Miracle-dz/UniFAR-FTUs huggingface dataset:
EXACT AND ASYMPTOTICALLY ROBUST PERMUTATION TESTS

Given independent samples from P and Q, two-sample permutation tests allow one to construct exact level tests when the null hypothesis is P=Q. On the other hand, when comparing or testing particular parameters $\theta$ of P and Q, such as their means or medians, permutation tests need not be level $\alpha$, or even approximately level $\alpha$ in large samples. Under very weak assumptions for comparing estimators, we provide a general test procedure whereby the asymptotic validity of the permutation test holds while retaining the exact rejection probability $\alpha$ in finite samples when the underlying distributions are identical. The ideas are broadly applicable and special attention is given to the k-sample problem of comparing general parameters, whereby a permutation test is constructed which is exact level $\alpha$ under the hypothesis of identical distributions, but has asymptotic rejection probability $\alpha$ under the more general null hypothesis of equality of parameters. A Monte Carlo simulation study is performed as well. A quite general theory is possible based on a coupling construction, as well as a key contiguity argument for the multinomial and multivariate hypergeometric distributions.
Earliest Intercept Geometry Guidance to improve mid-course guidance in area air-defence

This paper describes a mid-course guidance strategy based on the Earliest Intercept Geometry (EIG) Guidance. An analytical solution and performance validation will be addressed for generalized mid-course guidance problem in area air-defence to improve rechability and performance. The EIG is generated for a wide range of possible manoeuvres of the challenging missile based on the guidance algorithm using differential geometry concepts. The main idea is that a mid-course guidance law can defend the area as long as it assures that the depending area and objects are always within the defended area defined by EIG. The velocity of Intercept Point in EIG is analytically derived to control the Intercept Geometry and the defended area. The proposed method can be applied in deciding a missile launch window and launch point for the launch phase.
A new set of primers for COI amplification from freshwater microcrustaceans

Despite the contribution of DNA barcoding towards understanding the biodiversity and distribution of species, the success of COI amplification has been quite variable when it comes to freshwater zooplankton (Elías‐Gutiérrez & Valdez‐Moreno 2008; Jeffery et al. 2011). Some genera of microcrustaceans seem to be more difficult to amplify than others. For example, Macrothrix, Scapholeberis, Diaphanosoma and cyclopoids have yielded limited results. Among several possible reasons for the inability to barcode freshwater microcrustaceans is that there does not exist a specific set of primers for COI amplification. To this end, we developed a zooplankton – specific set of primers, which significantly increased average amplification success (20% increase). With these primers, we observed an overall success of over 70% for Sididae and Chydoridae, and more than 80% for Daphniidae, Moinidae, Bosminidae, Macrothricidae, Ilyocryptidae and Diaptomidae. We also demonstrate a simple alteration to a common specimen fixation method that increases the overall recovery of barcodes from freshwater zooplankton. Collectively, we believe our results will greatly aid the recovery of barcodes from these difficult groups.
Exercise and Depression: Causal Sequence Using Cross-Lagged Panel Correlation Analysis

This study sought to determine what kind of causal relationship, if any, exists between exercise and depression. A university student population (N = 178) was given the Godin Leisure Time Exercise Questionnaire and the Beck Depression Inventory-II at two time points separated by approximately one month. Cross-lagged panel correlation was used to make causal inferences based on the strength of the temporal relationships. After meeting the assumptions of synchronicity and stationarity, there was no significant difference between the cross-lagged correlations (ZPF =-0.4599, p = 0.65). Thus, no single causal pathway was dominant. While equal cross-lagged correlations can indicate spuriousness, it can also signify reciprocal causation. Exercise was not clearly the cause of reductions in depression, but neither was depression clearly the cause of physical inactivity. More complex causal pathways, such as reciprocal causation, warrant further investigation.
Dynamics of Deterministic and Stochastic Paired ExcitatoryInhibitory Delayed Feedback

We examine the effects of paired delayed excitatory and inhibitory feedback on a single integrateandfire neuron with reversal potentials embedded within a feedback network. These effects are studied using bifurcation theory and numerical analysis. The feedback occurs through modulation of the excitatory and inhibitory conductances by the previous firing history of the neuron; as a consequence, the feedback also modifies the membrane time constant. Such paired feedback is ubiquitous in the nervous system. We assume that the feedback dynamics are slower than the membrane time constant, which leads to a rate model formulation. Our article provides an extensive analysis of the possible dynamical behaviors of such simple yet realistic neural loops as a function of the balance between positive and negative feedback, with and without noise, and offers insight into the potential behaviors such loops can exhibit in response to time-varying external inputs. With excitatory feedback, the system can be quiescent, can be periodically firing, or can exhibit bistability between these two states. With inhibitory feedback, quiescence, oscillatory firing rates, and bistability between constant and oscillatory firing-rate solutions are possible. The general case of paired feedback exhibits a blend of the behaviors seen in the extreme cases and can produce chaotic firing. We further derive a condition for a dynamically balanced paired feedback in which there is neither bistability nor oscillations. We also show how a biophysically plausible smoothing of the firing function by noise can modify the existence and stability of fixed points and oscillations of the system. We take advantage in our mathematical analysis of the existence of an invariant manifold, which reduces the dimensionality of the dynamics, and prove the stability of this manifold. The novel computational challenges involved in analyzing such dynamics with and without noise are also described. Our results demonstrate that a paired delayed feedback loop can act as a sophisticated computational unit, capable of switching between a variety of behaviors depending on the input current, the relative strengths and asymmetry of the two parallel feedback pathways, and the delay distributions and noise level.
Borna Disease Virus Requires Cholesterol in both Cellular Membrane and Viral Envelope for Efficient Cell Entry

ABSTRACT Borna disease virus (BDV), the prototypic member of the family Bornaviridae within the order Mononegavirales, provides an important model for the investigation of viral persistence within the central nervous system (CNS) and of associated brain disorders. BDV is highly neurotropic and enters its target cell via receptor-mediated endocytosis, a process mediated by the virus surface glycoprotein (G), but the cellular factors and pathways determining BDV cell tropism within the CNS remain mostly unknown. Cholesterol has been shown to influence viral infections via its effects on different viral processes, including replication, budding, and cell entry. In this work, we show that cell entry, but not replication and gene expression, of BDV was drastically inhibited by depletion of cellular cholesterol levels. BDV G-mediated attachment to BDV-susceptible cells was cholesterol independent, but G localized to lipid rafts (LR) at the plasma membrane. LR structure and function critically depend on cholesterol, and hence, compromised structural integrity and function of LR caused by cholesterol depletion likely inhibited the initial stages of BDV cell internalization. Furthermore, we also show that viral-envelope cholesterol is required for BDV infectivity.
Intestinal Transport of Aminopterin Enantiomers in Dogs and Humans with Psoriasis Is Stereoselective: Evidence for a Mechanism Involving the Proton-Coupled Folate Transporter

N-[4-[[(2,4-diamino-6-pterdinyl)methyl]amino]benzoyl]-l/d-glutamic acid (l/d-AMT) is an investigational drug in phase 1 clinical development that consists of the l-and d-enantiomers of aminopterin (AMT). l/d-AMT is obtained from a novel process for making the l-enantiomer (l-AMT), a potent oral anti-inflammatory agent. The purpose of these studies was to characterize oral uptake and safety in the dog and human of each enantiomer alone and in combination and provide in vitro evidence for a mechanism of intestinal absorption. This is the first report of l /d-AMT in humans. In dogs (n = 40) orally dosed with l-AMT or d-AMT absorption was stereoselective for the l-enantiomer (6- to 12-fold larger peak plasma concentration after oral administration and area under the plasma concentration-time curve at 0–4 h; p < 0.001). d-AMT was not toxic at the maximal dose tested (82.5 mg/kg), which was 100-fold larger than the maximal nonlethal l-AMT dose (0.8 mg/kg). Dogs (n = 10) and humans with psoriasis (n = 21) orally administered l-AMT and l /d-AMT at the same l-enantiomer dose resulted in stereoselective absorption (absent d-enantiomer in plasma), bioequivalent l-enantiomer pharmacokinetics, and equivalent safety. Thus, the d-enantiomer in l/d-AMT did not perturb l-enantiomer absorption or alter the safety of l-AMT. In vitro uptake by the human proton-coupled folate transporter (PCFT) demonstrated minimal transport of d-AMT compared with l-AMT, mirroring the in vivo findings. Enantiomer selectivity by PCFT was attributable almost entirely to decreased binding affinity rather than changes in transport rate. Collectively, our results demonstrate a strong in vitro-in vivo correlation implicating stereoselective transport by PCFT as the mechanism underlying stereoselective absorption observed in vivo.
Evaluating relationships between symptom duration and persistence of rheumatoid arthritis: does a window of opportunity exist? Results on the Leiden Early Arthritis Clinic and ESPOIR cohorts

Background A prolonged symptom or disease duration at treatment initiation is associated with unfavourable outcomes in rheumatoid arthritis (RA). It is unknown whether this relation is linear, referring to a common ‘the-earlier-the-better principle’, or whether a transient time frame in which the disease is more susceptible to treatment exists, referring to a ‘window of opportunity’. To elucidate this, we evaluated the shape of the associations of symptom duration with persistence of RA. Methods Patients with 1987 RA treated with disease modifying antirheumatic drugs (DMARDs) in the Leiden Early Arthritis Clinic (EAC, n=738) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n=533) were studied. Cox proportional hazards regression models using natural cubic splines were performed; the log-HR on DMARD-free sustained remission (the opposite of RA persistence) during 5-year follow-up was plotted against symptom duration. Discrimination was measured using time-dependent receiver operator characteristic curves. Subanalyses were performed stratified for the DMARDs used (methotrexate or other conventional DMARDs) and for anticitrullinated peptide antibody (ACPA). Results 11.5% (85/738) and 5.4% (29/533) of EAC and ESPOIR RA patients achieved DMARD-free sustained remission. In both cohorts and all analyses, the curves depicting the log-HRs on remission in relation to symptom duration were not linear. The symptom duration with optimal discriminative ability was 14.9 weeks (95% CI 12.3 to 16.0; area under the curve (AUC) 0.61) in the EAC and 19.1 weeks (95% CI 12.3 to 28.0; AUC 0.59) in ESPOIR. For ACPA-positive RA, this was 11.4 weeks (95% CI 7.7 to 79.0; AUC 0.56) and for ACPA-negative RA 15.0 weeks (95% CI 9.7 to 48.7; AUC 0.56). Conclusions The association between symptom duration and RA persistence is not linear, suggesting the presence of a confined period in which RA is more susceptible to treatment.
The mononuclear phagocyte system of the pig as a model for understanding human innate immunity and disease

The biology of cells of the mononuclear phagocyte system has been studied extensively in the mouse. Studies of the pig as an experimental model have commonly been consigned to specialist animal science journals. In this review, we consider some of the many ways in which the innate immune systems of humans differ from those of mice, the ways that pigs may address the shortcomings of mice as models for the study of macrophage differentiation and activation in vitro, and the biology of sepsis and other pathologies in the living animal. With the completion of the genome sequence and the characterization of many key regulators and markers, the pig has emerged as a tractable model of human innate immunity and disease that should address the limited, predictive value of rodents in preclinical studies.
Smad3 controls β-1,3-glucuronosyltransferase 1 expression in rat nucleus pulposus cells: implications of dysregulated expression in disc disease.

OBJECTIVE To study the regulation of expression of β-1,3-glucuronosyltransferase 1 (GlcAT-1), an important regulator of glycosaminoglycan (GAG) synthesis, by Smad3 in nucleus pulposus (NP) cells. METHODS GlcAT-1 expression was examined in rat NP and anulus fibrosus (AF) cells treated with transforming growth factor β (TGFβ). The effects of Smad signaling and Smad suppression on GlcAT-1 were examined in rat NP cells. GlcAT-1 expression was analyzed in the discs of Smad3-null mice and in degenerated human NP tissue. RESULTS TGFβ increased the expression of GlcAT-1 in rat NP but not rat AF cells. Suppression of GlcAT-1 promoter activity was evident with dominant-negative ALK-5 (DN-ALK-5). Cotransfection with Smad3 strongly induced promoter activity independent of TGFβ. Bioinformatics analysis indicated the presence of several Smad binding sites in the promoter; deletion analysis showed that the region between -274 and -123 bp was required for Smad3 response. DN-Smad3, Smad 3 small interfering RNA, and Smad7 strongly suppressed basal as well as TGFβ-induced promoter activity. Induction of promoter activity by Smad3 was significantly blocked by DN-Smad3; Smad7 had a very small effect. Lentiviral transduction of NP cells with short hairpin RNA Smad3 resulted in a decrease in GlcAT-1 expression and accumulation of GAG. Compared to wild-type mice, significantly lower expression of GlcAT-1 was seen in the discs of Smad3-null mice. Analysis of degenerated human NP tissue specimens showed no positive correlation between GlcAT-1 and TGFβ expression. Moreover, isolated cells from degenerated human tissue showed a lack of induction of GlcAT-1 expression following TGFβ treatment, suggesting an altered response. CONCLUSION Our findings demonstrate that in healthy NP cells, the TGFβ-Smad3 axis serves as a regulator of GlcAT-1 expression. However, an altered responsiveness to TGFβ during disc degeneration may compromise GAG synthesis.
Dose-Response Relationship Between Cigarette Smoking and Risk of Ischemic Stroke in Young Women

Background and Purpose— Although cigarette smoking is known to be a risk factor for ischemic stroke, there are few data on the dose-response relationship between smoking and stroke risk in a young ethnically diverse population. Methods— We used data from the Stroke Prevention in Young Women Study, a population-based case-control study of risk factors for ischemic stroke in women aged 15 to 49 years to examine the relationship between cigarette smoking and ischemic stroke. Historical data, including smoking history, was obtained through standardized interviews. Odds ratios (OR) were estimated using logistic regression. Cases (n=466) were women with stroke in the greater Baltimore-Washington area, and controls (n=604) were women free of a stroke history identified by random digit dialing. Results— After multivariable adjustment, the OR comparing current smokers to never smokers was 2.6 (P<0.0001); no difference in stroke risk was observed between former smokers and never smokers. Adjusted OR increased with increasing number of cigarettes smoked per day (OR=2.2 for 1 to 10 cigs/d; 2.5 for 11 to 20 cigs/d; 4.3 for 21 to 39 cigs/d; 9.1 for 40 or more cigs/d). Conclusion— These results suggest a strong dose-response relationship between cigarette smoking and ischemic stroke risk in young women and reinforce the need for aggressive smoking cessation efforts in young adults.
Pineal proteins upregulate specific antioxidant defense systems in the brain

The neuroendocrine functions of the pineal affect a wide variety of glandular and nervous system processes. Beside melatonin (MEL), the pineal gland secretes and expresses certain proteins essential for various physiological functions. It has been suggested that the pineal gland may also have an antioxidant role due to secretory product other than MEL. Therefore, the present study was designed to study the effect of buffalo (Bubalus bubalis) pineal proteins (PP) on the antioxidant defense system in the brain of female rats. The twenty-four rats were taken in present study and were divided into four groups: control (0 day), control (28 day), vehicle control and buffalo PP. The PP was injected 100 µg/kg BW intraperitoneal (i.p.) daily for 28 days. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GR) and reduced glutathione (GSH) concentration and the levels of lipid peroxidation (LPO) in the brain tissue were measured to assess the antioxidant systems. These enzymes protect from adverse effects of free radicals and help in amelioration of oxidative stress. Buffalo pineal proteins administration did not cause any effect on brain LPO, whereas GPx, GR and GSH were significantly (p < 0.05) decreased. However, SOD and CAT activities were increased to significant levels than the control in PP treated rats. Our study herein suggested that buffalo (Bubalus bubalis) pineal proteins upregulates specific antioxidant defense systems and can be useful in control of various oxidative stress-induced neuronal diseases.
A Wireless Micro Inertial Measurement Unit (IMU)

In this paper, we present a wireless micro inertial measurement unit (IMU) with the smallest volume and weight requirements available at the moment. With a size of 22 mm × 14 mm × 4 mm (1.2 cm3), this IMU provides full control over the data of a three-axis accelerometer, a three-axis gyroscope, and a three-axis magnetometer. It meets the design prerequisites of a space-saving design and eliminates the need for hard-wired data communication, while still being competitive with state-of-the-art commercially available MEMS IMUs. A CC430 microcontroller sends the collected raw data to a base station wirelessly with a maximum sensor sample rate of 640 samples/s. Thereby, the IMU performance is optimized by moving data post processing to the base station. This development offers important features in portable applications with their significant size and weight requirements. Due to its small size, the IMU can be integrated into clothes or shoes for accurate position estimation in mobile applications and location-based services. We demonstrate the performance of the wireless micro IMU in a localization experiment where it is placed on a shoe for pedestrian tracking. With sensor data-fusion based on a Kalman filter combined with the zero velocity update, we can precisely track a person in an indoor area.
Influence of benzodiazepines on antiparkinsonian drug treatment in levodopa users

Objectives– Animal studies showed that benzodiazepines decrease the concentration of dopamine in the striatum. Benzodiazepines may therefore affect the treatment of Parkinson’s disease. This study determined whether start of a benzodiazepine in patients on levodopa was followed by a faster increase of antiparkinsonian drug treatment. Methods– Data came from the PHARMO database, which includes information on drug dispensing for all residents of six Dutch cities. Selected were all patients aged 55 years and older who used levodopa for at least 360 days. The rate of increase of antiparkinsonian drug treatment was compared between starters of a benzodiazepine and controls who did not start a benzodiazepine with the use of Cox’s proportional hazard model. Results– Identified were 45 benzodiazepine starters (27 women, mean age 76.4 years) and 169 controls (83 women, 74.3 years). Antiparkinsonian drug treatment increased faster in the benzodiazepine group; relative risk was 1.44 (95% confidence interval 0.80–2.59). Conclusion– This study has not found any statistically significant increase in antiparkinsonian drug treatment when a benzodiazepine was started in a small population of chronic levodopa users.
Atomic Structure of Cucumber Necrosis Virus and the Role of the Capsid in Vector Transmission

ABSTRACT Cucumber Necrosis Virus (CNV) is a member of the genus Tombusvirus and has a monopartite positive-sense RNA genome packaged in a T=3 icosahedral particle. CNV is transmitted in nature via zoospores of the fungus Olpidium bornovanus. CNV undergoes a conformational change upon binding to the zoospore that is required for transmission, and specific polysaccharides on the zoospore surface have been implicated in binding. To better understand this transmission process, we have determined the atomic structure of CNV. As expected, being a member of the Tombusvirus genus, the core structure of CNV is highly similar to that of Tomato bushy stunt virus (TBSV), with major differences lying on the exposed loops. Also, as was seen with TBSV, CNV appears to have a calcium binding site between the subunits around the quasi-3-fold axes. However, unlike TBSV, there appears to be a novel zinc binding site within the β annulus formed by the N termini of the three C subunits at the icosahedral 3-fold axes. Two of the mutations causing defective transmission map immediately around this zinc binding site. The other mutations causing defective transmission and particle formation are mapped onto the CNV structure, and it is likely that a number of the mutations affect zoospore transmission by affecting conformational transitions rather than directly affecting receptor binding.
Systemic Fibrinolytic Therapy in the Presence of Absolute Contraindication; a Case Series

In massive pulmonary embolism (PE), fibrinolytic therapy is a potential lifesaving treatment; therefore, if other treatments are not available, the physicians encounter this question: can we accept the risk of complications from fibrinolytic therapy, especially intracranial hemorrhage, in the presence of absolute contraindication, in order to save the patient’s life? Here, we describe three cases of massive PE with absolute contraindication for fibrinolytic therapy who presented to emergency department following dyspnea. Since, surgical or catheter embolectomy were not available and patients were very high risk for transferring to another hospital, systemic fibrinolytic was administered. The patients improved clinically and were discharged from hospital. It seems that, if no other acceptable treatments are available, physicians could consider fibrinolytic therapy, even at the presence of contraindication, to save the patient’s life.