Miracle-dz/UniFAR-FTUs huggingface dataset:
ESR1 alterations and metastasis in estrogen receptor positive breast cancer

Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1 ) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum of ESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.
Enhanced Inhibition of Tumorigenesis Using Combinations of miRNA-Targeted Therapeutics

The search for effective strategies to inhibit tumorigenesis remains one of the most relevant scientific challenges. Among the most promising approaches is the direct modulation of the function of short non-coding RNAs, particularly miRNAs. These molecules are propitious targets for anticancer therapy, since they perform key regulatory roles in a variety of signaling cascades related to cell proliferation, apoptosis, migration, and invasion. The development of pathological states is often associated with deregulation of miRNA expression. The present review describes in detail the strategies aimed at modulating miRNA activity that invoke antisense oligonucleotide construction, such as small RNA zippers, miRNases (miRNA-targeted artificial ribonucleases), miRNA sponges, miRNA masks, anti-miRNA oligonucleotides, and synthetic miRNA mimics. The broad impact of developed miRNA-based therapeutics on the various events of tumorigenesis is also discussed. Above all, the focus of this review is to evaluate the results of the combined application of different miRNA-based agents and chemotherapeutic drugs for the inhibition of tumor development. Many studies indicate a considerable increase in the efficacy of anticancer therapy as a result of additive or synergistic effects of simultaneously applied therapies. Different drug combinations, such as a cocktail of antisense oligonucleotides or multipotent miRNA sponges directed at several oncogenic microRNAs belonging to the same/different miRNA families, a mixture of anti-miRNA oligonucleotides and cytostatic drugs, and a combination of synthetic miRNA mimics, have a more complex and profound effect on the various events of tumorigenesis as compared with treatment with a single miRNA-based agent or chemotherapeutic drug. These data provide strong evidence that the simultaneous application of several distinct strategies aimed at suppressing different cellular processes linked to tumorigenesis is a promising approach for cancer therapy.
Autosomal STR Variation in a Basque Population: Vizcaya Province

ABSTRACT We have characterized 68 unrelated Basque individuals from Vizcaya, Spain, for 13 tetrameric short tandem repeat (STR) loci: CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, TPOX, and VWA. Interpopulational analyses were also performed for 21 European and North African population data sets for nine of the STRs typed in the Basque sample. Heterozygosity values for the Vizcayan Basques were found to be high, ranging from 0.662 to 0.882, and none of the STR loci significantly deviated from Hardy-Weinberg equilibrium. Based on the comparative population data set, the average GST score is 0.7%, indicating a low degree of genetic differentiation. However, neighbor-joining trees and multidimensional-scaling plots of DA genetic distances indicate that the Vizcayan Basques are an outlier relative to both neighboring Iberians and North African populations.
Myocarditis in Humans and in Experimental Animal Models

Myocarditis is defined as an inflammation of the cardiac muscle. In humans, various infectious and non-infectious triggers induce myocarditis with a broad spectrum of histological presentations and clinical symptoms of the disease. Myocarditis often resolves spontaneously, but some patients develop heart failure and require organ transplantation. The need to understand cellular and molecular mechanisms of inflammatory heart diseases led to the development of mouse models for experimental myocarditis. It has been shown that pathogenic agents inducing myocarditis in humans can often trigger the disease in mice. Due to multiple etiologies of inflammatory heart diseases in humans, a number of different experimental approaches have been developed to induce myocarditis in mice. Accordingly, experimental myocarditis in mice can be induced by infection with cardiotropic agents, such as coxsackievirus B3 and protozoan parasite Trypanosoma cruzi or by activating autoimmune responses against heart-specific antigens. In certain models, myocarditis is followed by the phenotype of dilated cardiomyopathy and the end stage of heart failure. This review describes the most commonly used mouse models of experimental myocarditis with a focus on the role of the innate and adaptive immune systems in induction and progression of the disease. The review discusses also advantages and limitations of individual mouse models in the context of the clinical manifestation and the course of the disease in humans. Finally, animal-free alternatives in myocarditis research are outlined.
Antimicrobial Effects on Swine Gastrointestinal Microbiota and Their Accompanying Antibiotic Resistome

Antimicrobials are the most commonly prescribed drugs in the swine industry. While antimicrobials are an effective treatment for serious bacterial infections, their use has been associated with major adverse effects on health. It has been shown that antimicrobials have substantial direct and indirect impacts on the swine gastrointestinal (GI) microbiota and their accompanying antimicrobial resistome. Antimicrobials have also been associated with a significant public health concern through selection of resistant opportunistic pathogens and increased emergence of antimicrobial resistance genes (ARGs). Since the mutualistic microbiota play a crucial role in host immune regulation and in providing colonization resistance against potential pathogens, the detrimental impacts of antimicrobial treatment on the microbiota structure and its metabolic activity may lead to further health complications later in life. In this review, we present an overview of antimicrobial use in the swine industry and their role in the emergence of antimicrobial resistance. Additionally, we review our current understanding of GI microbiota and their role in swine health. Finally, we investigate the effects of antimicrobial administration on the swine GI microbiota and their accompanying antibiotic resistome. The presented data is crucial for the development of robust non-antibiotic alternative strategies to restore the GI microbiota functionality and guarantee effective continued use of antimicrobials in the livestock production system.
Impression cytology study of epithelial phenotype of ocular surface reconstructed by preserved human amniotic membrane.

OBJECTIVE To determine the epithelial phenotype of the ocular surface reconstructed by preserved human amniotic membrane. METHODS Impression cytology was performed in 6 patients who received a large patch of amniotic membrane for conjunctival surface reconstruction during removal of acquired melanosis, conjunctival intraepithelial neoplasia, or bilateral inferior conjunctival chalasis, or for corneal surface reconstruction during removal of pannus associated with limbal deficiency caused by aniridia, toxic epidermal necrolysis, or chemical burn. RESULTS The nongoblet epithelial cells covering the amniotic membrane were uniformly smaller and the cell density was almost twice that of age- and sex-matched normal control eyes at the corresponding site, and the goblet cell density was almost 10 times that of the control (both P < .05; Student paired t test) (N = 7 eyes). Furthermore, the conjunctival epithelial phenotype with goblet cells was found on corneal surfaces of all 3 patients with limbal deficiency. CONCLUSIONS The success of conjunctival surface reconstruction correlated well with recovery of the conjunctival epithelial phenotype. The lack of corneal epithelial phenotype even on an avascular corneal stroma supports the concept that conjunctival transdifferentiation does not occur in vivo, and indicates that additional limbal stem cell transplantation is needed for effective corneal surface reconstruction in patients with limbal deficiency.
Genome-Wide Characterization and Expression Analysis of Soybean TGA Transcription Factors Identified a Novel TGA Gene Involved in Drought and Salt Tolerance

The TGA transcription factors, a subfamily of bZIP group D, play crucial roles in various biological processes, including the regulation of growth and development as well as responses to pathogens and abiotic stress. In this study, 27 TGA genes were identified in the soybean genome. The expression patterns of GmTGA genes showed that several GmTGA genes are differentially expressed under drought and salt stress conditions. Among them, GmTGA17 was strongly induced by both stress, which were verificated by the promoter-GUS fusion assay. GmTGA17 encodes a nuclear-localized protein with transcriptional activation activity. Heterologous and homologous overexpression of GmTGA17 enhanced tolerance to drought and salt stress in both transgeinc Arabidopsis plants and soybean hairy roots. However, RNAi hairy roots silenced for GmTGA17 exhibited an increased sensitivity to drought and salt stress. In response to drought or salt stress, transgenic Arabidopsis plants had an increased chlorophyll and proline contents, a higher ABA content, a decreased MDA content, a reduced water loss rate, and an altered expression of ABA- responsive marker genes compared with WT plants. In addition, transgenic Arabidopsis plants were more sensitive to ABA in stomatal closure. Similarly, measurement of physiological parameters showed an increase in chlorophyll and proline contents, with a decrease in MDA content in soybean seedlings with overexpression hairy roots after drought and salt stress treatments. The opposite results for each measurement were observed in RNAi lines. This study provides new insights for functional analysis of soybean TGA transcription factors in abiotic stress.
Reconstruction and Simulation of a Scaffold Model of the Cerebellar Network

Reconstructing neuronal microcircuits through computational models is fundamental to simulate local neuronal dynamics. Here a scaffold model of the cerebellum has been developed in order to flexibly place neurons in space, connect them synaptically and endow neurons and synapses with biologically-grounded mechanisms. The scaffold model can keep neuronal morphology separated from network connectivity, which can in turn be obtained from convergence/divergence ratios and axonal/dendritic field 3D geometries. We first tested the scaffold on the cerebellar microcircuit, which presents a challenging 3D organization, at the same time providing appropriate datasets to validate emerging network behaviors. The scaffold was designed to integrate the cerebellar cortex with deep cerebellar nuclei (DCN), including different neuronal types: Golgi cells, granule cells, Purkinje cells, stellate cells, basket cells and DCN principal cells. Mossy fiber (mf) inputs were conveyed through the glomeruli. An anisotropic volume (0.077 mm3) of mouse cerebellum was reconstructed, in which point-neuron models were tuned toward the specific discharge properties of neurons and were connected by exponentially decaying excitatory and inhibitory synapses. Simulations using pyNEST and pyNEURON showed the emergence of organized spatio-temporal patterns of neuronal activity similar to those revealed experimentally in response to background noise and burst stimulation of mossy fiber bundles. Different configurations of granular and molecular layer connectivity consistently modified neuronal activation patterns, revealing the importance of structural constraints for cerebellar network functioning. The scaffold provided thus an effective workflow accounting for the complex architecture of the cerebellar network. In principle, the scaffold can incorporate cellular mechanisms at multiple levels of detail and be tuned to test different structural and functional hypotheses. A future implementation using detailed 3D multi-compartment neuron models and dynamic synapses will be needed to investigate the impact of single neuron properties on network computation.
Seed storage behaviour of tropical members of the aquatic basal angiosperm genus Nymphaea L. (Nymphaeaceae)

The ex situ seed storage behaviour of four species of Australian waterlilies (Nymphaea) was investigated. Seeds of all species were found to be desiccation tolerant; however, most collections lost viability rapidly, even under standard genebank conditions (i.e. 15% RH and 15°C).
Psychometric Properties and Factor Structure of the Chinese Version of the Hospital Anxiety and Depression Scale in People Living With HIV

The population of people living with HIV (PLWH) is growing in number and usually results in mental health problems that impact their quality of life. Therefore, valid instruments and screening methods for psychological disorders are of great significance. The Hospital Anxiety and Depression Scale (HADS) reveals good psychometric properties, but shows ambiguous results in factor structure. This study aims to evaluate psychometric properties in terms of the internal reliability and structure validity of the Chinese version of the HADS (C-HADS) in a large sample of PLWH in China. The C-HADS was administered to 4,102 HIV-infected adults at an HIV clinic in China. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were performed to examine the factor structure. Measurement invariance was assessed across gender and course of infection. Internal reliability was also assessed. A bifactor model with anomalous loadings of items 7, 8, and 10 fits the data best and holds measurement invariance across gender and course of infection. Internal reliability was good with all Cronbach’s alphas > 0.70 and Spearman’s ρ between 0.30 and 0.70. The C-HADS has good psychometric properties in terms of internal reliability and structure validity of a bifactor model. The C-HADS is recommended to be used as a total scale that measures general psychological distress, instead of anxiety and depression separately, when applied to PLWH. Further studies are needed to evaluate criterion validity, the cutoff score, and the effect of wording and scoring of the HADS.
[Pathophysiology of dehydration].

The pathophysiology of dehydration is reviewed. The normal response to dehydration, i.e. decreased effective arterial blood volume or effective circulating volume is described. Due to water retention and drinking following stimulation of ADH secretion and thirst, osmoregulation is overruled by volume conservatory mechanisms, which lead to hyponatremia. Only patients with impaired mental function or those who are unable to drink will develop a progressive water deficit--with or without salt depletion--recognizable by hypernatremia. Decreased effective arterial blood volume and hypernatremia affect cerebral function in a way that perception of external stimuli as well as perception of pain will be impaired. Alert dehydrated patients are disturbed mainly by thirst and dryness of the mouth. Both symptoms are perceived more intensely by young than by elderly persons. Dryness of the mouth increase thirst on its own. Distress by thirst and oral dryness increases as a function of the level and the rapidity of developing hypernatremia. The simple act of filling the oral cavity with fluid and swallowing alleviates thirst in the absence of any change in plasma sodium concentration. Thirst quenching efficacy is increased by administering chilled hypotonic fluid with lemon or other fruit acid added (for stimulation of salivation).
Seasonal Shift of the Diurnal Cycle of Rainfall Over Medellin's Valley, Central Andes of Colombia (1998–2005)

The spatiotemporal variability of precipitation in regions of complex mountainous terrains constitutes one of the most challenging research topics of geosciences. This paper explores hourly precipitation data from a set of 25 stations spanning the period 1998 to 2005 within northwestern Colombia, in the Aburra Valley and the neighboring San Nicolas plateau (75.16W-6N and 75.66W-6.6N) which accounts for a land area of approximately 4000 km2. Our aim is to identify the main features of the diurnal cycle of precipitation over this complex terrain. We found that the average diurnal cycle of rainfall in the study region is bimodal at regional scale although it results from the superposition of two unimodal diurnal cycles shifting its phase throughout the seasons of the year. From October to April, average diurnal rainfall peaks in the afternoon hours (13:00-16:00 LST) but from May to September, the phase of the diurnal cycle changes to midnight hours (22:00-02:00 LST). Three low-level jets (LLJs), namely Caribbean, CHOCO, and the so-called Corriente de los Andes Orientales (CAO), are relevant to explain the seasonal shift of the diurnal cycle given their modulation of the seasonal variation of moisture sources and transport over this region. During June-July-August, moisture from afternoon evaporation processes at the bottom of the inter-Andean Magdalena Valley, located at the east of the study region, is transported by anabatic and easterly trade winds and contribute to explain the midnight and early morning peak. The life cycle of convective processes influences the orographic nature of rainfall distribution and timing in the region since deep convective cores are related with the afternoon peak, whereas wide convective cores with the early morning peak.
The Repetitive DNA Composition in the Natural Pesticide Producer Tanacetum cinerariifolium: Interindividual Variation of Subtelomeric Tandem Repeats

Dalmatian pyrethrum (Tanacetum cinerariifolium (Trevir.) Sch. Bip. ), a plant species endemic to the east Adriatic coast, is used worldwide for production of the organic insecticide, pyrethrin. Most studies concerning Dalmatian pyrethrum have focused on its morphological and biochemical traits relevant for breeding. However, little is known about the chromosomal evolution and genome organization of this species. Our study aims are to identify, classify, and characterize repetitive DNA in the T. cinerariifolium genome using clustering analysis of a low coverage genomic dataset. Repetitive DNA represents about 71.63% of the genome. T. cinerariifolium exhibits linked 5S and 35S rDNA configuration (L-type). FISH reveals amplification of interstitial telomeric repeats (ITRs) in T. cinerariifolium. Of the three newly identified satellite DNA families, TcSAT1 and TcSAT2 are located subterminally on most of T. cinerariifolium chromosomes, while TcSAT3 family is located intercalary within the longer arm of two chromosome pairs. FISH reveals high levels of polymorphism of the TcSAT1 and TcSAT2 sites by comparative screening of 28 individuals. TcSAT2 is more variable than TcSAT1 regarding the number and position of FISH signals. Altogether, our data highlights the dynamic nature of DNA sequences associated with subtelomeres in T. cinerariifolium and suggests that subtelomeres represent one of the most dynamic and rapidly evolving regions in eukaryotic genomes.
CTLA4 Message Reflects Pathway Disruption in Monogenic Disorders and Under Therapeutic Blockade

CTLA-4 is essential for immune tolerance. Heterozygous CTLA4 mutations cause immune dysregulation evident in defective regulatory T cells with low levels of CTLA-4 expression. Biallelic mutations in LRBA also result in immune dysregulation with low levels of CTLA-4 and clinical presentation indistinguishable from CTLA-4 haploinsufficiency. CTLA-4 has become an immunotherapy target whereby its blockade with a monoclonal antibody has resulted in improved survival in advanced melanoma patients, amongst other malignancies. However, this therapeutic manipulation can result in autoimmune/inflammatory complications reminiscent of those seen in genetic defects affecting the CTLA-4 pathway. Despite efforts made to understand and establish disease genotype/phenotype correlations in CTLA-4-haploinsufficiency and LRBA-deficiency, such relationships remain elusive. There is currently no specific immunological marker to assess the degree of CTLA-4 pathway disruption or its relationship with clinical manifestations. Here we compare three different patient groups with disturbances in the CTLA-4 pathway—CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients. Assessment of CTLA4 mRNA expression in these patient groups demonstrated an inverse correlation between the CTLA4 message and degree of CTLA-4 pathway disruption. CTLA4 mRNA levels from melanoma patients under therapeutic CTLA-4 blockade (ipilimumab) were increased compared to patients with either CTLA4 or LRBA mutations that were clinically stable with abatacept treatment. In summary, we show that increased CTLA4 mRNA levels correlate with the degree of CTLA-4 pathway disruption, suggesting that CTLA4 mRNA levels may be a quantifiable surrogate for altered CTLA-4 expression.
Smoking-induced changes in epithelial lining fluid volume, cell density and protein.

Bronchoalveolar lavage has proved a useful research technique for recovering cellular and molecular contents of the lower respiratory tract. Because the recovered fluid is variably diluted, an accurate estimation of molecular and cellular concentrations can only be made if the epithelial lining fluid volume recovered is also known. It has been suggested that smoking may alter epithelial lining fluid volume by reducing clearance or by stimulating production and, thus, affect the interpretation of bronchoalveolar lavage studies. In this study, urea was used as an endogenous marker of epithelial lining fluid volume in a comparison of 26 smokers and 31 nonsmokers. The mean epithelial lining fluid volume recovered from smokers was significantly greater than that of nonsmokers (2.4 +/- 1.40 ml vs 1.2 +/- 0.75 ml, p less than 0.005). The total cellular concentration in the bronchoalveolar lavage fluid in smokers was also greater (94.2 +/- 46 x 10(6) vs 33.9 +/- 21.5 x 10(6) cells per 300 ml lavage), even when corrected for bronchoalveolar lavage volume recovered (63.1 +/- 32.5 x 10(6) vs 24.9 +/- 13.3 x 10(6) cells per 100 ml recovered lavage fluid). This was true for macrophage, lymphocyte and neutrophil cell numbers. However, when corrected for the apparent epithelial lining fluid volume, only the macrophage count remained significantly higher in the smokers compared with nonsmokers (30.66 +/- 20.7 x 10(6) vs 18.21 +/- 8.6 x 10(6) macrophages.ml-1 ELF). In addition, concentrations of albumin and immunoglobulin M (IgM) were significantly lower in smokers after correction for epithelial lining fluid volume. These results highlight smoking as a confounding factor in the interpretation of bronchoalveolar lavage data. (ABSTRACT TRUNCATED AT 250 WORDS)