Miracle-dz/UniFAR-FTUs huggingface dataset:
Human CD34+ Hematopoietic Stem Cell–Engrafted NSG Mice: Morphological and Immunophenotypic Features

Immunodeficient mice engrafted with human immune cells represent an innovative tool to improve translatability of animal models for the study of human diseases. Immunophenotyping in these mice focuses on engraftment rates and cellular differentiation in blood and secondary lymphoid organs, and is predominantly carried out by FACS (fluorescent activated cell sorting) analysis; information on the morphological aspects of engraftment and the prevalence of histologic lesions is limited. We histologically examined 3- to 6-month-old NSG mice, naïve or engrafted with CD34+ human hemopoietic stem cells (HSC), and employed a quantitative immunohistochemical approach to identify human and murine cell compartments, comparing the results with the FACS data. NSG mice mainly exhibited incidental findings in lungs, kidneys, testes, and adrenal glands. A 6-month-old NSG mouse had a mediastinal lymphoblastic lymphoma. The lymphoid organs of NSG mice lacked typical lymphoid tissue architecture but frequently exhibited small periarteriolar leukocyte clusters in the spleen. Mice engrafted with human HSC frequently showed nephropathy, ovarian atrophy, cataract, and abnormal retinal development, lesions considered secondary to irradiation. In addition, 20% exhibited multisystemic granulomatous inflammatory infiltrates, dominated by human macrophages and T cells, leading to the observed 7% mortality and morbidity. Immunophenotypic data revealed variable repopulation of lymphoid organs with hCD45+ human cells, which did not always parallel the engraftment levels measured via FACS. The study describes the most common pathological features in young NSG mice after human HSC engraftment. As some of these lesions contribute to morbidity, morphological assessment of the engraftment at tissue level might help improve immunophenotypic evaluations of this animal model.
Pituitary Iron Deposition and Endocrine Complications in Patients with β-Thalassemia: From Childhood to Adulthood

Abstract The endocrinological complications are a great concern in transfusion-dependent β-thalassemia (β-thal) patients. The pituitary iron deposition is regarded as the main cause of hormonal changes in thalassemic patients. In this study, our aim was to explore the association between endocrinological complications and pituitary iron overload by magnetic resonance imaging (MRI). Fifty transfusion-dependent thalassemia (TDT) patients were recruited for the study. Pituitary MRIs of patients were taken using a 1.5 Tesla Philips MRI machine. There was at least one clinical endocrine complication in two of three patients. The iron accumulation was moderate in the liver (60.0%) and was mild in hypophysis (16.0%) and in heart (8.0%). The hypogonadism and diabetes mellitus (DM) were not seen with a significantly increased pituitary iron burden. The hypogonadism was related to cardiac iron deposition (p = 0.04). The short stature was associated with a hepatic iron overload (p = 0.05). The conventional follow-up of patients with TDT might be inadequate and screening of patients with MRI of hypophysis along with heart and liver leads to better results.
An Overview of Methods for Cardiac Rhythm Detection in Zebrafish

The heart is the most important muscular organ of the cardiovascular system, which pumps blood and circulates, supplying oxygen and nutrients to peripheral tissues. Zebrafish have been widely explored in cardiotoxicity research. For example, the zebrafish embryo has been used as a human heart model due to its body transparency, surviving several days without circulation, and facilitating mutant identification to recapitulate human diseases. On the other hand, adult zebrafish can exhibit the amazing regenerative heart muscle capacity, while adult mammalian hearts lack this potential. This review paper offers a brief description of the major methodologies used to detect zebrafish cardiac rhythm at both embryonic and adult stages. The dynamic pixel change method was mostly performed for the embryonic stage. Other techniques, such as kymography, laser confocal microscopy, artificial intelligence, and electrocardiography (ECG) have also been applied to study heartbeat in zebrafish embryos. Nevertheless, ECG is widely used for heartbeat detection in adult zebrafish since ECG waveforms’ similarity between zebrafish and humans is prominent. High-frequency ultrasound imaging (echocardiography) and modern electronic sensor tag also have been proposed. Despite the fact that each method has its benefits and limitations, it is proved that zebrafish have become a promising animal model for human cardiovascular disease, drug pharmaceutical, and toxicological research. Using those tools, we conclude that zebrafish behaviors as an excellent small animal model to perform real-time monitoring for the developmental heart process with transparent body appearance, to conduct the in vivo cardiovascular performance and gene function assays, as well as to perform high-throughput/high content drug screening.
Relationship Between Chronic Stress and Heart Rate Over Time Modulated by Gender in a Cohort of Office Workers: Cross-Sectional Study Using Wearable Technologies

Background Chronic stress is increasing in prevalence and is associated with several physical and mental disorders. Although it is proven that acute stress changes physiology, much less is known about the relationship between physiology and long-term stress. Continuous measurement of vital signs in daily life and chronic stress detection algorithms could serve this purpose. For this, it is paramount to model the effects of chronic stress on human physiology and include other cofounders, such as demographics, enabling the enrichment of a population-wide approach with individual variations. Objective The main objectives of this study were to investigate the effect of chronic stress on heart rate (HR) over time while correcting for weekdays versus weekends and to test a possible modulation effect by gender and age in a healthy cohort. Methods Throughout 2016 and 2017, healthy employees of technology companies were asked to participate in a 5-day observation stress study. They were required to wear two wearables, of which one included an electrocardiogram sensor. The derived HR was averaged per hour and served as an output for a mixed design model including a trigonometric fit over time with four harmonics (periods of 24, 12, 8, and 6 hours), gender, age, whether it was a workday or weekend day, and a chronic stress score derived from the Perceived Stress Scale (PSS) as predictors. Results The study included 328 subjects, of which 142 were female and 186 were male participants, with a mean age of 38.9 (SD 10.2) years and a mean PSS score of 13.7 (SD 6.0). As main effects, gender (χ21=24.02, P<.001); the hour of the day (χ21=73.22, P<.001); the circadian harmonic (χ22=284.4, P<.001); and the harmonic over 12 hours (χ22=242.1, P<.001), over 8 hours (χ22=23.78, P<.001), and over 6 hours (χ22=82.96, P<.001) had a significant effect on HR. Two three-way interaction effects were found. The interaction of age, whether it was a workday or weekend day, and the circadian harmonic over time were significantly correlated with HR (χ22=7.13, P=.03), as well as the interaction of gender, PSS score, and the circadian harmonic over time (χ22=7.59, P=.02). Conclusions The results show a relationship between HR and the three-way interaction of chronic stress, gender, and the circadian harmonic. The modulation by gender might be related to evolution-based energy utilization strategies, as suggested in related literature studies. More research, including daily cortisol assessment, longer recordings, and a wider population, should be performed to confirm this interpretation. This would enable the development of more complete and personalized models of chronic stress.
IgY Targeting Bacterial Quorum-Sensing Molecules in Implant-Associated Infections

Background: Implant-associated infections are still a major complication in the field of orthopedics. Bacteria can form biofilms on implant surfaces, making them more difficult to detect and treat. Since standard antibiotic therapy is often impaired in biofilm infections, particular interest is directed towards finding treatment alternatives. Biofilm-formation is a well-organized process during which bacteria communicate via quorum-sensing molecules (QSM). The aim of this study was to inhibit bacterial communication by directing avian IgY against specific QSM. Methods: Chicken were immunized against the following QSM: (1) AtlE, a member of the autolysin family which mediates attachment to a surface in Staphylococcus epidermidis; (2) GroEL, the bacterial heat shock protein; (3) PIA (polysaccharide intercellular adhesion), which is essential for cell–cell adhesion in biofilms. Staphylococcus epidermidis biofilms were grown and inhibition of biofilm-formation by IgYs was evaluated. Additionally, human osteoblasts were cultivated and biocompatibility of IgYs was tested. Results: We were able to demonstrate that all IgYs reduced biofilm-formation, also without prior immunization. Therefore, the response was probably not specific with regard to the QSM. Osteoblasts were activated by all IgYs which was demonstrated by microscopy and an increased release of IL-8. Conclusions: In conclusion, avian IgY inhibits biofilm-formation, though the underlying mechanism is not yet clear. However, adverse effects on local tissue cells (osteoblasts) were also observed.
Prejudice and Feeling of Threat towards Syrian Refugees: The Moderating Effects of Precarious Employment and Perceived Low Outgroup Morality

Refugees frequently experience traumatic situations that result in the deterioration of their psychological well-being. In addition, perceived prejudice and discrimination against them by the host society can worsen their mental health. In this research study, using a Spanish sample, prejudice towards Syrian refugees is analyzed taking into account feeling of threat (realistic or symbolic), precarious employment, and perceived outgroup morality. Using a total of 365 participants, our results reveal that individuals feel more prejudice towards refugees when the former scored higher in realistic threat and symbolic threat, were in a highly precarious situation of employment and perceived refugees as being more immoral. Furthermore, it was found that persons who scored high in realistic threat and at the same time were in a situation of precarious employment, were those who displayed greater prejudice. The results likewise pointed to individuals who scored high in symbolic threat and in outgroup morality as being those who felt greater rejection towards the refugees. Accordingly, our results confirm the importance of feeling of threat in relation to prejudice, and highlight two important moderating factors: precarious employment and perceived outgroup morality.
MicroRNAs Profiling in HIV, HCV and HIV/HCV Coinfected Patients.

BACKGROUND Human immunodeficiency virus (HIV) an hepatitis C virus (HCV) infections are important public health issues. OBJECTIVE This study aimed to assess the association between microRNAs expression level and immunological and viral markers in HIV, HCV, and HIV/HCV coinfected patients. METHOD The expression level of miR-29, miR-149, miR-199, miR-let7, miR-223, miR-155, miR-122, and miR-150 was evaluated in 20 HIV, 20 HCV, 20 coinfected patients and 20 healthy controls using real-time PCR assay. HIV and HCV viral loads were measured by real-time PCR and also, CD4+ T-lymphocyte count was measured by the PIMA CD4 analyzer. RESULT The miRNA expression pattern in each mentioned group showed significantly different expression profiles, but some miRNA species were shared between the groups. MiR-122 and miR-155 were up-regulated while miR-29 and miR-223 were down-regulated in three patients groups compared to healthy controls. A significant positive correlation was observed between the expression of miR-122 and HIV/HCV loads. But, miR-29 and let-7 were negatively correlated with HIV load, and miR149 and let-7 were negatively correlated with HCV load. Also, miR-155 was positively correlated with HCV load. MiR-122 and miR-199 were negatively while others were positively correlated with CD4+ T cell count. CONCLUSION These miRNAs are probably involved in the clinical progression and pathogenesis of HIV and HCV infections. Therefore, determining and manipulating of these miRNAs can lead to opening a new gate to control of these important infections.
Antibiotic treatment during early childhood and risk of type 1 diabetes in children: A national birth cohort study

Antibiotics are widely used during childhood infections and influence the composition of the microbiota, which is established during the first years of life. Evidence from animal models of type 1 diabetes shows that antibiotics might accelerate disease progression, and altered intestinal microbiota has been reported in association with type 1 diabetes in humans. We aimed to test the hypothesis that early exposure to antibiotics (0‐24 months of age) was associated with an increased risk of childhood type 1 diabetes development.
Optimal Treatment of Cam Morphology May Change the Natural History of Femoroacetabular Impingement

Background: There is debate in the literature whether cam morphology is associated with increased risk for hip osteoarthritis. The capability of femoroplasty to alter the natural history of cam morphology is still in question. Purpose: To (1) investigate the correlation between cam morphology and damage to the articular cartilage and (2) assess whether correction of the cam morphology affects survivorship of the joint, progression to arthroplasty, and functional patient-reported outcome scores. Study Design: Cohort study; Level of evidence, 3. Methods: Data were prospectively collected for patients presenting for hip arthroscopy between February 2008 and April 2017. Cases were divided into 3 groups: control group with an alpha angle <50° pre- and postoperatively, treated group with an alpha angle >55° preoperatively and <50° postoperatively, and a group with an alpha angle >55° pre- and postoperatively. All patients had minimum 2-year postoperative follow-up for the modified Harris Hip Score, the Non-arthritic Hip Score, and visual analog scale for pain. Conversion to total hip arthroplasty was recorded. Results: A 1:1:1 match successfully yielded 98 hips for each group. Follow-up time was 50.77 ± 24.60 months (mean ± SD). The pre- and postoperative mean alpha angles were 45.2°± 3.4° and 40.6°± 4.3° in the control group, respectively; 66.2°± 8.4° and 42.3°± 5.9° in the treated group; and 68.5°± 9.4° and 61.4°± 7.6° in the alpha >55° group. Intraoperatively, the alpha >55° and treated groups had greater acetabular cartilage damage than the control group (P = .0245 and P = .0036, acetabular labrum articular disruption, respectively; P = .0347 and P = .0211, acetabular Outerbridge). The alpha >55° group achieved the patient acceptable symptomatic state for the modified Harris Hip Score (58.2%) significantly less than the treated (75.5%; P = .0100) and control (73.5%; P = .0239) groups. Progression to arthroplasty was significantly higher in the alpha >55° group (n = 17) when compared with the control (n = 8) and treated (n = 10) groups (P = .0034 and P = .0338, respectively). Conclusion: Cam deformity was associated with higher-grade damage of the acetabular articular cartilage. An alpha angle >55° after surgery was associated with lower native hip joint survivability and less successful functional outcomes when compared with that of treated cam deformity as well as no deformity. These data suggest that correcting the cam deformity may positively affect the natural history of these patients.
Hyperbaric oxygen protects against myocardial ischemia-reperfusion injury through inhibiting mitochondria dysfunction and autophagy

Our previous study demonstrated that hyperbaric oxygen (HBO) improves heart function predominantly through reducing oxygen stress, modulating energy metabolism and inhibiting cell apoptosis. The present study aimed to investigate the protective effects of HBO on mitochondrial function and autophagy using rats with a ligated left anterior descending artery. The cardioprotective effects of HBO were mainly evaluated using ELISA, fluorescent probes, transmission electron microscopy and reverse transcription-quantitative PCR (RT-qPCR). HBO pretreatment for 14 days (once a day) using a 0.25 MPa chamber improved mitochondrial morphology and decreased the number of autophagic vesicles, as observed using a transmission electron microscope. HBO pretreatment significantly increased the levels of ATP, ADP, energy charge and the opening of the mitochondrial permeability transition pore, but decreased the levels of AMP, cytochrome c and reactive oxygen species. Moreover, HBO pretreatment significantly increased the gene or protein expression levels of eIF4E-binding protein 1, mammalian target of rapamycin (mTOR), mitochondrial DNA, NADH dehydrogenase subunit 1, mitofusin 1 and mitofusin 2, whereas it decreased the gene or protein expression levels of autophagy-related 5 (Atg5), cytochrome c, dynamin-related protein 1 and p53, as determined using RT-qPCR or immunohistochemistry. In conclusion, HBO treatment was observed to protect cardiomyocytes during myocardial ischemia-reperfusion injury (MIRI) by preventing mitochondrial dysfunction and inhibiting autophagy. Thus, these results provide novel evidence to support the use of HBO as a potential agent for the mitigation of MIRI.
Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The Drosophila model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with Drosophila models for EIEE and discuss the future development of their practical use.
The Inflammatory Potential of Diet is Associated with Breast Cancer Risk in Urban Argentina: A Multilevel Analysis

Abstract Dietary patterns have been associated with breast cancer (BC) in Argentina. However, little evidence exists relating the inflammatory potential of diet and BC in Latin American countries and how this may relate to rurality. The aim of the present study was to evaluate the association between the Dietary Inflammatory Index (DII®) and BC considering urbanization contexts in Córdoba, Argentina. A frequency-matched case-control study (317 BC cases, 526 controls) was conducted from 2008 through 2016. DII scores were computed based on dietary intake assessed by a validated food frequency questionnaire. Multi-level logistic regression models were fit to evaluate the association between DII and BC, following adjustment for age, body mass index, age at menarche, number of children, smoking habits, socio-economic status and family history of BC as first-level covariates and urbanization level as the contextual variable. Increasing DII score showed significant positive associations with BC risk (ORtertile3vs.tertile1 1.34; 95%CI 1.05, 1.70). The association was stronger in overweight and obese women (ORtertile3vs.tertile1 1.98; 95%CI 1.86, 2.10). The DII effect on BC was higher with increased urbanization. A pro-inflammatory diet, reflected by higher DII scores, was positively associated with BC, especially in overweight women and with increased urbanization.
Synthesis, Anti-proliferative Activity, and Molecular Docking Study of New Series of 1,3-5-Triazine Schiff Base Derivatives

Based on the use of s-triazine as a scaffold, we report here a new series of s-triazine Schiff base derivatives and their anti-proliferative activity against two cancer cell lines: human breast carcinoma (MCF-7), and colon cancer (HCT-116) compared with tamoxifen as a reference compound. Several derivatives exhibited growth inhibition activity in the sub-micromolar range. The results reveal that the s-triazine Schiff base derivatives showed varied activities and that the substituents on the s-triazine core have a great effect on the anti-proliferative activity. Compounds with a piperidino and benzylamino substituent on the s-triazine moiety 4b and 4c were most effective in both cell lines compared to the reference compound used. In addition, compound 4b has a para chlorine atom on the benzylidine residue, demonstrating the most potent activity with IC50 values of 3.29 and 3.64 µM in MCF-7 and HCT-116, respectively. These results indicate that in general, the nature of the substituents on the triazine core and the type of substituent on the benzilyldene ring significantly influenced the anti-proliferative activity. The results obtained from the anti-proliferative activity and the molecular docking study indicate that s-triazine-hydrazone derivatives may be an excellent scaffold for the development of new anti-cancer agents.
BCL11A enhancer edited hematopoietic stem cells persist in rhesus monkeys without toxicity.

Gene editing of the erythroid-specific BCL11A enhancer in hematopoietic stem and progenitor cells (HSPCs) from sickle cell disease (SCD) patients induces fetal hemoglobin (HbF) without detectable toxicity as assessed by mouse xenotransplant. Here, we evaluated autologous engraftment and HbF induction potential of erythroid-specific BCL11A enhancer edited HSPCs in four non-human primates. We utilized a single guide RNA (sgRNA) with identical human and rhesus target sequences to disrupt a GATA1 binding site at the BCL11A +58 erythroid enhancer. Cas9 protein and sgRNA ribonucleoprotein complex (RNP) was electroporated into rhesus HSPCs, followed by autologous infusion after myeloablation. We found that gene edits persisted in peripheral blood (PB) and bone marrow (BM) for up to 101 weeks similarly for BCL11A enhancer or control locus (AAVS1) targeted cells. Biallelic BCL11A enhancer editing resulted in robust γ-globin induction, with the highest levels observed during stress erythropoiesis. Indels were evenly distributed across PB and BM lineages. Off-target edits were not observed. Non-homologous end-joining repair alleles were enriched in engrafting HSCs. In summary, we find that edited HSCs can persist for at least 101 weeks post-transplant, and biallelic edited HSCs provide substantial HbF levels in PB red blood cells, together supporting further clinical translation of this approach.