Miracle-dz/UniFAR-FTUs huggingface dataset:
Association of Diabetes Mellitus on Cardiac Remodeling, Quality of Life, and Clinical Outcomes in Heart Failure With Reduced and Preserved Ejection Fraction

Background Diabetes mellitus frequently coexists with heart failure (HF), but few studies have compared the associations between diabetes mellitus and cardiac remodeling, quality of life, and clinical outcomes, according to HF phenotype. Methods and Results We compared echocardiographic parameters, quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire), and outcomes (1‐year all‐cause mortality, cardiovascular mortality, and HF hospitalization) between HF patients with and without type 2 diabetes mellitus in the prospective ASIAN‐HF (Asian Sudden Cardiac Death in Heart Failure) Registry, as well as community‐based controls without HF. Adjusted Cox proportional hazards models were used to assess the association of diabetes mellitus with clinical outcomes. Among 5028 patients with HF and reduced ejection fraction (HFrEF; EF <40%) and 1139 patients with HF and preserved EF (HFpEF; EF ≥50%), the prevalences of type 2 diabetes mellitus were 40.2% and 45.0%, respectively (P=0.003). In both HFrEF and HFpEF cohorts, diabetes mellitus (versus no diabetes mellitus) was associated with smaller indexed left ventricular diastolic volumes and higher mitral E/e′ ratio. There was a predominance of eccentric hypertrophy in HFrEF and concentric hypertrophy in HFpEF. Patients with diabetes mellitus had lower Kansas City Cardiomyopathy Questionnaire scores in both HFpEF and HFrEF, with more prominent differences in HFpEF (P interaction<0.05). In both HFpEF and HFrEF, patients with diabetes mellitus had more HF rehospitalizations (adjusted hazard ratio, 1.27; 95% CI, 1.05–1.54; P=0.014) and higher 1‐year rates of the composite of all‐cause mortality/HF hospitalization (adjusted hazard ratio, 1.22; 95% CI, 1.05–1.41; P=0.011), with no differences between HF phenotypes (P interaction>0.05). Conclusions In HFpEF and HFrEF, type 2 diabetes mellitus is associated with smaller left ventricular volumes, higher mitral E/e′ ratio, poorer quality of life, and worse outcomes, with several differences noted between HF phenotypes. Clinical Trial Registration URL: http://www.clinicaltrials. gov. Unique identifier: NCT01633398.
The iron-regulated vacuolar Legionella pneumophila MavN protein is a transition-metal transporter

Significance Iron is essential for microbial growth, and minimizing iron acquisition by pathogens is a cornerstone of the nutritional immunity response. Nevertheless, strategies by which intracellular pathogens circumvent these defenses are poorly understood. Herein, we demonstrate that the highly conserved Legionella effector protein MavN is the conduit for iron piracy by the bacterium. We map the in-membrane topology of MavN and pinpoint mutations that render the protein incompetent for sustaining Legionella intracellular proliferation. MavN iron transport activity was reconstituted in vitro and mutations identified as critical for growth were similarly detrimental to iron uptake. Our findings illuminate mechanistic details of iron accrual by Legionella and illustrate a scheme by which opportunistic bacteria can procure a limited but crucial nutrient. Legionella pneumophila causes a potentially fatal form of pneumonia by replicating within macrophages in the Legionella-containing vacuole (LCV). Bacterial survival and proliferation within the LCV rely on hundreds of secreted effector proteins comprising high functional redundancy. The vacuolar membrane-localized MavN, hypothesized to support iron transport, is unique among effectors because loss-of-function mutations result in severe intracellular growth defects. We show here an iron starvation response by L. pneumophila after infection of macrophages that was prematurely induced in the absence of MavN, consistent with MavN granting access to limiting cellular iron stores. MavN cysteine accessibilities to a membrane-impermeant label were determined during macrophage infections, revealing a topological pattern supporting multipass membrane transporter models. Mutations to several highly conserved residues that can take part in metal recognition and transport resulted in defective intracellular growth. Purified MavN and mutant derivatives were directly tested for transporter activity after heterologous purification and liposome reconstitution. Proteoliposomes harboring MavN exhibited robust transport of Fe2+, with the severity of defect of most mutants closely mimicking the magnitude of defects during intracellular growth. Surprisingly, MavN was equivalently proficient at transporting Fe2+, Mn2+, Co2+, or Zn2+. Consequently, flooding infected cells with either Mn2+ or Zn2+ allowed collaboration with iron to enhance intracellular growth of L. pneumophila ΔmavN strains, indicating a clear role for MavN in transporting each of these ions. These findings reveal that MavN is a transition-metal-ion transporter that plays a critical role in response to iron limitation during Legionella infection.
The Impact of Genomic and Traditional Selection on the Contribution of Mutational Variance to Long-Term Selection Response and Genetic Variance

De novo mutations (DNM) create new genetic variance and are an important driver for long-term selection response. We hypothesized that genomic selection exploits mutational variance less than traditional selection methods such as mass selection or selection on pedigree-based breeding values, because DNM in selection candidates are not captured when the selection candidates’ own phenotype is not used in genomic selection, DNM are not on SNP chips and DNM are not in linkage disequilibrium with the SNP on the chip. We tested this hypothesis with Monte Carlo simulation. From whole-genome sequence data, a subset of ∼300,000 variants was used that served as putative markers, quantitative trait loci or DNM. We simulated 20 generations with truncation selection based on breeding values from genomic best linear unbiased prediction without (GBLUP_no_OP) or with own phenotype (GBLUP_OP), pedigree-based BLUP without (BLUP_no_OP) or with own phenotype (BLUP_OP), or directly on phenotype. GBLUP_OP was the best strategy in exploiting mutational variance, while GBLUP_no_OP and BLUP_no_OP were the worst in exploiting mutational variance. The crucial element is that GBLUP_no_OP and BLUP_no_OP puts no selection pressure on DNM in selection candidates. Genetic variance decreased faster with GBLUP_no_OP and GBLUP_OP than with BLUP_no_OP, BLUP_OP or mass selection. The distribution of mutational effects, mutational variance, number of DNM per individual and nonadditivity had a large impact on mutational selection response and mutational genetic variance, but not on ranking of selection strategies. We advocate that more sustainable genomic selection strategies are required to optimize long-term selection response and to maintain genetic diversity.
Ethiopian muscids (Diptera, Muscidae) egg-carriers of Stylogaster Macquart (Diptera, Conopidae).

We here report for the first time on the presence of three species of the conopid genus Stylogaster Macquart (Diptera, Conopidae) in Ethiopia, viz. S. nitens Brunetti, S. westwoodi Smith and Stylogaster sp. We further screened 908 muscid flies (Diptera, Muscidae) for the presence of impaled eggs of Stylogaster and recorded eggs on 89 individuals (9.8%). Eggs were impaled on eight species, viz. Limnophora translucida Stein, Musca lusoria Wiedemann, Musca splendens Pont, Neomyia chrysopyga (Emden), Pseudohelina nigritarsis (Jaennicke), Stomoxys omega Newstead, Stomoxys taeniatus Bigot and Stomoxys varipes (Bezzi). The maximum number of eggs found on a single muscid was six. We illustrated the dissected eggs. L. translucida, M. lusoria, M. splendens, N. chrysopyga and S. varipes are reported as new muscid hosts species for Stylogaster.
Antitumor effect of insulin‐like growth factor‐1 receptor inhibition in head and neck squamous cell carcinoma

The insulin‐like growth factor‐1 receptor (IGF1R) has been implicated in therapeutic resistance in head and neck squamous cell carcinoma (HNSCC), and small molecule tyrosine kinase inhibitors (TKIs) of IGF1R activity may have anticancer activity. Therefore, the relationship between survival and IGF1R expression was assessed for oral cavity (OC) cancer, and the antitumor effects of two IGF1R‐TKIs, OSI‐906 and BMS‐754807, were evaluated in HNSCC cell lines in vitro.
Consumption of Milk and Alternatives and Their Contribution to Nutrient Intakes among Canadian Adults: Evidence from the 2015 Canadian Community Health Survey—Nutrition

As a staple food and dense source of nutrients, milk and alternatives play an important role in nutrient adequacy. The aims of this study were to quantify the consumption of milk and alternatives within Canadian self-selected diets and determine their contribution to intakes of nutrients and energy. First, 24-h dietary recalls from the 2015 Canadian Community Health Survey—Nutrition were used to assess 1-d food and nutrient intakes among Canadian adults ≥19 y (n = 13,616). Foods were classified as milk and alternatives according to the 2007 Canada’s Food Guide. Descriptive statistics were used to calculate daily servings of milk and alternatives by different age groups and demographic characteristics. Population ratios were used to discern their contribution to total intakes of nutrients and energy. Mean daily servings (±SE) were highest for milk (0.60 ± 0.02) and cheese (0.42 ± 0.01), intermediate for frozen dairy (0.16 ± 0.01) and yoghurt (0.14 ± 0.01), and lowest for soy and other dairy (<0.03). Intakes were lowest among Canadians 51 + y (1.3 ± 0.03), females (1.25 ± 0.03), non-Caucasians (1.06 ± 0.05), those with less than a secondary education (1.19 ± 0.05), and British Columbians (1.17 ± 0.05). Milk and alternatives contributed >20% to total intakes of calcium (52.62 ± 0.46%), vitamin D (38.53 ± 0.78%), saturated fat (28.84 ± 0.51%), vitamin B12 (27.73 ± 0.57%), vitamin A (26.16 ± 0.58%), phosphorus (24.76 ± 0.35%), and riboflavin (24.43 ± 0.37%), of which milk was the top source. Milk and alternatives contribute substantially to nutrient intakes and thus warrant further attention in terms of mitigating nutrient inadequacy among the Canadian population.
Demographics in Patients Receiving Matrix-Assisted Chondrocyte Implantation (MACI) in the Ankle

Objective. To compare demographics and cartilage lesion characteristics of patients enrolled in clinical trials investigating autologous chondrocyte implantation (ACI) in the ankle joint with those actually scheduled for matrix-assisted chondrocyte implantation (MACI) using database records. Design. Anonymized data from patients scheduled for MACI treatment in the ankle in Australia/Asia and Europe were obtained from the Genzyme/Sanofi database. Average age, defect size, and male-female ratio were analyzed and compared by country. A literature search was performed on PubMed and Google Scholar and clinical cohort studies and prospective comparative trials using ACI and related treatments in the ankle joint were identified. Weighted average age, weighted defect size, and male-female ratio were analyzed and compared with database data. Results. The 167 patients included from the databases from Europe and Australia had a mean age of 33.4 years (range 14-64 years) and a mean defect size of 2.27 cm2 (range 0.25-16 cm2). Male-female ratio was 4:3. Patients from European countries were significantly younger and had significantly larger defects compared with patients from Australia. From the literature search a total of 472 patients were included from 28 studies. The mean age was 32.2 years (range 15-62 years). Male-female ratio was 3:2. Weighted mean size was 1.94cm2 (range 0.3-16). There were no significant differences between previous studies and databases. Conclusion. No differences in sizes and age were found between patients enrolled in clinical trials and patients scheduled for MACI outside clinical trials. The sizes of treated defects followed the general recommendations. There were, however, significant differences between countries.
Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism

Abstract Background Permanent primary congenital hypothyroidism (CH) can be caused by thyroid dysgenesis or dyshormonogenesis. A molecular genetic study is recommended in dyshormonogenesis, in syndromic hypothyroidism and when there is a family history of CH. The aim of this study was to identify a monogenic etiology for CH in selected individuals from a cohort of primary permanent CH. Methods From an initial cohort of 79 patients with permanent CH (3–19 years), 11 patients were selected for molecular analyses. Nine patients with dyshormonogenesis (normal in-situ gland or goiter) were screened for causative variants, by next-generation sequencing (NGS), in 28 genes known to be responsible for CH. One patient with a family history of CH was screened for the paired-box gene 8 (PAX8) gene and another patient with a syndromic CH was screened for the NKX2-1 gene. Results We found a monogenic basis of disease in eight patients, involving the thyroid peroxidase (TPO) gene (four patients), the thyroglobulin (TG) gene (two patients), and the PAX8 and NKX2-1 genes (one patient each). Two patients were heterozygotes, one harboring a variant in the TG gene and the other in the SLC5A5 gene. In one patient, we found no potential causative variants in any of the 28 genes screened. We described five novel variants: three in the TG gene, one in the NKX2-1 and one in the SLC5A5 gene, all of them classified as pathogenic. Conclusions In eight of the 11 screened patients, a monogenic disease was found. These results highlight the advantage of using an NGS panel and provide further data regarding the molecular basis of CH.
Therapeutic effect of transplantation of human bone marrow-derived mesenchymal stem cells on neuron regeneration in a rat model of middle cerebral artery occlusion

Human bone marrow-derived mesenchymal stromal cells (hBMSCs) have been revealed to be beneficial for the regeneration of tissues and cells in several diseases. The present study aimed to elucidate the mechanisms underlying the effect of hBMSC transplantation on neuron regeneration in a rat model of middle cerebral artery occlusion (MCAO). The hBMSCs were isolated, cultured and identified. A rat model of MCAO was induced via the modified Longa method. Neurological severity scores (NSS) were adopted for the evaluation of neuronal function in the model rats after cell transplantation. Next, the expression levels of nestin, β-III-tubulin (β-III-Tub), glial fibrillary acidic protein (GFAP), HNA and neuronal nuclear antigen (NeuN) were examined, as well as the positive expression rates of human neutrophil alloantigen (HNA), nestin, NeuN, β-III-Tub and GFAP. The NSS, as well as the mRNA and protein expression of nestin, decreased at the 1st, 2nd, 4 and 8th weeks, while the mRNA and protein expression of NeuN, β-III-Tub and GFAP increased with time. In addition, after treatment, the MCAO rats showed decreased NSS and mRNA and protein expression of nestin, but elevated mRNA and protein expression of NeuN, β-III-Tub and GFAP at the 2nd, 4 and 8th weeks, and decreased positive expression of HNA and nestin with enhanced expression of NeuN, β-III-Tub and GFAP. Therefore, the present findings demonstrated that hBMSC transplantation triggered the formation of nerve cells and enhanced neuronal function in a rat model of MCAO.
Extracellular Vesicles in the Blood of Dogs with Cancer—A Preliminary Study

Simple Summary Extracellular vesicles are a diverse population of submicron-sized structures released from cells under physiological and pathological conditions. Due to their size, their role in cell-to-cell communication in cancer is currently being discussed. In blood, the most abundant population is platelet-derived extracellular vesicles. The aim of this study was to estimate the absolute number and the origin of extracellular vesicles in the blood of healthy dogs and of dogs with various types of cancer. The number of extracellular vesicles derived from platelets, leukocytes, and T lymphocytes was significantly higher in dogs with cancer compared to healthy controls. Estimation of platelet-derived extracellular vesicle (PEV) and leukocyte-derived EV counts may provide a useful biological marker in dogs with cancer. Abstract Extracellular vesicles (EVs) are a heterogeneous population of submicron-sized structures released during the activation, proliferation, or apoptosis of various types of cells. Due to their size, their role in cell-to-cell communication in cancer is currently being discussed. In blood, the most abundant population of EVs is platelet-derived EVs (PEVs). The aim of this study was to estimate the absolute number and the origin of EVs in the blood of healthy dogs and of dogs with various types of cancer. The EV absolute number and cellular origin were examined by flow cytometry technique. EVs were classified on the basis of surface annexin V expression (phosphatidylserine PS+) and co-expression of specific cellular markers (CD61, CD45, CD3, CD21). The number of PEVs was significantly higher in dogs with cancer (median: 409/µL, range: 42–2748/µL vs. median: 170/µL, range: 101–449/µL in controls). The numbers of EVs derived from leukocytes (control median: 86/µL, range: 40–240/µL; cancer median: 443/µL, range: 44–3 352/µL) and T cells (control median: 5/µL, range: 2–66/µL; cancer median: 108/µL, range: 3–1735/µL) were higher in dogs with neoplasia compared to healthy controls. The estimation of PEV and leukocyte-derived EV counts may provide a useful biological marker in dogs with cancer.
Multi-organ assessment via a 9.4-Tesla MRS evaluation of metabolites during the embryonic development of cleft palate induced by dexamethasone

The aim of the present study was to determine the association between maternal metabolism and development of the fetal palate, and to suggest a potential non-invasive prenatal diagnostic method for fetal cleft palate (CP). Dexamethasone (DXM) was used to create a CP mouse model. A 9.4-Tesla (T) magnetic resonance spectroscopy (MRS) imager was used to measure an array of metabolites in the maternal serum, placental tissue, amniotic fluid and fetal palates. Multivariate statistical analysis was performed using SIMCA-P 14.1 software. Following DXM treatment, variations were detected in multiple metabolites in the female mice and their fetuses based on 9.4T MRS. It was indicated that in the experimental group during CP formation, leucine, valine, creatine, acetate and citrate levels in the palatal tissue were lower, whereas lactate, alanine, proline/inositol and glutamate-containing metabolite levels were higher, compared with the levels in the control group. In placental tissue and amniotic fluid, succinate and choline levels were lower in the experimental group. The relative concentrations of cholesterol and lipids in palatal tissues from mice treated with DXM were higher compared with the concentrations in tissues from mice in the control group, with the exception of (CH2)n lipids. In the placental tissue, the alteration in cholesterol level exhibited the opposite trend. Lipid levels for the different lipid forms varied and most of them were unsaturated lipids.
TLR induces reorganization of the IgM-BCR complex regulating murine B-1 cell responses to infections

In mice, neonatally-developing, self-reactive B-1 cells generate steady levels of natural antibodies throughout life. B-1 cells can, however, also rapidly respond to infections with increased local antibody production. The mechanisms regulating these two seemingly very distinct functions are poorly understood, but have been linked to expression of CD5, an inhibitor of BCR-signaling. Here we demonstrate that TLR-mediated activation of CD5+ B-1 cells induced the rapid reorganization of the IgM-BCR complex, leading to the eventual loss of CD5 expression, and a concomitant increase in BCR-downstream signaling, both in vitro and in vivo after infections of mice with influenza virus and Salmonella typhimurium. Both, initial CD5 expression and TLR-mediated stimulation, were required for the differentiation of B-1 cells to IgM-producing plasmablasts after infections. Thus, TLR-mediated signals support participation of B-1 cells in immune defense via BCR-complex reorganization.
A novel drug delivery system of mixed micelles based on poly(ethylene glycol)‐poly(lactide) and poly(ethylene glycol)‐poly(ɛ‐caprolactone) for gambogenic acid

In this study, a novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)‐poly(lactide) (mPEG‐PLA) and poly(ethylene glycol)‐poly(ɛ‐caprolactone) (mPEG‐PCL), used as a novel nanocarrier to encapsulate gambogenic acid (GNA). GNA‐loaded mixed polymeric micelles (GNA‐MMs) was prepared by cosolvent evaporation method. The mean average size of GNA‐MMs was (83.23 ± 1.06) nm (n = 3) and entrapment efficiency (EE%) of GNA‐MMs was (90.18 ± 2.59) % (n = 3) as well as (12.36 ± 0.64) % (n = 3) for drug loading (DL%). Transmission electron microscopy revealed that the GNA‐MMs were spherical with “core‐shell” structures. Compared with free GNA solution, in vitro release of GNA from GNA‐MMs showed a two‐phase sustained release profile: an initial relatively fast phase and followed by a slower release phase. Pharmacokinetic results also indicated that the GNA‐MMs have longer systemic circulation time and slower plasma elimination rate than free GNA solution. Moreover, the in vitro cytotoxicity assay showed that the IC50 values on HepG2 cells for GNA‐MMs and free GNA were (5.67 ± 0.02) μM and (9.02 ± 0.03) μM, respectively. In addition, GNA‐MMs significantly increased the HepG2 cellular apoptosis in a concentration‐dependent manner. In conclusion, the results showed that mPEG‐PLA/mPEG‐PCL mixed micelles may serve as an ideal drug delivery system for GNA to prolong drug circulation time in body, enhance bioavailability and retained its potent antitumor effect.
Improved periodontal disease and prevention of tooth loss in osteoporosis patients receiving once-yearly zoledronic acid: a randomized clinical trial.

OBJECTIVE This randomized, clinical trial investigated whether zoledronic acid combined with oral health maintenance can improve periodontal disease associated with osteoporosis, thus reducing the risk of tooth loss. METHODS Participants were those of the ZONE (ZOledroNate treatment in efficacy to osteoporosis) study. None of the participants had symptomatic periodontal disease at baseline. Participants received either zoledronic acid (5 mg; n = 333 [male 21, female 312]) or placebo (n = 332 [male 19, female 313]) once yearly for 2 years, and their age was 74.0 ± 5.3 (65-88) and 74.3 ± 5.4 (65-87) years, respectively. Participants were instructed to maintain good oral hygiene at baseline and every 3 months. Participants with signs or symptoms involving their oral cavity at the monthly visit with their physician were referred to dentists for examination of oral disease. All cases were included to analyze adverse events in this study. Testing for significance was conducted using Fisher exact test (P < 0.05). RESULTS The incidence of oral adverse events was significantly higher in the control group (67 cases, 20.2%) than in the zoledronic acid group (47 cases, 14.1%; P = 0.04). The frequency of symptomatic periodontal disease observed during the study was significantly higher in the control group (40 cases, 12.0%) than in the zoledronic acid group (18 cases, 5.4%; P = 0.002). Loss of teeth was more frequent in the control group (36 cases, 10.8%) than in the zoledronic acid group (24 cases, 7.2%), although the difference was not significant. CONCLUSIONS Zoledronic acid effectively prevented symptomatic periodontal disease in patients with osteoporosis who maintained good oral hygiene. : Video Summary: Supplemental Digital Content 1, http://links.lww. com/MENO/A438.