Miracle-dz/UniFAR-FTUs huggingface dataset:
IFT25 is required for the construction of the trypanosome flagellum

ABSTRACT Intraflagellar transport (IFT), the movement of protein complexes responsible for the assembly of cilia and flagella, is remarkably conserved from protists to humans. However, two IFT components (IFT25 and IFT27) are missing from multiple unrelated eukaryotic species. In mouse, IFT25 (also known as HSPB11) and IFT27 are not required for assembly of several cilia with the noticeable exception of the flagellum of spermatozoa. Here, we show that the Trypanosoma brucei IFT25 protein is a proper component of the IFT-B complex and displays typical IFT trafficking. By performing bimolecular fluorescence complementation assays, we reveal that IFT25 and IFT27 interact within the flagellum in live cells during the IFT process. IFT25-depleted cells construct tiny disorganised flagella that accumulate IFT-B proteins (with the exception of IFT27, the binding partner of IFT25) but not IFT-A proteins. This phenotype is comparable to the one following depletion of IFT27 and shows that IFT25 and IFT27 constitute a specific module that is necessary for proper IFT and flagellum construction in trypanosomes. Possible reasons why IFT25 and IFT27 would be required for only some types of cilia are discussed. Summary: The IFT25 protein of Trypanosoma brucei is required for construction of its flagellum, a situation equivalent to the mouse sperm flagellum but not to primary cilia.
Amelioration of nitrate uptake under salt stress by ectomycorrhiza with and without a Hartig net

Summary Salt stress is an important environmental cue impeding poplar nitrogen nutrition. Here, we characterized the impact of salinity on proton‐driven nitrate fluxes in ectomycorrhizal roots and the importance of a Hartig net for nitrate uptake. We employed two Paxillus involutus strains for root colonization: MAJ, which forms typical ectomycorrhizal structures (mantle and Hartig net), and NAU, colonizing roots with a thin, loose hyphal sheath. Fungus‐colonized and noncolonized Populus × canescens were exposed to sodium chloride and used to measure root surface pH, nitrate (NO 3 −) flux and transcription of NO3 − transporters (NRTs; PcNRT1.1, ‐1.2, ‐2.1), and plasmalemma proton ATPases (HAs; PcHA4, ‐8, ‐11). Paxillus colonization enhanced root NO 3 − uptake, decreased surface pH, and stimulated NRTs and HA4 of the host regardless the presence or absence of a Hartig net. Under salt stress, noncolonized roots exhibited strong net NO 3 − efflux, whereas beneficial effects of fungal colonization on surface pH and HAs prevented NO 3 − loss. Inhibition of HAs abolished NO 3 − influx under all conditions. We found that stimulation of HAs was crucial for the beneficial influence of ectomycorrhiza on NO 3 − uptake, whereas the presence of a Hartig net was not required for improved NO 3 − translocation. Mycorrhizas may contribute to host adaptation to salt‐affected environments by keeping up NO 3 − nutrition.
TUMORIGENESIS AND NEOPLASTIC PROGRESSION Association of High miR-182 Levels with Low-Risk Prostate Cancer

opyright a 2019 American Society for Inve his is an open access article under the CC B ttps://doi.org/10.1016/j.ajpath. 2018.12. 014 A subset of men with prostate cancer develops aggressive disease. We sought to determine whether miR-182, an miRNA with reported oncogenic functions in the prostate, is associated with biochemical recurrence and aggressive disease. Prostate epithelial miR-182 expression was quantified via in situ hybridization of two prostate tissue microarrays and by laser-capture microdissection of prostate epithelium. miR-182 was significantly higher in cancer epithelium than adjacent benign epithelium (P < 0.0001). The ratio of cancer to benign miR-182 expression per patient was inversely associated with recurrence in a multivariate logistic regression model (odds ratio Z 0.18; 95% CI, 0.03e0.89; P Z 0.044). Correlation of miR-182 with mRNA expression in laser-capture microdissected benign prostate epithelium was used to predict prostatic miR-182 targets. Genes that were negatively correlated with miR-182 were enriched for its predicted targets and for genes previously identified as upregulated in prostate cancer metastases. miR-182 expression was also negatively correlated with genes previously identified as up-regulated in primary prostate tumors from African American patients, who are at an increased risk of developing aggressive prostate cancer. Taken together, these results suggest that although miR-182 is expressed at higher levels in localized prostate cancer, its levels are lower in aggressive cancers, suggesting a biphasic role for this miRNA that may be exploited for prognostic and/or therapeutic purposes to reduce prostate cancer progression. (Am J Pathol 2019, 189: 911e923; https://doi.org/10.1016/j.ajpath.2018.12.014)
Medium-term effects of a two-desk sit/stand workstation on cognitive performance and workload for healthy people performing sedentary work: a secondary analysis of a randomised controlled trial

Abstract Implementing sit/stand workstations in sedentary work environments is a common way to reduce sedentary time, but their medium-term effect on cognitive performance is unclear. To address this circumstance, eighteen office workers participated in a two-arm, randomised controlled cross-over trial (ClinicalTrials.gov Identifier: NCT02825303), either working at a traditional (sit) or an interventional (sit/stand) workplace for 23 weeks. Cognitive performance (working speed, reaction time, concentration performance, accuracy), workload and relevant covariates (salivary cortisol level, heart rate, physical activity, sitting time) were measured pre- and post-intervention under laboratory conditions. MANOVA and RMANOVA results did not show differences in performance parameters and workload, respectively, between sit/stand and traditional workplace users. Differences in text editing accuracy and cortisol levels for sit/stand workstation users indicate potential connectivity to cognitive parameters which should be further examined with large-scale studies. Practitioner summary: Medium-term effects of working at sit/stand workstations on cognitive performance and workload are unexplored. This randomised controlled trial suggests that cognitive performance and workload are unaffected for sit/stand workstation users after 23 weeks of use. However, accuracy appeared to improve and physiological stress appeared to be altered. Abbreviations: BMI: body mass index; IPAQ: International physical activity questionnaire; MET: metabolic equivalent of task; MANOVA: multivariate ANOVA; NASA TLX: NASA task load index; RMANOVA: repeated measures ANOVA GRAPHICAL ABSTRACT
OMERACT Development of a Core Domain Set of Outcomes for Shared Decision-making Interventions

Objective. The Outcome Measures in Rheumatology (OMERACT) Shared Decision Making (SDM) Working Group aims to determine the core outcome domain set for measuring the effectiveness of SDM interventions in rheumatology trials. Methods. A white paper was developed to clarify the draft core domain set. It was then used to prepare for interviews to investigate reasons for lack of consensus on it and to suggest further improvements. Results. OMERACT scientists/clinicians (n = 13) and patients (n = 10) suggested limiting the core domain set to outcome domains, removing process domains, and clarifying remaining domains. Conclusion. A revised core domain set will undergo further consensus-building.
Home Appliance Management System for Monitoring Digitized Devices Using Cloud Computing Technology in Ubiquitous Sensor Network Environment

The number of service techniques available for digitized home appliances is rapidly increasing as a result of various advances in digital technology. Users can now easily control and monitor home appliances via sensor networks formed among home appliances in ubiquitous environments. However, home appliances generate such large amounts of metadata about their status every month that in order to provide home appliance monitoring services to users, an approach that is able to store, analyze, and process these large amounts of metadata is needed. We propose a system that uses UPnP to collect metadata from home appliances and cloud computing technology to store and process the metadata collected from ubiquitous sensor network environments. Our proposed system utilizes a home gateway and is designed and implemented using UPnP technology to search for and collect device features and service information. It also provides a function for transmitting the metadata from the home appliances to a cloud-based data server that uses Hadoop-based technology to store and process the metadata collected by a home appliance monitoring service.
Assessment of local influence for the analysis of agreement

The concordance correlation coefficient (CCC) and the probability of agreement (PA) are two frequently used measures for evaluating the degree of agreement between measurements generated by two different methods. In this paper, we consider the CCC and the PA using the bivariate normal distribution for modeling the observations obtained by two measurement methods. The main aim of this paper is to develop diagnostic tools for the detection of those observations that are influential on the maximum likelihood estimators of the CCC and the PA using the local influence methodology but not based on the likelihood displacement. Thus, we derive first‐ and second‐order measures considering the case‐weight perturbation scheme. The proposed methodology is illustrated through a Monte Carlo simulation study and using a dataset from a clinical study on transient sleep disorder. Empirical results suggest that under certain circumstances first‐order local influence measures may be more powerful than second‐order measures for the detection of influential observations.
Rehabilitation Exercises for the Gluteus Medius Muscle Segments: An Electromyography Study.

Context: Many different rehabilitation exercises have been recommended in the literature to target the gluteus medius (GMed) muscle based mainly on single-electrode, surface electromyography (EMG) measures. With the GMed consisting of 3 structurally and functionally independent segments, there is uncertainty on whether these exercises will target the individual segments effectively. Objective: To measure individual GMed segmental activity during 6 common, lower-limb rehabilitation exercises in healthy young adults, and determine if there are significant differences between the exercises for each segment. Method: With fine-wire EMG electrodes inserted into the anterior, middle, and posterior segments of the GMed muscle, 10 healthy young adults performed 6 common, lower-limb rehabilitation exercises. Main Outcome Measures: Recorded EMG activity was normalized, then reported and compared with median activity for each of the GMed segments across the 6 exercises. Results: For the anterior GMed segment, high activity was recorded for the single-leg squat (48% maximum voluntary isometric contraction [MVIC]), the single-leg bridge (44% MVIC), and the resisted hip abduction-extension exercise (41% MVIC). No exercises recorded high activity for the middle GMed segment, but for the posterior GMed segment very high activity was recorded by the resisted hip abduction-extension exercise (69% MVIC), and high activity was generated by the single-leg squat (48% MVIC) and side-lie hip abduction (43% MVIC). For each of the GMed segments, there were significant differences (P < .05) in the median EMG activity levels between some of the exercises and the side-lie clam with large effect sizes favoring these exercises over the side-lie clam. Conclusions: Open-chain hip abduction and single-limb support exercises appear to be effective options for recruiting the individual GMed segments with selection dependent on individual requirements. However, the side-lie clam does not appear to be effective at recruiting the GMed segments, particularly the anterior and middle segments.
Where Do We Go from Here? Nonresponse and Social Measurement

Surveys undergird government statistical systems and social scientific research throughout the world. Rates of nonresponse are rising in cross-sectional surveys (those conducted during a fixed period of time and not repeated). Although this trend worries those concerned with the validity of survey data, there is no necessary relationship between the rate of nonresponse and the degree of bias. A high rate of nonresponse merely creates the potential for bias, but the degree of bias depends on how factors promoting nonresponse are related to variables of interest. Nonresponse can be reduced by offering financial incentives to respondents and by careful design before entering the field, creating a trade-off between cost and potential bias. When bias is suspected, it can be countered by weighting individual cases by the inverse of their response propensity. Response propensities are typically estimated using a logistic regression equation to predict the dichotomous outcome of survey participation as a function of auxiliary variables. The Multi-level Integrated Database Approach employs multiple databases to collect as much information as possible about the target sample during the initial sampling stage and at all possible levels of aggregation to maximize the accuracy of estimated response propensities.
Striatal spreading depolarization: Possible implication in levodopa‐induced dyskinetic‐like behavior

Spreading depolarization (SD) is a transient self‐propagating wave of neuronal and glial depolarization coupled with large membrane ionic changes and a subsequent depression of neuronal activity. Spreading depolarization in the cortex is implicated in migraine, stroke, and epilepsy. Conversely, spreading depolarization in the striatum, a brain structure deeply involved in motor control and in Parkinson's disease (PD) pathophysiology, has been poorly investigated.
Ranking Reversible Covalent Drugs: From Free Energy Perturbation to Fragment Docking

Reversible covalent inhibitors have drawn increasing attention in drug design, as they are likely more potent than noncovalent inhibitors and less toxic than covalent inhibitors. Despite those advantages, the computational prediction of reversible covalent binding presents a formidable challenge because the binding process consists of multiple steps and quantum mechanics (QM) level calculation is needed to estimate the covalent binding free energy. It has been shown that the dissociation rates and the equilibrium dissociation constants vary significantly even with similar warheads, due to noncovalent interactions. We have previously used a simplistic two-state model for predicting the relative binding selectivity of reversible covalent inhibitors ( J. Am. Chem. Soc. 2017, 139 , 17945 ). Here we go beyond binding selectivity and demonstrate that it is possible to use free energy perturbation (FEP) molecular dynamics (MD) to calculate the overall reversible covalent binding using a specially designed thermodynamic cycle. We show that FEP can predict the varying binding free energies of the analogs sharing a common warhead. More importantly, our results revealed that the chemical modification away from warhead alters the binding affinity at both noncovalent and covalent binding states, and the computational prediction can be improved by considering the binding free energy of both states. Furthermore, we explored the possibility of using a more rapid computational method, site-identification by ligand competitive saturation (SILCS), to rank the same set of reversible covalent inhibitors. We found that the fragment docking to a set of precomputed fragment maps produces a reasonable ranking. In conclusion, two independent approaches provided consistent results that the covalent binding state is suitable for the initial ranking of the reversible covalent drug candidates. For lead-optimization, the FEP approach designed here can provide more rigorous and detailed information regarding how much the covalent and noncovalent binding states are contributing to the overall binding affinity, thus offering a new avenue for fine-tuning the noncovalent interactions for optimizing reversible covalent drugs.
Toxic but tasty – temporal dynamics and network architecture of heme‐responsive two‐component signaling in Corynebacterium glutamicum

Heme is an essential cofactor and alternative iron source for almost all bacterial species but may cause severe toxicity upon elevated levels and consequently, regulatory mechanisms coordinating heme homeostasis represent an important fitness trait. A remarkable scenario is found in several corynebacterial species, e.g. Corynebacterium glutamicum and Corynebacterium diphtheriae, which dedicate two paralogous, heme‐responsive two‐component systems, HrrSA and ChrSA, to cope with the Janus nature of heme. Here, we combined experimental reporter profiling with a quantitative mathematical model to understand how this particular regulatory network architecture shapes the dynamic response to heme. Our data revealed an instantaneous activation of the detoxification response (hrtBA) upon stimulus perception and we found that kinase activity of both kinases contribute to this fast onset. Furthermore, instant deactivation of the PhrtBA promoter is achieved by a strong ChrS phosphatase activity upon stimulus decline. While the activation of detoxification response is uncoupled from further factors, heme utilization is additionally governed by the global iron regulator DtxR integrating information on iron availability into the regulatory network. Altogether, our data provide comprehensive insights how TCS cross‐regulation and network hierarchy shape the temporal dynamics of detoxification (hrtBA) and utilization (hmuO) as part of a global homeostatic response to heme.
The orientation of foliicolous lichen campylidia with respect to water runoff and its significance for propagule dispersal.

PREMISE OF THE STUDY Some common leaf-dwelling lichen fungi produce asexual spores (conidia) within curved, dorsiventral structures called campylidia. Their shape and tendency to face in the same direction have generated speculation about how dispersal is accomplished. Here we tested the hypothesis that campylidia orient their spore-producing surface against runoff currents and examined the effects of hydration to better understand the spore dispersal mechanism. METHODS Palm leaves bearing lichens (Calopadia) were surveyed with a dissecting microscope for campylidia with fibrous debris entangled around the base. Where possible, the direction of runoff flow was inferred from the position of the entangled debris; the angle between this direction and that toward which the spore-producing side faced was calculated for 67 campylidia. Other fresh-collected campylidia were photographed in the air-dry state and again after hydration. KEY RESULTS Orientation of campylidia was strongly correlated with direction of runoff flow, such that the spore-producing side faced against oncoming runoff. Hydration of campylidia quickly resulted in swelling of the conidial mass beneath a thin flap of tissue covering the conidiogenous surface. The flap then bulged outward, exposing the conidial mass from above within its pocket-like compartment. CONCLUSIONS Our results support previous contentions that water impact against campylidia is important in spore dispersal. However, the morphology of hydrated campylidia and their strong tendency to face upstream suggest that water currents impact laterally upon the thin tissue covering the hydrated conidial mass, thereby extruding spores apically. We contrast these findings with previous suggestions that campylidia act as splash cups.
The telomere length of peripheral blood cells is associated with the risk of ischemic stroke in Han population of northern China

Background: Telomere length is closely related to the onset and prognosis of ischemic stroke. This study was to investigate the relationship between telomere length and the incidence of ischemic stroke in Han population of northern China. Methods: In the present study, 152 patients with ischemic stroke were selected as the case group, and 152 healthy persons were used as the control group. Detection of telomere length was done by real-time polymerase chain reaction after extraction of genomic DNA from peripheral venous blood. Results: Our results showed that the telomere length of the patients in the case group was significantly lower than that of the control group (Z = −11.843, P < .0001). Further analysis found that the telomere length of the control group was inversely correlated with age (r = −0.234, P = .004), and the telomere length and homocysteine (HCY) were inversely correlated in the case group (r = −0.176, P = .03), especially in women (r = −0.357, P = .024). Multivariate regression analysis showed that telomere length was a protective factor for ischemic stroke (odds ratio [OR] 95% confidence interval [95% CI] = 0.748 [0.681–0.823], &bgr; = −0.29, P < .0001). The receiver operating characteristic curve showed that telomere length was a good diagnostic biomarker of ischemic stroke (area under the curve: 0.894, sensitivity: 84.7%, specificity: 93.4%). Conclusion: Our results indicate that shorter telomere length has some connection with the risk of ischemic stroke in the northern Chinese Han population. Telomere length might serve as a potential candidate biomarker for ischemic stroke. This requires a large sample to be further verified.
Fold-change detection of NF-κB at target genes with different transcript outputs

The transcription factor NF-κB promotes inflammatory and stress-responsive gene transcription across a range of cell types in response to the cytokine tumor necrosis factor-α (TNF). Although NF-κB signaling exhibits significant variability across single cells, some target genes exhibit fold-change detection of NF-κB, which may buffer against stochastic variation in signaling molecules. However, this observation was made at target genes supporting high levels of TNF-inducible transcription. It is unknown if fold-change detection is maintained at NF-κB target genes with low levels of TNF-inducible transcription, for which stochastic promoter events may be more pronounced. Here we used a microfluidic cell-trapping device to measure how TNF-induced activation of NF-κB controls transcription in single Jurkat T cells at the promoters of integrated HIV and the endogenous cytokine gene IL6, which produce only a few transcripts per cell. We tracked TNF-stimulated NF-κB RelA nuclear translocation by live-cell imaging and then quantified transcript number by RNA FISH in the same cell. We found that TNF-induced transcription correlates with fold change in nuclear NF-κB with similar strength at low versus high abundance target genes. A computational model of TNF-NF-κB signaling, which implements fold-change detection from competition for binding to κB motifs, was sufficient to reproduce fold-change detection across the experimentally measured range of transcript outputs. Nevertheless, we found that gene-specific trends in transcriptional noise and levels of promoter-bound NF-κB predicted by the model were inconsistent with our experimental observations at low abundance gene targets. Our results reveal a gap in our understanding of RelA-mediated transcription for low abundance transcripts and suggest that cells use additional biological mechanisms to maintain robustness of NF-κB fold-change detection while tuning transcriptional output.