Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein

CDA type I is a rare hereditary anemia, characterized by relative reticulocytopenia, and congenital anomalies. It is caused by biallelic mutations in one of the two genes: (i) CDAN1, encoding Codanin-1, which is implicated in nucleosome assembly and disassembly; (ii) C15orf41, which is predicted to encode a divalent metal ion-dependent restriction endonuclease with a yet unknown function. We described two cases of CDA type I, identifying the novel variant, Y94S, in the DNA binding domain of C15orf41, and the H230P mutation in the nuclease domain of the protein. We first analyzed the gene expression and the localization of C15orf41. We demonstrated that C15orf41 and CDAN1 gene expression is tightly correlated, suggesting a shared mechanism of regulation between the two genes. Moreover, we functionally characterized the two variants, establishing that the H230P leads to reduced gene expression and protein level, while Y94S induces a slight decrease of expression. We demonstrated that C15orf41 endogenous protein exhibits nuclear and cytosolic localization, being mostly in the nucleus. However, no altered nuclear-cytosolic compartmentalization of mutated C15orf41 was observed. Both mutants accounted for impaired erythroid differentiation in K562 cells, and H230P mutant also exhibits an increased S-phase of the cell cycle in these cells. Our functional characterization demonstrated that the two variants have different effects on the stability of the mutated mRNA, but both resulted in impaired erythroid maturation, suggesting the block of cell cycle dynamics as a putative pathogenic mechanism for C15orf41-related CDA I.
Simultaneous and Positively Correlated NET Formation and Autophagy in Besnoitia besnoiti Tachyzoite-Exposed Bovine Polymorphonuclear Neutrophils

Given that B. besnoiti tachyzoites infect host endothelial cells of vessels in vivo, they become potential targets for professional phagocytes [e.g., polymorphonuclear neutrophils (PMN)] when in search for adequate host cells or in case of host cell lysis. It was recently reported that B. besnoiti-tachyzoites can efficiently be trapped by neutrophil extracellular traps (NETs) released by bovine PMN. So far, the potential role of autophagy in parasite-triggered NET formation is unclear. Thus, we here analyzed autophagosome formation and activation of AMP-activated protein kinase α (AMPKα) in potentially NET-forming innate leukocytes being exposed to B. besnoiti tachyzoites. Blood was collected from healthy adult dairy cows, and bovine PMN were isolated via density gradient centrifugation. Scanning electron microscopy confirmed PMN to undergo NET formation upon contact with B. besnoiti tachyzoites. Nuclear area expansion (NAE) analysis and cell-free and anchored NETs quantification were performed in B. besnoiti-induced NET formation. Interestingly, tachyzoites of B. besnoiti additionally induced LC3B-related autophagosome formation in parallel to NET formation in bovine PMN. Notably, both rapamycin- and wortmannin-treatments failed to influence B. besnoiti-triggered NET formation and autophagosome formation. Also, isolated NETs fail to induce autophagy suggesting independence between both cellular processes. Finally, enhanced phosphorylation of AMP activated kinase α (AMPKα), a key regulator molecule of autophagy, was observed within the first minutes of interaction in tachyzoite-exposed PMN thereby emphasizing that B. besnoiti-triggered NET formation indeed occurs in parallel to autophagy.
Monarch Butterfly Distribution and Breeding Ecology in Idaho and Washington

Studies of monarch butterflies (Danaus plexippus) and their milkweed (Asclepias spp.) host plants in North America have focused primarily on monarch populations ranging east of the Rocky Mountains. We report the first systematic assessment of monarch butterfly and milkweed populations in the western states of Idaho and Washington, states at the northern tier of western monarch breeding range. Results of our 2-year study (2016–2017) offer new insights into monarch breeding habitat distribution, characteristics, and threat factors in our 2 states. We documented milkweeds and breeding monarchs in all 16 climate divisions in our study area. Milkweed and breeding monarch phenologies were examined with evidence supporting 2, and possibly 3 monarch generations produced in Idaho and Washington. Key monarch breeding habitats were moist-soil sites within matrices of grasslands, wetlands, deciduous forest, and shrub-steppe supporting large, contiguous, and high-density milkweed stands. Co-occurrence of showy milkweed (A. speciosa) and swamp milkweed (A. incarnata) was an important indicator of productive monarch breeding habitat in Idaho. Nectar plants were generally limited in quantity and richness across the study area, particularly in late summer, and included frequently-used non-native, invasive species. Primary threats at milkweed sites were invasive plant species, herbicide application, and mowing, followed by secondary threats of recreational disturbance, livestock grazing, insecticide application, loss of floodplain function, and wildfire. We provide management recommendations and research needs to address ongoing stressors and knowledge gaps in Idaho and Washington with the goal of conserving monarchs and their habitats in the West.
Corticomuscular Coherence for Upper Arm Flexor and Extensor Muscles During Isometric Exercise and Cyclically Isokinetic Movement

Cortical-muscular functional coupling reflects the interaction between the cerebral cortex and the muscle activities. Corticomuscular coherence (CMC) has been extensively revealed in sustained contractions of various upper- and lower-limb muscles during static and dynamic force outputs. However, it is not well-understood that the CMC modulation mechanisms, i.e., the relation between a cerebral hemisphere and dynamic motor controlling limbs at constant speeds, such as isokinetic movement. In this paper, we explore the CMC between upper arm flexors/extensors movement and motor cortex during isometric exercise and cyclically isokinetic movement. We also provide further insights of frequency-shift and the neural pathway mechanisms in isokinetic movement by evaluating the coherence between motor cortex and agonistic or antagonistic muscles. This study is the first to investigate the relationship between cortical-muscular functional connections in elbow flexion-extension movement with constant speeds. The result shows that gamma-range coherence for isokinetic movement is greatly increased compared with isometric exercise, and significant CMC is observed in the entire flexion-extension stage regardless the nature of muscles contraction, although dominant synchronization of cortical oscillation and muscular activity resonated in sustained contraction stage principally. Besides, the CMC for extensors and flexors are explicitly consistent in contraction stage during cyclically isokinetic elbow movement. It is concluded that cortical-muscular coherence can be dynamically modulated as well as selective by cognitive demands of the body, and the time-varying mechanisms of the synchronous motor oscillation exist in healthy individuals during dynamic movement.
Melanopsin and Cone Photoreceptor Inputs to the Afferent Pupil Light Response

Background: Retinal photoreceptors provide the main stage in the mammalian eye for regulating the retinal illumination through changes in pupil diameter, with a small population of melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) forming the primary afferent pathway for this response. The purpose of this study is to determine how melanopsin interacts with the three cone photoreceptor classes in the human eye to modulate the light-adapted pupil response. Methods: We investigated the independent and combined contributions of the inner and outer retinal photoreceptor inputs to the afferent pupil pathway in participants with trichromatic color vision using a method to independently control the excitations of ipRGCs, cones and rods in the retina. Results: We show that melanopsin-directed stimuli cause a transient pupil constriction generated by cones in the shadow of retinal blood vessels; desensitizing these penumbral cone signals uncovers a signature melanopsin pupil response that includes a longer latency (292 ms) and slower time (4.1x) and velocity (7.7x) to constriction than for cone-directed stimuli, and which remains sustained post-stimulus offset. Compared to melanopsin-mediated pupil responses, the cone photoreceptor-initiated pupil responses are more transient with faster constriction latencies, higher velocities and a secondary constriction at light offset. The combined pupil responses reveal that melanopsin signals are additive with the cone signals. Conclusions: The visual system uses the L–, M–, and S–cone photoreceptor inputs to the afferent pupil pathway to accomplish the tonic modulations of pupil size to changes in image contrast. The inner retinal melanopsin-expressing ipRGCs mediate the longer-term, sustained pupil constriction to set the light-adapted pupil diameter during extended light exposures.
Genetic Differentiation of Eastern Honey Bee (Apis cerana) Populations Across Qinghai-Tibet Plateau-Valley Landforms

Many species of high-altitude plateaus tend to be narrowly distributed along river valleys at lower elevations due to a limitation of suitable habitats. The eastern honeybee (Apis cerana) is such a species and this study explored the effects of long and narrow geographic distributions on honeybee populations. Genetic differentiation and diversity were assessed across populations of the southeastern Qinghai-Tibet Plateau. A total of 492 honeybee samples from eight sampling sites in four valleys were analyzed for the genetic differentiation and diversity of 31 microsatellite loci and mitochondrial tRNAleu-COII fragments. The following results were obtained: (1) Microsatellite genetic differentiation coefficients (FST) ranged from 0.06 to 0.16, and mitochondrial FST estimates ranged from 0.18 to 0.70 for different sampling sites in the same valley, indicating genetic differentiation. (2) Honeybees in adjacent valleys were also genetically differentiated. The FST of microsatellites and mitochondria were 0.04–0.29 and 0.06–0.76, respectively. (3) Likely a result of small population sizes, the observed genetic diversity was low. The observed impedance of honeybee gene flow among valleys increased both genetic differentiation and population numbers in the Qinghai-Tibet Plateau. This study contributes significantly to the current understanding of the mechanism underlying population genetic differentiation and highlights the potential effects of utilizing genetic resources that are subject to the ecological conditions of the long and narrow geographic distributions of plateau-valley landforms.
The Effects of Surgical Antiseptics and Time Delays on RNA Isolated From Human and Rodent Peripheral Nerves

Peripheral Nerve Injury (PNI) is common following blunt or penetrating trauma with an estimated prevalence of 2% among the trauma population. The resulting economic and societal impacts are significant. Nerve regeneration is a key biological process in those recovering from neural trauma. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) and RNA sequencing (RNA seq) are investigative methods that are often deployed by researchers to characterize the cellular and molecular mechanisms that underpin this process. However, the ethical and practical challenges associated with studying human nerve injury have meant that studies of nerve injury have largely been limited to rodent models of renervation. In some circumstances it is possible to liberate human nerve tissue for study, for example during reconstructive nerve repair. This complex surgical environment affords numerous challenges for optimizing the yield of RNA in sufficient quantity and quality for downstream RT-qPCR and/or RNA seq applications. This study characterized the effect of: (1) Time delays between surgical liberation and cryopreservation and (2) contact with antiseptic surgical reagents, on the quantity and quality of RNA isolated from human and rodent nerve samples. It was found that time delays of greater than 3 min between surgical liberation and cryopreservation of human nerve samples significantly decreased RNA concentrations to be sub-optimal for downstream RT-qPCR/RNA seq applications (<5 ng/μl). Minimizing the exposure of human nerve samples to antiseptic surgical reagents significantly increased yield of RNA isolated from samples. The detrimental effect of antiseptic reagents on RNA yield was further confirmed in a rodent model where RNA yield was 8.3-fold lower compared to non-exposed samples. In summary, this study has shown that changes to the surgical tissue collection protocol can have significant effects on the yield of RNA isolated from nerve samples. This will enable the optimisation of protocols in future studies, facilitating characterisation of the cellular and molecular mechanisms that underpin the regenerative capacity of the human peripheral nervous system.
Satellite Salinity Observing System: Recent Discoveries and the Way Forward

Advances in L-band microwave satellite radiometry in the past decade, pioneered by ESA’s SMOS and NASA’s Aquarius and SMAP missions, have demonstrated an unprecedented capability to observe global sea surface salinity (SSS) from space. Measurements from these missions are the only means to probe the very-near surface salinity (top cm), providing a unique monitoring capability for the interfacial exchanges of water between the atmosphere and the upper-ocean, and delivering a wealth of information on various salinity processes in the ocean, linkages with the water cycle and climate, and constraints for ocean prediction models. The satellite SSS data are complimentary to the existing in situ systems such as Argo that provide accurate depiction of large-scale salinity variability in the open ocean but under-sample mesoscale variability, coastal oceans and marginal seas, and energetic regions such as boundary currents and fronts. In particular, salinity remote sensing has proven valuable to systematically monitor the open oceans as well as coastal regions up to approximately 40 km from the coasts . This is critical to addressing societally relevant topics, such as land-sea linkages, coastal-open ocean exchanges, research in the carbon cycle, near-surface mixing, and air-sea exchange of gas and mass. In this paper, we provide a community perspective on the major achievements of satellite SSS for the aforementioned topics, the unique capability of satellite salinity observing system and its complementarity with other platforms, uncertainty characteristics of satellite SSS, and measurement versus sampling errors in relation to in situ salinity measurements. We also discuss the need for technological innovations to improve the accuracy, resolution, and coverage of satellite SSS, and the way forward to both continue and enhance salinity remote sensing as part of the integrated Earth Observing System in order to address societal needs.
Part I. Analysis of data gaps pertaining to Salmonella enterica serotype Typhi infections in low and medium human development index countries, 1984–2005

SUMMARY There are only 10 contemporary, population-based studies of typhoid fever that evaluate disease incidence using blood culture for confirmation of cases. Reported incidence ranged from 13 to 976/100 000 persons per year. These studies are likely to have been done preferentially in high- incidence sites which makes generalization of data difficult. Only five of these studies reported mortality. Of these the median (range) mortality was 0% (0–1·8%). Since study conditions usually involved enhanced clinical management of patients and the studies were not designed to evaluate mortality as an outcome, their usefulness for generalizing case-fatality rates is uncertain. No contemporary population-based studies reported rates of complications. Hospital-based typhoid fever studies reported median (range) complication rates of 2·8% (0·6–4·9%) for intestinal perforation and case-fatality rates of 2·0% (0–14·8%). Rates of complications other than intestinal perforation were not reported in contemporary hospital-based studies. Hospital-based studies capture information on the most severe illnesses among persons who have access to health-care services limiting their generalizability. Only two studies have informed the current understanding of typhoid fever age distribution curves. Extrapolation from population-based studies suggests that most typhoid fever occurs among young children in Asia. To reduce gaps in the current understanding of typhoid fever incidence, complications, and case-fatality rate, large population-based studies using blood culture confirmation of cases are needed in representative sites, especially in low and medium human development index countries outside Asia.
Safety-Specific Leadership, Goal Orientation, and Near-Miss Recognition: The Cross-Level Moderating Effects of Safety Climate

Near-miss recognition is an increasingly important area of research in safety management. Drawing on the self-determination theory, we ask whether and how safety-specific transformational leadership and safety-specific active transactional leadership promote near-miss recognition. We also explore the boundary condition by focusing on the moderating role of safety climate. We analyzed time-lagged data from 370 participants, and found that safety-specific transformational leadership enhances employees’ near-miss recognition (by enhancing their learning goal orientation), and that safety-specific active transactional leadership also positively influences employees’ near-miss recognition (by stimulating their performance goal orientation). In addition, we show that safety climate strengthens the relationship between safety-specific transactional leadership and employees’ performance goal orientation, but does not affect the relationship between safety-specific transformational leadership and employees’ learning goal orientation. We discuss the implications and limitations of the research.
Physical Performance During High-Intensity Resistance Exercise in Normoxic and Hypoxic Conditions

Abstract Scott, BR, Slattery, KM, Sculley, DV, Hodson, JA, and Dascombe, BJ. Physical performance during high-intensity resistance exercise in normoxic and hypoxic conditions. J Strength Cond Res 29(3): 807–815, 2015—This study aimed to determine whether different levels of hypoxia affect physical performance during high-intensity resistance exercise or subsequent cardiovascular and perceptual responses. Twelve resistance-trained young men (age, 25.3 ± 4.3 years; height, 179.0 ± 4.5 cm; body mass, 83.4 ± 9.1 kg) were tested for 1 repetition maximum (1RM) in the back squat and deadlift. Following this, participants completed 3 separate randomized trials of 5 × 5 repetitions at 80% 1RM, with 3 minutes rest between sets, in normoxia (NORM; fraction of inspired oxygen [FIO2] = 0.21), moderate-level hypoxia (FIO2 = 0.16), or high-level hypoxia (FIO2 = 0.13) by a portable hypoxic unit. Peak and mean force and power variables were monitored during exercise. Arterial oxygen saturation (SpO2), heart rate (HR), and rating of perceived exertion (RPE) were assessed immediately following each set. No differences in force or power variables were evident between conditions. Similar trends were evident in these variables across each set and across the exercise session in each condition. SpO2 was lower in hypoxic conditions than in NORM, whereas HR was higher following sets performed in hypoxia. There were no differences between conditions in RPE. These results indicate that a hypoxic stimulus during high-intensity resistance exercise does not alter physical performance during repetitions and sets or affect how strenuous exercise is perceived to be. This novel training strategy can be used without adversely affecting the physical training dose experienced and may provide benefits over the equivalent training in NORM.
CANVAS 1: the first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections.

OBJECTIVES Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a common cause of complicated skin and skin structure infections (cSSSIs). Increasing antibiotic resistance and significant morbidity in cSSSIs have led to a need for new effective and safe therapies. Ceftaroline fosamil, a novel parenteral cephalosporin with excellent in vitro activity against Gram-positive pathogens, including MRSA, and many Gram-negative pathogens, was evaluated as therapy for cSSSIs in a large multicentre study. The primary study objective was to determine non-inferiority [lower limit of 95% confidence interval (CI), -10%] in the clinical cure rate achieved with ceftaroline fosamil monotherapy compared with that achieved with vancomycin plus aztreonam in the clinically evaluable (CE) and modified intent-to-treat (MITT) patient populations. METHODS Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). Clinical and microbiological response, adverse events (AEs) and laboratory tests were assessed. Registration number NCT00424190 (http://clinicaltrials.gov/ct2/show/NCT00424190). RESULTS Of 702 enrolled patients, 353 received ceftaroline fosamil and 349 received vancomycin plus aztreonam. Baseline characteristics of treatment groups were comparable. Clinical cure rates were similar for ceftaroline fosamil and vancomycin plus aztreonam in the CE (91.1%, 288/316 versus 93.3%, 280/300; 95% CI, -6.6, 2.1) and MITT (86.6%, 304/351 versus 85.6%, 297/347; 95% CI, -4.2, 6.2) populations, respectively. The clinical cure rate for MRSA cSSSIs was 95.1% (78/82) for ceftaroline fosamil and 95.2% (59/62) for vancomycin plus aztreonam. The microbiological success rate was also similar for ceftaroline fosamil and vancomycin overall, and for MRSA. The rates of AEs, serious AEs, deaths and discontinuations because of an AE were similar for ceftaroline fosamil and vancomycin plus aztreonam. The most common AEs for ceftaroline fosamil and vancomycin plus aztreonam were diarrhoea (3.4% versus 3.2%), nausea (5.7% versus 4.6%), headache (5.1% versus 3.7%) and pruritus (3.1% versus 8.4%), respectively. CONCLUSIONS Ceftaroline fosamil achieved high clinical cure and microbiological success rates, was efficacious for cSSSIs caused by MRSA and other common cSSSI pathogens and was generally well tolerated. Ceftaroline fosamil has the potential to provide a monotherapy alternative for treatment of cSSSIs.
Influence of Extracellular K+ Concentrations on Quinidine‐induced K+ Current Inhibition in Rat Ventricular Myocytes

Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+]o) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (IK), the transient outward current (Ito), and the inward rectifier potassium current (IK1), as measured in isolated rat ventricular cells using patch‐clamp techniques.