Miracle-dz/UniFAR-FTUs huggingface dataset:
Hypoxia‐mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus

Brain‐derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF‐mediated pro‐death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague–Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro‐BDNF and alteration in N‐linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose‐regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase β (Trkβ) in non‐raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkβ from non‐raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkβ from non‐raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation‐induced alteration in raft dynamics which is promotes p75 receptor‐mediated death signalling in hippocampal neurons during chronic hypoxia.
ClinVar at five years: Delivering on the promise

The increasing application of genetic testing for determining the causes underlying Mendelian, pharmacogenetic, and somatic phenotypes has accelerated the discovery of novel variants by clinical genetics laboratories, resulting in a critical need for interpreting the significance of these variants and presenting considerable challenges. Launched in 2013 at the National Center for Biotechnology Information, National Institutes of Health, ClinVar is a public database for clinical laboratories, researchers, expert panels, and others to share their interpretations of variants with their evidence. The database holds 600,000 submitted records from 1,000 submitters, representing 430,000 unique variants. ClinVar encourages submissions of variants reviewed by expert panels, as expert consensus confers a high standard. Aggregating data from many groups in a single database allows comparison of interpretations, providing transparency into the concordance or discordance of interpretations. In its first five years, ClinVar has successfully provided a gateway for the submission of medically relevant variants and interpretations of their significance to disease. It has become an invaluable resource for the clinical genetics community seeking guidance from consensus interpretations. Building on the platform of providing transparency and leveraging aggregation of variant interpretations, ClinVar is now well positioned to help the clinical genetics community improve interpretations.
Decidualization of Human Endometrial Stromal Fibroblasts is a Multiphasic Process Involving Distinct Transcriptional Programs

Decidual stromal cells differentiate from endometrial stromal fibroblasts (ESFs) under the influence of progesterone and cyclic adenosine monophosphate (cAMP) and are essential for implantation and the maintenance of pregnancy. They evolved in the stem lineage of placental (eutherian) mammals coincidental with the evolution of implantation. Here we use the well-established in vitro decidualization protocol to compare early (3 days) and late (8 days) gene transcription patterns in immortalized human ESF. We document extensive, dynamic changes in the early and late decidual cell transcriptomes. The data suggest the existence of an early signal transducer and activator of transcription (STAT) pathway dominated state and a later nuclear factor κB (NFKB) pathway regulated state. Transcription factor expression in both phases is characterized by putative or known progesterone receptor (PGR) target genes, suggesting that both phases are under progesterone control. Decidualization leads to proliferative quiescence, which is reversible by progesterone withdrawal after 3 days but to a lesser extent after 8 days of decidualization. In contrast, progesterone withdrawal induces cell death at comparable levels after short or long exposure to progestins and cAMP. We conclude that decidualization is characterized by a biphasic gene expression dynamic that likely corresponds to different phases in the establishment of the fetal–maternal interface.
Regulation and Assembly of Actomyosin Contractile Rings in Cytokinesis and Cell Repair

Cytokinesis and single‐cell wound repair both involve contractile assemblies of filamentous actin (F‐actin) and myosin II organized into characteristic ring‐like arrays. The assembly of these actomyosin contractile rings (CRs) is specified spatially and temporally by small Rho GTPases, which trigger local actin polymerization and myosin II contractility via a variety of downstream effectors. We now have a much clearer view of the Rho GTPase signaling cascade that leads to the formation of CRs, but some factors involved in CR positioning, assembly, and function remain poorly understood. Recent studies show that this regulation is multifactorial and goes beyond the long‐established Ca2+‐dependent processes. There is substantial evidence that the Ca2+‐independent changes in cell shape, tension, and plasma membrane composition that characterize cytokinesis and single‐cell wound repair also regulate CR formation. Elucidating the regulation and mechanistic properties of CRs is important to our understanding of basic cell biology and holds potential for therapeutic applications in human disease. In this review, we present a primer on the factors influencing and regulating CR positioning, assembly, and contraction as they occur in a variety of cytokinetic and single‐cell wound repair models. Anat Rec, 301:2051–2066, 2018. © 2018 Wiley Periodicals, Inc.
Role of the Advanced Practice Provider in Clinical Trials: Contributions to the Management of Patients Receiving Inotuzumab Ozogamicin

© 2017 Harborside Press® Successfully conducting oncology clinical trials requires the involvement of various research personnel. Advanced practice providers (APPs) are integral members of the team and play a vital role in identifying and enrolling appropriate patients, educating participants, and providing supportive care throughout the process. Clinical research is crucial for developing new, more effective treatments and helping us to learn more about the efficacy and safety of existing therapies and novel combinations. Planning and conducting a clinical study involve several steps (Figure), and the various phases of clinical studies are designed to assess the appropriate dose, efficacy, and safety of new therapies (Table 1). In addition to advancing medical treatments and ensuring patient safety, maintaining data integrity is an important goal of clinical studies. In this article, we highlight the role of the APP in clinical research through the experiences of a physician assistant and a nurse practitioner, both of whom have been active in the management of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) treated with inotuzumab ozogamicin (InO) vs. the investigator’s choice of chemotherapy in the phase III INO-VATE trial.
Short Cycles via Low-Diameter Decompositions

We present improved algorithms for short cycle decomposition of a graph - a decomposition of an undirected, unweighted graph into edge-disjoint cycles, plus a small number of additional edges. Short cycle decompositions were introduced in the recent work of Chu et al. (FOCS 2018), and were used to make progress on several questions in graph sparsification. For all constants δ ∈ (0,1], we give an O(mnδ) time algorithm that, given a graph G, partitions its edges into cycles of length [MATH HERE], with O(n) extra edges not in any cycle. This gives the first subquadratic, in fact almost linear time, algorithm achieving polylogarithmic cycle lengths. We also give an m · [MATH HERE] time algorithm that partitions the edges of a graph into cycles of length [MATH HERE], with O(n) extra edges not in any cycle. This improves on the short cycle decomposition algorithms given by Chu et al. in terms of all parameters, and is significantly simpler. As a result, we obtain faster algorithms and improved guarantees for several problems in graph sparsification - construction of resistance sparsifiers, graphical spectral sketches, degree preserving sparsifiers, and approximating the effective resistances of all edges.
Quantifying the axonal pathways directly stimulated in therapeutic subcallosal cingulate deep brain stimulation

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is an emerging experimental therapy for treatment‐resistant depression. New developments in SCC DBS surgical targeting are focused on identifying specific axonal pathways for stimulation that are estimated from patient‐specific computational models. This connectomic‐based biophysical modeling strategy has proven successful in improving the clinical response to SCC DBS therapy, but the DBS models used to date have been relatively simplistic, limiting the precision of the pathway activation estimates. Therefore, we used the most detailed patient‐specific foundation for DBS modeling currently available (i.e., field‐cable modeling) to evaluate SCC DBS in our most recent cohort of six subjects, all of which were responders to the therapy. We quantified activation of four major pathways in the SCC region: forceps minor (FM), cingulum bundle (CB), uncinate fasciculus (UF), and subcortical connections between the frontal pole and the thalamus or ventral striatum (FP). We then used the percentage of activated axons in each pathway as regressors in a linear model to predict the time it took patients to reach a stable response, or TSR. Our analysis suggests that stimulation of the left and right CBs, as well as FM are the most likely therapeutic targets for SCC DBS. In addition, the right CB alone predicted 84% of the variation in the TSR, and the correlation was positive, suggesting that activation of the right CB beyond a critical percentage may actually protract the recovery process.
Elbow Joint Angle Estimation from Surface Electromyography Using Hammerstein-Wiener Models

Estimation of a model that relates the surface electromyography (sEMG) to the joint angle is of major importance to design human robot interfaces, to control biomimetic mechanisms and to model muscular systems. However, it is challenging to obtain information from electromyographic signals due to nonlinearities, unmodeled muscle dynamics, noise and interference. In this paper, we applied system identification methods to estimate the parameters of a Hammerstein Wiener model that relates sEMG from three muscles of the arm (biceps brachii, triceps brachii and brachioradialis) to the elbow joint angle. In order to determine an estimation model and a calibration procedure, a set of experiments were carried out with two subjects. The experiment consisted of a series of elbow flexion and extension movements with different weights (Okg, 1.5kg and 3kg) and two different types of movement: continuous and intermittent, with controlled velocity. The sEMG and angular data were recorded during the experiment. The chosen model for system identification was the Hammerstein-Wiener with Wavelet Network as input and output nonlinearities. A second experiment was conducted in a different day in order to validate the estimated models. The results show a procedure to estimate a model for the EMG-to-Joint Angle, showing high correlations and coefficient of determination as well as low Root-Mean-Square Errors (RMSE) with respect to the measured data: correlations of $94.90\pm . 92{\%}$, coefficients of determination of $0.8814 \pm 0.0978$ and RMSE values of $10.82 \pm 3.73^{\circ}$. These models are interesting candidates to help in the control of actuated prosthetic and orthotic devices.
Cramér-Rao bound analysis for joint target location and velocity estimation in frequency modulation based passive radar networks

With the wide spread availability and the favourable Doppler resolution, the frequency modulation (FM) commercial radio signals have become attractive for passive radar applications. Passive radar networks using multiple illuminators of opportunity and multichannel receivers have been shown to offer significant performance improvement owing to their advantage of signal and spatial diversities. In this study, the authors compute the joint Cramer–Rao lower bound (CRLB) for the target parameter (delay and Doppler) estimation error utilising FM commercial radio signals as illuminators of opportunity for passive radar network systems, where the non-coherent and coherent processing scenarios are considered. The numerical simulations are provided to show that the joint CRLB is not only a function of the transmitted waveforms but also of the relative geometry between the target and the passive radar networks for both non-coherent and coherent cases. The expressions for joint CRLB are an important performance metric for target parameter estimation in FM-based passive radar networks.
Relationship between buprenorphine adherence and relapse, health care utilization and costs in privately and publicly insured patients with opioid use disorder

Background Treatment for opioid use disorder is important because of the negative health, societal and economic consequences of illicit opioid use, but treatment adherence can be a challenge. This study assessed the association between buprenorphine medication-assisted treatment (MAT) adherence and relapse, health care utilization and costs. Patients and methods Patients with opioid use disorder who were newly initiating a buprenorphine MAT regimen were identified in the 2008–2014 MarketScan® Commercial and Medicaid Databases and followed for 12 months after their earliest outpatient pharmacy claim for buprenorphine. Adherence was categorized using proportion of days covered (PDC) with buprenorphine, and patients with PDC≥0.80 were classified as adherent. Descriptive and adjusted analyses compared relapse prevalence, utilization and costs, all measured in the 12 months following buprenorphine MAT initiation, of adherent patients to patients in non-adherent PDC categories (PDC<0.20, 0.20≤PDC<0.40, 0.40≤PDC<0.60, 0.60≤PDC<0.80). Results Adherent patients were 37.1% of the Commercial sample (N=16,085) and 41.3% of the Medicaid sample (N=5,688). In both samples, non-adherent patients were significantly more likely than adherent patients to relapse and to have hospitalizations and emergency department visits. As a result, as buprenorphine MAT adherence increased, pharmacy costs increased, but medical costs decreased. Total costs (pharmacy plus medical costs) in the 12 months following buprenorphine MAT initiation decreased with adherence in Commercial patients ($28,525 for PDC<0.20 to $17,844 for PDC≥0.80). A slight decrease in total costs in the 12 months following buprenorphine MAT initiation was also observed in Medicaid patients ($21,292 for PDC<0.20 to $18,621 for PDC≥0.80). After adjustment, total costs of adherent patients in the Commercial sample ($17,519) were significantly lower compared with those of non-adherent patients (range $20,294–$24,431). In the Medicaid sample, adjusted total costs were not significantly different between adherence groups. Conclusion Buprenorphine MAT adherence in the 12 months following treatment was associated with reduced odds of relapse and reduced unadjusted medical costs. For Commercial patients who were adherent to treatment, the adjusted total costs were predicted to be 30% lower than those for patients with PDC<0.20.
Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis

Objective To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS). Methods This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer’s disease, 19 with Parkinson’s disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology. Results Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time. Conclusions Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.
Identity inference of genomic data using long-range familial searches

Detecting familial matches Recent advances in DNA technology and companies that provide array-based testing have led to services that collect, share, and analyze volunteered genomic information. Privacy concerns have been raised, especially in light of the use of these services by law enforcement to identify suspects in criminal cases. Testing models of relatedness, Erlich et al. show that many individuals of European ancestry in the United States—even those that have not undergone genetic testing—can be identified on the basis of available genetic information. These results indicate a need for procedures to help maintain genetic privacy for individuals. Science, this issue p. 690 Genetic privacy is difficult to maintain in light of forensic searches of genetic genealogical databases. Consumer genomics databases have reached the scale of millions of individuals. Recently, law enforcement authorities have exploited some of these databases to identify suspects via distant familial relatives. Using genomic data of 1.28 million individuals tested with consumer genomics, we investigated the power of this technique. We project that about 60% of the searches for individuals of European descent will result in a third-cousin or closer match, which theoretically allows their identification using demographic identifiers. Moreover, the technique could implicate nearly any U.S. individual of European descent in the near future. We demonstrate that the technique can also identify research participants of a public sequencing project. On the basis of these results, we propose a potential mitigation strategy and policy implications for human subject research.
The engineering of the giant dragonflies of the Permian: revised body mass, power, air supply, thermoregulation and the role of air density

ABSTRACT An engineering examination of allometric and analogical data on the flight of giant Permian insects (Protodonata, Meganeura or griffinflies) indicates that previous estimates of the body mass of these insects are too low and that the largest of these insects (wingspan of 70 cm or more) would have had a mass of 100–150 g, several times greater than previously thought. Here, the power needed to generate lift and fly at the speeds typical of modern large dragonflies is examined together with the metabolic rate and subsequent heat generated by the thoracic muscles. This evaluation agrees with previous work suggesting that the larger specimens would rapidly overheat in the high ambient temperatures assumed in the Permian. Various extant mechanisms of thermoregulation are modelled and quantified, including behaviour, radiation and the constraints on convective respiration and evaporation imposed by air flow through spiracles. However, the effects of these on cooling an overheated insect are found to be limited. Instead, an examination of the heat budget in the flight medium indicates that, at about 1.6 bar (160 kPa), thermoregulation supply enters into equilibrium and, even at high ambient temperatures, overheating can be avoided and enough oxygen sourced. This approach indicates how fossil biology can be used to examine past atmospheres. Summary: The giant dragonflies of the Permian would have rapidly overheated during flight. It is proposed that thermal equilibrium could have been maintained through aspects of physiology, behaviour and higher air density.
Olodaterol for the treatment of chronic obstructive pulmonary disease: a narrative review

ABSTRACT Introduction: Inhaled bronchodilators are the key-stone of chronic obstructive pulmonary disease (COPD) management. Olodaterol 5 µg, a long-acting β2-adrenoceptor agonist (LABA) is one such bronchodilator indicated as a once-daily maintenance therapy. Areas covered: This article reviews the several trials that have assessed olodaterol as a COPD therapy. It covers safety and tolerability data and provides the reader with an expert opinion on its use as a treatment for COPD. Expert opinion: Olodaterol improves lung function for 24 h and reduces rescue medication use. It may also improve dyspnea, exercise tolerance, and health-related quality of life. It is well tolerated with an acceptable cardiovascular and respiratory adverse event profile. There is some evidence that olodaterol, as well as other LABAs, can reduce exacerbation frequency, but not FEV1 decline and death. LABAs alone are indicated in group A/B COPD subjects. Olodaterol and indacaterol are administered once-daily and may offer an adherence advantage over other LABAs with more frequent dosing schedules. Co-administration of an olodaterol/tiotropium fixed dose combination in a single inhaler device is recommended as step-up in group A/B COPD subjects not sufficiently treated by olodaterol alone or as initial therapy in those with severe exertional dyspnea.
Multivariate-Time-Series-Driven Real-time Anomaly Detection Based on Bayesian Network

Anomaly detection is an important research direction, which takes the real-time information system from different sensors and conditional information sources into consideration. Based on this, we can detect possible anomalies expected of the devices and components. One of the challenges is anomaly detection in multivariate-sensing time-series in this paper. Based on this situation, we propose RADM, a real-time anomaly detection algorithm based on Hierarchical Temporal Memory (HTM) and Bayesian Network (BN). First of all, we use HTM model to evaluate the real-time anomalies of each univariate-sensing time-series. Secondly, a model of anomalous state detection in multivariate-sensing time-series based on Naive Bayesian is designed to analyze the validity of the above time-series. Lastly, considering the real-time monitoring cases of the system states of terminal nodes in Cloud Platform, the effectiveness of the methodology is demonstrated using a simulated example. Extensive simulation results show that using RADM in multivariate-sensing time-series is able to detect more abnormal, and thus can remarkably improve the performance of real-time anomaly detection.