Miracle-dz/UniFAR-FTUs huggingface dataset:
Discrepancies between parent and child ratings of anxiety in children with autism spectrum disorder

Co‐occurring anxiety is common in children with autism spectrum disorder (ASD). However, inconsistencies across parent and child reports of anxiety may complicate the assessment of anxiety in this population. The present study examined parent and child anxiety ratings in children with ASD with and without anxiety disorders and tested the association between parent–child anxiety rating discrepancy and ASD symptom severity. Participants included children aged 8–16 years in three diagnostic groups: ASD with co‐occurring anxiety disorders (ASD + Anxiety; n = 34), ASD without co‐occurring anxiety disorders (ASD; n = 18), and typically developing healthy controls (TD; n = 50). Parents and children completed ratings of child anxiety using the Multidimensional Anxiety Rating Scale. Patterns of parent and child anxiety ratings differed among the three groups, with parent ratings exceeding child ratings only in the ASD + Anxiety group. Parents reported higher levels of child anxiety in the ASD + Anxiety versus ASD group, whereas children reported comparable levels of anxiety in the two groups. Among children with ASD, ASD symptom severity was positively associated with the degree to which parent ratings exceeded child ratings. Results suggest that children with ASD and co‐occurring anxiety disorders endorse some anxiety symptoms but may underreport overall levels of anxiety. In addition, ASD symptom severity might increase discrepancies in parent–child anxiety ratings. These findings suggest a unique and valuable role of child anxiety ratings and suggest that both parent and child anxiety ratings should be considered in light of children's ASD symptom severity and used to guide further assessment. Autism Res 2020, 13: 93–103. © 2019 International Society for Autism Research, Wiley Periodicals, Inc.
Multi-level experiences and determinants of alcohol misuse and illicit drug use among occupational groups at high-risk of HIV in sub-Saharan Africa: A thematic synthesis of qualitative findings

ABSTRACT Occupational groups at high-risk of HIV in sub-Saharan Africa (SSA) may be at increased risk of substance use because of occupation-related factors. We synthesised qualitative data on determinants and context of alcohol misuse and illicit drug use in these groups. We systematically searched five databases for qualitative studies reporting on alcohol misuse or illicit drug use in fisherfolk, uniformed personnel, miners, truckers, motorcycle taxi riders, and sex workers in SSA. Qualitative data and interpretations were extracted and synthesised using a systematic iterative process to capture themes and overarching concepts. We searched for papers published prior to January 2018. We identified 5692 papers, and included 21 papers in our review, published from 1993 to 2017. Most studies were conducted among fisherfolk (n = 4) or sex workers (n = 12). Ten papers reported on alcohol use alone, three on illicit drug use alone and eight on both. Substance use was commonly examined in the context of work and risky behaviour, key drivers identified included transactional sex, availability of disposable income, poverty, gender inequalities and work/living environments. Substance use was linked to risky behaviour and reduced perceived susceptibility to HIV. Our review underscores the importance of multilevel, integrated HIV prevention and harm reduction interventions in these settings.
Live-cell imaging of single mRNA dynamics using split superfolder green fluorescent proteins with minimal background

The MS2 system, with an MS2 binding site (MBS) and an MS2 coat protein fused to a fluorescent protein (MCP–FP), has been widely used to fluorescently label mRNA in live cells. However, one of its limitations is the constant background fluorescence signal generated from free MCP–FPs. To overcome this obstacle, we used a superfolder GFP (sfGFP) split into two or three nonfluorescent fragments that reassemble and emit fluorescence only when bound to the target mRNA. Using the high-affinity interactions of bacteriophage coat proteins with their corresponding RNA binding motifs, we showed that the nonfluorescent sfGFP fragments were successfully brought close to each other to reconstitute a complete sfGFP. Furthermore, real-time mRNA dynamics inside the nucleus as well as the cytoplasm were observed by using the split sfGFPs with the MS2–PP7 hybrid system. Our results demonstrate that the split sfGFP systems are useful tools for background-free imaging of mRNA with high spatiotemporal resolution.
Structure and Dynamics of a Site-Specific Labeled Fc Fragment with Altered Effector Functions

Antibody-drug conjugates (ADCs) are a class of biotherapeutic drugs designed as targeted therapies for the treatment of cancer. Among the challenges in generating an effective ADC is the choice of an effective conjugation site on the IgG. One common method to prepare site-specific ADCs is to engineer solvent-accessible cysteine residues into antibodies. Here, we used X-ray diffraction and hydrogen-deuterium exchange mass spectroscopy to analyze the structure and dynamics of such a construct where a cysteine has been inserted after Ser 239 (Fc-239i) in the antibody heavy chain sequence. The crystal structure of this Fc-C239i variant at 0.23 nm resolution shows that the inserted cysteine structurally replaces Ser 239 and that this causes a domino-like backward shift of the local polypeptide, pushing Pro 238 out into the hinge. Proline is unable to substitute conformationally for the wild-type glycine at this position, providing a structural reason for the previously observed abolition of both FcγR binding and antibody-dependent cellular cytotoxicity. Energy estimates for the both the FcγR interface (7 kcal/mol) and for the differential conformation of proline (20 kcal/mol) are consistent with the observed disruption of FcγR binding, providing a quantifiable case where strain at a single residue appears to disrupt a key biological function. Conversely, the structure of Fc-C239i is relatively unchanged at the intersection of the CH2 and CH3 domains; the site known to be involved in binding of the neonatal Fc receptor (FcRn), and an alignment of the Fc-C239i structure with an Fc structure in a ternary Fc:FcRn:HSA (human serum albumin) complex implies that these favorable contacts would be maintained. Hydrogen deuterium exchange mass spectroscopy (HDX-MS) data further suggest a significant increase in conformational mobility for the Fc-C239i protein relative to Fc that is evident even far from the insertion site but still largely confined to the CH2 domain. Together, the findings provide a detailed structural and dynamic basis for previously observed changes in ADC functional binding to FcγR, which may guide further development of ADC designs.
Million-fold sensitivity enhancement in proteopathic seed amplification assays for biospecimens by Hofmeister ion comparisons

Significance Detection of aggregated proteins in human tissues represents a challenging, yet proven, avenue for diagnosing neurodegenerative diseases. For therapeutic advances to occur, an accurate and early diagnosis must be made, which would ideally rely on a biomarker that can track the progression of the disease. One challenging aspect to this approach is achieving enough sensitivity to detect very low (sometimes attogram, 10−18 g) amounts of aggregates in diagnostically available tissues. Here, we show that this level of sensitivity can be achieved through optimization of the ionic environment in which these aggregates are amplified through their self-seeding ability. The use of weakly or strongly hydrated anions can enhance the seeded-polymerization-based detection of aggregates from biological tissues, thus potentially enhancing the diagnostic capability of these assays. Recent work with prion diseases and synucleinopathies indicates that accurate diagnostic methods for protein-folding diseases can be based on the ultrasensitive, amplified measurement of pathological aggregates in biospecimens. A better understanding of the physicochemical factors that control the seeded polymerization of such aggregates, and their amplification in vitro, should allow improvements in existing assay platforms, as well as the development of new assays for other proteopathic aggregates. Here, we systematically investigated the effects of the ionic environment on the polymerization of tau, α-synuclein, and the prion protein (PrP) induced by aggregates in biospecimens. We screened salts of the Hofmeister series, a relative ordering of strongly and weakly hydrated salts that tend to precipitate or solubilize proteins. We found that sensitivities of tau-based assays for Alzheimer’s seeds and PrP-based assays for prions were best in weakly hydrated anions. In contrast, we saw an inverse trend with different tau-based assays, improving detection sensitivity for progressive supranuclear palsy seeds by ≈106. Hofmeister analysis also improved detection of sporadic Creutzfeldt–Jakob disease prions in human nasal brushings and chronic wasting disease prions in deer-ear homogenates. Our results demonstrate strong and divergent influences of ionic environments on the amplification and detection of proteopathic seeds as biomarkers for protein-folding diseases.
A model of indirect cell death caused by tumor vascular damage after high-dose radiotherapy.

There is increasing evidence that high doses of radiation, like those delivered in Stereotactic Body Radiation Therapy (SBRT), trigger indirect mechanisms of cell death. Such effect seems to be two-fold: high doses may trigger an immune-response, and; may cause vascular damage, leading to cell starvation and death. Development of mathematical response models including indirect death may help clinicians to design SBRT optimal schedules. Despite increasing experimental literature on indirect tumor cell death caused by vascular damage, efforts on modeling this effect have been limited. In this work we present a biomathematical model of this effect. In our model, tumor oxygenation is obtained by solving the reaction-diffusion equation; radiation kills tumor cells according to the linear-quadratic model, and also endothelial cells (EC), which can trigger loss of functionality of capillaries. Capillary death will affect tumor oxygenation, driving nearby tumor cells into severe hypoxia. Capillaries can recover functionality due to EC proliferation. Tumor cells entering a predetermined severe hypoxia status die according to a hypoxia-death model. This model fits recently published experimental data showing the effect of vascular damage on surviving fractions. It fits surviving fraction curves, and qualitatively reproduces experimental values of percentages of functional capillaries 48h post-irradiation, and hypoxic cells pre- and 48h post-irradiation. This model is useful for exploring aspects of tumor and endothelial cell response to radiation and constitutes a stepping stone towards modeling indirect tumor cell death caused by vascular damage and accounting for this effect during SBRT planning.
Late‐onset hypogonadism: a concept comes of age

The term Late‐onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as ‘a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)’. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age‐related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US‐initiated 7 T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that ‘in men >65 years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits’. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.
Investigating the Protective Effect of Gross Saponins of Tribulus terrestris Fruit against Ischemic Stroke in Rat Using Metabolomics and Network Pharmacology

Stroke is one of the leading causes of death and long-term disability worldwide. Gross saponins of Tribulus terrestris fruit (GSTTF) has been used for neuroprotective therapy on convalescents of ischemic stroke. But the related therapeutic mechanisms have not yet been well investigated. This study aimed to investigate the protective effects of GSTTF on ischemic stroke using metabolomics coupled with network pharmacology analysis. The rat urine sample was collected and profiled by an LC-MS-based metabolomics approach. The pathway analysis was performed based on the highlighted biomarkers, then the network pharmacology approach was applied to screen the potential therapeutic targets of GSTTF. Metabolomics analysis showed that a series of metabolic perturbations occurred in the middle cerebral artery occlusion (MCAO) group compared with the sham group. Gross saponins of Tribulus terrestris fruit can change the MCAO-induced urine metabolic deviations in a reverse manner via regulating multiple metabolic pathways. Two proteins, inducible nitric oxide synthase (NOS2) and glycogen synthase kinase-3 beta (GSK3B), were highlighted by the network pharmacology analysis, which may be the potential therapeutic targets for the GSTTF against ischemic stroke. This study provides an overview of the mechanism of MCAO-induced ischemic stroke and investigates the efficacy of GSTTF in the treatment of ischemic stroke. Further study is needed to reveal its underlying mechanisms more clearly.
Oral Anticoagulant Therapy—When Art Meets Science

Anticoagulant treatment is extremely important and frequently encountered in the therapy of various cardiovascular diseases. Vitamin K antagonists (VKA) are in use for the prevention and treatment of arterial and venous thromboembolism, despite the introduction of new direct-acting oral anticoagulants (NOAC). The VKA still have the clear recommendation in patients with a mechanical prosthetic heart valve replacement or moderate to severe mitral stenosis of the rheumatic origin, in deep vein thrombosis associated with congenital thrombophilia, and in cases where NOAC are prohibited by social condition (financial reason) or by comorbidities (extreme weight, severe renal or liver disease). VKA dosing required to reach the targeted therapeutic range varies largely between patients (inter-individual variability). This inter-individual variability depends on multiple environmental factors such as age, mass, diet, etc. but it is also influenced by genetic determinism. About 30 genes implicated in the metabolism coumarins derivatives were identified, the most important being CYP2C9 and VKORC, each with several polymorphisms. Herein, we review the data regarding genetic alterations in general and specific populations, highlight the diagnosis options in particular cases presenting with genetic alteration causing higher sensitivity and/or resistance to VKA therapy and underline the utility of NOAC in solving such rare and difficult problems.
Mutation of ten-eleven translocation-2 is associated with increased risk of autoimmune disease in patients with myelodysplastic syndrome

Background/Aims Myelodysplastic syndrome (MDS) is caused by genetic and epigenetic alteration of hematopoietic precursors and immune dysregulation. Approximately 20% of patients with MDS develop an autoimmune disease (AID). Here, we investigated whether particular genetic mutations are associated with AID in patients with MDS. Methods Eighty-eight genetic mutations associated with myeloid malignancy were sequenced in 73 MDS patients. The association between these mutations and AID was then analyzed. Results The median age of the 73 MDS patients was 70 years (interquartile range, 56 to 75), and 49 (67.1%) were male. AID was observed in 16 of 73 patients (21.9%). Mutations were detected in 57 (78.1%) patients. The percentage (68.8% vs. 80.7%, p = 0.32) and the mean number of mutations (1.8 ± 1.6 vs. 2.2 ± 1.8, p = 0.34) in MDS patients with or without AID were similar. However, the ten-eleven translocation- 2 (TET2) mutation rate was significantly higher in patients with AID than in those without (31.3% vs. 5.3%, respectively; p = 0.001). All TET2 mutations were variants of strong clinical significance. Conclusions Mutation of TET2 in patients with MDS may be associated with increased risk of developing AID.
Epithelial morphogenesis in the Drosophila egg chamber requires Parvin and ILK

Integrins are the major family of transmembrane proteins that mediate cell-matrix adhesion and have a critical role in epithelial morphogenesis. Integrin function largely depends on the indirect connection of the integrin cytoplasmic tail to the actin cytoskeleton through an intracellular protein network, the integrin adhesome. What is currently unknown is the role of individual integrin adhesome components in epithelia dynamic reorganization. Drosophila egg chamber consists of the oocyte encircled by a monolayer of somatic follicle epithelial cells that undergo specific cell shape changes. Egg chamber morphogenesis depends on a developmental array of cell-cell and cell-matrix signalling events. Recent elegant work on the role of integrins in the Drosophila egg chamber has indicated their essential role in the early stages of oogenesis when the pre-follicle cells assemble into the follicle epithelium. Here, we have focused on the functional requirement of two key integrin adhesome components, Parvin and Integrin-Linked Kinase (ILK). Both proteins are expressed in the developing ovary from pupae to the adult stage and display enriched expression in terminal filament and stalk cells, while their genetic removal from early germaria results in severe disruption of the subsequent oogenesis, leading to female sterility. Combining genetic mosaic analysis of available null alleles for both Parvin and Ilk with conditional rescue utilizing the UAS/Gal4 system, we found that Parvin and ILK are required in pre-follicle cells for germline cyst encapsulation and stalk cell morphogenesis. Collectively, we have uncovered novel developmental functions for both Parvin and ILK, which closely synergize with integrins in epithelia.
The asynchronous state's relation to large scale potentials in cortex.

Understanding the relation between large-scale potentials (M/EEG) and their underlying neural activity can improve the precision of research and clinical diagnosis. Recent insights into cortical dynamics highlighted a state of strongly reduced spike count correlations, termed the asynchronous state (AS). The AS has received considerable attention from experimenters and theorists alike, regarding its implications for cortical dynamics and coding of information. But how reconcilable are these vanishing correlations in the AS with large-scale potentials such as M/EEG observed in most experiments? Typically the latter are assumed to be based on underlying correlations in activity, in particular between subthreshold potentials. We survey the occurrence of the AS across brain states, regions and layers and argue for a reconciliation of this seeming disparity: large-scale potentials are either observed (1) at transitions between cortical activity states, which entail transient changes in population firing rate, as well as during the AS (2) on the basis of sufficiently large, asynchronous populations that only need to exhibit weak correlations in activity. Cells with no or little spiking activity can contribute to large-scale potentials via their subthreshold currents, while they do not contribute to the estimation of spiking correlations, defining the AS. Further, (3) the AS occurs only within particular cortical regions and layers associated with the currently selected modality, allowing for correlations at other times and between other areas and layers.
Modeling the Stiffness of Coupled and Uncoupled Recycled Cotton Fibers Reinforced Polypropylene Composites

The stiffness of a composite material is mainly affected by the nature of its phases and its contents, the dispersion of the reinforcement, as well as the morphology and mean orientation of such reinforcement. In this paper, recovered dyed cotton fibers from textile industry were used as reinforcement for a polypropylene matrix. The specific dye seems to decrease the hydrophilicity of the fibers and to increase its chemical compatibility with the matrix. The results showed a linear evolution of the Young’s moduli of the composites against the reinforcement contents, although the slope of the regression line was found to be lower than that for other natural strand reinforced polypropylene composites. This was blamed on a growing difficulty to disperse the reinforcements when its content increased. The micromechanics analysis returned a value for the intrinsic Young’s modulus of the cotton fibers that doubled previously published values. The use of two different micromechanics models allowed evaluating the impact of the morphology of the fibers on the Young’s modulus of a composite.
The Antithrombotic Function of Sphingosine-1-Phosphate on Human Adipose-Stem-Cell-Recellularized Tissue Engineered Vascular Graft In Vitro

Adipose stem cells (ASCs) show potential in the recellularization of tissue engineerined vascular grafts (TEVGs). However, whether sphingosine-1-phosphate (S1P) could further enhance the adhesion, proliferation, and antithrombosis of ASCs on decellularized vascular scaffolds is unknown. This study investigated the effect of S1P on the recellularization of TEVGs with ASCs. Human ASCs were derived from lipoaspirate. Scaffolds were derived from human umbilical arteries (HUAs) with treatment of 0.1% sodium dodecyl sulfate (SDS) for 48 h (decellularized HUAs; DHUAs). The adhesion, proliferation, and antithrombotic functions (kinetic clotting time and platelet adhesion) of ASCs on DHUAs with S1P or without S1P were evaluated. The histology and DNA examination revealed a preserved structure and the elimination of the nuclear component more than 95% in HUAs after decellularizaiton. Human ASCs (hASCs) showed CD29(+), CD73(+), CD90(+), CD105(+), CD31(–), CD34(–), CD44(–), HLA-DR(–), and CD146(–) while S1P-treated ASCs showed marker shifting to CD31(+). In contrast to human umbilical vein endothelial cells (HUVECs), S1P didn’t significantly increase proliferation of ASCs on DHUAs. However, the kinetic clotting test revealed prolonged blood clotting in S1P-treated ASC-recellularized DHUAs. S1P also decreased platelet adhesion on ASC-recellularized DHUAs. In addition, S1P treatment increased the syndecan-1 expression of ASCs. TEVG reconstituted with S1P and ASC-recellularized DHUAs showed an antithrombotic effect in vitro. The preliminary results showed that ASCs could adhere to DHUAs and S1P could increase the antithrombotic effect on ASC-recellularized DHUAs. The antithrombotic effect is related to ASCs exhibiting an endothelial-cell-like function and preventing of syndecan-1 shedding. A future animal study is warranted to prove this novel method.