Miracle-dz/UniFAR-FTUs huggingface dataset:
Demonstrating the Protective Efficacy of the Novel Fluoroquinolone Finafloxacin against an Inhalational Exposure to Burkholderia pseudomallei

ABSTRACT Burkholderia pseudomallei is the causative agent of melioidosis, a serious disease endemic in Southeast Asia and Northern Australia. Antibiotic treatment is lengthy and relapse often occurs. Finafloxacin is a novel fluoroquinolone with increased antibacterial activity in acidic conditions in contrast to other fluoroquinolones which demonstrate reduced activity at a lower pH. Therefore, finafloxacin may have improved efficacy against B. pseudomallei, which can survive within host cells where the local pH is acidic. In vitro analysis was performed using MICs, minimal bactericidal concentrations (MBCs), time-kill assays, persister cell assays, and macrophage assays. Finafloxacin showed increased bactericidal activity at pH 5 in comparison to pH 7 and ciprofloxacin at pH 5. In vivo studies in BALB/c mice included pharmacokinetic studies to inform an appropriate dosing regimen. Finafloxacin efficacy was evaluated in an inhalational murine model of melioidosis where antibiotic treatment was initiated at 6 or 24 h postchallenge and continued for 14 days, and mice were observed for 63 days. The survival of infected mice following 14 days of treatment was 80%, 60% or 0% for treatments initiated at 6 h and 60%, 30% or 0% for treatments initiated at 24 h for finafloxacin, co-trimoxazole, or ciprofloxacin, respectively. In summary, finafloxacin has increased bactericidal activity for B. pseudomallei under acidic conditions in vitro and improves survival in a murine model of melioidosis compared with those for ciprofloxacin. Furthermore, finafloxacin improves bacteriological clearance compared with that of co-trimoxazole, suggesting it may offer an effective postexposure prophylaxis against B. pseudomallei.
Farnesoid X Receptor Agonists Obeticholic Acid and Chenodeoxycholic Acid Increase Bile Acid Efflux in Sandwich-Cultured Human Hepatocytes: Functional Evidence and Mechanisms

The farnesoid X receptor (FXR) is a nuclear receptor that regulates genes involved in bile acid homeostasis. FXR agonists, obeticholic acid (OCA) and chenodeoxycholic acid (CDCA), increase mRNA expression of efflux transporters in sandwich-cultured human hepatocytes (SCHH). This study evaluated the effects of OCA and CDCA treatment on the uptake, basolateral efflux, and biliary excretion of a model bile acid, taurocholate (TCA), in SCHH. In addition, changes in the protein expression of TCA uptake and efflux transporters were investigated. SCHH were treated with 1 µM OCA, 100 µM CDCA, or vehicle control for 72 hours followed by quantification of deuterated TCA uptake and efflux over time in Ca2+-containing and Ca2+-free conditions (n = 3 donors). A mechanistic pharmacokinetic model was fit to the TCA mass-time data to obtain estimates for total uptake clearance (CLUptake), total intrinsic basolateral efflux clearance (CLint,BL), and total intrinsic biliary clearance (CLint,Bile). Modeling results revealed that FXR agonists significantly increased CLint,BL by >6-fold and significantly increased CLint,Bile by 2-fold, with minimal effect on CLUptake. Immunoblotting showed that protein levels of the basolateral transporter subunits organic solute transporter α and β (OSTα and OSTβ) in FXR agonist-treated SCHH were significantly induced by >2.5- and 10-fold, respectively. FXR agonist-mediated changes in the expression of other TCA transporters in SCHH were modest. In conclusion, this is the first report demonstrating that OCA and CDCA increased TCA efflux in SCHH, which contributed to reduced intracellular TCA concentrations. Increased basolateral efflux of TCA was consistent with increased OSTα/β protein expression in OCA- and CDCA-treated SCHH.
The tunnel magneto-Seebeck effect in magnetic tunnel junctions with MgAl2O4 barrier: paving the way towards spin caloritronic applications

The topic of the doctoral thesis at hand is the tunnel magneto-Seebeck (TMS) effect, which is a textbook example of the emerging research field of spin caloritronics. Spin caloritronics deals with the interplay of charge, heat and spin currents with the goal of developing new data storage techniques or the improvement of existing technologies. In particular, it focuses on the waste heat of today's devices. With the TMS effect it is possible to convert a temperature difference, which extends over several nanometers only, to a measurable voltage based on spin currents. For this, magnetic tunnel junctions are used, which are the foundation of many research areas and applications. In this work, MgAl2O4 (MAO) is investigated as tunnel barrier in comparison to the frequently used MgO. By now, several methods are available to create a temperature difference in tunnel junctions to study the tunnel magneto-Seebeck effect. Within this work, the laser-induced heating is used in order to compare its results with an intrinsic TMS effect, which is determined by a mathematical symmetry analysis of the experimental results. The most important results of these investigations are the unsuitability of the symmetry analysis with regard to the identification of an intrinsic TMS effect and the material-independent doubling of the switching ratio in case of thick barriers. Due to its low thermal conductivity, MAO presents itself as suitable candidate for the generation of thermovoltages. Furthermore, simulations of the temperature distributions offer new insights into the thermal conductivity of a thin insulating film. Overall, this work contributes to a fundamental understanding of thermally induced and spin-current based effects in nanostructures and paves the way towards future technical applications.
Gene expression profiling of skeletal muscle after volumetric muscle loss

Volumetric muscle loss (VML), usually occurring following traumatic injury, results in a composite loss of muscle mass. These injuries manifest as decreased strength and functional impairments. Clinically, these injuries often heal with fibrosis, as opposed to skeletal muscle regeneration. This study examines the healing patterns of a skeletal muscle following VML in a murine model. Eight‐week old male C57BL/6J mice used in the study underwent either bilateral VML injury or cryoinjury, a widely used model known to induce skeletal muscle regeneration. Skeletal muscle was harvested at 2 and 4 weeks following injury and subjected to histological analysis. H&E staining demonstrated skeletal muscle regeneration following cryoinjury, but not VML, at either timepoint post‐injury. Additionally, samples were analyzed using a wound‐healing PCR array to identify differentially regulated genes of interest in VML and cryoinjury, as compared to noninjured controls. The gene array data further demonstrated prolonged inflammation and increased pro‐fibrotic activity in the VML injured muscles, as compared to cryoinjury. In addition, IGF1, a known myogenic factor, was significantly decreased following VML, as compared to cryoinjury, in both ELISA and PCR. This study offers an insight into the pathophysiology of VML injury and reveals a gene profile of a nonregenerating skeletal muscle.
Critical thermal limits of bumblebees (Bombus impatiens) are marked by stereotypical behaviors and are unchanged by acclimation, age or feeding status

ABSTRACT Critical thermal limits often determine species distributions for diverse ectotherms and have become a useful tool for understanding past and predicting future range shifts in response to changing climates. Despite recently documented population declines and range shifts of bumblebees (genus Bombus), the few measurements of thermal tolerance available for the group have relied on disparate measurement approaches. We describe a novel stereotypical behavior expressed by bumblebee individuals during entry into chill coma. This behavioral indicator of minimum critical temperature (CTmin) occurred at ambient temperatures of 3–5°C (approximately 7–9°C core temperatures) and was accompanied by a pronounced CO2 pulse, indicative of loss of spiracle function. Maximum critical temperature (CTmax) was indicated by the onset of muscular spasms prior to entering an unresponsive state and occurred at ambient temperatures of approximately 52–55°C (42–44°C core temperatures). Measurements of CTmin and CTmax were largely unaffected by acclimation, age or feeding status, but faster ramping rates significantly increased CTmax and decreased CTmin. This high-throughput approach allows rapid measurement of critical thermal limits for large numbers of individuals, facilitating large-scale comparisons among bumblebee populations and species – a key step in determining current and future effects of climate on these critical pollinators. Summary: Stereotypical behaviors at extreme temperatures correspond to loss of muscular function, and yield repeatable estimates of CTmin and CTmax for bumble bees.
NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in human hypopharyngeal cells

We previously demonstrated that acidic bile activates NF‐κB, deregulating the expression of oncogenic miRNA markers, in pre‐malignant murine laryngopharyngeal mucosa. Here, we hypothesize that the in vitro exposure of human hypopharyngeal cells to acidic bile deregulates cancer‐related miRNA markers that can be reversed by BAY 11‐7082, a pharmacologic NF‐κB inhibitor. We repetitively exposed normal human hypopharyngeal primary cells and human hypopharyngeal keratinocytes to bile fluid (400 μmol/L), at pH 4.0 and 7.0, with/without BAY 11‐7082 (20 μmol/L). We centred our study on the transcriptional activation of oncogenic miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375, miR‐451a and NF‐κB‐related genes, previously linked to acidic bile‐induced pre‐neoplastic events. Our novel findings in vitro are consistent with our hypothesis demonstrating that BAY 11‐7082 significantly reverses the acidic bile‐induced oncogenic miRNA phenotype, in normal hypopharyngeal cells. BAY 11‐7082 strongly inhibits the acidic bile‐induced up‐regulation of miR‐192 and down‐regulation of miR‐451a and significantly decreases the miR‐21/375 ratios, previously related to poor prognosis in hypopharyngeal cancer. This is the first in vitro report that NF‐κB inhibition reverses acidic bile‐induced miR‐21, miR‐155, miR‐192, miR‐34a, miR‐375 and miR‐451a deregulations in normal human hypopharyngeal cells, suggesting that acidic bile‐induced events are directly or indirectly dependent on NF‐κB signalling.
Learning Multiple Tasks with Multilinear Relationship Networks

Deep networks trained on large-scale data can learn transferable features to promote learning multiple tasks. Since deep features eventually transition from general to specific along deep networks, a fundamental problem of multi-task learning is how to exploit the task relatedness underlying parameter tensors and improve feature transferability in the multiple task-specific layers. This paper presents Multilinear Relationship Networks (MRN) that discover the task relationships based on novel tensor normal priors over parameter tensors of multiple task-specific layers in deep convolutional networks. By jointly learning transferable features and multilinear relationships of tasks and features, MRN is able to alleviate the dilemma of negative-transfer in the feature layers and under-transfer in the classifier layer. Experiments show that MRN yields state-of-the-art results on three multi-task learning datasets.
Platelet packing density is an independent regulator of the hemostatic response to injury

Essentials Platelet packing density in a hemostatic plug limits molecular movement to diffusion. A diffusion‐dependent steep thrombin gradient forms radiating outwards from the injury site. Clot retraction affects the steepness of the gradient by increasing platelet packing density. Together, these effects promote hemostatic plug core formation and inhibit unnecessary growth.
Mapping the Allosteric Action of Antagonists A740003 and A438079 Reveals a Role for the Left Flipper in Ligand Sensitivity at P2X7 Receptors

P2X7 receptor (P2X7R) activation requires ∼100-fold higher concentrations of ATP than other P2X receptor (P2XR) subtypes. Such high levels are found during cellular stress, and P2X7Rs consequently contribute to a range of pathophysiological conditions. We have used chimeric and mutant P2X7Rs, coupled with molecular modeling, to produce a validated model of the binding mode of the subtype-selective antagonist A438079 at an intersubunit allosteric site. Within the allosteric site large effects on antagonist action were found for point mutants of residues F88A, D92A, F95A, and F103A that were conserved or similar between sensitive/insensitive P2XR subtypes, suggesting that these side-chain interactions were not solely responsible for high-affinity antagonist binding. Antagonist sensitivity was increased with mutations that remove the bulk of side chains around the center of the binding pocket, suggesting that the dimensions of the pocket make a significant contribution to selectivity. Chimeric receptors swapping the left flipper (around the orthosteric site) reduced both ATP and antagonist sensitivity. Point mutations within this region highlighted the contribution of a P2X7R-specific aspartic acid residue (D280) that modeling suggests forms a salt bridge with the lower body region of the receptor. The D280A mutant removing this charge increased ATP potency 15-fold providing a new insight into the low ATP sensitivity of the P2X7R. The ortho- and allosteric binding sites form either side of the β-strand Y291-E301 adjacent to the left flipper. This structural linking may explain the contribution of the left flipper to both agonist and antagonist action.
Efficacy and Safety of Deep Brain Stimulation in Tourette Syndrome: The International Tourette Syndrome Deep Brain Stimulation Public Database and Registry

Importance Collective evidence has strongly suggested that deep brain stimulation (DBS) is a promising therapy for Tourette syndrome. Objective To assess the efficacy and safety of DBS in a multinational cohort of patients with Tourette syndrome. Design, Setting, and Participants The prospective International Deep Brain Stimulation Database and Registry included 185 patients with medically refractory Tourette syndrome who underwent DBS implantation from January 1, 2012, to December 31, 2016, at 31 institutions in 10 countries worldwide. Exposures Patients with medically refractory symptoms received DBS implantation in the centromedian thalamic region (93 of 163 [57.1%]), the anterior globus pallidus internus (41 of 163 [25.2%]), the posterior globus pallidus internus (25 of 163 [15.3%]), and the anterior limb of the internal capsule (4 of 163 [2.5%]). Main Outcomes and Measures Scores on the Yale Global Tic Severity Scale and adverse events. Results The International Deep Brain Stimulation Database and Registry enrolled 185 patients (of 171 with available data, 37 females and 134 males; mean [SD] age at surgery, 29.1 [10.8] years [range, 13-58 years]). Symptoms of obsessive-compulsive disorder were present in 97 of 151 patients (64.2%) and 32 of 148 (21.6%) had a history of self-injurious behavior. The mean (SD) total Yale Global Tic Severity Scale score improved from 75.01 (18.36) at baseline to 41.19 (20.00) at 1 year after DBS implantation (P < .001). The mean (SD) motor tic subscore improved from 21.00 (3.72) at baseline to 12.91 (5.78) after 1 year (P < .001), and the mean (SD) phonic tic subscore improved from 16.82 (6.56) at baseline to 9.63 (6.99) at 1 year (P < .001). The overall adverse event rate was 35.4% (56 of 158 patients), with intracranial hemorrhage occurring in 2 patients (1.3%), infection in 4 patients with 5 events (3.2%), and lead explantation in 1 patient (0.6%). The most common stimulation-induced adverse effects were dysarthria (10 [6.3%]) and paresthesia (13 [8.2%]). Conclusions and Relevance Deep brain stimulation was associated with symptomatic improvement in patients with Tourette syndrome but also with important adverse events. A publicly available website on outcomes of DBS in patients with Tourette syndrome has been provided.
Does Religiosity Account for Lower Rates of Advance Care Planning by Older African Americans?

Objectives Advance care planning (ACP) is associated with higher quality care at the end of life and increased odds of receiving hospice care and of dying at home. Older African Americans are less likely to complete advance directives (ADs) or discuss life-sustaining treatment preferences. This study examined whether religiosity accounts for race disparities. Method Analyses were conducted with Health and Retirement Study data (1,180 African Americans, 5,681 Whites). Two forms of ACP were regressed on race, five measures of religiosity, and demographic, health, and health care covariates. Results Whites were twice as likely to engage in ACP. Including religiosity predictors did not close these gaps. Frequency of service attendance was positively associated with AD completion for both White and African American participants. Relationships between religious affiliation and advance care discussion varied by race. For White participants only, more frequent prayer was associated with higher odds of advance care discussion. Discussion Although religiosity is often proposed as a reason for low rates of ACP among African Americans, religiosity measures did not explain race differences. Distinct aspects of religiosity were associated with ACP both negatively and positively, and these relationships varied by type of ACP and by race.
Forces of Tool-Tissue Interaction to Assess Surgical Skill Level

Importance The application of optimal forces between surgical instruments and tissue is fundamental to surgical performance and learning. To date, this force has not been measured clinically during the performance of microsurgery. Objectives To establish a normative catalog of force profiles during the performance of surgery, to compare force variables among surgeons with different skill levels, and to evaluate whether such a force-based metric determines or differentiates skill level. Design, Setting, and Participants Through installation of strain gauge sensors, a force-sensing bipolar forceps was developed, and force data were obtained from predetermined surgical tasks at the Foothills Medical Centre, University of Calgary, a tertiary care center that serves Southern Alberta, Canada. Sixteen neurosurgeons (3 groups: novice, intermediate, and experienced) performed surgery on 26 neurosurgical patients with various conditions. Normative baseline force ranges were obtained using the force profiles (mean and maximum forces and force variability) from the experienced surgeons. Standardized force profiles and force errors (high force error [HFE], low force error [LFE], and force variability error [FVE]) were analyzed and compared among surgeons with different skill levels. Main Outcomes and Measures Each trial of the forceps use was termed successful or unsuccessful. The force profiles and force errors were analyzed and compared. Results This study included 26 patients (10 [38%] male and 16 [62%] female; mean [SD] age, 43 [15] years) undergoing neurosurgery by 16 surgeons (6 in the novice group, 5 in the intermediate group, and 5 in the experienced group). Unsuccessful trial–incomplete significantly correlated with LFE and FVE, and unsuccessful trial–bleeding correlated with HFE and FVE. The force strengths exerted by novice surgeons were significantly higher than those of experienced surgeons (0.74 vs 0.00; P < .001), and force variability decreased from novice (0.43) to intermediate (0.28) to experienced (0.00) surgeons; however, these differences varied among surgical tasks. The rate of HFE and FVE inversely correlated with surgeon level of experience (HFE, 0.27 for novice surgeons, 0.12 for intermediate surgeons, and 0.05 for experienced surgeons; FVE, 0.16 for novice surgeons, 0.10 for intermediate surgeons, and 0.05 for experienced surgeons). The rate of LFE significantly increased in intermediate (0.12) and novice (0.10) surgeons compared with experienced surgeons (0.04; P < .001). There was no difference in LFE between intermediate and novice surgeons. Stepwise discriminant analysis revealed that combined use of these error rates could accurately discriminate the groups (87.5%). Conclusions and Relevance Force-sensing bipolar forceps and force analysis may help distinguish surgeon skill level, which is particularly important as surgical education shifts to a competency-based paradigm.
Drug transport to brain with targeted nanoparticles

SummaryNanoparticle drug carriers consist of solid biodegradable particles in size ranging from 10 to 1000 nm (50–300 nm generally). They cannot freely diffuse through the blood-brain barrier (BBB) and require receptor-mediated transport through brain capillary endothelium to deliver their content into the brain parenchyma. Polysorbate 80-coated polybutylcyano-acrylate nanoparticles can deliver drugs to the brain by a still debated mechanism. Despite interesting results these nanoparticles have limitations, discussed in this review, that may preclude, or at least limit, their potential clinical applications. Long-circulating nanoparticles made of methoxypoly(ethylene glycol)-polylactide or poly(lactide-co-glycolide) (mPEG-PLA/PLGA) have a good safety profiles and provide drug-sustained release. The availability of functionalized PEG-PLA permits to prepare target-specific nanoparticles by conjugation of cell surface ligand. Using peptidomimetic antibodies to BBB transcytosis receptor, brain-targeted pegylated immunonanoparticles can now be synthesized that should make possible the delivery of entrapped actives into the brain parenchyma without inducing BBB permeability alteration. This review presents their general properties (structure, loading capacity, pharmacokinetics) and currently available methods for immunonanoparticle preparation.
Theta band oscillations reflect more than entrainment: behavioral and neural evidence demonstrates an active chunking process

Parsing continuous acoustic streams into perceptual units is fundamental to auditory perception. Previous studies have uncovered a cortical entrainment mechanism in the delta and theta bands (~1–8 Hz) that correlates with formation of perceptual units in speech, music, and other quasi‐rhythmic stimuli. Whether cortical oscillations in the delta‐theta bands are passively entrained by regular acoustic patterns or play an active role in parsing the acoustic stream is debated. Here, we investigate cortical oscillations using novel stimuli with 1/f modulation spectra. These 1/f signals have no rhythmic structure but contain information over many timescales because of their broadband modulation characteristics. We chose 1/f modulation spectra with varying exponents of f, which simulate the dynamics of environmental noise, speech, vocalizations, and music. While undergoing magnetoencephalography (MEG) recording, participants listened to 1/f stimuli and detected embedded target tones. Tone detection performance varied across stimuli of different exponents and can be explained by local signal‐to‐noise ratio computed using a temporal window around 200 ms. Furthermore, theta band oscillations, surprisingly, were observed for all stimuli, but robust phase coherence was preferentially displayed by stimuli with exponents 1 and 1.5. We constructed an auditory processing model to quantify acoustic information on various timescales and correlated the model outputs with the neural results. We show that cortical oscillations reflect a chunking of segments, > 200 ms. These results suggest an active auditory segmentation mechanism, complementary to entrainment, operating on a timescale of ~200 ms to organize acoustic information.