Miracle-dz/UniFAR-FTUs huggingface dataset:
A Functional 12T-Insertion Polymorphism in the ATP1A1 Promoter Confers Decreased Susceptibility to Hypertension in a Male Sardinian Population

Identification of susceptibility genes for essential hypertension in humans has been a challenge due to its multifactorial pathogenesis complicated by gene-gene and gene-environment interactions, developmental programing and sex specific differences. These concurrent features make identification of causal hypertension susceptibility genes with a single approach difficult, thus requiring multiple lines of evidence involving genetic, biochemical and biological experimentation to establish causal functional mutations. Here we report experimental evidence encompassing genetic, biochemical and in vivo modeling that altogether support ATP1A1 as a hypertension susceptibility gene in males in Sardinia, Italy. ATP1A1 encodes the α1Na,K-ATPase isoform, the sole sodium pump in vascular endothelial and renal tubular epithelial cells. DNA-sequencing detected a 12-nucleotide long thymidine (12T) insertion(ins)/deletion(del) polymorphism within a poly-T sequence (38T vs 26T) in the ATP1A1 5’-regulatory region associated with hypertension in a male Sardinian population. The 12T-insertion allele confers decreased susceptibility to hypertension (P = 0.035; OR = 0.50 [0.28–0.93]) accounting for 12.1 mmHg decrease in systolic BP (P = 0.02) and 6.6 mmHg in diastolic BP (P = 0.046). The ATP1A1 promoter containing the 12T-insertion exhibited decreased transcriptional activity in in vitro reporter-assay systems, indicating decreased α1Na,K-ATPase expression with the 12T-insertion, compared with the 12T-deletion ATP1A1 promoter. To test the effects of decreased α1Na,K-ATPase expression on blood pressure, we measured blood pressure by radiotelemetry in three month-old, highly inbred heterozygous knockout ATP1A1+/− male mice with resultant 58% reduction in ATP1A1 protein levels. Male ATP1A1+/− mice showed significantly lower blood pressure (P < 0.03) than age-matched male wild-type littermate controls. Concordantly, lower ATP1A1 expression is expected to lower Na-reabsorption in the kidney thereby decreasing sodium-associated risk for hypertension and sodium-induced endothelial stiffness and dysfunction. Altogether, data support ATP1A1 as a hypertension susceptibility gene in a male Sardinian population, and mandate further investigation of its involvement in hypertension in the general population.
Is restlessness best understood as a process? Reflecting on four boys’ restlessness during music therapy in kindergarten

ABSTRACT ADHD can be considered an internationally recognized framework for understanding children’s restlessness. In this context, children’s restlessness is understood as a symptom of neurodevelopmental disorder. However, there are other possible understandings of children’s restlessness. In this article, we explore four boys’ collaborative and creative process as it is described and understood by three adults. The process is framed by a community music therapy project in a Norwegian kindergarten, and we describe four interrelated phases of this process: Exploring musical vitality and cooperation, Consolidating positions, Performing together, and Discovering ripple effects. We discuss these results in relation to seven qualities central to a community music therapy approach: participation, resource orientation, ecology, performance, activism, reflexivity and ethics. We argue that in contrast to a diagnostic approach that entails a focus on individual problems, a community music therapy approach can shed light on adult and systemic contributions to children’s restlessness.
An Ecosystem-Based Approach to Assess the Status of a Mediterranean Ecosystem, the Posidonia oceanica Seagrass Meadow

Biotic indices, which reflect the quality of the environment, are widely used in the marine realm. Sometimes, key species or ecosystem engineers are selected for this purpose. This is the case of the Mediterranean seagrass Posidonia oceanica, widely used as a biological quality element in the context of the European Union Water Framework Directive (WFD). The good quality of a water body and the apparent health of a species, whether or not an ecosystem engineer such as P. oceanica, is not always indicative of the good structure and functioning of the whole ecosystem. A key point of the recent Marine Strategy Framework Directive (MSFD) is the ecosystem-based approach. Here, on the basis of a simplified conceptual model of the P. oceanica ecosystem, we have proposed an ecosystem-based index of the quality of its functioning, compliant with the MSFD requirements. This index (EBQI) is based upon a set of representative functional compartments, the weighting of these compartments and the assessment of the quality of each compartment by comparison of a supposed baseline. The index well discriminated 17 sites in the north-western Mediterranean (French Riviera, Provence, Corsica, Catalonia and Balearic Islands) covering a wide range of human pressure levels. The strong points of the EBQI are that it is easy to implement, non-destructive, relatively robust, according to the selection of the compartments and to their weighting, and associated with confidence indices that indicate possible weakness and biases and therefore the need for further field data acquisition.
Three-Dimensional Mid-Air Acoustic Manipulation by Ultrasonic Phased Arrays

The essence of levitation technology is the countervailing of gravity. It is known that an ultrasound standing wave is capable of suspending small particles at its sound pressure nodes. The acoustic axis of the ultrasound beam in conventional studies was parallel to the gravitational force, and the levitated objects were manipulated along the fixed axis (i.e. one-dimensionally) by controlling the phases or frequencies of bolted Langevin-type transducers. In the present study, we considered extended acoustic manipulation whereby millimetre-sized particles were levitated and moved three-dimensionally by localised ultrasonic standing waves, which were generated by ultrasonic phased arrays. Our manipulation system has two original features. One is the direction of the ultrasound beam, which is arbitrary because the force acting toward its centre is also utilised. The other is the manipulation principle by which a localised standing wave is generated at an arbitrary position and moved three-dimensionally by opposed and ultrasonic phased arrays. We experimentally confirmed that expanded-polystyrene particles of 0.6 mm, 1 mm, and 2 mm in diameter could be manipulated by our proposed method.
CAR T cell therapy for multiple myeloma: where are we now and where are we headed?

Abstract While recent progress has been made in the management of multiple myeloma, it remains a highly fatal malignancy especially among patients with relapsed-refractory disease. Immunotherapy with adoptive T cells targeting myeloma-associated antigens are at various stages of development and have brought about a new hope for cure. This is a review on the emerging field of adoptively transferred engineered T cell based approaches, with an in-depth focus on chimeric antigen receptors (CAR) targeting multiple myeloma. The recent results from CAR T cells targeting B cell maturation antigen are encouraging but eventual resistance to the CAR T cell therapies remain problematic. With newer approaches in therapies for multiple myeloma, the role of transplantation is evolved to form a platform for T cell therapies.
Peripartum cardiomyopathy – from pathogenesis to treatment

At the beginning of the 21st century, cardiac diseases remain the main cause of death in pregnant women in many countries. One of the most common cardiovascular diseases associated with pregnancy is peripartum cardiomyopathy (PPCM) [1]. The etiology of this disease is unknown, but factors such as infection, inflammation and autoimmunological processes may underlie the pathogenesis of its development [2]. The symptoms of this pathology are typical for a left ventricle (LV) cardiac insufficiency, however, due to the specific physiological condition during pregnancy and peripartum, its first signs may be masked by complaints typical for normal pregnancy [1]. Furthermore, its clinical course may differ, one course being cardiac failure, with abrupt deterioration of the patient’s condition and mortality rate reaching up to 28% and another course being normalization of cardiac insufficiency parameters in 23% of the patients after 6 months [3–5]. PPCM is a rare condition, however, it represents a serious risk of death and therefore, it is crucial to have current knowledge of it to enable its differentiation and treatment. In this publication, we present the most recent reports on the etiopathogenesis, diagnosis and treatment of patients with PPCM.
Proliferation-Stimulating Effect of Colony Stimulating Factor 2 on Porcine Trophectoderm Cells Is Mediated by Activation of Phosphatidylinositol 3-Kinase and Extracellular Signal-Regulated Kinase 1/2 Mitogen-Activated Protein Kinase

Colony-stimulating factor 2 (CSF2), also known as granulocyte macrophage colony-stimulating factor, facilitates mammalian embryonic development and implantation. However, biological functions and regulatory mechanisms of action of porcine endometrial CSF2 in peri-implantation events have not been elucidated. The aim of present study was to determine changes in cellular activities induced by CSFs and to access CSF2-induced intracellular signaling in porcine primary trophectoderm (pTr) cells. Differences in expression of CSF2 mRNA in endometrium from cyclic and pregnant gilts were evaluated. Endometrial CSF2 mRNA expression increases during the peri-implantation period, Days 10 to 14 of pregnancy, as compared to the estrous cycle. pTr cells obtained in Day 12 of pregnancy were cultured in the presence or absence of CSF2 (20 ng/ml) and LY294002 (20 µM), U0126 (20 µM), rapamycin (20 nM), and SB203580 (20 µM). CSF2 in pTr cell culture medium at 20 ng/ml significantly induced phosphorylation of AKT1, ERK1/2, MTOR, p70RSK and RPS6 protein, but not STAT3 protein. Also, the PI3K specific inhibitor (LY294002) abolished CSF2-induced increases in p-ERK1/2 and p-MTOR proteins, as well as CSF2-induced phosphorylation of AKT1. Changes in proliferation and migration of pTr cells in response to CSF2 were examined in dose- and time-response experiments. CSF2 significantly stimulated pTr cell proliferation and, U0126, rapamycin and LY294002 blocked this CSF2-induced proliferation of pTr cells. Collectively, during the peri-implantation phase of pregnancy in pigs, endometrial CSF2 stimulates proliferation of trophectoderm cells by activation of the PI3K-and ERK1/2 MAPK-dependent MTOR signal transduction cascades.
Combinatorial Assembly of Small Molecules into Bivalent Antagonists of TrkC or TrkA Receptors

A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3), nerve growth factor (NGF), or brain-derived neurotrophic factor (BDNF). These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f) are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b) are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.
The Role of the Carbohydrate Recognition Domain of Placental Protein 13 (PP13) in Pregnancy Evaluated with Recombinant PP13 and the DelT221 PP13 Variant

Introduction Placental protein 13 (PP13), a placenta specific protein, is reduced in the first trimester of pregnancy in women who subsequently develop preeclampsia. A naturally occurring PP13 deletion of thymidine at position 221 (DelT221 or truncated variant) is associated with increased frequency of severe preeclampsia. In this study we compared the full length (wildtype) PP13 and the truncated variant. Methods Full length PP13 or its DelT221 variant were cloned, expressed and purified from E-Coli. Both variants were administrated into pregnant rats at day 8 of pregnancy for slow release (>5 days) through osmotic pumps and rat blood pressure was measured. Animals were sacrificed at day 15 or day 21 and their utero-placental vasculature was examined. Results The DelT221 variant (11 kDA) lacked exon 4 and a part of exon 3, and is short of 2 amino acids involved in the carbohydrate (CRD) binding of the wildtype (18 kDA). Unlike the wildtype PP13, purification of DelT221 variant required special refolding. PP13 specific poly- clonal antibodies recognized both PP13 and DelT221 but PP13 specific monoclonal antibodies recognized only the wildtype, indicating the loss of major epitopes. Wildtype PP13 mRNA and its respective proteins were both lower in PE patients compared to normal pregnancies. The DelT221 mutant was not found in a large Caucasian cohort. Pregnant rats exposed to wildtype or DelT221 PP13 variants had significantly lower blood pressure compared to control. The wildtype but not the DelT221 mutant caused extensive vein expansion. Conclusion This study revealed the importance of PP13 in regulating blood pressure and expanding the utero-placental vasculature in pregnant rats. PP13 mutant lacking amino acids of the PP13 CRD domain fails to cause vein expansion but did reduce blood pressure. The study provides a basis for replenishing patients at risk for preeclampsia by the full length but not the truncated PP13.
Human Wharton’s Jelly Mesenchymal Stem Cells Plasticity Augments Scar-Free Skin Wound Healing with Hair Growth

Human mesenchymal stem cells (MSCs) are a promising candidate for cell-based transplantation and regenerative medicine therapies. Thus in the present study Wharton’s Jelly Mesenchymal Stem Cells (WJ-MSCs) have been derived from extra embryonic umbilical cord matrix following removal of both arteries and vein. Also, to overcome the clinical limitations posed by fetal bovine serum (FBS) supplementation because of xenogeneic origin of FBS, usual FBS cell culture supplement has been replaced with human platelet lysate (HPL). Apart from general characteristic features of bone marrow-derived MSCs, wharton jelly-derived MSCs have the ability to maintain phenotypic attributes, cell growth kinetics, cell cycle pattern, in vitro multilineage differentiation plasticity, apoptotic pattern, normal karyotype-like intrinsic mesenchymal stem cell properties in long-term in vitro cultures. Moreover, the WJ-MSCs exhibited the in vitro multilineage differentiation capacity by giving rise to differentiated cells of not only mesodermal lineage but also to the cells of ectodermal and endodermal lineage. Also, WJ-MSC did not present any aberrant cell state upon in vivo transplantation in SCID mice and in vitro soft agar assays. The immunomodulatory potential assessed by gene expression levels of immunomodulatory factors upon exposure to inflammatory cytokines in the fetal WJ-MSCs was relatively higher compared to adult bone marrow-derived MSCs. WJ-MSCs seeded on decellularized amniotic membrane scaffold transplantation on the skin injury of SCID mice model demonstrates that combination of WJ-MSCs and decellularized amniotic membrane scaffold exhibited significantly better wound-healing capabilities, having reduced scar formation with hair growth and improved biomechanical properties of regenerated skin compared to WJ-MSCs alone. Further, our experimental data indicate that indocyanin green (ICG) at optimal concentration can be resourcefully used for labeling of stem cells and in vivo tracking by near infrared fluorescence non-invasive live cell imaging of labelled transplanted cells, thus proving its utility for therapeutic applications.
Insects Can Count: Sensory Basis of Host Discrimination in Parasitoid Wasps Revealed

The solitary parasitoid Leptopilina heterotoma is one of the best studied organisms concerning the ecology, behaviour and physiology of host discrimination. Behavioural evidence shows that L. heterotoma uses its ovipositor to discriminate not only between parasitized and unparasitized Drosophila melanogaster larvae, but also to discriminate between hosts with different numbers of parasitoid eggs. The existing knowledge about how and when the parasitoid marks the host motivated us to unravel the chemosensory basis of host discrimination by L. heterotoma that allows it to choose the “best” host available. In this paper we report on electrophysiological recordings of multi-neural responses from the single taste sensillum on the tip of the unpaired ovipositor valve. We stimulated this sensillum with haemolymph of unparasitized, one-time-parasitized and two-times-parasitized Drosophila larvae. We demonstrate for the first time that quantitative characteristics of the neural responses to these haemolymph samples differed significantly, implying that host discrimination is encoded by taste receptor neurons in the multi-neuron coeloconic ovipositor sensillum. The activity of three of the six neurons present in the sensillum suffices for host discrimination and support the hypothesis that L. heterotoma females employ an ensemble code of parasitization status of the host.
Mitochondria and Cytoprotection

Mitochondrion is an eukaryotic double-membrane bound organelle that arose from a bacterial endosymbiont. Its circular DNA is small, as many genes were transferred to nucleus during evolution, and almost exclusively maternally inherited. Mitochondria harbor highly regulated biogenesis activities (division and fusion) and motility, establish interorganellar contacts, and perform/house multiple and interconnected cellular functions, as diverse as ATP production (via oxidative phosphorylation), parts of pyrimidine and lipid biosynthetic pathways (including the fatty acid β-oxidation pathway), reactive oxygen species production and detoxification, and metal metabolism (synthesizing heme and Fe–S clusters). Mitochondria also participate in calcium homeostasis, metabolic sensing, innate immunity, autophagy, and cell death regulation. The coordination of these functions contributes to the cell and life balance and mitochondrial dysfunction is consequently associated with many human diseases.
Nano‐sized TiO2‐reinforced natural rubber composites prepared by latex compounding method

This paper addresses nano‐sized titanium dioxide (TiO2) reinforced natural rubber composites. Micro‐sized TiO2 is simultaneously prepared to make a comparison with the composites containing nano‐sized TiO2. To improve the dispersion of TiO2, this study also suggests a new method of incorporating TiO2. Aqueous dispersions of micro‐ and nano‐sized TiO2 at the loadings of 0, 2, 4, 6, and 8 parts by weight per hundred parts of resin were dispersed in natural rubber latex, and then the resulting compounds were dried prior to mixing it with other ingredients on a two‐roll mill. By applying this technique, the homogeneity of the compound is significantly improved. This can be clearly seen from the enhancement of tensile properties and morphological characteristics where the optimum loading was found at 6 parts by weight per hundred parts of resin of micro‐ and nano‐sized TiO2. Adding TiO2 results in delayed scorch times and curing times wherein the curing process of filled compounds is shorter than the unfilled compound. J. VINYL ADDIT. TECHNOL. , 23:200–209, 2017. © 2015 Society of Plastics Engineers
Biodiversity of Actinobacteria from the South Pacific and the Assessment of Streptomyces Chemical Diversity with Metabolic Profiling

Recently, bioprospecting in underexplored habitats has gained enhanced focus, since new taxa of marine actinobacteria can be found, and thus possible new metabolites. Actinobacteria are in the foreground due to their versatile production of secondary metabolites that present various biological activities, such as antibacterials, antitumorals and antifungals. Chilean marine ecosystems remain largely unexplored and may represent an important source for the discovery of bioactive compounds. Various culture conditions to enrich the growth of this phylum were used and 232 bacterial strains were isolated. Comparative analysis of the 16S rRNA gene sequences led to identifying genetic affiliations of 32 genera, belonging to 20 families. This study shows a remarkable culturable diversity of actinobacteria, associated to marine environments along Chile. Furthermore, 30 streptomycete strains were studied to establish their antibacterial activities against five model strains, Staphylococcus aureus, Listeria monocytogenes, Salmonella enterica, Escherichia coli and Pseudomonas aeruginosa, demonstrating abilities to inhibit bacterial growth of Gram-positive bacteria. To gain insight into their metabolic profiles, crude extracts were submitted to liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis to assess the selection of streptomycete strains with potentials of producing novel bioactive metabolites. The combined approach allowed for the identification of three streptomycete strains to pursue further investigations. Our Chilean marine actinobacterial culture collection represents an important resource for the bioprospection of novel marine actinomycetes and its metabolites, evidencing their potential as producers of natural bioproducts.
Prevalence of metabolic syndrome and its selected determinants among urban adult women in South Delhi, India

Aims Metabolic syndrome is a clustering of cardiovascular risk factors. Asian Indians, particularly women, have been reported to be at higher risk of developing metabolic syndrome. We aimed to estimate the prevalence of metabolic syndrome and its selected known determinants among adult Asian Indian women of lower socioeconomic status. Methods We conducted a cross-sectional study over a period of 1 year from January 2008 to December 2008 in South Delhi, which included 300 women (>20 years) recruited through multistage systematic random sampling. Blood pressure and anthropometric measurements were taken. Biochemical tests were performed on blood samples collected after overnight fasting. Metabolic syndrome was defined using updated National Cholesterol Education Program/Adult Treatment Panel-III (NCEP/ATP-III) guidelines with modified waist circumference for Indians and International Diabetes Federation (IDF) criteria. Results The overall prevalence of metabolic syndrome was 29.6% (95% CI 23.8 to 36.0) and 20.4% (95% CI 15.3 to 26.1) using NCEP/ATP-III and IDF criteria, respectively. The risk of metabolic syndrome increased with age and calorie intake. Most (203 (90%)) of the study participants were involved in physical activity with a low metabolic equivalent (MET) score but one-fifth (19.5%) had a calorie intake recommended for women involved in vigorous activity. Conclusions The high prevalence of metabolic syndrome among women of lower socioeconomic status is a cause of concern, and calls for an effective public health response.