study was to determine whether the introduction of let-7d into fibroblasts alters their mesenchymal properties.

Characterization of CFTR High Expresser cells in the intestine.

The CFTR High Expresser (CHE) cells express eightfold higher levels of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel compared with neighboring enterocytes and were first identified by our laboratory (Ameen et al., Gastroenterology 108: 1016, 1995). We used double-label immunofluorescence microscopy to further study these enigmatic epithelial cells in rat intestine in vivo or ex vivo.

Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury.

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells.

Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons.

In mature neurons, GABA is the primary inhibitory neurotransmitter. In contrast, in developing neurons, GABA exerts excitatory actions, and in some neurons GABA-mediated excitatory synaptic activity is more prevalent than glutamate-mediated excitation. Hypothalamic neuropeptides that modulate cognitive arousal and energy homeostasis, hypocretin/orexin and neuropeptide Y (NPY), evoked reversed effects on synaptic actions that were dependent on presynaptic GABA release onto melanin-concentrating hormone (MCH) neurons.

Differential signal pathway activation and 5-HT function: the role of gut enterochromaffin cells as oxygen sensors.

The chemomechanosensory function of the gut enterochromaffin (EC) cell enables it to respond to dietary agents and mechanical stretch. We hypothesized that the EC cell, which also sensed alterations in luminal or mucosal oxygen level, was physiologically sensitive to fluctuations in O(2). Given that low oxygen levels induce 5-HT production and secretion through a hypoxia inducible factor 1α (HIF-1α)-dependent pathway, we also hypothesized that increasing O(2) would reduce 5-HT production and secretion.

Synapse maturation is enhanced in the binocular region of the retinocollicular map prior to eye opening.

In the developing visual system of mammals, retinal axons from the two eyes compete for postsynaptic partners. After eye opening, this process is regulated in part by homeostatically constrained competition for synaptic connectivity with target neurons. However, prior to eye opening, the functional and synaptic basis of binocular map development is unclear.

Vasopressin and oxytocin excite MCH neurons, but not other lateral hypothalamic GABA neurons.

Neurons that synthesize melanin-concentrating hormone (MCH) colocalize GABA, regulate energy homeostasis, modulate water intake, and influence anxiety, stress, and social interaction. Similarly, vasopressin and oxytocin can influence the same behaviors and states, suggesting that these neuropeptides may exert part of their effect by modulating MCH neurons. Using whole cell recording in MCH-green fluorescent protein (GFP) transgenic mouse hypothalamic brain slices, we found that both vasopressin and oxytocin evoked a substantial excitatory effect.

In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans.

Native cowhage spicules, and heat-inactivated spicules containing histamine or capsaicin, evoke similar sensations of itch and nociceptive sensations in humans. In ongoing studies of the peripheral neural mechanisms of chemical itch and pain in the mouse, extracellular electrophysiological recordings were obtained, in vivo, from the cell bodies of mechanosensitive nociceptive neurons in response to spicule stimuli delivered to their cutaneous receptive fields (RFs) on the distal hindlimb. A total of 43 mechanosensitive, cutaneous, nociceptive neurons with axonal conduction velocities in the C-fiber range (C-nociceptors) were classified as CM if responsive to noxious mechanical stimuli, such as pinch, or CMH if responsive to noxious mechanical and heat stimuli (51°C, 5 s).

Rare mutations in the human Na-K-Cl cotransporter (NKCC2) associated with lower blood pressure exhibit impaired processing and transport function.

The Na-K-Cl cotransporter (NKCC2) is the major salt transport pathway in the thick ascending limb of Henle's loop and is part of the molecular mechanism for blood pressure regulation. Recent screening of ∼3,000 members of the Framingham Heart Study identified nine rare independent mutations in the gene encoding NKCC2 (SLC12A1) associated with clinically reduced blood pressure and protection from hypertension (Ji WZ, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State M, Levy D, Lifton RP. Nat Genet 40: 592-599, 2008).

A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain.

Low-carbohydrate, high-fat ketogenic diets (KD) have been suggested to be more effective in promoting weight loss than conventional caloric restriction, whereas their effect on hepatic glucose and lipid metabolism and the mechanisms by which they may promote weight loss remain controversial. The aim of this study was to explore the role of KD on liver and muscle insulin sensitivity, hepatic lipid metabolism, energy expenditure, and food intake. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in mice fed a KD or regular chow (RC).

Laboratories, museums, and the comparative perspective: Alan A. Boyden's quest for objectivity in serological taxonomy, 1924-1962.

The rise of experimentation and the decline of natural history constitute the historiographic backbone to most narratives about the history of the life sciences in the twentieth century. As I argue here, however, natural history practices, such as the collection adn comparison of data from numerous species, adn experimental practices have actually converged throughout the century, giving rise to a new hybrid research culture which is essential to the contemporary life sciences. Looking at some examples of researchers who studied experimentally the relationships between organisms offers a unique window into how the norms, values, and practices of natural history entered the laboratory and, conversely, how the norms, values, and practices of experimentation transformed natural history.

"Smite this sleeping world awake": Edward Burne-Jones and "The legend of the briar rose".

Challenging entrenched preconceptions about the supposed escapism and conservatism of Edward Burne-Jones's art, this paper seeks to establish his monumental painted series, "The Legend of the Briar Rose," as a fundamentally radical and confrontational work. Critics have long viewed it as an endorsement of sleepy stasis, antithetical to the political activism espoused by his friend William Morris. By unraveling the intertwining themes of the series -- the transformative dream vision, artistic labor, the decorative mode, and social egalitarianism -- the "Briar Rose" series is revealed instead to be dramatization of the struggle for personal, social, artistic, and even environmental awakening.

Polio chronicles: warm springs and disability politics in the 1930s.

During the 1920s and 1930s, disabled polio survivors initiated a campaign which made them active, dissenting subjects in public discourse about disease and disability. Its source was a core of Warm Springs patients who wanted more than a healing refuge. They were well aware of the need to construct a new image of the disabled, and saw the resort's high public profile as a potent weapon in a cultural war to remake popular images of the disabled, whether as pathetic charitable objects or as horrific movie villains.