Miracle-dz/UniFAR-FTUs huggingface dataset:
Challenges to Bringing Personalized Medicine to a Low-Resource Setting in Peru

We provide an overview of the challenges that low-resource setting cities are facing, including a lack of global implementation of cancer screening programs, accurate data and statistics that may aid the health authorities and guide future public health activities, as well as reorient strategies, interventions and budgets to promote lifestyles that help prevent disease. Current cancer care does not fully reflect ethnic, cultural, environmental and resource differences. Herein, we described a snapshot of the cancer mortality and morbidity from a hospital that cares a rural and low-income population from Peru, called Chimbote (316,966 inhabitants) and showed the limitation of access to oncological care and genetic services. The city is located in the region of Ancash, which is a department of Northern Peru. Of note, we identified a greater proportion of cancer cases than previously described, with a young age of onset and differential profile of the most frequent cancers. With the emergence of increasingly effective interventions, it becomes paramount that populations living in resource-limited settings have access to cancer services and participate in genetics and genomic research.
Exploring the binding of resveratrol to an oncogene promoter DNA sequence d(CCAATTGG)2 through multispectroscopic, nuclear magnetic resonance and molecular dynamics studies

We report the interaction of resveratrol with an octamer DNA sequence d(CCAATTGG)2, present in the promoter region of many oncogenes, using a combination of absorption, fluorescence, calorimetric and nuclear magnetic resonance techniques to probe the binding. Resveratrol binds to the duplex sequence with a binding constant 2.20×106 M−1 in absorption studies. A ligandduplex stoichiometry of 2.2:1 was obtained with binding constant varying from 109 to 106M−1 with the concentration of DNA varied in fluorescence titration measurements. Spectral changes indicated external binding of resveratrol to duplex DNA. Circular dichroism data displayed minimal variation suggesting external binding. Melting temperatures of DNA and its 1:1 complex showed a difference of approximately 2.25°C, which supports the external binding. Nuclear magnetic resonance data showed resveratrol binds to the minor groove region near the AT basepair from the nuclear Overhauser effect spectroscopic cross peaks. Distance restrained molecular dynamics was employed in explicit solvent condition to obtain the lowest energy structure. The complex was stable and retained the B-DNA conformation. Findings in this study identify resveratrol as a minor groove binder to the AT region of DNA and pave the way for exploring resveratrol and its analogues as promising anticancer/antibacterial drug.
Antitrypanosomal and Antileishmanial Activity of Chalcones and Flavanones from Polygonum salicifolium

Trypanosomiasis and leishmaniasis are a group of neglected parasitic diseases caused by several species of parasites belonging to the family Trypansomatida. The present study investigated the antitrypanosomal and antileishmanial activity of chalcones and flavanones from Polygonum salicifolium, which grows in the wetlands of Iraq. The phytochemical evaluation of the plant yielded two chalcones, 2′,4′-dimethoxy-6′-hydroxychalcone and 2′,5′-dimethoxy-4′,6′-dihydroxychalcone, and two flavanones, 5,7-dimethoxyflavanone and 5,8-dimethoxy-7-hydroxyflavanone. The chalcones showed a good antitrypanosomal and antileishmanial activity while the flavanones were inactive. The EC50 values for 2′,4′-dimethoxy-6′-hydroxychalcone against Trypanosoma brucei brucei (0.5 μg/mL), T. congolense (2.5 μg/mL), and Leishmania mexicana (5.2 μg/mL) indicated it was the most active of the compounds. None of the compounds displayed any toxicity against a human cell line, even at 100 µg/mL, or cross-resistance with first line clinical trypanocides, such as diamidines and melaminophenyl arsenicals. Taken together, our study provides significant data in relation to the activity of chalcones and flavanones from P. salicifolium against both parasites in vitro. Further future research is suggested in order to investigate the mode of action of the extracted chalcones against the parasites.
Optimization of Cutinase Purification using a Hydrophobic Interaction Membrane Chromatographic Process by Response Surface Methodology

Several methods have been demonstrated in the recovery and purification of cutinase; however, hydrophobic interaction membrane chromatography (HIMC) has yet to be implemented for this purpose. In this study, two factors, that is, buffer pH and ammonium sulphate concentration for HIMC operation, were optimized using response surface methodology (RSM), aiming to obtain the highest cutinase purification factor and recovery possible. The experimental design used was a central composite design (CCD) comprised of 13 experimental runs. The analysis of variance (ANOVA) indicated that a quadratic model best represented the system. Based on the R 2 values, it can be concluded that around 90% of the variability in the system can be explained by the fitted models. The optimized HIMC conditions were buffer pH 6.0 and 1.3 M ammonium sulphate, which was expected to provide 27-fold cutinase purification factor and 85% recovery. However, the actual values deviated from the predicted values with 13% and 18% error, respectively. The statistical analysis showed that only the ammonium sulphate concentration had a great influence on cutinase purification factor. Meanwhile, for cutinase recovery, both parameters were important in determining the optimal condition for cutinase adsorption and desorption to the chromatographic media.
A Framework to Guide the Implementation of Best Practice Clinical Learning Environments in Community General Practice: Australia

Clinical education/training is increasingly being expanded to community general practice settings (primary care clinics led by doctors). This plays an important role in developing a skilled “primary-care ready” workforce. However, there is limited information to guide the implementation of high-quality learning environments suitable for the range of general practices and clinical learners they oversee. We aimed to develop a consensus-based framework to address this. A co-design participatory action research method involved working with stakeholders to agree a project plan, collect and interpret data and endorse a final framework. As a starting point, an initial draft framework was adapted from an existing framework, the Best Practice Clinical Learning Environment (BPCLE) Framework. We gathered feedback about this from a national GP Supervisor Liaison Officer Network (SLON) (experienced GP clinical supervisors) during a 90-minute face-to-face focus group. They rated their agreement with the relevance of objectives and elements, advising on clear terminology and rationale for including/excluding various components. The resulting framework was refined and re-tested with the SLON and wider GP educational stakeholders until a final graphically designed version was endorsed. The resulting “GP Clinical Learning Environment” (GPCLE) Framework is applicable for planning and benchmarking best practice learning environments in general practice.
Gauging Gait Disorders with a Method Inspired by Motor Control Theories: A Pilot Study in Friedreich’s Ataxia

To date, it has been challenging for clinicians and researchers alike to use the multiple outcome measures available to create a meaningful clinical picture and perform effective longitudinal follow-up. It has been found that instrumented gait analysis can provide information associated with a patient’s performance and help to remedy the shortcomings of the currently available outcome measures. The goal of this methodological article is to set the background and justify a new outcome measure inspired by the motor control theories to analyze gait using spatiotemporal parameters. The method is applied in a population of individuals living with Friedreich’s ataxia (FRDA), a neurodegenerative disease. The sample population consisted of 19 subjects, 11 to 65 years of age with FRDA, who either ambulated independently, with a cane, or with a rollator. Three scores based on the distance from healthy normative data were used: Organization Score, Variability Score, and an overall measurement, the Global Ambulation Score. The scores were then compared to the Scale for Assessment and Rating of Ataxia (SARA) Gait Score (SARA-GS), a clinical scale currently being used for gait analysis in FRDA. Organization Scores demonstrated a longitudinal deterioration in the gait characteristics from independent ambulators to those who ambulated with a rollator. Variability Scores mostly reflected dynamic instability, which became greater as the requirement of an ambulation aid or the switch from a cane to a rollator was imminent. The global value given by the Global Ambulation Score, which takes into consideration both the Organization Score, the Variability Score, and the level of assistive device, demonstrated a logarithmic relationship with the SARA-GS. Overall, these results highlight that both components introduced should be analyzed concurrently and suggest that the Global Ambulation Score may be a valuable outcome measure for longitudinal disease progression.
Protective effect of Zataria multiflora Boiss. and its main compound, rosmarinic acid, against malathion induced oxidative stress and apoptosis in HepG2 cells

Abstract Malathion (MT) is one of the most widely used organophosphorus insecticides which induces toxicity through oxidative stress induction, free radical production and acetylcholinesterase inhibition. In this work, HepG2 cells were used to determine the effect of Zataria multiflora methanolic extract (MEZM) and rosmarinic acid (RA) on MT-induced cytotoxicity, oxidative stress, and apoptosis. Total phenolic content (TPC) and total flavonoid content (TFC) were determined and plant was further standardized based on RA content using HPLC method. The cultured HepG2 cells were pretreated with MEZM (1 μg/ml) and RA (0.1 μg/ml) for 4 h and exposed to MT (100 μM). Cell viability, oxidative stress biomarkers, ROS production, and cell death were examined after 24 h. The amount of RA was determined 73.48 mg/g dried extract. IC50 values of MEZM and MT were 368.56 μg/ml and 99.43 μM, respectively. Pretreatment with MEZM and RA decreased the cytotoxicity, oxidative stress, and cell percentage in the late apoptosis and necrosis stages induced by MT. There was no significant difference between MEZM and RA effects. The present study showed the significant protective effects of MEZM against toxicity induced by MT in hepatocytes which can be attributed to the plant antioxidant constituents including RA.
Deep learning‐enabled imaging flow cytometry for high‐speed Cryptosporidium and Giardia detection

Imaging flow cytometry has become a popular technology for bioparticle image analysis because of its capability of capturing thousands of images per second. Nevertheless, the vast number of images generated by imaging flow cytometry imposes great challenges for data analysis especially when the species have similar morphologies. In this work, we report a deep learning‐enabled high‐throughput system for predicting Cryptosporidium and Giardia in drinking water. This system combines imaging flow cytometry and an efficient artificial neural network called MCellNet, which achieves a classification accuracy >99.6%. The system can detect Cryptosporidium and Giardia with a sensitivity of 97.37% and a specificity of 99.95%. The high‐speed analysis reaches 346 frames per second, outperforming the state‐of‐the‐art deep learning algorithm MobileNetV2 in speed (251 frames per second) with a comparable classification accuracy. The reported system empowers rapid, accurate, and high throughput bioparticle detection in clinical diagnostics, environmental monitoring and other potential biosensing applications.
Identification of circular RNAs as novel biomarkers and potentially functional competing endogenous RNA network for myelodysplastic syndrome patients

Circular RNAs (circRNAs) have been identified to exert vital biological functions and can be used as new biomarkers in a number of tumors. However, little is known about the functions of circRNAs in myelodysplastic syndrome (MDS). Here, we aimed to investigate circRNA expression profiles and to investigate the functional and clinical value of circRNAs in MDS. Differential expression of circRNAs between MDS and control subjects was analyzed using circRNA arrays, in which we identified 145 upregulated circRNAs and 224 downregulated circRNAs. Validated by real‐time quantitative PCR between 100 MDS patients and 20 controls, three upregulated (hsa_circRNA_100352, hsa_circRNA_104056, and hsa_circRNA_104634) and three downregulated (hsa_circRNA_103846, hsa_circRNA_102817, and hsa_circRNA_102526) circRNAs matched the arrays. The receiver operating characteristic curve analysis of these circRNAs showed that the area under the curve was 0.7266, 0.8676, 0.7349, 0.7091, 0.8806, and 0.7472, respectively. Kaplan‐Meier survival analysis showed that only hsa_circRNA_100352, hsa_circRNA_104056, and hsa_circRNA_102817 were significantly associated with overall survival. Furthermore, we generated a competing endogenous RNA network focused on hsa_circRNA_100352, hsa_circRNA_104056, and hsa_circRNA_102817. Analyses using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes showed that the three circRNAs were linked with some important cancer‐related functions and pathways.
Systematic Proteome and Lysine Succinylome Analysis Reveals Enhanced Cell Migration by Hyposuccinylation in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with poor therapeutic outcomes. However, the alterations in proteins and posttranslational modifications (PTMs) leading to the pathogenesis of ESCC remain unclear. Here, we provide the comprehensive characterization of the proteome, phosphorylome, lysine acetylome, and succinylome for ESCC and matched control cells using quantitative proteomic approach. We identify abnormal protein and PTM pathways, including significantly downregulated lysine succinylation sites in cancer cells. Focusing on hyposuccinylation, we reveal that this altered PTM was enriched on enzymes of metabolic pathways inextricably linked with cancer metabolism. Importantly, ESCC malignant behaviors such as cell migration are inhibited once the level of succinylation was restored in vitro or in vivo. This effect was further verified by mutations to disrupt succinylation sites in candidate proteins. Meanwhile, we found that succinylation has a negative regulatory effect on histone methylation to promote cancer migration. Finally, hyposuccinylation is confirmed in primary ESCC specimens. Our findings together demonstrate that lysine succinylation may alter ESCC metabolism and migration, providing new insights into the functional significance of PTM in cancer biology.
Endothelial Nitric Oxide Synthase Knockdown in Human Stem Cells Impacts Mitochondrial Biogenesis and Adipogenesis: Live-Cell Real-Time Fluorescence Imaging

We carried out live-cell real-time fluorescence imaging to follow the effects of genetic (siRNA) knockdown (KD) of endothelial nitric oxide synthase (eNOS) on mitochondrial biogenesis and adipogenesis in human mesenchymal stem cells (hMSCs). We report here that eNOS KD in hMSCs blocks mitochondrial biogenesis and adipogenesis. The transfer of mitochondria from normal hMSCs to eNOS-deficient hMSCs restores adipogenesis. Furthermore, cell-free mitochondria purified from normal hMSCs also restores adipogenesis in eNOS-deficient cells. Thus, eNOS and NO signaling are essential for mitochondrial biogenesis, and mitochondrial activity is indispensable for adipogenesis in hMSC differentiation. We mapped the path and identified the mechanisms of mitochondrial transfer. We captured real-time images of differentiated mature adipocytes in mitosis and replication. These results reveal that human stem cell-differentiated fat cells are capable of replication. This new finding offers novel insights into our understanding of fat cell expansion and the development of obesity. Real-time imaging in live cells allows synchronized investigation of mitochondrial biogenesis and adipogenesis in stem cell differentiation without reducing living cells to nonliving samples for functional analysis. Live-cell real-time imaging can thus be a faithful and immediate tool for molecular diagnostic medicine. Furthermore, our results suggest that mitochondrial remodeling can be a useful approach in treating adiposity, diabetes, and abnormalities in energy metabolism and vascular signaling.
Activation of GABAergic Neurons in the Rostromedial Tegmental Nucleus and Other Brainstem Regions Promotes Sedation and Facilitates Sevoflurane Anesthesia in Mice

Many general anesthetics potentiate gamma-aminobutyric acid (GABA) A receptors but their neuroanatomic sites of action are less clear. GABAergic neurons in the rostromedial tegmental nucleus (RMTg) send inhibitory projections to multiple arousal-promoting nuclei, but the role of these neurons in modulating consciousness is unknown. In this study, designer receptors exclusively activated by designer drugs (DREADDs) were targeted to RMTg GABAergic neurons of Vgat-ires-Cre mice. DREADDs expression was found in the RMTg and other brainstem regions. Activation of these neurons decreased movement and exploratory behavior, impaired motor coordination, induced electroencephalogram (EEG) oscillations resembling nonrapid eye movement (NREM) sleep without loss of righting and reduced the dose requirement for sevoflurane-induced unconsciousness. These results suggest that GABAergic neurons in the RMTg and other brainstem regions promote sedation and facilitate sevoflurane-induced unconsciousness.
Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life

Yolk sac erythropoiesis is not replaced by hematopoietic stem cell–derived progeny up until birth. Yolk sac–derived erythroid progenitors require 10-fold lower concentrations of erythropoietin for differentiation, which confers a competitive advantage over progenitors of hematopoietic stem cell origin.
Forced swim stressor: Trends in usage and mechanistic consideration

The acquired immobility response during the “forced swim test (FST)” is not a rodent model of depression, but the test has some validity in predicting a compound's antidepressant potential. Nevertheless, 60% of the about 600 papers that were published annually the past 2 years label the rodent's immobility response as depression‐like behaviour, but the relative contribution per country is changing. When the Editors‐in‐Chief of 5 journals publishing most FST papers were asked for their point of view on labelling immobility as depression‐like behaviour and despair, they responded that they primarily rely on the reviewers regarding scientific merit of the submission. One Editor informs authors of the recent NIMH notice (https://grants.nih.gov/grants/guide/notice‐files/NOT‐MH‐19‐053.html) which encourages investigators to use animal models “for” addressing neurobiological questions rather than as model “of” specific mental disorders. The neurobiological questions raised by use of the FST fall in two categories. First, research on the role of endocrine and metabolic factors, with roots in the 1980s, and with focus on the bottom‐up action of glucocorticoids on circuits processing salient information, executive control and memory consolidation. Second, recent findings using novel technological and computational advances that have allowed great progress in charting top‐down control in the switch from active to passive coping with the inescapable stressor executed by neuronal ensembles of the medial prefrontal cortex via the peri‐aquaductal grey. It is expected that combining neural top‐down and endocrine bottom‐up approaches will provide new insights in the role of stress‐coping and adaptation in pathogenesis of mental disorders.
Helminth-derived cystatins: the immunomodulatory properties of an Ascaris lumbricoides cystatin

Abstract Abstract Helminth infections such as ascariasis elicit a type 2 immune response resembling that involved in allergic inflammation, but differing to allergy, they are also accompanied with strong immunomodulation. This has stimulated an increasing number of investigations, not only to better understand the mechanisms of allergy and helminth immunity but to find parasite-derived anti-inflammatory products that could improve the current treatments of chronic non-communicable inflammatory diseases such as asthma. A great number of helminth-derived immunomodulators have been discovered and some of them extensively analysed, showing their potential use as anti-inflammatory drugs in clinical settings. Since Ascaris lumbricoides is one of the most successful parasites, several groups have focused on the immunomodulatory properties of this helminth. As a result, several excretory/secretory components and purified molecules have been analysed, revealing interesting anti-inflammatory activities potentially useful as therapeutic tools. One of these molecules is A. lumbricoides cystatin, whose genomic, cellular, molecular, and immunomodulatory properties are described in this review.
Defect Filling Method of Sensor Encapsulation Based on Micro-Nano Composite Structure with Parylene Coating

The demand for waterproofing of polymer (parylene) coating encapsulation has increased in a wide variety of applications, especially in the waterproof protection of electronic devices. However, parylene coatings often produce pinholes and cracks, which will reduce the waterproof effect as a protective barrier. This characteristic has a more significant influence on sensors and actuators with movable parts. Thus, a defect filling method of micro-nano composite structure is proposed to improve the waterproof ability of parylene coatings. The defect filling method is composed of a nano layer of Al2O3 molecules and a micro layer of parylene polymer. Based on the diffusion mechanism of water molecules in the polymer membrane, defects on the surface of polymer encapsulation will be filled and decomposed into smaller areas by Al2O3 nanoparticles to delay or hinder the penetration of water molecules. Accordingly, the dense Al2O3 nanoparticles are utilized to fill and repair the surface of the organic polymer by low-rate atomic layer deposition. This paper takes the pressure sensor as an example to carry out the corresponding research. Experimental results show that the proposed method is very effective and the encapsulated sensors work properly in a saline solution after a period of time equivalent to 153.9 days in body temperature, maintaining their accuracy and precision of 2 mmHg. Moreover, the sensors could improve accuracy by about 43% after the proposed encapsulation. Therefore, the water molecule anti-permeability encapsulation would have broad application prospects in micro/nano-device protection.