Miracle-dz/UniFAR-FTUs huggingface dataset:
Structure of HIV-1 RT/dsRNA initiation complex prior to nucleotide incorporation

Significance RT is a key enzyme in the life cycle of HIV, and is targeted by multiple antiviral drugs. Although for most of its function RT binds a dsDNA or RNA–DNA template–primer substrate, initiation of reverse transcription involves binding of dsRNA. The current study presents a structure of an RT/dsRNA complex that has the basic components of a reverse transcription initiation complex (RTIC). The unique structural features help understand the significantly slower rate of nucleotide incorporation by an RTIC compared with a catalytically efficient reverse transcription elongation complex. This complex may help in designing new experiments for understanding the intricate and slow process of reverse transcription initiation. The initiation phase of HIV reverse transcription has features that are distinct from its elongation phase. The first structure of a reverse transcription initiation complex (RTIC) that trapped the complex after incorporation of one ddCMP nucleotide was published recently [Larsen KP, et al. (2018) Nature 557:118–122]. Here we report a crystal structure of a catalytically active HIV-1 RT/dsRNA complex that mimics the state of the RTIC before the first nucleotide incorporation. The structure reveals that the dsRNA-bound conformation of RT is closer to that of RT bound to a nonnucleoside RT inhibitor (NNRTI) and dsDNA; a hyperextended thumb conformation helps to accommodate the relatively wide dsRNA duplex. The RNA primer 3′ end is positioned 5 Å away from the polymerase site; however, unlike in an NNRTI-bound state in which structural elements of RT restrict the movement of the primer, the primer terminus of dsRNA is not blocked from reaching the active site of RT. The observed structural changes and energetic cost of bringing the primer 3′ end to the priming site are hypothesized to explain the slower nucleotide incorporation rate of the RTIC. An unusual crystal lattice interaction of dsRNA with its symmetry mate is reminiscent of the RNA architecture within the extended vRNA–tRNALys3 in the RTIC. This RT/dsRNA complex captures the key structural characteristics and components of the RTIC, including the RT conformational changes and interactions with the dsRNA primer-binding site region, and these features have implications for better understanding of RT initiation.
Topical calcineurin inhibitors in the treatment of oral lichen planus: a systematic review and meta‐analysis

TCS (topical corticosteroids) are the first‐line drug in the treatment of oral lichen planus (OLP). However, the value of topical calcineurin inhibitors (TCI) including tacrolimus, pimecrolimus and ciclosporin for OLP is still controversial.
Correlates of physical, psychological, and social frailty among formerly incarcerated, homeless women

Abstract Frailty is a deficit accumulation in physical, psychological and social domains. Correlates of frailty were explored among formerly incarcerated, homeless women (N = 130, Mage = 38.9). Significant correlates of physical frailty were age, years homeless, prior violence, witnessing less violence, drug dependence, PTSD symptoms and tangible support. Significant correlates of psychological frailty were age, years homeless, witnessed violence, jail time, divorced less, drug use/dependence, prison time, methamphetamine use, and bodily pain. Significant correlates of social frailty were drug use, emotional regulation, and daily alcohol use. Reentry interventions are needed for formerly incarcerated, homeless women who experience physical, psychological and social frailty.
Is There a Positive Association Between Working Memory Capacity and Mind Wandering in a Low-Demand Breathing Task? A Preregistered Replication of a Study by Levinson, Smallwood, and Davidson (2012)

Levinson, Smallwood, and Davidson (2012, Experiment 2) found that working memory capacity (WMC) correlated positively with mind-wandering rates measured by thought probes in a breath-awareness task but was unassociated with the tendency to self-catch mind wandering. Here, I sought to replicate the associations between mind wandering and WMC in Levinson et al.’s breath-awareness task. The data from the current study, collected from 315 subjects (ns differed among analyses) and two measures of WMC, suggest that if WMC correlates with probe-caught mind wandering, the association is most likely negative. In addition, the evidence regarding self-caught mind wandering is consistent with that found by Levinson et al. for the sum of self-caught responses, but when self-caught responses were considered in proportion to probe-caught mind wandering, modest evidence was found for a positive association with WMC.
Angiotropism in primary cutaneous melanoma is associated with disease progression and distant metastases: A retrospective study of 179 cases

Angiotropism is the histopathological correlate of pericytic mimicry and extravascular migratory metastasis (EVMM), a mechanism of melanoma spread by migration along the external surface of blood and lymphatic vessels. The frequency of angiotropism in primary cutaneous melanoma and the clinical utility of its detection remain unclear.
Coupling Effect of Porosity and Cell Size on the Deformation Behavior of Al Alloy Foam under Quasi-Static Compression

Closed-cell AlCu5Mn alloy foam with porosity range of ~45–90% were fabricated by the melt-foaming route. The pore structure of the fabricated Al alloy foam was analyzed and the coupling effect of porosity and cell size on the quasi-static compression behavior of the foam was investigated. The results show that the cell size of the foam decreases with the porosity decline from the view of the contribution rate to the porosity and the hierarchical pore structure characteristics becomes obvious when the foam porosity is low; the compression stress–strain curves of the foams with high porosity (>74%) are serrated due to the large cell size being easy to deform and more strain needed to let the stress recover. Meanwhile, the compression curve of the foams with low porosity (<74%) are smooth without serration, which is attributed to the hierarchical pore structure and less strain needed to let the stress recovery.
Negligible Role for Deletion Mediated by cDC1 in CD8+ T Cell Tolerance

Deletion of CD8+ T cells by dendritic cells (DCs) is recognized as a critical mechanism of immune tolerance to self-antigens. Although DC-mediated peripheral deletion of autoreactive CD8+ T cells has been demonstrated using T cells reactive to model Ags, its role in shaping the naturally occurring polyclonal CD8+ T cell repertoire has not been defined. Using Batf3−/− mice lacking cross-presenting CD8α+ and CD103+ DCs (also known as type 1 conventional [cDC1]), we demonstrate that peripheral deletion of CD8+ T cells reactive to a model tissue Ag is dependent on cDC1. However, endogenous CD8+ T cells from the periphery of Batf3−/− mice do not exhibit heightened self-reactivity, and deep TCR sequencing of CD8+ T cells from Batf3−/− and Batf3+/+ mice reveals that cDC1 have a minimal impact on shaping the peripheral CD8+ T cell repertoire. Thus, although evident in reductionist systems, deletion of polyclonal self-specific CD8+ T cells by cDC1 plays a negligible role in enforcing tolerance to natural self-ligands. Key Points Batf3-lineage cDC1 are required for peripheral CD8+ T cell deletion. The absence of cDC1 does not increase CD8+ T cell autoreactivity or alter the TCR repertoire. Peripheral deletion by cDC1 does not significantly contribute to CD8+ T cell tolerance to self.
Heteranthery in Clarkia: pollen performance of dimorphic anthers contradicts expectations.

PREMISE OF THE STUDY Wild plant species that require the services of pollen-feeding insects for reliable pollination may evolve features that attract and reward their mutualistic partners. Heterantherous species have been proposed to exhibit a "division of labor" whereby "feeding anthers" (which produce pollen that may be consumed by an insect) are distinguished from "reproductive anthers" (which produce pollen more likely to contribute to reproduction). In some heterantherous species, including Clarkia unguiculata (Onagraceae), these two anther types differ with respect to stamen length, anther size, pollen production, and pollen color. METHODS The primary goal of this study was to test one component of the "division of labor" hypothesis by comparing the performance of the pollen produced by each type of anther in C. unguiculata. To achieve this goal, under greenhouse conditions, we hand pollinated and assessed pollen performance (using epifluorescence microscopy) within ~228 flowers. KEY RESULTS The pollen produced by the two anther types differed significantly with respect to both stigma and style penetration. The inner series of anthers produce pollen with higher performance than the outer series of longer, dark red anthers. CONCLUSIONS These findings contradict previous descriptions of the genus, reporting that the inner diminutive series of anthers in Clarkia produce "abortive and nonfunctional" pollen. We outline the future research required to demonstrate the ecological function of heteranthery in this iconic wildflower group.
Age-Related Decreases in the Retrieval Practice Effect Directly Relate to Changes in Alpha-Beta Oscillations

The retrieval (or testing) of information leads to better memory performance compared with reencoding. This phenomenon is known as “testing effect” or “retrieval practice effect” and has been primarily described in behavioral studies with healthy young subjects. However, possible age-related changes and their associated underlying neural processes, in particular neural oscillations, remain unclear. To address this issue, we used a previously established paradigm in healthy young (N = 27) and elderly (N = 28) male and female human adults while their brain activity was being recorded using EEG. Subjects viewed prefamiliarized scene images intermixed with new scenes and classified them as indoor versus outdoor (encoding task) or old versus new (retrieval task). Subsequently, subjects performed a recognition memory task 10 min and 24 h after encoding. Behaviorally, both age groups showed the testing effect at both time points but, importantly, it was less pronounced in the elderly. At the neural level, the retrieval compared with the encoding task was accompanied by power decreases in the alpha (9–12 Hz) and beta bands (13–30 Hz), possibly reflecting task demands, and this difference was more pronounced in the elderly. Finally, a correlation analysis revealed that those elderly who displayed a more pronounced testing effect exhibited a neural pattern that was more similar to the younger subjects. These findings provide evidence that the testing effect decreases across the life span, and they suggest that changes in alpha-beta oscillations play a direct role. SIGNIFICANCE STATEMENT Learning new and retrieving old information is part of everyday human life. Understanding how learning processes can be optimized therefore has direct applications in the realm of educational and rehabilitative contexts. Here, we show that retrieval practice is a strategy to optimize encoding into long-term memory in both young and elderly humans. Importantly, retrieval practice was significantly reduced in the elderly and closely related to changes in alpha (9–13 Hz) and beta band (13–30 Hz) oscillations. Our findings suggest that decreased retrieval practice effects across the life span contribute to, and may reflect, age-related declines in memory performance. They further provide new insights into the underlying neural mechanisms and point toward future avenues for neuro-modulatory interventions.
Wnt and RUNX2 mediate cartilage breakdown by osteoarthritis synovial fibroblast‐derived ADAMTS‐7 and ‐12

Failure of therapeutic approaches for the treatment of osteoarthritis (OA) based on the inhibition of metalloproteinases, might be because of their constitutive expression in homeostasis, together with their network complexity. The knowledge of this network would contribute to selective target pathological conditions. In this sense, blockade of mediators produced by neighbouring joint cells, such as synovial fibroblasts (SF), would prevent cartilage damage. Thus, we studied the contribution of ADAMTS‐7 and ‐12 from SF to cartilage oligomeric matrix protein (COMP) degradation, and the signalling pathways involved in their expression. We report for the first time in SF, the involvement of ERK‐Runx2 axis and Wnt/β‐catenin signalling in ADAMTS‐12 and ADAMTS‐7 expressions, respectively, with the subsequent consequences in COMP degradation from cartilage extracellular matrix. After stimulation with IL‐1β or fibronectin fragments, we showed that ERK inhibition decreased Runx2 activation and ADAMTS‐12 expression in OA‐SF, also reducing Fn‐fs‐induced COMP degradation. Blockage of Wnt signalling by DKK1 reduced ADAMTS‐7 and COMP degradation in OA‐SF as well. In addition, Wnt7B expression was induced by IL‐1β and by itself, also increasing ADAMTS‐7. Our results could contribute to the development of disease‐modifying OA drugs targeting ADAMTS‐7 and ‐12 for the prevention of extracellular matrix components degradation like COMP.
On track towards improved regional development? – Impacts of the Svealand rail line on labour earnings in the Mälaren region

This paper studies the impacts on productivity following an investment in regional high-speed rail in the Mälaren region in Sweden. It uses wage earnings as a measure of productivity and proposes to capture agglomeration effects by measuring changes in effective labour force density induced by the transport improvement across municipalities in the region. This change in effective labour force density is then used as a continuous measure of treatment, in order to estimate the effect of the Svealand line introduction on labour earnings. While the transport improvement had a large impact on the connectivity and commuting patterns in affected municipalities, we find estimates of wage elasticities with respect to agglomeration that are in line with or smaller than average values from previous literature. The productivity effects, estimated over a ten-year time period, are shown to be rather modest and concentrated to the regions whose connectivity to the greater Stockholm area was directly affected. We also find that the main results do not materialize when a much shorter time period is used for analysis, indicating that a rather long adjustment time needs to occur before any effects can be seen.
Optimization of In Vitro Culture Conditions of Sturgeon Germ Cells for Purpose of Surrogate Production

Simple Summary The sturgeon is among the most ancient of actinopterygian fishes. Most species of sturgeon are listed as critically endangered due to habitat alteration caused by damming of rivers, pollution and overharvesting. Germ cell transplant is a useful tool to save these endangered species. To expand germ cell populations and sustain the supply for long periods for transplant, we established basal culture conditions for sturgeon germ cells. Germ cell mitotic activity has been enhanced by eliminating gonad somatic cells, supplementing with growth factor and using an alternative to fetal bovine serum. The optimal condition identified was purified germ cells cultured in serum-free medium supplemented with leukemia inhibitory factor (LIF) and glial cell line-derived neurotrophic factor (GDNF) at 21 °C. Cultured sterlet germ cells showed development after transplant into Russian sturgeon. The study provided useful information for sturgeon germ cell culture. Abstract To expand germ cell populations and provide a consistent supply for transplantation, we established basal culture conditions for sturgeon germ cells and subsequently increased their mitotic activity by eliminating gonad somatic cells, supplementing with growth factor, and replacing fetal bovine serum (FBS). The initial basal culture conditions were Leibovitz’s L-15 medium (pH 8.0) supplemented with 5% FBS (p < 0.001) at 21 °C. Proliferation of germ cells was significantly enhanced and maintained for longer periods by elimination of gonad somatic cells and culture under feeder-cell free conditions, with addition of leukemia inhibitory factor and glial-cell-derived neurotrophic factor (p < 0.001). A serum-free culture medium improved germ cell proliferation compared to the L-15 with FBS (p < 0.05). Morphology remained similar to that of fresh germ cells for at least 40 d culture. Germline-specific gene expression analysis revealed no significant changes to germ cells before and after culture. Sterlet Acipenser ruthenus germ cells cultured more than 40 days showed development after transplant into Russian sturgeon Acipenser gueldenstaedtii. Polymerase chain reaction showed 33.3% of recipient gonads to contain sterlet cells after four months. This study developed optimal culture condition for sturgeon germ cells. Germ cells after 40 d culture developed in recipient gonads. This study provided useful information for culture of sturgeon germ cells.
X-linked myotubular myopathy

Objectives Because X-linked myotubular myopathy (XLMTM) is a rare neuromuscular disease caused by mutations in the MTM1 gene with a large phenotypic heterogeneity, to ensure clinical trial readiness, it was mandatory to better quantify disease burden and determine best outcome measures. Methods We designed an international prospective and longitudinal natural history study in patients with XLMTM and assessed muscle strength and motor and respiratory functions over the first year of follow-up. The humoral immunity against adeno-associated virus serotype 8 was also monitored. Results Forty-five male patients aged 3.5 months to 56.8 years were enrolled between May 2014 and May 2017. Thirteen patients had a mild phenotype (no ventilation support), 7 had an intermediate phenotype (ventilation support less than 12 hours a day), and 25 had a severe phenotype (ventilation support 12 or more hours a day). Most strength and motor function assessments could be performed even in very weak patients. Motor Function Measure 32 total score, grip and pinch strengths, and forced vital capacity, forced expiratory volume in the first second of exhalation, and peak cough flow measures discriminated the 3 groups of patients. Disease history revealed motor milestone loss in several patients. Longitudinal data on 37 patients showed that the Motor Function Measure 32 total score significantly decreased by 2%. Of the 38 patients evaluated, anti–adeno-associated virus type 8 neutralizing activity was detected in 26% with 2 patients having an inhibitory titer >1:10. Conclusions Our data confirm that XLMTM is slowly progressive for male survivors regardless of their phenotype and provide outcome validation and natural history data that can support clinical development in this population. ClinicalTrials.gov identifier NCT02057705.
Epidermomycosis at the Avicenne Military Hospital in Marrakech: 6-Year Review

Introduction: Epidermomycoses are superficial yeast infections that affect the epidermis outside the intertrigo. The aim of our work is to draw up a clinico-epidemiological profile of epidermomycoses diagnosed in the mycology parasitology laboratory of the Avicenne military hospital in Marrakech. Materials and methods: This is a retrospective study carried out over a period of 6 years (January 2013 to December 2018) including all the cases of epidermomycosis diagnosed. After collecting clinical information, a direct examination of the samples is carried out before culture on Sabouraud media with incubation at 27 ° C. The identification of the identity was based on the speed of growth, macroscopic aspects and microscopic colonies. The identification of yeasts was based on the filamentation and assimilation of sugars test: Api 20C. Results: Epidermomycosis was confirmed in 108 cases or 57% compared to all of the samples examined. The sex ratio M / F is 0.74, the average age is 35.5 years. Outpatients are the majority (86%). the prevalence of superficial dermatophyte mycoses was 81.4% followed by yeasts (14.6%) and molds (4%). Isolated dermatophytes are dominated by a single species Trichophyton rubrum (92%), yeasts by Candida albicans (45%) Conclusion: Epidermycosis is still a frequent reason for consultation in dermatology. In the face of any clinical suspicion, the mycological diagnosis remains the diagnosis of certainty and for therapeutic orientation. Keyword: Superficial mycoses; Dermatophytes; Yeasts; Non-dermatophytic filamentous fungi. Copyright @ 2020: This is an open-access article distributed under the terms of the Creative Commons Attribution license which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use (NonCommercial, or CC-BY-NC) provided the original author and sources are credited.
Two Birds, One Stone: Double Hits on Tumor Growth and Lymphangiogenesis by Targeting Vascular Endothelial Growth Factor Receptor 3

Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of VEGF-C/VEGFR3 signaling in lymphatic endothelial cells (LECs) was shown to enhance the proliferation of LECs and the formation of lymphatic vessels, leading to increased lymphatic metastasis of tumor cells. In the past decade, the expression and pathological roles of VEGFR3 in tumor cells have been described. Moreover, the VEGF-C/VEGFR3 axis has been implicated in regulating immune tolerance and suppression. Therefore, the inhibition of the VEGF-C/VEGFR3 axis has emerged as an important therapeutic strategy for the treatment of cancer. In this review, we discuss the current findings related to VEGF-C/VEGFR3 signaling in cancer progression and recent advances in the development of therapeutic drugs targeting VEGF-C/VEGFR3.
Marker assisted screening of breeding population of wheat segregating for stripe rust resistance using SSR markers

Screening of F2 population from cross WH711 (susceptible parent) and PBW698 (resistant parent) against stripe rust was done on the basis of field reaction of yellow rust and 12 morphlogical traits. The genotyping of parents was done by using 80 SSR markers out of which 11 were found polymorphic. These 11 markers were used to screen 250 individuals of F2 population. Mendelian inheritance was followed by five markers viz. Xgwm631, Cfa2040, Xsps3000, Barc76 and Xgwm 130 which segregated according to expected ratio of 1:2:1 with chisquare values 5.78, 4.23, 2.75, 9.2 and 7.6 respectively. Single marker analysis showed markers Xgwm631, Cfa2040 (Yr2, Yr6), Xsps3000 (Yr10), Xgwm130 (Yr7), Xwmc407 (Lr17), Barc46, Xgwm413 (Yr15), Barc187 (Yr27) and Xgwm273 (YrH52) were linked with yellow rust locus at 0.01% of significance hence these genes may be present in the breeding population. Cfa2040 was found linked with flag leaf area, number of spikelets and Barc181 with spike weight locus. Markers on chromosomes 7A and 1B showed LOD values 6.64 and 6.86 conferring tight linkage with yellow rust locus thus can be used for MAS.
Interactive comment on “Age-ranked hydrological budgets and a travel time description of catchment hydrology” by R. Rigon et al

We thank the reviewer for her/his observations, which helped us improve our manuscript. This response tries to use the practice of the interactive discussion, and does not yet produce a new manuscript, which will be submitted after the closure of the review phase, upon request of the Editor. We introduce here, however, the main adjustments that we will make in the final version of the revised paper based upon the reviewer’s suggestions.