Mechanistic modeling in neuroscience aims to explain observed phenomena in terms of underlying causes. However, determining which model parameters agree with complex and stochastic neural data ...presents a significant challenge. We address this challenge with a machine learning tool which uses deep neural density estimators-trained using model simulations-to carry out Bayesian inference and retrieve the full space of parameters compatible with raw data or selected data features. Our method is scalable in parameters and data features and can rapidly analyze new data after initial training. We demonstrate the power and flexibility of our approach on receptive fields, ion channels, and Hodgkin-Huxley models. We also characterize the space of circuit configurations giving rise to rhythmic activity in the crustacean stomatogastric ganglion, and use these results to derive hypotheses for underlying compensation mechanisms. Our approach will help close the gap between data-driven and theory-driven models of neural dynamics.
Both non-alcoholic fatty liver disease (NAFLD) and the multitarget complexity of microRNA (miR) suppression have recently raised much interest, but the in vivo impact and context-dependence of ...hepatic miR-target interactions are incompletely understood. Assessing the relative in vivo contributions of specific targets to miR-mediated phenotypes is pivotal for investigating metabolic processes.
We quantified fatty liver parameters and the levels of miR-132 and its targets in novel transgenic mice overexpressing miR-132, in liver tissues from patients with NAFLD, and in diverse mouse models of hepatic steatosis. We tested the causal nature of miR-132 excess in these phenotypes by injecting diet-induced obese mice with antisense oligonucleotide suppressors of miR-132 or its target genes, and measured changes in metabolic parameters and transcripts.
Transgenic mice overexpressing miR-132 showed a severe fatty liver phenotype and increased body weight, serum low-density lipoprotein/very low-density lipoprotein (LDL/VLDL) and liver triglycerides, accompanied by decreases in validated miR-132 targets and increases in
. Likewise, liver samples from both patients with NAFLD and mouse models of hepatic steatosis or non-alcoholic steatohepatitis (NASH) displayed dramatic increases in miR-132 and varying decreases in miR-132 targets compared with controls. Furthermore, injecting diet-induced obese mice with anti-miR-132 oligonucleotides, but not suppressing its individual targets, reversed the hepatic miR-132 excess and hyperlipidemic phenotype.
Our findings identify miR-132 as a key regulator of hepatic lipid homeostasis, functioning in a context-dependent fashion via suppression of multiple targets and with cumulative synergistic effects. This indicates reduction of miR-132 levels as a possible treatment of hepatic steatosis.
Circular RNAs (circRNAs) are brain‐abundant RNAs of mostly unknown functions. To seek their roles in Parkinson's disease (PD), we generated an RNA sequencing resource of several brain region tissues ...from dozens of PD and control donors. In the healthy substantia nigra (SN), circRNAs accumulate in an age‐dependent manner, but in the PD SN this correlation is lost and the total number of circRNAs reduced. In contrast, the levels of circRNAs are increased in the other studied brain regions of PD patients. We also found circSLC8A1 to increase in the SN of PD individuals. CircSLC8A1 carries 7 binding sites for miR‐128 and is strongly bound to the microRNA effector protein Ago2. Indeed, RNA targets of miR‐128 are also increased in PD individuals, suggesting that circSLC8A1 regulates miR‐128 function and/or activity. CircSLC8A1 levels also increased in cultured cells exposed to the oxidative stress‐inducing agent paraquat but were decreased in cells treated with the neuroprotective antioxidant regulator drug Simvastatin. Together, our work links circSLC8A1 to oxidative stress‐related Parkinsonism and suggests further exploration of its molecular function in PD.
Synopsis
In human brains, circRNA levels are region specific and inversely correlate to editing. In PD circRNAs are reduced in SN and accumulation correlation with age is lost. CircSLC8A1 increases in PD and oxidation, is bound to Ago2 and sponges miR128 targets, modulating neuronal survival and aging.
CircRNA levels to be brain region‐specific and are inversely correlate to the editing of Alu repeats.
In the healthy substantia nigra (SN), circRNAs accumulate in an age‐dependent manner, but in the Parkinson's Disease (PD) SN, this correlation is lost and the total number of circRNAs is reduced.
CircSLC8A1 levels increase in the SN of PD individuals and in cultured cells exposed to the oxidative stress‐inducing agent Paraquat.
CircSLC8A1 carries 7 binding sites for miR‐128 and is strongly bound to Ago2. Indeed, RNA targets of miR‐128 are also increased in PD individuals, suggesting that circSLC8A1 regulates miR‐128 function and/or activity.
In human brains, circRNA levels are region specific and inversely correlate to editing. In PD circRNAs are reduced in SN and accumulation correlation with age is lost. CircSLC8A1 increases in PD and oxidation, is bound to Ago2 and sponges miR128 targets, modulating neuronal survival and aging.
Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in ...parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease.
Recurrent Aphthous Stomatitis Akintoye, Sunday O., BDS, DDS, MS; Greenberg, Martin S., DDS, FDSRCS
The Dental clinics of North America
58, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Recurrent aphthous stomatitis (RAS) is the most common ulcerative disease affecting the oral mucosa. RAS occurs mostly in healthy individuals and has an atypical clinical presentation in ...immunocompromised individuals. The etiology of RAS is still unknown, but several local, systemic, immunologic, genetic, allergic, nutritional, and microbial factors, as well as immunosuppressive drugs, have been proposed as causative agents. Clinical management of RAS using topical and systemic therapies is based on severity of symptoms and the frequency, size, and number of lesions. The goals of therapy are to decrease pain and ulcer size, promote healing, and decrease the frequency of recurrence.
Fusing left and right eye images into a single view is dependent on precise ocular alignment, which relies on coordinated eye movements. During movements of the head this alignment is maintained by ...numerous reflexes. Although rodents share with other mammals the key components of eye movement control, the coordination of eye movements in freely moving rodents is unknown. Here we show that movements of the two eyes in freely moving rats differ fundamentally from the precisely controlled eye movements used by other mammals to maintain continuous binocular fusion. The observed eye movements serve to keep the visual fields of the two eyes continuously overlapping above the animal during free movement, but not continuously aligned. Overhead visual stimuli presented to rats freely exploring an open arena evoke an immediate shelter-seeking behaviour, but are ineffective when presented beside the arena. We suggest that continuously overlapping visual fields overhead would be of evolutionary benefit for predator detection by minimizing blind spots.
Dynamic pulmonary CT of children Greenberg, S Bruce
American journal of roentgenology (1976),
08/2012, Letnik:
199, Številka:
2
Journal Article
Recenzirano
Wide-detector CT allows simultaneous imaging of the entire airway and lungs in small children. Images acquired in multiple phases by continuous scanning during respiration are viewed dynamically, ...allowing more complete airway and pulmonary evaluation than possible with static protocols. The purpose of this study was to evaluate whether low-dose techniques can be applied to dynamic pulmonary CT of small children.
The study included 24 infants and small children with persistent respiratory difficulty who underwent dynamic pulmonary CT (11 with IV contrast administration, 13 without contrast administration). No significant difference in patient age was present in the two groups. Continuous-mode wide-detector scans were obtained at 350-millisecond gantry rotation for a total of 1.4 seconds at 80 kVp. Some contrast-enhanced studies for simultaneous vascular and airway evaluation were performed at slightly greater tube current. The effective dose for each patient was calculated, and the Student t test was performed to compare effective dose measurements.
All studies were of diagnostic quality, frequently yielding critical information not available with other diagnostic tests. The mean effective dose for all patients was 1.7 (SD, 1.1) mSv. In the group who received contrast material, the mean effective dose was greater (1.9 SD, 1.4 mSv) than in the group who did not receive contrast material (1.5 SD, 0.7 mSv), but the difference was not significant (p = 0.4).
Wide-detector dynamic CT is ideal for evaluation of the airway and lungs in infants and small children with persistent respiratory distress. Effective doses are low, typically less than 2 mSv.
As the ground war in Vietnam escalated in the late 1960s, the US government leveraged the so-called doctor draft to secure adequate numbers of medical personnel in the armed forces. Among newly ...minted physicians’ few alternatives to military service was the Clinical Associate Training Program at the National Institutes of Health. Though only a small percentage of applicants were accepted, the elite program launched an unprecedented number of remarkable scientific careers that would revolutionize medicine at the end of the twentieth century. Medal Winners recounts this overlooked chapter and unforeseen byproduct of the Vietnam War through the lives of four former NIH clinical associates who would go on to become Nobel laureates. Raymond S. Greenberg traces their stories from their pre-NIH years and apprenticeships through their subsequent Nobel Prize–winning work, which transformed treatment of heart disease, cancer, and other diseases. Greenberg shows how the Vietnam draft unintentionally ushered in a golden era of research by bringing talented young physicians under the tutelage of leading scientists and offers a lesson in what it may take to replicate such a towering center of scientific innovation as the NIH in the 1960s and 1970s.
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