Miracle-dz/UniFAR-FTUs huggingface dataset:
Developmental origins for semilunar valve stenosis identified in mice harboring congenital heart disease-associated GATA4 mutation

ABSTRACT Congenital heart defects affect ∼2% of live births and often involve malformations of the semilunar (aortic and pulmonic) valves. We previously reported a highly penetrant GATA4 p.Gly296Ser mutation in familial, congenital atrial septal defects and pulmonic valve stenosis and showed that mice harboring the orthologous G295S disease-causing mutation display not only atrial septal defects, but also semilunar valve stenosis. Here, we aimed to characterize the role of Gata4 in semilunar valve development and stenosis using the Gata4G295Ski/wt mouse model. GATA4 is highly expressed in developing valve endothelial and interstitial cells. Echocardiographic examination of Gata4G295Ski/wt mice at 2 months and 1 year of age identified functional semilunar valve stenosis predominantly affecting the aortic valve with distal leaflet thickening and severe extracellular matrix (ECM) disorganization. Examination of the aortic valve at earlier postnatal timepoints demonstrated similar ECM abnormalities consistent with congenital disease. Analysis at embryonic timepoints showed a reduction in aortic valve cushion volume at embryonic day (E)13.5, predominantly affecting the non-coronary cusp (NCC). Although total cusp volume recovered by E15.5, the NCC cusp remained statistically smaller. As endothelial to mesenchymal transition (EMT)-derived cells contribute significantly to the NCC, we performed proximal outflow tract cushion explant assays and found EMT deficits in Gata4G295Ski/wt embryos along with deficits in cell proliferation. RNA-seq analysis of E15.5 outflow tracts of mutant embryos suggested a disease state and identified changes in genes involved in ECM and cell migration as well as dysregulation of Wnt signaling. By utilizing a mouse model harboring a human disease-causing mutation, we demonstrate a novel role for GATA4 in congenital semilunar valve stenosis. This article has an associated First Person interview with the joint first authors of the paper. Summary: Cellular and molecular characterization of a mutant mouse, harboring a human disease-causing GATA4 variant, identifies cellular deficits in endothelial-to-mesenchymal transition and proliferation that cause abnormal valve remodeling and resultant stenosis.
Exploring Associations between Interindividual Differences in Taste Perception, Oral Microbiota Composition, and Reported Food Intake

The role of taste perception, its relationship with oral microbiota composition, and their putative link with eating habits and food intake were the focus of the present study. A sample of 59 reportedly healthy adults (27 male, 32 female; age: 23.3 ± 2.6 years) were recruited for the study and taste thresholds for basic tastes, food intake, and oral microbiota composition were evaluated. Differences in taste perception were associated with different habitual food consumption (i.e., frequency) and actual intake. Subjects who were orally hyposensitive to salty taste reported consuming more bakery and salty baked products, saturated-fat-rich products, and soft drinks than hypersensitive subjects. Subjects hyposensitive to sweet taste reported consuming more frequently sweets and desserts than the hypersensitive group. Moreover, subjects hypersensitive to bitter taste showed higher total energy and carbohydrate intakes compared to those who perceived the solution as less bitter. Some bacterial taxa on tongue dorsum were associated with gustatory functions and with vegetable-rich (e.g., Prevotella) or protein/fat-rich diets (e.g., Clostridia). Future studies will be pivotal to confirm the hypothesis and the potential exploitation of oral microbiome as biomarker of long-term consumption of healthy or unhealthy diets.
A Competitive Distribution Theory of Neocortical Dynamics

Peristimulus inhibition in sensory pathways is generally attributed to lateral inhibitory connections. However, in the neocortex circuitry is incompletely understood at present, and in some cases there is an apparent mismatch between observed inhibitory effects and intracortical inhibitory connections. This paper studies the hypothesis that an additional mechanism, competitive distribution of activation, underlies some inhibitory effects in cortex. Analysis of a mathematical model based on this hypothesis predicts that per stimulus inhibitory effects can be caused by competitive distribution of activation, and computer simulations confirm these predictions by demonstrating Mexican Hat patterns of lateral interactions, transformation of initially diffuse activity patterns into tightly focused "islands" of activation, and edge enhancement. The amount of inhibition can be adjusted by varying the intensity of the underlying competitive process. The concept of competitive distribution of activation provides an important perspective for interpreting neocortical and thalamocortical circuitry and can serve as a guide for further morphological and physiological studies. For example, it provides an explanation for the existence of recurrent cortex-to-thalamus connections that perform a logical AND-operation, and predicts the existence of analogous neocortical circuitry.
Preface Gunther Paul

Biographical notes: Gunther Paul studied Engineering and Ergonomics at TU Darmstadt in Germany, where he received his Master in Mechatronics and PhD in Ergonomics. After working at TU Darmstadt, he joined Ford and remained in product development, IT and manufacturing engineering functions in the automotive industry in Europe until 2009; when he moved to Australia and established the Ergolab research group at the University of South Australia. He is now reading OHS and Ergonomics at Queensland University of Technology, co-chairing the IEA technical committee for human simulation and virtual environments, and researching comfort-related, biomechanical DHM for product design and musculoskeletal workload assessment.
Genetic analyses led to the discovery of a super-active mutant of the RNA polymerase I

Most transcriptional activity of exponentially growing cells is carried out by the RNA Polymerase I (Pol I), which produces a ribosomal RNA (rRNA) precursor. In budding yeast, Pol I is a multimeric enzyme with 14 subunits. Among them, Rpa49 forms with Rpa34 a Pol I-specific heterodimer (homologous to PAF53/CAST heterodimer in human Pol I), which might be responsible for the specific functions of the Pol I. Previous studies provided insight in the involvement of Rpa49 in initiation, elongation, docking and releasing of Rrn3, an essential Pol I transcription factor. Here, we took advantage of the spontaneous occurrence of extragenic suppressors of the growth defect of the rpa49 null mutant to better understand the activity of Pol I. Combining genetic approaches, biochemical analysis of rRNA synthesis and investigation of the transcription rate at the individual gene scale, we characterized mutated residues of the Pol I as novel extragenic suppressors of the growth defect caused by the absence of Rpa49. When mapped on the Pol I structure, most of these mutations cluster within the jaw-lobe module, at an interface formed by the lobe in Rpa135 and the jaw made up of regions of Rpa190 and Rpa12. In vivo, the suppressor allele RPA135-F301S restores normal rRNA synthesis and increases Pol I density on rDNA genes when Rpa49 is absent. Growth of the Rpa135-F301S mutant is impaired when combined with exosome mutation rrp6Δ and it massively accumulates pre-rRNA. Moreover, Pol I bearing Rpa135-F301S is a hyper-active RNA polymerase in an in vitro tailed-template assay. We conclude that RNA polymerase I can be engineered to produce more rRNA in vivo and in vitro. We propose that the mutated area undergoes a conformational change that supports the DNA insertion into the cleft of the enzyme resulting in a super-active form of Pol I.
Hematological Malignancy-Derived Small Extracellular Vesicles and Tumor Microenvironment: The Art of Turning Foes into Friends

Small extracellular vesicles (small EVs) are commonly released by all cells, and are found in all body fluids. They are implicated in cell to cell short- and long-distance communication through the transfer of genetic material and proteins, as well as interactions between target cell membrane receptors and ligands anchored on small EV membrane. Beyond their canonical functions in healthy tissues, small EVs are strategically used by tumors to communicate with the cellular microenvironment and to establish a proper niche which would ultimately allow cancer cell proliferation, escape from the immune surveillance, and metastasis formation. In this review, we highlight the effects of hematological malignancy-derived small EVs on immune and stromal cells in the tumor microenvironment.
Risk Factors for Extended-Spectrum β-Lactamase-Producing Enterobacteriaceae Carriage in Patients Admitted to Intensive Care Unit in a Tertiary Care Hospital in Thailand.

Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) are important causes of serious infections in intensive care unit (ICU). This study aimed to investigate the risk factors for intestinal carriage of ESBL-PE among patients admitted to ICU, subsequent ESBL-PE infections, and outcomes of these patients. This study prospectively collected rectal swabs from 215 ICU patients in Northern Thailand and ESBL-PE were isolated. A high prevalence of ESBL-PE carriage (134/215, 62.3%) at ICU admission was observed, with Escherichia coli representing the predominant organism (67.5%) followed by Klebsiella pneumoniae (19.4%). Multivariate logistic regression analysis identified chronic renal disease as the independent risk factor for ESBL-PE carriage (p = 0.009; adjusted odds ratio = 4.369; 95% confidence interval = 1.455-13.119). Among colonized patients, 2.2% (3/134) developed ESBL-PE infections during ICU stay. Phylogenetic analysis of E. coli (n = 108) showed that the predominant group was group A (38.0%), followed by groups B1 (17.6%), D (15.7%), B2 (14.8%), C (7.4%), and F (6.5%). Multilocus sequence typing analysis of the pathogenic groups B2, D, and F revealed 11 different sequence types (STs), with ST131 (n = 13) as the most prevalent, followed by ST648 (n = 5), ST38 (n = 4), ST393 (n = 3), and ST1193 (n = 3). These results are of concern since ESBL-PE may be a prerequisite for endogenous infections and potentially disseminate within the hospital. This is the first study describing ESBL-PE carriage among patients at ICU admission and subsequent ESBL-PE infections in Thailand.
The Value of Elasticity Contrast Index in the Differential Diagnosis of Thyroid Solid Nodules.

OBJECTIVES To assess the clinical value of elasticity contrast index (ECI) in differentiating malignant thyroid nodules from benign ones. METHODS Conventional ultrasound and elastography with pulsation of the carotid artery used as the compression source were retrospectively reviewed on 175 patients (143 females and 32 males; mean ± SD age, 45.17 ± 11.45 years) with 236 solid nodules (113 malignant and 123 benign). All nodules were confirmed by fine-needle aspiration or surgery to be accurately diagnosed. Elasticity contrast index values were computed and used to quantify local stiffness contrast within a nodule as determined with elastography. Elasticity contrast index values between the malignant and benign groups were compared and then related with pathological results. Diagnostic performance of this method was evaluated with use of the receiver operating characteristic curve. RESULTS Mean ± SD ECI values for malignant thyroid nodules were significantly greater than those for benign nodules (3.67 ± 1.20 vs 1.80 ± 0.74, P < 0.01). Area under the receiver operating characteristic curve of ECI values was 0.907 (95% confidence interval, 0.867-0.948), and the best cutoff point was 2.16, leading to a sensitivity of 90.3%, specificity of 82.9%, positive predictive value of 83.7% and negative predictive value of 91.2%. CONCLUSIONS Elasticity contrast index values can serve as a useful parameter in the differential diagnosis of solid thyroid nodules. With the use of ECI values, objective quantitative information on the tumor stiffness can be achieved to improve diagnostic confidence.
Outcome of expandable endoprosthesis: A single centre retrospective review

Purpose: Expandable endoprosthesis allows limb salvage in children with an option to leading a better life. However, the revision rate and implant-related complications impose as a limitation in the skeletal immature. This study investigates the functional outcomes and complications related to expandable endoprosthesis in our centre. Materials and Methods: Twenty surviving patients with expandable endoprosthesis from 2006 till 2015 were scored using Musculoskeletal Tumour Society (MSTS) outcomes instrument and reviewed retrospectively for range of motion of respected joints, limb length discrepancy, number of surgeries performed, complications and oncological outcomes. Patients with less than 2 years of follow-up were excluded from this study. Results: Forty-five percentage patients reached skeletal maturity with initial growing endoprosthesis and 25% of patients were revised to adult modular prosthesis. One hundred fifty-seven surgeries were performed over the 9-year period. The average MSTS score was 90.83%. The mortality rate was 10% within 5 years due to advanced disease. Infection and implant failure rate was 15% each. The event-free survival was 50% and overall survival rate was 90%. Conclusion: There is no single best option for reconstruction in skeletally immature. This study demonstrates a favourable functional and survival outcome of paediatric patients with expandable endoprosthesis. The excellent MSTS functional scores reflect that patients were satisfied and adjusted well to activities of daily living following surgery despite the complications.
Age and seasonal variation in the transition rates and detectability of Plasmodium falciparum malaria

The effect of acquired immunity on the duration of Plasmodium falciparum infections is unclear, although this is an important term in models of malaria transmission. It is problematical to determine the duration of infections because of the difficulty of distinguishing persisting infections from new ones, and because parasite densities are often transiently below the limit of detection. We recently developed a dynamic model for infection incidence, clearance and detection of multiple genotype P. falciparum infections and fitted it to a panel dataset from a longitudinal study in Northern Ghana. We now extend this model to allow for seasonal and age variation in infection rates and also age dependence in clearance and in detectability of infections. These models indicate that there is seasonal variation in the infection rate, and age dependence in detectability. The best fitting models had no age dependence in infection or clearance rates, suggesting that acquired immunity mainly affects detectability.
A Large-Scale Genome-Wide Association Analyses of Ethiopian Sorghum Landrace Collection Reveal Loci Associated With Important Traits

The eastern Africa region, Ethiopia and its surroundings, is considered as the center of origin and diversity for sorghum, and has contributed to global sorghum genetic improvement. The germplasm from this region harbors enormous genetic variation for various traits but little is known regarding the genetic architecture of most traits. Here, 1425 Ethiopian landrace accessions were phenotyped under field conditions for presence or absence of awns, panicle compactness and shape, panicle exsertion, pericarp color, glume cover, plant height and smut resistance under diverse environmental conditions in Ethiopia. In addition, F1 hybrids obtained from a subset of 1341 accessions crossed to an A1 cytoplasmic male sterile line, ATx623, were scored for fertility/sterility reactions. Subsequently, genotyping-by-sequencing generated a total of 879,407 SNPs from which 72,190 robust SNP markers were selected after stringent quality control (QC). Pairwise distance-based hierarchical clustering identified 11 distinct groups. Of the genotypes assigned to either one of the 11 sub-populations, 65% had high ancestry membership coefficient with the likelihood of more than 0.60 and the remaining 35% represented highly admixed accessions. A genome-wide association study (GWAS) identified loci and SNPs associated with aforementioned traits. GWAS based on compressed mixed linear model (CMLM) identified SNPs with significant association (FDR ≤ 0.05) to the different traits studied. The percentage of total phenotypic variation explained with significant SNPs across traits ranged from 2 to 43%. Candidate genes showing significant association with different traits were identified. The sorghum bHLH transcription factor, ABORTED MICROSPORES was identified as a strong candidate gene conditioning male fertility. Notably, sorghum CLAVATA1 receptor like kinase, known for regulation of plant growth, and the ETHYLENE RESPONSIVE TRANSCRIPTION FACTOR gene RAP2-7, known to suppress transition to flowering, were significantly associated with plant height. In addition, the YELLOW SEED1 like MYB transcription factor and TANNIN1 showed strong association with pericarp color validating previous observations. Overall, the genetic architecture of natural variation representing the complex Ethiopian sorghum germplasm was established. The study contributes to the characterization of genes and alleles controlling agronomic traits, and will serve as a source of markers for molecular breeding.
Universal Adhesives: Setting Characteristics and Reactivity with Dentin

The aim of the study was to evaluate the performance of six commercially available universal dental adhesives: Adhese Universal (ADU), All-Bond Universal (ABU), Clearfil Universal Bond Quick (CBQ), G-Premio Bond (GPB), Prelude One (PRO) and Scotchbond Universal (SBU). The properties tested were: (a) degree of C=C conversion (DC%); (b) Vickers micro-hardness (VHN); (c) extent of oxygen inhibition (OI/μm), all related with the adhesive film properties; (d) extent of dentin demineralisation (DM%), insoluble salt formation (AS%); and (e) shear bond strength (SBS, self-etch mode) related to the adhesive-dentin interactions. Statistical analysis (α = 0.05) was performed by one-way ANOVA and Tukey’s test (DC%, VHN, OI, DM% AS%) and Weibull analysis (SBS, σ0-β). The DC ranged from 67.2–82.5% (all >GPB), OI from 5.6–18.6 μm (SBU > ADU, GPB, ABU > CBQ > PRO), microhardness from 1.1–6.6 VHN (SBU > ADU > ABU > CBQ > PRO > GPB: not measurable), DM from 69.3% (GPB) to 16–12.5% (CBQ, SBU, ADU) and 13.2–10.6% (ABU, ADU, PRO), in homogeneous groups and AS from 26–15.9% (ABU, CBQ > GPB, PRO, ADU, SBU). For SBS the σ0 (characteristic life) ranged from 29.3–16.6 MPa (CBQ, ADU, ABU, SBU > PRO > GPB), the β (reliability) from 5.1–9.7 (p > 0.05). All failure modes were of mixed type (adhesive and composite cohesive). Although all these adhesives were based on the 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP) adhesive monomer, the different co-monomers, solvents and catalysts led to variations in their film properties, reactivity and bonding capacity with dentin.
Blocking tombusvirus replication through the antiviral functions of DDX17-like RH30 DEAD-box helicase

Positive-stranded RNA viruses replicate inside cells and depend on many co-opted cellular factors to complete their infection cycles. To combat viruses, the hosts use conserved restriction factors, such as DEAD-box RNA helicases, which can function as viral RNA sensors or as effectors by blocking RNA virus replication. In this paper, we have established that the plant DDX17-like RH30 DEAD-box helicase conducts strong inhibitory function on tombusvirus replication when expressed in plants and yeast surrogate host. The helicase function of RH30 was required for restriction of tomato bushy stunt virus (TBSV) replication. Knock-down of RH30 levels in Nicotiana benthamiana led to increased TBSV accumulation and RH30 knockout lines of Arabidopsis supported higher level accumulation of turnip crinkle virus. We show that RH30 DEAD-box helicase interacts with p33 and p92pol replication proteins of TBSV, which facilitates targeting of RH30 from the nucleus to the large TBSV replication compartment consisting of aggregated peroxisomes. Enrichment of RH30 in the nucleus via fusion with a nuclear retention signal at the expense of the cytosolic pool of RH30 prevented the re-localization of RH30 into the replication compartment and canceled out the antiviral effect of RH30. In vitro replicase reconstitution assay was used to demonstrate that RH30 helicase blocks the assembly of viral replicase complex, the activation of the RNA-dependent RNA polymerase function of p92pol and binding of p33 replication protein to critical cis-acting element in the TBSV RNA. Altogether, these results firmly establish that the plant DDX17-like RH30 DEAD-box helicase is a potent, effector-type, restriction factor of tombusviruses and related viruses. The discovery of the antiviral role of RH30 DEAD-box helicase illustrates the likely ancient roles of RNA helicases in plant innate immunity.
Exergaming-Based Dexterity Training in Persons With Parkinson Disease: A Pilot Feasibility Study

Background and Purpose: Many individuals with Parkinson disease (PD) suffer from impaired dexterity, which impacts activities of daily living and quality of life. Exergaming, video game-based training with augmented virtual reality, may have value for improving function. The aim of the present pilot study was to comprehensively evaluate the feasibility of a dexterity training program using exergaming, in individuals with PD. Methods: Ten participants with PD (aged between 55 and 75 years, Hoehn and Yahr stages II-IV) trained over a period of 4 weeks, twice a week for 30 minutes. Baseline (T0) and postintervention (T1) assessments were done. Primary outcomes with respect to feasibility were the adherence rate, open-end questions, the level of participation (Pittsburgh Rehabilitation Participation Scale), and the usability (System Usability Scale). Dexterous function was measured with the Nine-Hole Peg Test and the Dexterity Questionnaire-24. Upper limb motor impairment was assessed by a modified version of the Movement Disorders Society Unified Parkinson's Disease Rating Scale III. Finally, quality of life was assessed by the 39-item Parkinson's Disease Questionnaire (PDQ-39). Results: Adherence rate was 99%, motivation increased significantly from 3.9 to 4.8 (Pittsburgh Rehabilitation Participation Scale, P = 0.03), and system usability of the exergaming system was acceptable to very good. Regarding potential efficacy, participants with impaired dexterity at T0 significantly improved in the Nine-Hole Peg Test and the PDQ-39. Discussions and Conclusions: The outcomes of this pilot study suggest that exergaming is feasible and has potential to improve dexterity in individuals with PD. Its efficacy should be investigated in a properly powered randomized controlled trial. Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A270).