Miracle-dz/UniFAR-FTUs huggingface dataset:
Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner

Key Points Innate immune and stool microbiome signatures of HEU children are region specific. Differences in HEU immune responses were unrelated to the microbiome. Future immune studies of HEU children must be studied across diverse settings. Visual Abstract In both high- and low-income countries, HIV-negative children born to HIV-positive mothers (HIV exposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not been investigated. To address this, we compared the innate response and the stool microbiome of 2-y-old HEU and HUU children from Belgium, Canada, and South Africa to test the hypothesis that region-specific immune alterations directly correlate to differences in their stool microbiomes. We did not detect a universal immune or microbiome signature underlying differences between HEU versus HUU that was applicable to all children. But as hypothesized, population-specific differences in stool microbiomes were readily detected and included reduced abundances of short-chain fatty acid–producing bacteria in Canadian HEU children. Furthermore, we did not identify innate immune-microbiome associations that distinguished HEU from HUU children in any population. These findings suggest that maternal HIV infection is independently associated with differences in both innate immunity and the stool microbiome in a biogeographical population-specific way.
THBS2/CA19-9 Detecting Pancreatic Ductal Adenocarcinoma at Diagnosis Underperforms in Prediagnostic Detection: Implications for Biomarker Advancement

A blood biomarker panel of THBS2 and CA19-9 detects early stages of pancreatic ductal adenocarcinoma at diagnosis, but not when tested across a population up to 1 year earlier. Our findings suggest serial sampling over time, using prospectively collected samples for biomarker discovery, and more frequent screening of highrisk individuals. Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed too late for effective therapy. The classic strategy for early detection biomarker advancement consists of initial retrospective phases of discovery and validation with tissue samples taken from individuals diagnosed with disease, compared with controls. Using this approach, we previously reported the discovery of a blood biomarker panel consisting of thrombospondin-2 (THBS2) and CA19-9 that together could discriminate resectable stage I and IIa PDAC as well as stages III and IV PDAC, with c-statistic values in the range of 0.96 to 0.97 in two phase II studies. We now report that in two studies of blood samples prospectively collected from 1 to 15 years prior to a PDAC diagnosis (Mayo Clinic and PLCO cohorts), THBS2 and/or CA19-9 failed to discriminate cases from healthy controls at the AUC = 0.8 needed. We conclude that PDAC progression may be heterogeneous and for some individuals can be more rapid than generally appreciated. It is important that PDAC early-detection studies incorporate high-risk, prospective prediagnostic cohorts into discovery and validation studies. Prevention Relevance: A blood biomarker panel of THBS2 and CA19-9 detects early stages of pancreatic ductal adenocarcinoma at diagnosis, but not when tested across a population up to 1 year earlier. Our findings suggest serial sampling over time, using prospectively collected samples for biomarker discovery, and more frequent screening of high-risk individuals.
Optimization of Sampling for Monitoring Chemicals in the Food Supply Chain Using a Risk‐Based Approach: The Case of Aflatoxins and Dioxins in the Dutch Dairy Chain

Food safety monitoring faces the challenge of tackling multiple chemicals along the various stages of the food supply chain. Our study developed a methodology for optimizing sampling for monitoring multiple chemicals along the dairy supply chain. We used a mixed integer nonlinear programming approach to maximize the performance of the sampling in terms of reducing the risk of the potential disability adjusted life years (DALYs) in the population. Decision variables are the number of samples collected and analyzed at each stage of the food chain (feed mills, dairy farms, milk trucks, and dairy processing plants) for each chemical, given a predefined budget. The model was applied to the case of monitoring for aflatoxin B1/M1(AFB1/M1) and dioxins in a hypothetical Dutch dairy supply chain, and results were calculated for various contamination scenarios defined in terms of contamination fraction and concentrations. Considering various monitoring budgets for both chemicals, monitoring for AFB1/M1 showed to be more effective than for dioxins in most of the considered scenarios, because AFB1/M1 could result into more DALYs than dioxins when both chemicals are in same contamination fraction, and costs for analyzing one AFB1/M1 sample are lower than for one dioxins sample. The results suggest that relatively more resources be spent on monitoring AFB1/M1 when both chemicals’ contamination fractions are low; when both contamination fractions are higher, relatively more budget should be addressed to monitoring dioxins.
States of Pluripotency: Naïve and Primed Pluripotent Stem Cells

Pluripotent stem cells are classified into naïve and primed based on their growth characteristics in vitro and their potential to give rise to all somatic lineages and the germ line in chimeras. In this chapter, I describe the similarities and differences between the naïve and primed pluripotent states as exemplified by mouse embryonic stem cells (mESCs), mouse epiblast stem cells (mEpiSCs), human embryonic stem cells (hESCs), and human induced pluripotent stem cells (hiPSCs). I also review the efforts for derivation of naïve human pluripotent stem cells by manipulating culture conditions during reprogramming of somatic cells and attempts to revert primed hESCs to the naïve state. Understanding the requirements for induction and maintenance of the naïve pluripotent state will facilitate studies on early human embryonic development and understanding the mechanisms involved in X inactivation in vitro . In addition, the development of naïve hiPSCs will improve the efficiency of gene targeting for the purpose of modeling human diseases as well as for generating gene‐corrected autologous pluripotent stem cells for regenerative medicine.
Virtual screening and free energy estimation for identifying Mycobacterium tuberculosis flavoenzyme DprE1 inhibitors.

In Mycobacterium tuberculosis (MTB), the cell wall synthesis flavoenzyme decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) plays a crucial role in host pathogenesis, virulence, lethality and survival under stress. The emergence of different variants of drug resistant MTB are a major threat worldwide which essentially requires more effective new drug molecules with no major side effects. Here, we used structure based virtual screening of bioactive molecules from the ChEMBL database targeting DprE1, having bioactive 78,713 molecules known for anti-tuberculosis activity. An extensive molecular docking, binding affinity and pharmacokinetics profile filtering results in the selection four compounds, C5 (ChEMBL2441313), C6 (ChEMBL2338605), C8 (ChEMBL441373) and C10 (ChEMBL1607606) which may explore as potential drug candidates. The obtained results were validated with thirteen known DprE1 inhibitors. We further estimated the free-binding energy, solvation and entropy terms underlying the binding properties of DprE1-ligand interactions with the implication of MD simulation, MM/GBSA, MM/PBSA and MM/3D-RISM. Interestingly, we find that C6 shows the highest ΔG scores (-41.28 ± 3.51, -22.36 ± 3.17, -10.33 ± 5.70 kcal mol-1) in MM/GBSA, MM/PBSA and MM/3D-RISM assay, respectively. Whereas, the lowest ΔG scores (-35.31 ± 3.44, -13.67 ± 2.65, -3.40 ± 4.06 kcal mol-1) observed for CT319, the inhibitor co-crystallized with DprE1. Collectively, the results demonstrated that hit-molecules: C5, C6, C8 and C10 having better binding free energy and molecular affinity as compared to CT319. Thus, we proposed that selected compounds may be explored as lead molecules in MTB therapy.
Longitudinal and Transversal Elasticity of Natural and Artificial Materials for Musical Instrument Reeds

The reed is the primary component in single-reed woodwind instruments to generate the sound. The airflow of the player’s mouth is the energy source and the airflow is modulated by the reed. The oscillations of the reed control the airflow. Traditionally, instrument reeds are made out of natural cane (Arundo Donax), but in efforts to overcome variability problems, synthetic reeds have been introduced. Previous investigations mainly focused on natural cane reeds and direct elasticity measurements did not discriminate between elasticity moduli along different directions. In order to obtain the mechanical properties along the direction of the reed fibres and in the orthogonal direction separately, a three-point bending testing setup was developed, which accommodates the small samples that can be cut from an instrument reed. Static moduli of elasticity were acquired in both directions. Much higher ratios between longitudinal and transversal moduli were seen in the natural cane reed as compared to the artificial reeds. Wet natural reeds showed a strong decrease in moduli of elasticity as compared to dry reeds. Elasticity was significantly higher in artificial reeds. The force–displacement curves of the wet natural reed show hysteresis, whereas the artificial materials did not. In the cane reed, higher energy losses were found in the transversal direction compared to the longitudinal direction
Evolutionary systematics and biogeography of the arid habitat‐adapted rodent genus Gerbillus (Rodentia, Muridae): a mostly Plio‐Pleistocene African history

The systematics of the arid-adapted Old World Gerbillus rodent genus has always been challenging, with many different taxonomic arrangements proposed. Beyond such taxonomic aspects, the timing and geographical pattern of the evolutionary history of this group remains largely unknown. Based on mitochondrial (cytochrome b) and nuclear (interphotoreceptor retinoid-binding protein) sequences obtained from the specimens of 21 species, we conducted a phylogenetic analysis of the group, estimated the ages and putative ancestral ranges of its major lineages. Four major clades were clearly retrieved within Gerbillus, for which we propose a subgenus rank. We showed that the emergence of the genus dates back to the end of the Miocene, which corresponds to a period of aridification and C4 vegetation expansion in open habitats, while the four sublineages originated at the end of the Pliocene. Most subsequent diversification events occurred during the Pleistocene, a period characterized by recurrent climatic/environmental shifts with increasing aridification during the last two millions of years. Finally, we suggested that most of the Gerbillus evolutionary history took place in Africa. Only in a few instances did dispersal events from Africa to Asia give birth to extant Asian lineages, a pattern that contrasts with what has been found in many animal groups.
Teaching pursed-lip breathing through music: MELodica Orchestra for DYspnea (MELODY) trial rationale and protocol

ABSTRACT Background Patients with chronic obstructive pulmonary disease (COPD) commonly experience dyspnea, which may limit activities of daily living. Pursed-lip breathing improves dyspnea for COPD patients; however, access to pursed-lip breathing training is limited. Methods The proposed MELodica Orchestra for DYspnea (MELODY) study will be a single-site pilot study to assess the safety, feasibility, and efficacy of a music-based approach to teach pursed-lip breathing. Patients with COPD and moderate-severe dyspnea are randomized to intervention, education-control, or usual care control groups. Intervention patients meet twice weekly for eight weeks for melodica instruction, group music-making, and COPD education. Safety, feasibility, and efficacy is assessed qualitatively and quantitatively. Results This manuscript describes the rationale and methods of the MELODY pilot project. Conclusions If pilot data demonstrate efficacy, then a multi-site randomized control trial will be conducted to evaluate program effectiveness and implementation.
Using Apps in Formal Education to Improve Executive Functions in Preschoolers

The term Executive Functions (EFs) refers to a set of higher order cognitive processes that are critical for goal directed behaviour. They include inhibition (i.e., the ability to suppress task-irrelevant cognitive processing and ignore salient yet irrelevant features of the situation), shifting (i.e. the ability to switch between different operations or levels of processing), and updating (i.e. the ability to encode, hold and monitor incoming information in working memory, replacing information that is no longer relevant with new information). The most notable developmental change in children’s EFs occurs during the preschool period, and this is associable to and predictive of children’s general learning ability. For this reason, efforts to develop EFs in preschoolers is of vital importance. In recent years, only few studies have investigated the effect of EFs intervention on preschoolers, despite the potential preventive effect of early intervention on later developmental problems. A number of related solutions have been proposed over the years, including both paper-and-pencil activities and digital applications (e.g., software and videogames). However, few attempt have been made to integrate the many advantages of traditional, low-cost playful activities with the (often) powerful affordances of digital technologies. Hence, we propose just such a hybrid solution, with a set of mobile applications (apps) designed to foster EF development among early learners in education settings. We opted for such a solution as mobile apps have proved to be familiar, highly usable and well accepted among young children. At a more general level, this contribution seeks to provide useful input on the affordances and indicators that can help guide the effective choice of apps useful for developing EFs, and how these tools can be optimally introduced and employed in traditional teaching and learning programs.
Pimarane Diterpenoids from the Seeds of Caesalpinia minax as PTP1B Inhibitors and Insulin Sensitizers

Protein-tyrosine phosphatase 1B (PTP1B) has been considered as a promising target for treating insulin resistance. In searching for naturally occurring PTB1B antagonists, two new pimarane diterpenoids, named 2α-hydroxy-7-oxo-pimara-8(9),15-diene (1) and 19-hydroxy-2α-acetoxy-7-oxo-pimara-8(9),15-diene (2), were isolated from the seeds of Caesalpinia minax. Their structures were determined by extensive analysis of NMR and HR-ESIMS data, and their absolute configurations were determined by electronic circular dichroism (ECD) spectra. Compound 1 was disclosed as a competitive inhibitor of PTP1B with an IC50 (the half-maximal inhibitory concentration) value of 19.44 ± 2.39 µM and a Ki (inhibition constant) value of 13.69 ± 2.72 μM. Moreover, compound 1 dose-dependently promoted insulin-stimulated glucose uptake in C2C12 myotubes through activating insulin signaling pathway. Compound 1 might be further developed as an insulin sensitizer.
Colossal left main to right atrium fistula ligation complicated by left circumflex STEMI

Congenital left main (LM) coronary artery to right atrium fistulas with progression to aneurysm development are rare. Most patients remain asymptomatic, but for those with progressive symptoms, intervention is required. However, there are potential life‐threatening complications associated with surgical intervention. We present a case of an extremely rare markedly aneurysmal LM to right atrial fistula treated with surgical ligation complicated by inferolateral ST‐elevation myocardial infarction several days post‐operatively treated successfully using mechanical aspiration thrombectomy, a stent‐retriever, balloon angioplasty, and subsequent intravascular ultrasound‐guided percutaneous coronary intervention with drug‐eluting stent.
Evolutionary Analyses of Protein Interaction Networks

This chapter introduces evolutionary analyses of protein interaction networks and of proteins as components of the networks. The authors show relationships between proteins in the networks and their evolutionary rates. For understanding protein-protein interaction (PPI) divergence, duplicated genes are often compared because they are derived from a common ancestral gene. In order to reveal evolutionary mechanisms acting on the interactome it is necessary to compare PPIs across species. Investigation of co-localization of interacting genes in a genome shows that PPIs have an important role in the maintenance of a physical link between neighboring genes. The purpose of this chapter is to introduce methodologies for analyzing PPI data and to describe molecular evolution and comparative genomics insights gained from such studies.
Single-Image Visibility Restoration: A Machine Learning Approach and Its 4K-Capable Hardware Accelerator

In recent years, machine vision algorithms have played an influential role as core technologies in several practical applications, such as surveillance, autonomous driving, and object recognition/localization. However, as almost all such algorithms are applicable to clear weather conditions, their performance is severely affected by any atmospheric turbidity. Several image visibility restoration algorithms have been proposed to address this issue, and they have proven to be a highly efficient solution. This paper proposes a novel method to recover clear images from degraded ones. To this end, the proposed algorithm uses a supervised machine learning-based technique to estimate the pixel-wise extinction coefficients of the transmission medium and a novel compensation scheme to rectify the post-dehazing false enlargement of white objects. Also, a corresponding hardware accelerator implemented on a Field Programmable Gate Array chip is in order for facilitating real-time processing, a critical requirement of practical camera-based systems. Experimental results on both synthetic and real image datasets verified the proposed method’s superiority over existing benchmark approaches. Furthermore, the hardware synthesis results revealed that the accelerator exhibits a processing rate of nearly 271.67 Mpixel/s, enabling it to process 4K videos at 30.7 frames per second in real time.
Using a Human Papillomavirus Model to Study DNA Replication and Repair of Wild Type and Damaged DNA Templates in Mammalian Cells

Human papillomaviruses have 8kbp DNA episomal genomes that replicate autonomously from host DNA. During initial infection, the virus increases its copy number to 20–50 copies per cell, causing torsional stress on the replicating DNA. This activates the DNA damage response (DDR) and HPV replicates its genome, at least in part, using homologous recombination. An active DDR is on throughout the HPV life cycle. Two viral proteins are required for replication of the viral genome; E2 binds to 12bp palindromic sequences around the A/T rich origin of replication and recruits the viral helicase E1 via a protein–protein interaction. E1 forms a di-hexameric complex that replicates the viral genome in association with host factors. Transient replication assays following transfection with E1–E2 expression plasmids, along with an origin containing plasmid, allow monitoring of E1-E2 replication activity. Incorporating a bacterial lacZ gene into the origin plasmid allows for the determination of replication fidelity. Here we describe how we exploited this system to investigate replication and repair in mammalian cells, including using damaged DNA templates. We propose that this system has the potential to enhance the understanding of cellular components involved in DNA replication and repair.
Prognostic Impact of let-7e MicroRNA and Its Target Genes in Localized High-Risk Intestinal GIST: A Spanish Group for Research on Sarcoma (GEIS) Study

Simple Summary For intestinal localized high-risk gastrointestinal stromal tumors (GIST) patients’ new molecular biomarkers are urgently needed for a more accurate prognosis. In our study, miRNA profiling analyses was planned to explore new molecular biomarkers with potential prognostic role in this clinical context. Our data, revealed that 39 microRNAs (miRNAs) were significantly deregulated when comparing patients with disease relapsed versus non-relapsed cases. The underexpression of a specific miRNA let-7e and the overexpression of 4 of its target genes (ACVR1B, CASP3, COL3A1 and COL5A2) correlated significantly with worse relapse-free survival. Overall, our results suggest that miRNA profiling is a potential molecular tool useful for a more accurate prognosis for intestinal localized high-risk GIST patients. Abstract MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level, and they have been described as being associated with tumor prognosis. Here, miRNA profiling was planned to explore new molecular prognostic biomarkers in localized intestinal high-risk GIST. Paraffin tumor blocks of 14 and 86 patients were used in the discovery and expansion sets, respectively. GeneChip miRNA v3.0 was employed to identify the miRNAs differentially expressed between relapsed and non-relapsed patient samples, which were validated in the expansion set, by qRT-PCR. RT2 Profiler PCR Array was used for the screening of let-7e targets. Expression levels were correlated with relapse-free survival and overall survival. In the discovery set, 39 miRNAs were significantly deregulated, let-7e and miR-550 being the most underexpressed and overexpressed miRNAs in the relapsed group, respectively. In the expansion set, the underexpression of let-7e or the overexpression of 4 of its target genes (ACVR1B, CASP3, COL3A1, and COL5A2) were statistically associated with worse relapse-free survival. The expression of let-7e and 4 of its target genes are potential prognostic biomarkers in high-risk localized intestinal GIST. The expression of these genes is a potential molecular tool useful for a more accurate prognosis in this subset of GIST patients.
Approaches for Reactive Oxygen Species and Oxidative Stress Quantification in Epilepsy

Oxidative stress (OS) and excessive reactive oxygen species (ROS) production have been implicated in many neurological pathologies, including acute seizures and epilepsy. Seizure-induced damage has been demonstrated both in vitro and in several in vivo seizure and epilepsy models by direct determination of ROS, and by measuring indirect markers of OS. In this manuscript, we review the current reliable methods for quantifying ROS-related and OS-related markers in pre-clinical and clinical epilepsy studies. We first provide pieces of evidence for the involvement of different sources of ROS in epilepsy. We then discuss general methods and assays used for the ROS measurements, mainly superoxide anion, hydrogen peroxide, peroxynitrite, and hydroxyl radical in in vitro and in vivo studies. In addition, we discuss the role of these ROS and markers of oxidative injury in acute seizures and epilepsy pre-clinical studies. The indirect detection of secondary products of ROS such as measurements of DNA damage, lipid peroxidation, and protein oxidation will also be discussed. This review also discusses reliable methods for the assessment of ROS, OS markers, and their by-products in epilepsy clinical studies.