Miracle-dz/UniFAR-FTUs huggingface dataset:
EWS-FLI1–regulated Serine Synthesis and Exogenous Serine are Necessary for Ewing Sarcoma Cellular Proliferation and Tumor Growth

Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma, translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact Ewing sarcoma cellular metabolism, regulating expression of 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis. Here, we have examined the importance of serine metabolism in Ewing sarcoma tumorigenesis and evaluated the therapeutic potential of targeting serine metabolism in preclinical models of Ewing sarcoma. We show that PHGDH knockdown resulted in decreased Ewing sarcoma cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of Ewing sarcoma. In addition, the PHGDH inhibitor NCT-503 caused a dose-dependent decrease in cellular proliferation. Moreover, we report a novel drug combination in which nicotinamide phosphoribosyltransferase (NAMPT) inhibition, which blocks production of the PHGDH substrate NAD+, synergized with NCT-503 to abolish Ewing sarcoma cell proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited Ewing sarcoma cell proliferation and tumorigenesis, indicating that Ewing sarcoma cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for Ewing sarcoma tumorigenesis, and that targeting metabolic dependencies should be further investigated as a potential therapeutic strategy for Ewing sarcoma. In addition, the combination strategy presented herein may have broader clinical applications in other PHGDH-overexpressing cancers as well.
Proximate Composition, Amino Acid Profile, and Oxidative Stability of Slow-Growing Indigenous Chickens Compared with Commercial Broiler Chickens

The increased demand for chicken meat products has led to chickens with increased growth rates and heavier slaughter weights. This has had unintentional negative effects on the genetics of these animals, such as spontaneous, idiopathic muscle abnormalities. There has also been a shift in customer preference towards products from alternative farming systems such as organic and free-range. Indigenous purebred chickens, such as the Polverara, show potential in these systems as they are adapted to more extensive systems. The aim of the present study was to characterize the meat quality traits of the Polverara, by comparing the proximate composition and amino acid profile with that of a commercial Hybrid. In addition, the lipid and protein oxidation was analyzed after eight days of storage. A total of 120 leg meat samples, 60 Polverara and 60 Hybrid were analyzed. Polverara exhibited higher protein content, lower lipid content, and a better amino acid profile. These results indicate that the Polverara has better nutritional meat quality. However, Polverara also showed higher levels of lipid and protein oxidation. Therefore, further research is needed, especially in regards to the fatty acid profile and mineral content of the meat, which is known to affect oxidative stability.
Outcomes of bell-bottom technique compared to standard endovascular aneurysm repair

Objective The bell-bottom technique is a widely used technique to treat aortoiliac aneurysms with preservation of the hypogastric arteries. The published data are scarce with conflicting results regarding the evolution. The aim of this study was to compare the outcomes of patients submitted to endovascular abdominal aortic aneurysm repair with standard technique (S-EVAR) versus bell-bottom technique. Methods This retrospective cohort study compared the outcomes of standard endovascular aneurysm repair (<16 mm iliac limbs) and bell-bottom technique (≥16 mm iliac limbs) in a tertiary vascular center between 2010 and 2015. The end points of this study were type IB endoleak, reintervention and 30-day mortality. The follow-up protocol included CT scans within 30 days of implantation and 12 months. Duplex ultrasound was performed yearly thereafter. Results Two hundred and three patients were treated with bell-bottom technique (n = 84, mean age 72.2 ± 8.9) and S-EVAR (n = 119, mean age 72.7 ± 8.4). The overall 30-day mortality was 1.9%, with no significant difference between groups. There was higher prevalence of coronary heart disease in the bell-bottom technique group compared to the S-EVAR group (41.6% vs. 18.4%, p < 0.01). One patient in the S-EVAR group (0.85%) and four patients in the bell-bottom technique (4.6%) developed type IB endoleak. The mean follow-up period was 35.2 ± 30.4 months. By Kaplan-Meier analysis, freedom from type IB endoleak in 80 months was 85.2% in the bell-bottom technique group and 98.7% in the S-EVAR group (p = 0.05). The freedom from reintervention in 80 months was 74.0% in the bell-bottom technique group and 94.1% in the S-EVAR group (p = 0.6). Conclusions This study shows lower freedom from type IB endoleak in the bell-bottom group compared to the standard repair group. There is no significant difference in reoperation rate and 30-day mortality.
A Social-Cognitive Investigation of Young Adults Who Abuse Their Parents

Within the past decade, there has been an increase in research focusing on young people who abuse their parents. However, most research has narrowly focused on adolescent children, neglecting to investigate the nature, pattern, and factors related to child-to-parent abuse perpetrated by young adults. This article integrated two complementary social-cognitive theories of aggression to explore factors associated with perpetration of child-to-parent abuse among university students (N = 435, aged 18–25 years). Participants completed the Abusive Behavior by Children–Indices, a self-report measure that was designed to differentiate abusive and normative child-to-parent behavior. The results highlight that abuse is not limited to adolescent children, as one in seven young adults were categorized as abusive toward a parent over the previous 12 months. Sons were more likely than daughters to report abusing their parents. Specifically, sons disclosed greater rates of father abuse than daughters, but similar rates of mother abuse. Hierarchical logistic regression found that exposure to marital violence, parent-to-child aggression, trait anger, and aggressive scripts were significant predictors of both mother and father abuse. However, other factors related to abuse differed according to which parent was the target of abuse. For instance, male sex was a significant predictor of father abuse, whereas rumination and impulsive emotional regulation were significant predictors of mother abuse. Overall, father abuse was better explained by the model than mother abuse. The results suggest that although factors related to general aggressive behavior may be good predictors for father abuse, additional factors may be needed to explain mother abuse.
SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs

Significance: Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (H2S) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of H2S/SS in blood and/or tissues, and are amenable to treatment by H2S supplementation, development of safe and efficacious H2S donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents. Recent Advances: Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S8) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer. Critical Issues: Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ring-substituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by H2S and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. Future Directions: SG1002 is likely to emerge as the H2S donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate H2S without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of H2S donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic H2S prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new “supramolecular tuning” paradigm.
Biological studies on bark beetles of the Seychelles (Col., Scolytidae)

The biology of 17 species of scolytid bark beetles in the genera Coccotrypes, Cryphalus, Hypocryphalus and Hypothenemus, found on the island of Mahé in the Seychelles is discussed. Particular attention is paid to their distribution, host plants, gallery systems, breeding systems and potential economic importance. Eight species are recorded from the Seychelles for the first time. Brief notes are given on 7 further species recorded from the Seychelles but not found in this study. Two species, Hypothenemus birmanus and H. eruditus are potential pests of stressed seedlings and transplants. Species of Coccotrypes may reduce the regeneration of certain endemic trees and palms with large seeds.
An audiological profile of a cohort of school-aged children with HIV and AIDS attending an antiretroviral clinic in South Africa

Background Recent estimates reveal that there are approximately 280 000 children between the ages of birth and 14 years who are living with the human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) in South Africa. These children are living with a compromised immune system, are vulnerable to opportunistic infections and subsequent hearing loss. However, there is limited research on the nature and extent of this sensory impairment amongst school-aged children. Objective This study aimed to determine an audiological profile of a cohort of school-aged children attending an antiretroviral (ARV) clinic, describing the occurrence of hearing loss and nature in terms of degree, type, configuration and symmetry. Methods A non-experimental descriptive exploratory study was conducted, where 30 children aged between 6 and 12 years underwent diagnostic audiological assessments. Audiological procedures included case history, medical record review, otoscopic examination, immittance audiometry, pure-tone audiometry, speech audiometry, distortion product otoacoustic emissions (DPOAEs) and neurological auditory brainstem response (ABR) testing. The results were analysed descriptively using SPSS version 22 software. Results The results indicated abnormal otoscopic findings in half the participants, and consequently type C tympanograms were the most common. Of the 28 participants who could be assessed with pure-tone audiometry, 15 (54%) showed a hearing loss. A bilateral rising mild, conductive hearing loss was predominant. Thirteen (43%) of the participants could not be tested using DPOAE because of outer and middle-ear pathology. Neurological ABR testing revealed an abnormality in 18 (60%) of the participants suggesting the sensitivity of the ABR to detect subtle neurological changes. Conclusion Half the children in this study showed hearing loss, which has serious implications for the holistic management of the children within the health and educational contexts. Therefore, there is a need for audiological monitoring of children with HIV and AIDS. Keywords audiological profile; HIV; AIDS; hearing loss; school children.
RNA-Puzzles Round IV: 3D structure predictions of four ribozymes and two aptamers

RNA-Puzzles is a collective endeavor dedicated to the advancement and improvement of RNA 3D structure prediction. With agreement from crystallographers, the RNA structures are predicted by various groups before the publication of the crystal structures. We now report the prediction of 3D structures for six RNA sequences: four nucleolytic ribozymes and two riboswitches. Systematic protocols for comparing models and crystal structures are described and analyzed. In these six puzzles, we discuss (i) the comparison between the automated web servers and human experts; (ii) the prediction of coaxial stacking; (iii) the prediction of structural details and ligand binding; (iv) the development of novel prediction methods; and (v) the potential improvements to be made. We show that correct prediction of coaxial stacking and tertiary contacts is essential for the prediction of RNA architecture, while ligand binding modes can only be predicted with low resolution and simultaneous prediction of RNA structure with accurate ligand binding still remains out of reach. All the predicted models are available for the future development of force field parameters and the improvement of comparison and assessment tools.
Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy

Supplemental Digital Content is available in the text. Background: Mutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series. Methods: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. Results: DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant). Conclusions: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.
Bioinformatic analysis indicates that SARS-CoV-2 is unrelated to known artificial coronaviruses.

OBJECTIVE SARS-CoV-2 is responsible for the present coronavirus pandemic and some suggestions were made about its possible artificial origin. We, therefore, compared SARS-CoV-2 with such known viruses that were prepared in the laboratory and other relevant natural strains to estimate their genetic relatedness. MATERIALS AND METHODS BLAST and clustalW were used to identify and align viral sequences of SARS-CoV-2 to other animal coronaviruses (human, bat, mouse, pangolin) and related artificial constructs. Phylogenetics trees were then prepared using iTOL. RESULTS Our study supports the notion that known artificial coronaviruses, including the chimeric SL-SHC014-MA15 synthesized in 2015, differ too much from SARS-CoV-2 to hypothesize an artificial origin of the latter. On the contrary, our data support the natural origin of the COVID-19 virus, likely derived from bats, possibly transferred to pangolins, before spreading to man. CONCLUSIONS Speculations about the artificial origin of SARS-CoV-2 are most likely unfounded. On the contrary, when carefully handled, engineered organisms provide a unique opportunity to study biological systems in a controlled fashion. Biotechnology is a powerful tool to advance medical research and should not be abandoned because of irrational fears.
Strongyloides stercoralis seropositivity is not associated with increased symptoms in a remote Aboriginal community

Strongyloides stercoralis is a soil‐transmitted helminth, endemic in remote Aboriginal and Torres Strait Islander communities in northern Australia with estimates of prevalences up to 60%. Hyperinfection in the setting of immunosuppression is a rare, but well recognised cause of significant morbidity and mortality. However, the morbidity associated with chronic uncomplicated infection is less well characterised.
Magnetoelastic coupling associated with vacancy ordering and ferrimagnetism in natural pyrrhotite, Fe7S8

Magnetoelastic coupling associated with the hexagonal—monoclinic transition in a natural sample of the mineral pyrrhotite, Fe7S8, has been analysed in terms of separate coupling of spontaneous strains with two discrete order parameters, qv for Fe/vacancy ordering and qm for magnetic ordering. Coupling of the two order parameters separately with strain gives rise to two terms for coupling between them, λqm2qv2 and λqm2qv8, and a pattern of evolution in which qv varies continuously and qm discontinuously through a single transition point. The transition is ferrimagnetic and ferroelastic but the relatively slow relaxation rate for Fe/vacancy ordering, in comparison with magnetic ordering, results in elastic and anelastic properties which are quite different from those observed in other ferroic or multiferroic materials with two instabilities. Instead of classical elastic softening, there is stiffening of the elastic constants which scales with qm2 and qv2. Instead of the normal pattern of acoustic loss associated with the mobility and subsequent freezing for ferroelastic twin walls, the loss is consistently low throughout the temperature range 300 K–875 K.
Age‐dependent toxicity of diazinon and terbufos in european starlings (Sturnus vulgaris) and red‐winged blackbirds (Agelaius phoeniceus)

Adult European starlings (Sturnus vulgaris) are more resistant to poisoning by organophosphorous (OP) pesticides than are other passerine birds. Nestling starlings, however, are sensitive to OP intoxication. Both adult and nestling red‐winged blackbirds (Agelaius phoeniceus) are sensitive to OP toxicity and therefore may be a more representative model of the toxic response of passerine birds. The purpose of this study was to compare the toxicity ratio, as indicated by median lethal dose (LD50), of terbufos and diazinon in adult and nestling starlings and red‐winged blackbirds, and to compare cholinesterase (ChE) inhibition between species and among age groups. Red‐winged blackbirds are more sensitive to terbufos and diazinon intoxication than are European starlings, and the young of both species are more sensitive than the adults. When mortality is used as the endpoint, adult starlings are approximately 103 times less sensitive to terbufos intoxication than are 2‐d‐old starling chicks and 137 times less sensitive than adult red‐wings. Adult red‐wings were only 4.1 times less sensitive than 0 to 3‐d‐old red‐wing chicks. Adult starlings were approximately 47 times less sensitive to diazinon toxicity than 2‐d‐old starling nestlings and 65 times less sensitive than adult redwings. Adult red‐wings were 3.8 times less sensitive to diazinon than 0‐ to 3‐d‐old red‐wing nestlings. Plasma and brain ChE activity was depressed in starling and red‐wing adults in a dose‐dependent fashion, but the relationship between dose, and plasma and brain ChE depression was more evident in some nestling age groups than in others. Baseline ChE activity cannot be invoked to explain the sensitivity difference between species. Baseline ChE activities in both brain and plasma increase with age in both species. These changes may account in part for the greater sensitivity of the young as compared to the adult.
Transcriptional regulation of VCAM‐1 expression by tumor necrosis factor‐α in human tracheal smooth muscle cells: Involvement of MAPKs, NF‐κB, p300, and histone acetylation

Tumor necrosis factor‐α (TNF‐α) has been shown to induce the expression of adhesion molecules in airway resident cells and contribute to inflammatory responses. Here, the roles of mitogen‐activated protein kinases (MAPKs) and NF‐κB in TNF‐α‐induced expression of vascular cell adhesion molecule (VCAM)‐1 were investigated in human tracheal smooth muscle cells (HTSMCs). TNF‐α‐enhanced expression of VCAM‐1 protein and mRNA as well as phosphorylation of p42/p44 MAPK, p38, and JNK were significantly attenuated by inhibitors of MEK1/2 (U0126), p38 (SB202190), and JNK (SP600125). Transfection with dominant negative mutants of MEK1/2, ERK1, ERK2, p38, and JNK attenuated TNF‐α‐induced VCAM‐1 expression. Furthermore, TNF‐α‐induced VCAM‐1 expression was significantly blocked by a selective NF‐κB inhibitor helenalin. TNF‐α‐stimulated translocation of NF‐κB into the nucleus and degradation of IκB‐α was blocked by helenalin, but not by U0126, SB202190, or SP600125. VCAM‐1 promoter activity was enhanced by TNF‐α in HTSMCs transfected with VCAM‐1‐Luc, which was inhibited by helenalin, U0126, SB202190, and SP600125. Most surprisingly, VCAM‐1 expression was also significantly blocked by a selective inhibitor of p300, curcumin. NF‐κB transcription factor and p300 were associated with the VCAM‐1 promoter, which was dynamically linked to histone H3 acetylation stimulated by TNF‐α, as determined by chromatin immunoprecipitation assay. Moreover, the resultant enhancement of VCAM‐1 expression increased the adhesion of polymorphonuclear cells (PMNs) to monolayer of HTSMCs, which was blocked by helenalin, U0126, SB202190, or SP600125. These results suggest that in HTSMCs, activation of MAPK pathways, NF‐κB, and p300 is essential for TNF‐α‐induced VCAM‐1 expression. J. Cell. Physiol. 207: 174–186, 2006. © 2005 Wiley‐Liss, Inc.