Miracle-dz/UniFAR-FTUs huggingface dataset:
Somatic Mutations in Clonally Expanded T-lymphocytes in Patients with Chronic Graft-Versus-Host Disease

Graft-versus-host-disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation. GvHD patients have aberrant T cell expansions, which are thought to drive pathological immune activation. Here we report mechanistic insights that somatic mutations may account for persistent clonal T cell expansions in chronic GvHD (cGvHD). In an index patient suffering from cGVHD, we discovered persisting somatic MTOR, NFKB2, and TLR2 mutations in an expanded CD4+ T clone. In the screening cohort (n=135), the MTOR P2229R kinase domain mutation was detected in two additional cGvHD patients, but not in controls. Functional analysis of the discovered MTOR mutation indicated a gain-of-function alteration in translational regulation yielding in up-regulation of phosphorylated S6K1, S6, and AKT. Paired single-cell RNA and T cell receptor alpha and beta sequencing strongly supported cytotoxicity and abnormal proliferation of the clonally expanded CD4+ T cells. Real-time impedance measurements indicated increased cytotoxicity of mutated CD4 + T cells against the patient’s fibroblasts. High throughput drug-sensitivity testing suggested that mutations induce resistance to mTOR inhibitors but increase sensitivity for HSP90 inhibitors. Our findings suggest a novel explanation for the aberrant, persistent T cell activation in cGvHD, and pave the way for novel targeted therapies.
Maternal dietary selenium intake is associated with increased gestational length and decreased risk of preterm delivery

Abstract The first positive genome-wide association study on gestational length and preterm delivery showed the involvement of an Se metabolism gene. In the present study, we examine the association between maternal intake of Se and Se status with gestational length and preterm delivery in 72 025 women with singleton live births from the population-based, prospective Norwegian Mother, Father and Child Cohort Study (MoBa). A self-reported, semi-quantitative FFQ answered in pregnancy week 22 was used to estimate Se intake during the first half of pregnancy. Associations were analysed with adjusted linear and Cox regressions. Se status was assessed in whole blood collected in gestational week 17 (n 2637). Median dietary Se intake was 53 (interquartile range (IQR) 44–62) µg/d, supplements provided additionally 50 (IQR 30–75) µg/d for supplement users (n 23 409). Maternal dietary Se intake was significantly associated with prolonged gestational length (β per sd = 0·25, 95 % CI, 0·07, 0·43) and decreased risk of preterm delivery (n 3618, hazard ratio per sd = 0·92, 95 % CI, 0·87, 0·98). Neither Se intake from supplements nor maternal blood Se status was associated with gestational length or preterm delivery. Hence, the present study showed that maternal dietary Se intake but not intake of Se-containing supplements, during the first half of pregnancy was significantly associated with decreased risk of preterm delivery. Further investigations, preferably in the form of a large randomised controlled trial, are needed to elucidate the impact of Se on pregnancy duration.
Fabricating β-cyclodextrin based pH-responsive nanotheranostics as a programmable polymeric nanocapsule for simultaneous diagnosis and therapy

Background Fabrication of a smart drug delivery system that could dramatically increase the efficiency of chemotherapeutic drugs and reduce the side effects is still a challenge for pharmaceutical researchers. By the emergence of nanotechnology, a huge window was opened towards this goal, and a wide type of nanocarriers were introduced for delivering the chemotherapeutic to the cancer cells, among them are cyclodextrins with the ability to host different types of hydrophobic bioactive molecules through inclusion complexation process. Aim The aim of this study is to design and fabricate a pH-responsive theranostic nanocapsule based on cyclodextrin supramolecular nano-structure. Materials and methods This nanostructure contains iron oxide nanoparticles in the core surrounded with three polymeric layers including polymeric β-cyclodextrin, polyacrylic acid conjugated to sulfadiazine, and polyethylenimine functionalized with β-cyclodextrin. Sulfadiazine is a pH-responsive hydrophobic component capable of making inclusion complex with β-cyclodextrin available in the first and third layers. Doxorubicin, as an anti-cancer drug model, was chosen and the drug loading and release pattern were determined at normal and acidic pH. Moreover, the biocompatibility of the nanocapsule (with/without drug component) was examined using different techniques such as MTT assay, complement activation, coagulation assay, and hemolysis. Results The results revealed the successful preparation of a spherical nanocapsule with mean size 43±1.5 nm and negatively charge of −43 mV that show 160% loading efficacy. Moreover, the nanocapsule has an on/off switching release pattern in response to pH that leads to drug released in low acidic pH. The results of the biocompatibility tests indicated that this nano drug delivery system had no effect on blood and immune components while it could affect cancer cells even at very low concentrations (0.3 μg mL−1). Conclusion The obtained results suggest that this is a “switchable” theranostic nanocapsule with potential application as an ideal delivery system for simultaneous cancer diagnosis and therapy.
Universal phase behaviors of intracellular lipid droplets

Significance There is growing evidence suggesting that intracellular phase transitions play roles in biological functions. However, little is known about phase transitions of lipid droplets that are organelles involved in energy homeostasis. Here, we demonstrate a universal intracellular phase diagram of lipid droplets, consistent with the in vitro phase diagram, and reveal that cholesterol esters cause the liquid–liquid crystal phase transition under near-physiological conditions. We moreover combine in vivo and in vitro studies, together with the theory of confined liquid crystals, to suggest that the radial molecular alignments in the liquid crystallized lipid droplets are caused by an anchoring force at the droplet surface. These findings pave the way for a better understanding of their biological functions and diseases. Lipid droplets are cytoplasmic microscale organelles involved in energy homeostasis and handling of cellular lipids and proteins. The core structure is mainly composed of two kinds of neutral lipids, triglycerides and cholesteryl esters, which are coated by a phospholipid monolayer and proteins. Despite the liquid crystalline nature of cholesteryl esters, the connection between the lipid composition and physical states is poorly understood. Here, we present a universal intracellular phase diagram of lipid droplets, semiquantitatively consistent with the in vitro phase diagram, and reveal that cholesterol esters cause the liquid–liquid crystal phase transition under near-physiological conditions. We moreover combine in vivo and in vitro studies, together with the theory of confined liquid crystals, to suggest that the radial molecular alignments in the liquid crystallized lipid droplets are caused by an anchoring force at the droplet surface. Our findings on the phase transition of lipid droplets and resulting molecular organization contribute to a better understanding of their biological functions and diseases.
Identification of Mutations in SDR9C7 in Three Patients with Autosomal Recessive Congenital Ichthyosis

Journal Compilation © 2020 Acta Dermato-Venereologica. doi: 10.2340/00015555-3359 1https://doi.org/10.2340/00015555-3359 Congenital ichthyoses (CI) comprise a heterogeneous group of genetic diseases, which usually present at birth. They affect the entire skin and are characterized by hyperkeratosis and scaling, often associated with skin inflammation. There are many complications including ophthalmic and ear anomalies, pain and pruritus and cutaneous infections. The classification is based on the clinical presentation, and basically distinguishes between non-syndromic ichthyoses (including autosomal recessive congenital ichthyosis (ARCI) and syndromic ichthyoses (1). CI are primarily monogenic diseases with gene mutations leading to a defective skin barrier. To date, ARCI has been associated with a total of 12 genes including SDR9C7 and SULT2B1 for which only a very few families have been reported. We describe here 3 new patients with ARCI caused by mutations in SDR9C7, including 4 previously unreported mutations.
AREESat 50: A Semicentennial Celebration

I survey the 50-year history of the Annual Review of Ecology and Systematics, retitled Annual Review of Ecology, Evolution, and Systematics in 2003. An overview of reviews up through 2009 portrays much of the history of the series’ subject areas, revealing both lasting themes and great changes in emphasis, theory, evidence, and understanding. Much of the progress has resulted from conceptual innovation and from momentous advances in computation, data analysis, and molecular methodology, some of which have been reviewed in these volumes. Some of the most significant changes entail intercourse between formerly separate realms of study. If the remarkably long citation life of many reviews is any indication, contributions to this series have helped to shape research questions and conceptual development in ecology, evolution, and systematics and their applications to social concerns that range from antibiotic resistance to the ecological consequences of human actions.
Molecular characterization of Pasteurella multocida pfhaB1 gene fragment from buffalo and cattle isolates from Nusa Tenggara Timur Indonesia

Almost all regions in Nusa Tenggara Timur East Nusa Tenggara (NTT) Province Indonesia are endemic areas of Haemorragic Septicaemia (HS), which is caused by Pasteurella multocida (P. multocida ) Serotypes B: 2. The fragment pfhaB1gene is one of the virulence factors of P. multocida.The objective of this study was to determaine the phylogenetic, homology of P. multocidapfhaB1gene fragment of isolatedfrom Buffalo and Cattle in NTT. The P. multocida isolateswere re-cultured and further microscopic examined the biochemical tests, PCR, sequencing, homology, and phylogenetic relatedness test. P. multocida was observed as gram negative, coccobacilus, no growth on MacConkey Agar, does not produce H2S and gas, nonmotile and indole positive, does not produce urease enzymes, does not use citrate as a carbon source, does not ferment maltose and lactose but it does ferment glucose, sucrose and mannitol. ThepfhaB1gene fragmentfrom buffalo and cattle NTT isolates and also Katha strain vaccine showed DNA band 506 bp. P.multocida isolates from buffalo and cattle in NTT have 91% - 99% score homology with the comparative isolate. The isolate P. multocida from buffalo and cattle in NTT are in one cluster and their phylogenetic relatedness is close to isolates from Iran and India. It is concluded that the pfhaB1gene fragmentof P. multocida from buffalo and cattle isolates have phylogenetic relatedness close and homolog with the other comparative isolates. Keywords: Haemorrhagic Septicaemia; Nusa Tenggara Timur; Pasteurella multocida; pfhaB1gene
COP9 Signalosome CSN4 and CSN5 Subunits Are Involved in Jasmonate-Dependent Defense Against Root-Knot Nematode in Tomato

COP9 signalosome (CSN) is an evolutionarily conserved regulatory component of the ubiquitin/proteasome system that plays crucial roles in plant growth and stress tolerance; however, the mechanism of COP9-mediated resistance to root-knot nematodes (RKNs, e.g. Meloidogyne incognita) is not fully understood in plants. In the present study, we found that RKN infection in the roots rapidly increases the transcript levels of CSN subunits 4 and 5 (CSN4 and CSN5) and their protein accumulation in tomato (Solanum lycopersicum) plants. Suppression of CSN4 or CSN5 expression resulted in significantly increased number of egg masses and aggravated RKN-induced lipid peroxidation of cellular membrane but inhibited RKN-induced accumulation of CSN4 or CSN5 protein in tomato roots. Importantly, the RKN-induced accumulation of jasmonic acid (JA) and JA-isoleucine (JA-Ile), as well as the transcript levels of JA-related biosynthetic and signaling genes were compromised by CSN4 or CSN5 gene silencing. Moreover, protein–protein interaction assays demonstrated that CSN4 and CSN5B interact with the jasmonate ZIM domain 2 (JAZ2), which is the signaling component of the JA pathway. Silencing of CSN4 or CSN5 also compromises RKN-induced JAZ2 expression. Together, our findings indicate that CSN4 and CSN5 play critical roles in JA-dependent basal defense against RKN.
The impact of delirium on cognitive outcomes in population-based studies

ion of information from hospital records is feasible in terms of: (i) consent to access notes; (ii) retrieval (if deceased within last ten years); (iii) deriving information on altered mental status due to acute conditions. Clinical information can be assessed (by consensus) to determine if sufficient evidence for a retrospective diagnosis of delirium (based on CAM operationalisation of DSV-IV criteria) can be made. The derived exposure can be demonstrated in cases (dementia) and controls, in proportions consistent with delirium measures in Vantaa.
Structural insights into a Plasmodium falciparum IMC1 protein using bioinformatics tools

Alveolates (dinoflagellates, ciliates and apicomplexans) possess a characteristic cortical structure termed as the ‘pellicle’. Alveolate pellicle plays a structural role and helps define the cell shape in dinoflagellates and ciliates whereas in apicomplexans it plays an additional role in parasite motility and cytokinesis. The pellicle is composed of flattened membranous sacs which subtend immediately below the plasma membrane. These flattened sacs are termed as the ‘inner membrane complex’ (IMC) in apicomplexans. IMC proteins can be categorized according to their structural features into three groups namely multi - transmembrane proteins, alveolins and non - alveolins. Only a few members of IMC1 family of proteins are known in Plasmodium falciparum (Pf). Knock - out studies of IMC1 members in other Plasmodium species have demonstrated the role of these proteins in mechanical stability and motility of the parasite. Here, we used bioinformatics tools to gain insight into the structure of IMC1l. We predicted the partial 3 dimensional model of Pf IMC1l and propose that its α - helical region might be involved in binding to cytoskeletal proteins such as actin or myosin. The hydrophobic residues in the IMCp region of IMC1 proteins might be responsible for their attachment to the IMC membrane. PfIMC1 proteins were also found to have asparagine rich regions, N - or C - terminal palmitoylation sites and other motifs of functional significance. Being crucial structural elements of inner membrane complex, IMC1 proteins are likely to be potential antimalarial drug targets.
Economic evaluation of puberty induction of nulliparian Nellore heifers using intravaginal device and melengestrol acetate

The present study evaluates the economic viability of puberty induction in nulliparous Bos taurus indicus Nellore breed heifers using an intravaginal device of fourth-use and melengestrol acetate (MGA®). The experiment was undertaken in the Nossa Senhora Aparecida Farm, Terenos city, Mato Grosso do Sul, Brazil, and was utilized a completely randomized experimental design in a 2 × 3 factorial scheme. Two age classes were included in the study, which were divided into 348 precocious (early-cycle) heifers, aging 16-18 months, weighting an average of 264.6 kg and 543 conventional-cycle heifers aging 24-26 months averaging 346.8 kg. The three treatments were as follows: control without the induction of follicle formation (treatment 1); treatment 2: induction with an intravaginal implant (intravaginal implantation with a fourth-use progesterone implant on Day 0, withdrawal on Day 12, and application of 1 ml of intramuscular estradiol cypionate [ECP®]); and treatment 3, 2.3 g of MGA® during 12 days with supplement followed by 1 ml of intramuscular ECP® at the end of the treatment. Heifers induced via implantation had a higher rate of ovarian activity (presence of corpus luteum) during the early cycle (63.8% animals) while the conventional cycle (72.4%). This effect influenced the frequency of early stage anestrus (56%). Among the treatments evaluated, 72% of control heifers had no ovarian activity (absence of corpus luteum). In the group with implant induction the conception rates were 65.5% and 62.4% in early and conventional-cycle females, respectively. Puberty induction in Nellore heifers provides a high economic return. The protocol revealed highest efficiency compared to the control group.
Divergent Cl− and H+ pathways underlie transport coupling and gating in CLC exchangers and channels

The CLC family of anion transporting proteins is comprised of secondary active H+-coupled exchangers and of Cl− channels. Both functional subtypes play key roles in human physiology, and mutations causing their dysfunction lead to numerous genetic disorders. Current models suggest that the CLC exchangers do not utilize a classical ‘ping-pong’ mechanism of antiport, where the transporter sequentially interacts with one substrate at a time. Rather, in the CLC exchangers both substrates bind and translocate simultaneously while moving through partially congruent pathways. How ions of opposite electrical charge bypass each other while moving in opposite directions through a shared permeation pathway remains unknown. Here, we use MD simulations in combination with biochemical and electrophysiological measurements to identify a pair of highly conserved phenylalanine residues that form an aromatic pathway, separate from the Cl− pore, whose dynamic rearrangements enable H+ movement. Mutations of these aromatic residues impair H+ transport and voltage-dependent gating in the CLC exchangers. Remarkably, the role of the aromatic pathway is evolutionarily conserved in CLC channels. Using atomic-scale mutagenesis we show that the electrostatic properties and conformational flexibility of these aromatic residues are essential determinants of channel gating. Our results suggest that Cl− and H+ move through physically distinct and evolutionarily conserved routes through the CLC channels and transporters. We propose a unifying mechanism that describes the gating mechanism of CLC exchangers and channels.
THE RUMEN MICROBIOTA OF REINDEER (Rangifer tarandus) WITH CLINICAL MANIFESTATIONS OF NECROBACTERIOSIS

among other diseases of reindeer is one of the most significant, since it brings the most significant damage to the economic activity of the population of the Russian Arctic. This paper for the first time shows the obtained results on rumen microbiota composition differences between the clinically healthy Rangifer tarandus reindeer of the Russian Arctic and reindeer with necrobacteriosis. The purpose of the study was to characterize the distinctive features of rumen microbiota in the reindeer with the clinical manifestations of necrobacteriosis. The study was carried out on calves (4-6 months) and adults (3-6 years) animals, including clinically healthy individuals and those with necrobacteriosis. Samples of the rumen content were collected during the summer-autumn period in 2017 ( n = 3 from each age group) in the Yamalo-Nenets Autonomous District. The total number of bacteria and fungi of the class Neocallimastigales was analyzed by quantitative PCR, the composition of the bacterial commu- nity was analyzed by T-RFLP (terminal restriction fragment length polymorphism) method. In individuals with clinical manifestations of necrobacteriosis, a significantly higher content of fusobacte- ria was detected, 1.79-fold in adults (p < 0.05), and 2.65-fold in calves (p < 0.05). In sick animals of both age groups, there was a significantly higher presence of bacteria of the genus Staphylococus (p < 0.05) and the family Pseudomonadaceae (p < 0.05), some species of which may cause purulent-necrotic lesions of animals. The 4-6 month old calves showed a significant increase (p < 0.05) in the content of family Campylobacteriaceae and family Enterobacteriaceae compared to clinically healthy animals. At the same time healthy individuals showed a greater number of cellulolytic and acid- utilizing bacteria. In general, it was noted that the rumen microbiome of calves with clinical signs of necrobacteriosis is characterized by large changes compared to the adult animals. In particular, in young reindeer with necrobacteriosis, there was a significant increase in the Shannon’s diversity index of the rumen microbial community (p 0.05), which indicates a greater heterogeneity of the bacterial community compared to healthy individuals. In addition, a significant (p < 0.05) decrease of cellulolytic chytridiomycetes of the class Neocallimastigales was detected in the rumen of this ani- mal group. In this regard, the identified patterns may be due to the physiological features of this
Rearing programmes for breeding rabbits. Effect of early development and feeding on future reproductive performance of rabbit females and males.

1 Resumen 3 Resum 5 GENERAL INTRODUCTION 7 The importance of the journey 9 The preparation 11 Foetal blood vessels 12 Foetal position and uterine space 12 Litter size 13 The starting point 14 The first steps 15 Lactation 15 The post-weaning 16 Rearing period: the final stage 18 Females 19 Males 24 Hypotheses and objectives 25 References 26 PAPER I "EFFECTS OF FEEDING PROGRAMME ON THE PERFORMANCE AND ENERGY BALANCE OF NULLIPAROUS RABBIT DOES" 35 Abstract 37 Introduction 39 Material and methods 39 Diets 39 Animals and experimental procedure 41 Ultrasound measurements 42 Hormone and metabolite assays 43 Statistical Analysis 43 Results 44 Animal Performance 44 Metabolic and hormonal parameters 47 Discussion 4937 Introduction 39 Material and methods 39 Diets 39 Animals and experimental procedure 41 Ultrasound measurements 42 Hormone and metabolite assays 43 Statistical Analysis 43 Results 44 Animal Performance 44 Metabolic and hormonal parameters 47 Discussion 49 Acknowledgements 54 References 54 PAPER II "CONSEQUENCES OF REARING FEEDING PROGRAMME ON THE PERFORMANCE OF RABBIT FEMALES FROM FIRST TO SECOND PARTURITION" 57 Abstract 59 Introduction 61 Material and methods 61 Composition of experimental diets 62 Animals and experimental procedure 62 Ultrasound measurements 64 Hormone and metabolite assays 64 Milk chemical composition 65 Statistical analysis 65 Results 66 Discussion 72 Conclusions 75 Acknowledgements 76 References 7659 Introduction 61 Material and methods 61 Composition of experimental diets 62 Animals and experimental procedure 62 Ultrasound measurements 64 Hormone and metabolite assays 64 Milk chemical composition 65 Statistical analysis 65 Results 66 Discussion 72 Conclusions 75 Acknowledgements 76 References 76 PAPER III "EARLY DEVELOPMENT AND REPRODUCTIVE LIFESPAN OF RABBIT FEMALES: IMPLICATIONS OF GROWTH RATE, REARING DIET AND BODY CONDITION AT FIRST MATING" 79 Abstract 8