Miracle-dz/UniFAR-FTUs huggingface dataset:
Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.
Sur les glandes de Lathraea clandestina L.

ResumeEtude des differentes glandes rencontrees a l'interieur des cavites des ecailles de Lathraea clandestina L. ; description des glandes en bouclier et des glandes stipitees deja connues, mise en evidence d'un nouveau type de glande caracterise par un pedicelle trapu et par une tete de quatre a six cellules glandulaires a membrane fine. Une classification de ces glandes est proposee.L'observation du mode de developpement des glandes en bouclier et des glandes a pedicelle unicellulaire de type A permet ensuite de relever certaines contradictions avec les etudes anterieures et d'en faire une nouvelle description.
The Association Between Child Marriage and Domestic Violence in Afghanistan

Child marriage and intimate partner violence have been globally recognized as human rights violations. Both indicators can derail an individual’s future and have various public health implications. Previous studies have shown an association between child marriage and domestic violence in low- and middle-income countries; however, data in Afghanistan are not known. This study aimed to assess the association between child marriage and domestic violence in Afghanistan. We used nationally representative data collected by the Demographic and Health Surveys to conduct logistic regression analyses. Child marriage was separated into three categories: very early marriage (<15 years), early marriage (15–17 years), and adult marriage (≥18 years). Domestic violence was the response variable and was assessed as any violence, physical violence, emotional violence, and sexual violence. Of the sample (N = 21,324), 15% of the respondents were married before the age of 15; 35% were married between the ages of 15 and 17; and 50% were married as adults. After adjusting for current age, place of residence, and socioeconomic status, the odds of sexual violence were 22% higher among women who married before age 15 compared with those married as adults (OR = 1.22, 95% CI = [1.05, 1.40], p = .005). However, the odds of reporting any violence, physical violence, and emotional violence among those who married as children did not differ compared with those who married as adults. This may be due to a shift in traditional norms or underreporting in Afghanistan. This study adds to the body of research on child marriage and intimate partner violence, and specifically provides novel information on this association in Afghanistan.
Temperature drives caste-specific morphological clines in ants.

1. The morphology of organisms relates to most aspects of their life history and autecology. As such, elucidating the drivers of morphological variation along environmental gradients might give insight into processes limiting species distributions. In eusocial organisms, the concept of morphology is more complex than in solitary organisms. Eusocial insects such as ants exhibit drastic morphological differences between reproductive and worker castes. How environmental selection operates on the morphology of each caste, and whether caste-specific selection has fitness consequences is largely unknown, but potentially crucial to understand what limits ant species' distributions. 2. Here, we aimed to examine whether ant shape and body size co-varies with climate at the scale of an entire continent, and whether such relationship might be caste-specific. 3. We used 26,472 georeferenced morphometric measurements from 2206 individual ants belonging to 32 closely related North American species in the genus Formica to assess how ant morphology relates to geographic variation in the abiotic environment. 4. Although precipitation and seasonality explained some of the geographic variation in morphology, temperature was the best predictor. Specifically, geographic variation in body size was positively related to temperature, meaning that ants are smaller in cold than in warm environments. Moreover, the strength of the relationship between size and temperature was stronger for the reproductive castes (i.e. queens and males) than for the worker caste. The shape of workers and males also varied along these large-scale abiotic gradients. Specifically, the relative length of workers' legs, thoraxes and antennae positively related to temperature, meaning that they had shorter appendages in cold environments. In contrast, males had smaller heads, but larger thoraxes in more seasonal environments. 5. Overall, our results suggest that geographic variation in ambient temperature influences the morphology of ants, but that the strength of this effect is caste-specific. In conclusion, whereas ant ecology has traditionally focused on workers, our study shows that considering the ecology of the reproductive castes is imperative to move forward in this field.
Litterfall, decomposition and nutrient release in an age sequence of Alnus nepalensis plantation stands in the eastern Himalaya

(1) Litterfall in an age sequence (7, 17, 30, 46 and 56 years) of Alnus nepalensis D. Don plantation stands in the Kalimpong forest division of the Eastern Himalaya was compared over two years for quantity and temporal distribution. (2) Average annual litter production in the plantations ranged from 3 2 t ha-' (7-year stand) to 5-8 t haI (46-year stand). Litterfall showed marked seasonal distribution and peaked in dry winter. (3) Seasonal rates of decomposition were distinct, with the highest rate in the first three months (warm rainy season) followed by subsequent seasons of the year. Among different stands decomposition rate was highest in the 30-year stand, i.e. at the time of canopy closure. The pattern of nutrient release (K > Ca > P > N) was the same in all the stands and the actual amount of nutrient release (30 > 17 Z46 > 7 > 56-year stands) was related to mass loss. The energy-content loss in twenty-four months per unit area was highest (3098 kJ m-2) in the 30-year stand. (4) The quantities of nutrients released per unit area in twenty-four months were highest in the 30-year stand (nitrogen, 5 g m-2; phosphorus 0 14 g m-2; potassium, 1 17 g m-2; and calcium, 0 59 g m-2). The release of nitrogen (70-85 mg), phosphorus (4-5 mg), potassium (32-44 mg), calcium (16-20 mg) and energy loss (35-44 kJ) were maximum in the first three months and declined gradually with time. (5) Ash-free mass of decomposing litter remaining at different retrieval dates was associated with a narrowing of the C/N ratio. Decomposition of litter was related to mineral element concentrations in litter and environmental factors.
Effects of Manipulating Fibroblast Growth Factor Expression on Sindbis Virus Replication In Vitro and in Aedes aegypti Mosquitoes

Fibroblast growth factors (FGFs) are conserved among vertebrate and invertebrate animals and function in cell proliferation, cell differentiation, tissue repair, and embryonic development. A viral fibroblast growth factor (vFGF) homolog encoded by baculoviruses, a group of insect viruses, is involved in escape of baculoviruses from the insect midgut by stimulating basal lamina remodeling. This led us to investigate whether cellular FGF is involved in the escape of an arbovirus from mosquito midgut. In this study, the effects of manipulating FGF expression on Sindbis virus (SINV) replication and escape from the midgut of the mosquito vector Aedes aegypti were examined. RNAi-mediated silencing of either Ae. aegypti FGF (AeFGF) or FGF receptor (AeFGFR) expression reduced SINV replication following oral infection of Ae. aegypti mosquitoes. However, overexpression of baculovirus vFGF using recombinant SINV constructs had no effect on replication of these viruses in cultured mosquito or vertebrate cells, or in orally infected Ae. aegypti mosquitoes. We conclude that reducing FGF signaling decreases the ability of SINV to replicate in mosquitoes, but that overexpression of vFGF has no effect, possibly because endogenous FGF levels are already sufficient for optimal virus replication. These results support the hypothesis that FGF signaling, possibly by inducing remodeling of midgut basal lamina, is involved in arbovirus midgut escape following virus acquisition from a blood meal.
YAP in epithelium senses gut barrier loss to deploy defenses against pathogens

Pathogens commonly disrupt the intestinal epithelial barrier; however, how the epithelial immune system senses the loss of intestinal barrier as a danger signal to activate self-defense is unclear. Through an unbiased approach in the model nematode Caenorhabditis elegans, we found that the EGL-44/TEAD transcription factor and its transcriptional activator YAP-1/YAP (Yes-associated protein) were activated when the intestinal barrier was disrupted by infections with the pathogenic bacterium Pseudomonas aeruginosa PA14. Gene Ontology enrichment analysis of the genes containing the TEAD-binding sites revealed that “innate immune response” and “defense response to Gram-negative bacterium” were two top significantly overrepresented terms. Genetic inactivation of yap-1 and egl-44 significantly reduced the survival rate and promoted bacterial accumulation in worms after bacterial infections. Furthermore, we found that disturbance of the E-cadherin-based adherens junction triggered the nuclear translocation and activation of YAP-1/YAP in the gut of worms. Although YAP is a major downstream effector of the Hippo signaling, our study revealed that the activation of YAP-1/YAP was independent of the Hippo pathway during disruption of intestinal barrier. After screening 10 serine/threonine phosphatases, we identified that PP2A phosphatase was involved in the activation of YAP-1/YAP after intestinal barrier loss induced by bacterial infections. Additionally, our study demonstrated that the function of YAP was evolutionarily conserved in mice. Our study highlights how the intestinal epithelium recognizes the loss of the epithelial barrier as a danger signal to deploy defenses against pathogens, uncovering an immune surveillance program in the intestinal epithelium.
Efficacy and Safety of Pegylated Interferon for the Treatment of Chronic Hepatitis B in Children and Adolescents

Supplemental Digital Content is available in the text. Background: Pegylated interferon (PEG-IFN) has recently been approved for the treatment of chronic hepatitis B in children and adolescents. However, the exact efficacy and safety remains to be confirmed. Objectives: A systematic review and meta-analysis was performed to assess the efficacy and safety of PEG-IFN for the treatment of chronic hepatitis B in children and adolescents. Methods: Databases including MEDLINE/PubMed, Ovid-EMbase, the Cochrane Library and China National Knowledge Internet were searched to collect clinical trials examining the efficacy and safety of PEG-IFN in children and adolescents with confirmed hepatitis B virus infection. Data for treatment response, relapse, treatment discontinuations and adverse events were extracted and summarized. Results: A total of 10 clinical trials involving 658 patients were identified. Results indicate that 43% (95% confidence interval [CI]: 25%–61%) of the subjects treated with PEG-IFN achieved HBeAg serologic response, 18% (95% CI: 6%–35%) achieved HBsAg serologic response, 68% (95% CI: 55%–79%) achieved virologic response after the end of treatment and 60% (95% CI: 30%–87%) achieved sustained virologic response. Conclusion: Current evidence indicates that PEG-IFN is effective in children and adolescents with hepatitis B virus and that treatment discontinuation due to serious adverse events is infrequent.
A De novo Peptide from a High Throughput Peptide Library Blocks Myosin A -MTIP Complex Formation in Plasmodium falciparum

Apicomplexan parasites, through their motor machinery, produce the required propulsive force critical for host cell-entry. The conserved components of this so-called glideosome machinery are myosin A and myosin A Tail Interacting Protein (MTIP). MTIP tethers myosin A to the inner membrane complex of the parasite through 20 amino acid-long C-terminal end of myosin A that makes direct contacts with MTIP, allowing the invasion of Plasmodium falciparum in erythrocytes. Here, we discovered through screening a peptide library, a de-novo peptide ZA1 that binds the myosin A tail domain. We demonstrated that ZA1 bound strongly to myosin A tail and was able to disrupt the native myosin A tail MTIP complex both in vitro and in vivo. We then showed that a shortened peptide derived from ZA1, named ZA1S, was able to bind myosin A and block parasite invasion. Overall, our study identified a novel anti-malarial peptide that could be used in combination with other antimalarials for blocking the invasion of Plasmodium falciparum.
Brain metastasis PD-L1 and CD8 expression is dependent on primary tumor type and its PD-L1 and CD8 status

Background Brain metastases (Bmets) are frequent; however, limited data exist on the efficacy of immunotherapy in these lesions. The aims of the study were to analyze the immunohistochemical expressions of programmed death ligand 1 (PD-L1) and CD8 in Bmets and to compare them with their expressions in paired primary tumors, as well as correlate the results with clinicopathological features. Methods This is a retrospective study of 233 patients with Bmets and 111 paired primaries. Clinical, histological, and molecular data were recorded and compared with the immunohistochemical results of PD-L1 and CD8 expressions. The statistical analysis included χ2 test, Cramer’s V test, factorial analyses of variance, simple regression analysis, and Kaplan-Meier analysis with log-rank product limit estimation. Results PD-L1 expression was found in 23.6% of Bmets and in 29.0% of primary tumors with concordant expression between them in 75.5% of cases. Bmets PD-L1 expression was associated with primary tumor PD-L1 expression and the primary tumor type. Significant CD8 peritumoral expression was found in 68.6% of Bmets and in 87.7% of primary tumors. CD8 expression was concordant between primary and metastatic tumors in 73.3% of cases. Bmets CD8 expression was associated with primary tumor CD8 expression and primary tumor type. PD-L1 expression was associated with CD8 expression in both primary and metastatic tumors. The concordance between primary and metastatic tumor PD-L1 expression was independent of all factors studied. The concordance between primary and metastatic CD8 expressions was marginally associated to the time of Bmets development. No prognostic role for PD-L1 and CD8 expression in Bmets was found. Conclusion PD-L1 and CD8 Bmets expressions are associated with the primary tumor type and its PD-L1 and CD8 expressions. No factor predicts the discordance for PD-L1 expression, while time to Bmets development is associated with CD8 expression discordance.
The Genome of the Cauliflower Coral Pocillopora verrucosa

Abstract Climate change and ocean warming threaten the persistence of corals worldwide. Genomic resources are critical to study the evolutionary trajectory, adaptive potential, and genetic distinctiveness of coral species. Here, we provide a reference genome of the cauliflower coral Pocillopora verrucosa, a broadly prevalent reef-building coral with important ecological roles in the maintenance of reefs across the Red Sea, the Indian Ocean, and the Pacific Ocean. The genome has an assembly size of 380,505,698 bp with a scaffold N50 of 333,696 bp and a contig N50 of 75,704 bp. The annotation of the assembled genome returned 27,439 gene models of which 89.88% have evidence of transcription from RNA-Seq data and 97.87% show homology to known genes. A high proportion of the genome (41.22%) comprised repetitive elements in comparison to other cnidarian genomes, in particular in relation to the small genome size of P. verrucosa.
Muscle Activation Differences During Eccentric Hamstring Exercises

Background: The hamstring muscles play a critical role in the prevention of lower limb injuries. However, it is still unclear which exercises are more effective in terms of muscle activation. Hypothesis: In healthy individuals, there are differences between muscular activations of the biceps femoris (BF), semitendinosus (ST), and semimembranosus (SM) muscles during eccentric hamstring exercises. Study Design: Cross-sectional. Level of Evidence: Level 2. Methods: A total of 31 healthy participants (18 male; mean age, 22.5 years; SD, 3.1) were included in this study. The maximum voluntary isometric contraction of the hamstring muscles was measured using an isokinetic dynamometer. The participants were asked to perform one of the following exercises randomly (3 repetitions each): stiff-leg deadlift (SLDL), unilateral stiff-leg deadlift (USLDL), Nordic hamstring exercise (NHE), and ball leg curl (BLC). Activation of the BF, ST, and SM muscles was measured using surface electromyography during the exercises. In the statistical analysis of this study, factorial analysis of variance was used to compare the effects of each exercise on the muscle groups and to analyze which exercise type was more effective for each muscle group. Results: The NHE led to higher muscle activation than the other exercises (P < 0.001). When exercise type and muscle interaction were examined, SM activation was lower than BF (P = 0.04) and ST (P = 0.001) during NHE (P < 0.05). The highest level of muscular activation was recorded during the NHE in both male and female participants. Conclusion: The NHE may be the most effective exercise for the hamstring muscles as it leads to greater muscle activation. SLDL, USLDL, and BLC exercises may be preferred at the beginning of strength training programs since they lead to lower muscular activation compared with the NHE. Clinical Relevance: To select the optimum hamstring exercise, it is important to know the activation levels of the hamstring muscles during different eccentric exercises.
Adaptive differentiation of growth, energetics and behaviour between piscivore and insectivore juvenile rainbow trout (O. mykiss) along the Pace-of-Life continuum.

Adaptive trade-offs are fundamental mechanisms underlying phenotypic diversity, but the presence of generalizable patterns in multivariate adaptation and their mapping onto environmental gradients remain unclear. To understand how life-history affects multivariate trait associations, we examined relationships among growth, metabolism, anatomy and behaviour in rainbow trout juveniles from piscivore vs. insectivore ecotypes along an experimental gradient of food availability. We hypothesized that i) selection for larger size in piscivorous adults would select for higher juvenile growth at the cost of lower active metabolism; ii) elevated growth of piscivores would be supported by a greater productivity of their natal stream and more proactive foraging behaviours; and iii) general patterns of multivariate trait associations would match the predictions of the Pace-Of-Life Syndrome. Relative to insectivores, piscivorous fry showed a pattern of higher growth (+63%), maximum food intake (+33%), growth efficiency (+41%), and standard metabolic rate (SMR; +47%), but lower active metabolic capacity (maximum metabolic rate (MMR; -17%), aerobic scope (AS; -48%)), suggesting that faster piscivore growth is supported by greater food intake and digestive capacity but is traded-off against lower scope for active metabolism. A similar trade-off appeared among organ systems, with piscivorous fry exhibiting an 83% greater investment in average mass of organs associated with food consumption and processing (i.e. stomach and intestine), but an apparently smaller relative investment in organs involved in cardio-vascular or cognitive activities (heart and brain, respectively). Higher invertebrate drift in their natal rearing habitat, quicker behavioural transition to a novel food source and lower anxiety after a frightening event in piscivorous fry suggest that faster growth requires both proactive foraging behaviours and higher prey availability in the environment. Finally, the sampling of replicate insectivore populations confirmed their lower juvenile growth (-73% on average) and reduced environmental productivity of their natal streams (-45% lower drift abundance) relative to the piscivore ecotype. Our results suggest that selection for large adult body size influences selection on high juvenile growth, high basal metabolism and proactive behaviours, and that the intense phenotypic divergence between piscivorous and insectivorous rainbow trout may be constrained by environmental productivity.
Prognostic impact of additional mineralocorticoid receptor antagonists in octogenarian heart failure patients

Guideline‐directed medical therapy (GDMT) including beta‐blockers and renin–angiotensin system inhibitors is shown to reduce mortality risk in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). However, there is little evidence about the efficacy of additional administration of mineralocorticoid receptor antagonists (MRAs) with GDMT in patients ≥80 years presenting with HF. We aimed to investigate the prognostic impact of GDMT with MRA in relation to the age of patients with HF.