Miracle-dz/UniFAR-FTUs huggingface dataset:
Angelman syndrome: Current and emerging therapies in 2016

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a loss of the maternally‐inherited UBE3A; the paternal UBE3A is silenced in neurons by a mechanism involving an antisense transcript (UBE3A‐AS) at the unmethylated paternal locus. We reviewed all published information on the clinical trials that have been completed as well as the publicly available information on ongoing trials of therapies in AS. To date, all clinical trials that strove to improve neurodevelopment in AS have been unsuccessful. Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of an 8‐week open‐label trial using minocycline as a matrix metalloproteinase‐9 inhibitor were inconclusive, while a subsequent randomized placebo‐controlled trial suggested that treatment with minocycline for 8 weeks did not result in any neurodevelopmental gains. A 1‐year randomized placebo‐controlled trial using levodopa to alter the phosphorylation of calcium/calmodulin‐dependent kinase II did not lead to any improvement in neurodevelopment. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A‐AS. Artificial transcription factors are being developed to “super activate” UBE3A or inhibit UBE3A‐AS. Other strategies targeting specific pathways are briefly discussed. We also reviewed the medications that are currently used to treat seizures and sleep disturbances, which are two of the more common complications of AS. © 2016 Wiley Periodicals, Inc.
Racial and Ethnic Disparities in the Incidence of Esophageal Cancer in the United States, 1992–2013

Racial and ethnic disparities in the incidence of esophageal cancer have not been thoroughly characterized with quantitative health-disparity measures. Using data from 1992-2013 from 13 US cancer registries in the Surveillance, Epidemiology, and End Results database, we assessed such disparities according to histological type, based on a variety of disparity metrics. The age-standardized incidence rate of squamous cell carcinoma (SCC) was highest among black persons, while adenocarcinoma mainly affected white men. The rate of SCC decreased over time in all racial/ethnic groups, and this was most pronounced in black persons (by 5.7% per year among men and 5.0% among women). The adenocarcinoma rate rose among non-Hispanic whites and among black men. Racial/ethnic disparities in the incidence of total esophageal cancer decreased over time, which was due mainly to reduced disparities in SCC. The 2 absolute disparity measures-range difference and between-group variance-for adenocarcinoma rose by 3.2% and 6.8% per year, respectively, in men and by 1.8% and 5.3% per year, respectively, in women. This study demonstrates decreased racial/ethnic disparities in the incidence of esophageal SCC over time in the United States, while disparities increased in adenocarcinoma incidence as measured on the absolute scale.
Facing others’ misfortune: Personal distress mediates the association between maladaptive emotion regulation and social avoidance

Previous research has linked the use of certain emotion regulation strategies to the vicarious experience of personal distress (PD) and empathic concern (EC). However, it has not yet been tested whether (1) vicarious PD is positively associated with maladaptive emotion regulation strategies, (2) vicarious EC is positively associated with adaptive emotion regulation strategies or whether (3) PD and EC mediate the link between emotion regulation and reports of approach/avoidance in response to a person in distress. To that end, we assessed people’s reports of PD (i.e., anxious, troubled and upset) and EC (i.e., concerned, sympathetic and soft-hearted) in response to a video depicting a person in a threatening situation (n = 78). Afterwards, we assessed participants’ reports of avoidance and approach with regard to the character and their disposition to use maladaptive and adaptive emotion regulation strategies. Results showed that both PD and EC were positively related to maladaptive strategies and negatively related to adaptive strategies, and that the association between maladaptive regulation strategies (i.e., rumination) and the willingness to avoid the person in distress was mediated by reports of greater PD. This study thus expands previous evidence on the relationship between maladaptive regulation strategies and affective empathy and provides novel insights into the main role that PD plays in the association between maladaptive strategies and social avoidance.
The Body Acoustic: Ultrasonic Neuromodulation for Translational Medicine

For the greater part of the last century, ultrasound (US) has seen widespread use in applications ranging from materials science to medicine. The history of US in medicine has also seen promising success in clinical diagnostics and regenerative medicine. Recent studies have shown that US is able to manipulate the nervous system, leading toward potential treatment for various neuropathological conditions, a phenomenon known as ultrasonic neuromodulation (NM). Ultrasonic NM is a promising alternative to pharmaceuticals and surgery, due to high spatiotemporal resolution combined with the potentially noninvasive means of application. Current advances have made progress in establishing effective dosage limits, waveform parameters, and stimulus regimes in order to achieve desired effects in a variety of tissue and cell types. However, to date there has been limited systematic analysis of the complex variables involved in creating a therapeutic US stimulation regime specifically tailored to the nervous system. Without a fundamental understanding of the effects of US on neural tissue, including the surrounding bone, musculature, and vasculature, the safety and efficacy of US as an NM tool is yet to be determined. Advances in imaging technology and focusing hardware highlight new avenues for potential clinical applications for therapeutic ultrasonic stimulation. US may be an alternative to electrical and magnetic means of NM for targets in the central nervous system as well as in the peripheral and autonomic nervous systems. This review provides a historical perspective on the past, present, and future of US as a translational therapeutic.
Luminopsins integrate opto- and chemogenetics by using physical and biological light sources for opsin activation

Significance Although conventional optogenetics utilizing microbial photosensitive channels or pumps to control activity of neurons has enabled great progress in neuroscience, reliance on delivery of light by optic fibers implanted into the brain imposes certain logistical burdens and thus limits application of optogenetics. To expand their utility, we fused optogenetic probes with luciferase that emits biological light in the presence of a substrate and showed that the activity of neurons in vitro, ex vivo, and in vivo could be controlled by biological light in addition to physical light. Such fusion proteins, termed luminopsins, could prove invaluable for experimental and clinical neuroscience. Luminopsins are fusion proteins of luciferase and opsin that allow interrogation of neuronal circuits at different temporal and spatial resolutions by choosing either extrinsic physical or intrinsic biological light for its activation. Building on previous development of fusions of wild-type Gaussia luciferase with channelrhodopsin, here we expanded the utility of luminopsins by fusing bright Gaussia luciferase variants with either channelrhodopsin to excite neurons (luminescent opsin, LMO) or a proton pump to inhibit neurons (inhibitory LMO, iLMO). These improved LMOs could reliably activate or silence neurons in vitro and in vivo. Expression of the improved LMO in hippocampal circuits not only enabled mapping of synaptic activation of CA1 neurons with fine spatiotemporal resolution but also could drive rhythmic circuit excitation over a large spatiotemporal scale. Furthermore, virus-mediated expression of either LMO or iLMO in the substantia nigra in vivo produced not only the expected bidirectional control of single unit activity but also opposing effects on circling behavior in response to systemic injection of a luciferase substrate. Thus, although preserving the ability to be activated by external light sources, LMOs expand the use of optogenetics by making the same opsins accessible to noninvasive, chemogenetic control, thereby allowing the same probe to manipulate neuronal activity over a range of spatial and temporal scales.
High-dose lidocaine does not affect defibrillation efficacy: implications for defibrillation mechanisms.

This study assessed the effect of low (10 mg ⋅ kg-1 ⋅ h-1) and very high (18 mg ⋅ kg-1 ⋅ h-1) doses of lidocaine on defibrillation energy requirements (DER) to relate changes in indexes of sodium-channel blockade with changes in DER values using a dose-response study design. In group 1 (control; n = 6 pigs), DER values were determined at baseline and during treatment with 5% dextrose in water (D5W) and with D5W added to D5W. In group 2 ( n = 7), DER values were determined at baseline and during treatment with low-dose lidocaine followed by high-dose lidocaine. In group 3 ( n = 3), DER values were determined at baseline and high-dose lidocaine. Group 3 controlled for the order of lidocaine treatment with the addition of high-dose lidocaine after baseline. DER values in group 1 did not change during D5W. In group 2, low-dose lidocaine increased DER values by 51% ( P = 0.01), whereas high-dose lidocaine added to low-dose lidocaine reduced DER values back to within 6% of baseline values ( P = 0.02, low dose vs. high dose). DER values during high-dose lidocaine in group 3 also remained near baseline values (16.2 ± 2.7 to 12.9 ± 2.7 J), demonstrating that treatment order had no impact on group 2. Progressive sodium-channel blockade was evident as incremental reduction in ventricular conduction velocity as the lidocaine dose increased. Lidocaine also significantly increased ventricular fibrillation cycle length as the lidocaine dose increased. However, the greatest increase in DER occurred when ventricular fibrillation cycle length was minimally affected, demonstrating a negative correlation ( P = 0.04). In summary, lidocaine has an inverted U-shaped DER dose-response curve. At very high lidocaine doses, DER values are similar to baseline and tend to decrease rather than increase. Increased refractoriness during ventricular fibrillation may be the electrophysiological mechanism by which high-dose lidocaine limits the adverse effects that low-dose lidocaine has on DER values. However, there is a possibility that an unidentified action of lidocaine is responsible for these effects.
Intrinsic ANG II type 1 receptor stimulation contributes to recovery of postischemic mechanical function.

To determine whether intrinsic angiotensin II (ANG II) type 1 receptor (AT1-R) stimulation modulates recovery of postischemic mechanical function, we studied the effects of selective AT1-R blockade with losartan on proton production from glucose metabolism and recovery of function in isolated working rat hearts perfused with Krebs-Henseleit buffer containing palmitate, glucose, and insulin. Aerobic perfusion (50 min) was followed by global, no-flow ischemia (30 min) and reperfusion (30 min) in the presence ( n = 10) or absence ( n = 14) of losartan (1 μmol/l) or the cardioprotective adenosine A1receptor agonist N 6-cyclohexyladenosine (CHA, 0.5 μmol/l, n = 11). During reperfusion in untreated hearts (controls), left ventricular (LV) minute work partially recovered to 38% of aerobic baseline, whereas proton production increased to 155%. Compared with controls, CHA improved recovery of LV work to 79% and reduced proton production to 44%. Losartan depressed recovery of LV work to 0% without altering proton production. However, exogenous ANG II (1-100 nmol/l) in combination with losartan restored recovery of LV work during reperfusion in a concentration-dependent manner, suggesting that postischemic recovery of function depends on intrinsic AT1-R stimulation.
Zika Virus in the Americas — Yet Another Arbovirus Threat

recent of four unexpected arrivals of important arthropod-borne viral diseases in the Western Hemisphere over the past 20 years. It follows dengue, which entered this hemisphere stealthily over decades and then more aggressively in the 1990s; West Nile virus, which emerged in 1999; and chikungunya, which emerged in 2013. Are the successive migrations of these viruses unrelated, or do they reflect important new patterns of disease emergence? Furthermore, are there secondary health consequences of this arbovirus pandemic that set it apart from others? “Arbovirus” is a descriptive term applied to hundreds of predominantly RNA viruses that are transmitted by arthropods, notably mosquitoes and ticks. Arboviruses are often maintained in complex cycles involving vertebrates such as mammals or birds and blood-feeding vectors. Until recently, only a few arboviruses had caused clinically significant human diseases, including mosquito-borne alphaviruses such as chikungunya and flaviviruses such as dengue and West Nile. The most historically important of these is yellow fever virus, the first recognized viral cause of deadly epidemic hemorrhagic fever. Zika, which was discovered incidentally in Uganda in 1947 in the course of mosquito and primate surveillance,1 had until now remained an obscure virus confined to a narrow equatorial belt running across Africa and into Asia. The virus circulated predominantly in wild primates and arboreal mosquitoes such as Aedes africanus and rarely caused recognized “spillover” infections in humans, even in highly enzootic areas.2 Its current explosive pandemic reemergence is therefore truly remarkable.3 Decades ago, African researchers noted that aedes-transmitted Zika epizootics inexplicably tended to follow aedes-transmitted chikungunya epizootics and epidemics. An analogous pattern began in 2013, when chikungunya spread pandemically from west to east, and Zika later followed. Zika has now circled the globe, arriving not only in the Americas but also, in September, in the country of Cape Verde in West Africa, near its presumed ancient ancestral home. With the exception of West Nile virus, which is predominantly spread by culex-species mosquitoes, the arboviruses that recently reached the Western Hemisphere have been transmitted by aedes mosquitoes, especially the yellow fever vector mosquito A. aegypti. These viruses started to emerge millennia ago, when North African villagers began to store water in Zika Virus in the Americas — Yet Another Arbovirus Threat
Primary vagally mediated decelerations in heart rate during tonic rapid eye movement sleep in cats.

Rapid eye movement (REM) sleep results in profound state-dependent alterations in heart rate. The present study describes a novel phenomenon of a primary deceleration in heart rate that is not preceded or followed by increases in heart rate or arterial blood pressure and occurs primarily during tonic REM sleep. The goals were to characterize the primary decelerations and to provide insights on the underlying central and peripheral autonomic mechanisms. Cats were chronically implanted with electrodes to record electroencephalogram, pontogeniculooccipital wave activity in lateral geniculate nucleus, hippocampal theta rhythm, electromyogram, electrooculogram, respiration (diaphragm), and electrocardiogram. Arterial blood pressure was monitored from a carotid artery catheter. R-R interval fluctuations were continuously tracked using customized software. The muscarinic blocking agent glycopyrrolate (0.1 mg/kg iv) and the β-adrenergic blocking agent atenolol (0.3 mg/kg iv) were administered in alternating sequence with a 90- to 120-min interval. Glycopyrrolate immediately eliminated the decelerations during REM sleep. Atenolol alone had no effect on their frequency. These findings suggest that a change in the centrally induced pattern of autonomic activity to the heart is responsible for the primary decelerations, namely, a bursting of cardiac vagal efferent fiber activity.
Assessing the Impact of Germination and Sporulation Conditions on the Adhesion of Bacillus Spores to Glass and Stainless Steel by Fluid Dynamic Gauging

Abstract The adhesion of spores of 3 Bacillus species with distinctive morphologies to stainless steel and borosilicate glass was studied using the fluid dynamic gauging technique. Marked differences were observed between different species of spores, and also between spores of the same species prepared under different sporulation conditions. Spores of the food‐borne pathogen B. cereus were demonstrated to be capable of withstanding shear stresses greater than 1500 Pa when adhered to stainless steel, in contrast to spores of Bacillus subtilis and Bacillus megaterium, which detached in response to lower shear stress. An extended DLVO model was shown to be capable of predicting the relative differences in spore adhesion between spores of different species and different culture conditions, but did not predict absolute values of force of adhesion well. Applying the model to germinating spores showed a significant reduction in adhesion force shortly after triggering germination, indicating a potential strategy to achieve enhanced removal of spores from surfaces in response to shear stress, such as during cleaning‐in‐place procedures. Practical Application Spore‐forming bacteria are a concern to the food industry because they have the potential to cause food‐borne illness and product spoilage, while being strongly adhesive to processing surfaces and resistant to cleaning‐in‐place procedures. This work is of significance to the food processors and manufacturers because it offers insight to the properties of spore adhesion and identifies a potential strategy to facilitate the removal of spores during cleaning procedures.
Estimating the Comparative Effectiveness of Feeding Interventions in the Pediatric Intensive Care Unit: A Demonstration of Longitudinal Targeted Maximum Likelihood Estimation

Abstract Longitudinal data sources offer new opportunities for the evaluation of sequential interventions. To adjust for time-dependent confounding in these settings, longitudinal targeted maximum likelihood based estimation (TMLE), a doubly robust method that can be coupled with machine learning, has been proposed. This paper provides a tutorial in applying longitudinal TMLE, in contrast to inverse probability of treatment weighting and g-computation based on iterative conditional expectations. We apply these methods to estimate the causal effect of nutritional interventions on clinical outcomes among critically ill children in a United Kingdom study (Control of Hyperglycemia in Paediatric Intensive Care, 2008–2011). We estimate the probability of a child’s being discharged alive from the pediatric intensive care unit by a given day, under a range of static and dynamic feeding regimes. We find that before adjustment, patients who follow the static regime “never feed” are discharged by the end of the fifth day with a probability of 0.88 (95% confidence interval: 0.87, 0.90), while for the patients who follow the regime “feed from day 3,” the probability of discharge is 0.64 (95% confidence interval: 0.62, 0.66). After adjustment for time-dependent confounding, most of this difference disappears, and the statistical methods produce similar results. TMLE offers a flexible estimation approach; hence, we provide practical guidance on implementation to encourage its wider use.
Data processing can mask biology: towards better reporting of fungal barcoding data?

Fungal barcoding, that is the use of genetic markers to identify fungal species, has contributed enormously to the rise of mycorrhizal research in the last decade (van der Heijden et al., 2015) because it allows quick and easy en masse identification of species or higher taxonomic ranks and grouping of sequences into entities; this speeds up ecological analyses and the discovery of new species (Hibbett et al., 2011; Herr et al., 2015). Marker sequences allow the delineation of operational taxonomic units (OTUs) on the basis of sequence similarities (Lindahl et al., 2013). Specific cases of OTUs delimited across datasets are internal transcribed spacer (ITS)-based fungal Species Hypotheses (SH; K~oljalg et al., 2013) and small subunit (SSU) rRNA gene–based Glomeromycota Virtual Taxa (VT; € Opik et al., 2014), which allow a stable naming and databases of sequence-associated ecological metadata (SH; UNITE, K~oljalg et al., 2013; VT; MaarjAM, € Opik et al., 2010). Such OTUs allow us to answer ecological questions, such as the exploration of diversity patterns between habitats, hosts or experimental treatments (Merckx et al., 2012; Ohsowski et al., 2014), and to describe distribution ranges and large-scale patterns (Tedersoo et al., 2014; Davison et al., 2015). Moreover, the phylogenetic signal conveyed by the sequences can detect phylogenetic diversity patterns and identify phylogenetic signals in functional traits of organisms and communities (Martos et al., 2012;Grilli et al., 2015). Mycorrhizal fungal research often uses the nuclear ribosomal ITS (Box 1), now the most acknowledged taxonomic barcode for fungi (Schoch et al., 2012), especially in ectomycorrhizal (ECM) models. Molecular ecological research on Glomeromycota, the arbuscular mycorrhizal (AM) fungi, uses a broader range of markers, among which the nuclear SSU rRNA gene is most often used in community surveys, whilst the ITS and large subunit (LSU) rRNA gene are more common in taxonomic research into Glomeromycota (€ Opik et al., 2014). Alternative markers, such as the beta-tubulin gene, COI or RPB1 genes, are also being tested (reviewed in € Opik et al., 2014 andHart et al., 2015). While the data processing that delivers the final sequence in the International Nucleotide Sequence Database (INSD) is often well