Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Hinge Gap Width of a St. Jude Medical Bileaflet Mechanical Heart Valve on Blood Damage Potential—An In Vitro Micro Particle Image Velocimetry Study

The hinge regions of the bileaﬂet mechanical heart valve (BMHV) can cause blood element damage due to nonphysiological shear stress levels and regions of ﬂow stasis. Recently, a micro particle image velocimetry ( l PIV) system was developed to study whole ﬂow ﬁelds within BMHV hinge regions with enhanced spatial resolution under steady leakage ﬂow conditions. However, global velocity maps under pulsatile conditions are still necessary to fully understand the blood damage potential of these valves. The current study hypothesized that the hinge gap width will affect ﬂow ﬁelds in the hinge region. Accordingly, the blood damage potential of three St. Jude Medical (SJM) BMHVs with different hinge gap widths was investigated under pulsatile ﬂow conditions, using a l PIV system. The results demonstrated that the hinge gap width had a signiﬁcant inﬂu- ence during the leakage ﬂow phase in terms of washout and shear stress characteristics. During the leakage ﬂow, the largest hinge gap generated the highest Reynolds shear stress (RSS) magnitudes ( (cid:2) 1000N/m 2 ) among the three valves at the ventricular side of the hinge. At this location, all three valves indicated viscous shear stresses (VSS) greater than 30N/m 2 . The smallest hinge gap exhibited the lowest level of shear stress values, but had the poorest washout ﬂow characteristics among the three valves, demonstrating pro- pensity for ﬂow stasis and associated activated platelet accumulation potential. The results from this study indicate that the hinge is a critical component of the BMHV design, which needs to be optimized to ﬁnd the appropriate balance between reduction in ﬂuid shear stresses and enhanced washout during leakage ﬂow, to ensure minimal throm- botic complications. [DOI: 10.1115/1.4027935] These unique aspects of BMHV ﬂows found in the current l PIV study such as evaluating cycle to cycle variation and global velocity maps under micronscale ﬂow domains are not restricted to the hinge region. Previous studies indicated that large recircula- tion regions are formed upstream of the valve during the leakage phase [28,29]. In addition, strong regurgitant jets were observed in the B-datum plane and peripheral leakage regions located in the neighborhood of the hinge [29,30]. These combined factors can potentially trap damaged blood elements at these locations result- ing in thromboembolism. However, these ﬂow features are outside the scope of this study, which focus on ﬂow ﬁelds within the hinge regions.Theestablished technique from this study can be used to assess other critical regions in a BMHV such as leakage ﬂow through the B-datum gap, and ﬂow ﬁelds in the immediate vicinity of a hinge during the period of valve closure. This study has shown the fully pulsatile ﬂow characteristics of the three valve models with intri- cate hinge ﬂow structures. In addition, the study has demonstrated the application of the high-resolution l PIV system, which can aid in the design optimization of BMHVs.
TGF- (cid:1) and the Smad Signaling Pathway Support Transcriptomic Reprogramming during Epithelial-Mesenchymal Cell Transition □ D

Epithelial-mesenchymal transition (EMT) contributes to normal tissue patterning and carcinoma invasiveness. We show that transforming growth factor (TGF)- (cid:1) /activin members, but not bone morphogenetic protein (BMP) members, can induce EMT in normal human and mouse epithelial cells. EMT correlates with the ability of these ligands to induce growth arrest. Ectopic expression of all type I receptors of the TGF- (cid:1) superfamily establishes that TGF- (cid:1) but not BMP pathways can elicit EMT. Ectopic Smad2 or Smad3 together with Smad4 enhanced, whereas dominant-negative forms of Smad2, Smad3, or Smad4, and wild-type inhibitory Smad7, blocked TGF- (cid:1) –induced EMT. Transcriptomic analysis of EMT kinetics identiﬁed novel TGF- (cid:1) target genes with ligand-speciﬁc responses. Using a TGF- (cid:1) type I receptor that cannot activate Smads nor induce EMT, we found that Smad signaling is critical for regulation of all tested gene targets during EMT. One such gene, Id2 , whose expression is repressed by TGF- (cid:1) 1 but induced by BMP-7 is critical for regulation of at least one important myoepithelial marker, (cid:2) -smooth muscle actin, during EMT. Thus, based on ligand-speciﬁc responsiveness and evolutionary conservation of the gene expression patterns, we begin deciphering a genetic network downstream of TGF- (cid:1) and predict functional links to the control of cell proliferation and EMT. for corresponding signiﬁcant based on their expression using the K -means statistical algorithm that incorporated into GeneSpring 6.0 data mining software (Silicon For all time con- time point the condition of duplicate cell cultures treated in an identical as the TGF- (cid:1) 1–treated samples, with the only difference being that we replaced TGF- (cid:1) 1 with vehicle. Functional classiﬁcation of the regulated genes was performed manually based on exhaustive searches in PubMed All ﬁles con-taining the raw data of the microarray analysis have been deposited at the European Bioin-formatics Institute (Hinxton) and are publicly available with Acc. No. E- MEXP-139.
Beginning to Talk Like an Adult: Increases in Speech-like Utterances in Young Cochlear Implant Recipients and Toddlers with Normal Hearing

Background— Speech-like utterances containing rapidly combined consonants and vowels eventually dominate the prelinguistic and early word productions of toddlers who are developing typically (TD). It seems reasonable to expect a similar phenomenon in young cochlear implants (CI) recipients. This study sought to determine the number of months of robust hearing experience needed to achieve a majority of speech-like utterances in both of these groups. Methods— Speech samples were recorded at 3-month intervals during the first 2 years of CI experience, and between 6- and 24 months of age in TD children. Speech-like utterances were operationally defined as those belonging to the Basic Canonical Syllables (BCS) or Advanced Forms (AF) levels of the Consolidated Stark Assessment of Early Vocal Development-Revised. Results— On average, the CI group achieved a majority of speech- like utterances after 12 months, and the TD group after 18 months of robust hearing experience. The CI group produced greater percentages of speech-like utterances at each interval until 24-months, when both groups approximated 80%. Conclusion— Auditory deprivation did not limit progress in vocal development as young CI recipients showed more-rapid-than-typical speech development during the first 2 years of device use. Implications for the Infraphonological model of speech development are considered. and phonetic exploratory behavior.
Efficacy of Meta-Cognitive Therapy (MCT) for Adult ADHD

Objective— To examine the efficacy of a 12-week manualized Meta-Cognitive Therapy (MCT) group designed to enhance time-management, organization, and planning in adults with AD/HD. Method— Eighty-eight clinically referred adults who met DSM-IV criteria for ADHD based on clinical and structured diagnostic interviews and standardized questionnaires were stratified vis-à-vis ADHD medication use and otherwise randomly assigned to receive MCT or supportive psychotherapy in a group modality. MCT employs cognitive-behavioral principles and methods to impart skills and strategies in time-management, organization, and planning, and target depressogenic and anxiogenic cognitions that undermine effective self-management. The Support group controlled for non-specific aspects of treatment by providing support while avoiding discussion of cognitive-behavioral strategies. MCT and Support groups were comparable in gender (29% and 39% male, respectively) and age (41±11.59 yr and 42 ± 12.09 years, respectively). Therapeutic response was assessed by an independent (blind) evaluator via structured interview pre- and post-treatment, as well as by self-report and collateral informant behavioral ratings. Results— General linear models, comparing change from baseline between treatments, revealed statistically significant effects for independent evaluator, self-report, and collateral ratings of DSM-IV inattentive symptoms. Employing dichotomous indices of therapeutic response, a significantly greater proportion of MCT vs. Support group members demonstrated improvement. Logistic regression examining group differences in operationally defined response (controlling for baseline ADHD severity)
Alpha-1 -antitrypsin-Pittsburgh A Potent Inhibitor of Human Plasma Factor XIa, Kallikrein, and Factor Xllf

Alpha-l-antitrypsin-Pittsburgh is a human variant that resulted from a point mutation in the plasma protease inhibitor, a,-an-titrypsin (358 Met - Arg). This defect in the a,-antitrypsin molecule causes it to have greatly diminished anti-elastase activity but markedly increased antithrombin activity. In this report, we demonstrate that this variant protein also has greatly increased inhibitory activity towards the arginine-specific enzymes of the contact system of plasma proteolysis (Factor XIa, kallikrein, and Factor XIIf), in contrast to normal cal-antitrypsin, which has modest to no inhibitory activity towards these enzymes. We determined the second-order-inactivation rate constant (k") of purified, human Factor XIa by purified a,-antitrypsin-Pitts-burgh and found it to be 5.1 X 10' M- s'1 (230C), which is a 7,700-fold increase over the kV for Factor XIa by its major inhibitor, normal purified al-antitrypsin (i.e., 6.6 X 101 M-l s-1). Human plasma kallikrein, which is poorly inhibited by a,-an-titrypsin (k" = 4.2 M-l s1), exhibited a k" for a,-antitrypsin-Pittsburgh of8.9 X M- s'1 (a 21,000-fold increase), making it a more efficient inhibitor than either ofthe naturally occurring major inhibitors of kallikrein (Cl-inhibitor and a2-macroglob-ulin). Factor XIIf, which is not inhibited by normal a,-antitrypsin, displayed a k" for a,-antitrypsin-Pittsburgh of 2.5 X 104 M-s'1. This enhanced inhibitory activity is similar to the effect of a,-antitrypsin-Pittsburgh that has been reported for thrombin.
PLC β is Critical for T-cell Chemotaxis

Chemokines acting through G-protein-coupled receptors play an essential role in the immune response. Phosphatidylinositol-3-kinase and phospholipase-C are distinct signaling molecules that have been proposed in the regulation of chemokine-mediated cell migration. Studies with knockout mice have demonstrated a critical role for PI3K γ , but not PLC β , in G α i-coupled receptor-mediated neutrophil chemotaxis. We compared the chemotactic response of peripheral T-cells derived from wild type mice with mice containing loss-of-function mutations of either PI3K γ , or both of the two predominant lymphocyte PLC β isoforms (PLC β 2 and PLC β 3). Loss of PI3K γ did not significantly impair T-cell migration, whereas loss of PLC β 2 β 3 did. PI3K pharmacologic inhibition suggests that an isoform other than PI3K γ contributes to T-cell migration. Intracellular calcium chelation decreased the chemotactic response of wild type lymphocytes, which was not impaired by pharmacologic inhibition of PKC isoforms. SDF1 α induced calcium efflux was undetectable in PLC β 2 β 3-null lymphocytes suggesting that the migration defect is due to the impaired ability to increase intracellular calcium. This study demonstrates that, in contrast to neutrophils, phospholipid second messengers generated by PLC β and isoforms of PI3K, other than PI3K γ , play a critical role in T-lymphocyte chemotaxis. and cells stained with anti-CD44-FITC, -CD62L-Cychrome, and –CD45RB-PE were expressed as a percent of total lymphocytes isolated from peripheral lymph nodes of WT and PLC β 2 β 3 − / − mice. The mean, S.E. , and paired student’s t-test from D and E reflect data from 4–7 separate experiments. Transwell assay is chemotactic and PLC β / were isolated and placed in a Transwell chamber. The cells were incubated with 150 ng/ml SDF1 α placed above and below the filter to abolish the chemotactic gradient. After 3 hours at 37 °C, the cells were recovered from both the upper and lower chambers and counted by flow cytometry. The data are reflective of 3 separate experiments.
FoxP3 + regulatory T cells increase in number and function during experimental arthritis

Objective— CD4 + CD25 + FoxP3 + regulatory T cells (T R ) are critical regulators of autoimmunity. Yet, T R are paradoxically increased in RA patients and show variable activity in human studies. Our objective is to characterize the expansion and function of T R during the initiation and progression of experimental arthritis. Methods— To unequivocally identify T R , we crossed FoxP3 gfp mice to K/BxN to generate arthritic mice in which T R express green fluorescence protein. We examined the expansion and function of T R and effector T cells (T E ) during different stages of arthritis by flow cytometry and cell proliferation. Results— In K/BxN mice, thymic selection of KRN T cells resulted in an enrichment of FoxP3 + T R . T R numbers increased during arthritis with significant increases in the spleen and draining lymph node, indicating selective tropism to sites of disease. In contrast to the in vitro unresponsiveness when cultured by themselves, substantial fractions of T R proliferated in both non-arthritic and arthritic mice. However, they also underwent greater apoptosis thereby maintaining equilibrium with T E . Similarly, enhanced T R suppressive activity during arthritis was offset by greater resistance by their T E counterparts and antigen presenting cells. Conclusion— In this well established model of RA, the interplay of T E and T R in K/BxN mice recapitulated many features of human disease. We demonstrated an ordered expansion of T R during arthritis and the dynamic changes in T R and T E functions. By elucidating factors that govern T R and T E development in K/BxN gfp mice, we will gain insight into the pathophysiology and develop novel therapeutics for human RA.
Host factors in(cid:143) uencing viral persistence

With the aim of characterizing the antiviral immune response to a non-cytocidal virus, we studied the outcome of lymphocytic choriomeningitis virus infection in a number of gene knockout mouse strains. Two virus strains di¡ering markedly in their capacity to spread and replicate inside the murine host were used. Our results reveal that very di¡erent outcomes may be observed depending on virus strain and immunocompetence of the host. Thus while CD4 + cells are not critical during the initial phase of virus control, infectious virus reappear in mice lacking CD4 + cells, B cells or CD40 ligand. Reappearance of virus is associated with impaired long-term CD8 + T-cell mediated immune surveillance, and the time to virus resurgence is inversely correlated to the replication rate of the virus. Our studies also reveal that interferon- g is a central cytokine, and depending on the rate of virus replication, mice lacking the ability to produce interferon- g may develop either a severe, mostly fatal, T-cell mediated wasting syndrome or a chronic infection characterized by long-term coexistence of antiviral cytotoxic T lymphocytes and infectious virus. Mathematical modelling indicates that these di¡erent outcomes may be explained in relatively simple mathematical terms. This suggests that modelling may be used as a means to predict critical host and virus parameters. Therefore, combining mathematical modelling with precise, quantitative, in vivo analyses looks to be a promising approach in addressing central quantitative issues in immunobiology.
Immunohistochemical detection of epithelial-mesenchymal transition associated with stemness phenotype in anaplastic thyroid carcinoma

: Anaplastic thyroid carcinoma (ATC) is a highly aggressive neoplasm resistant to radiation and chemotherapy. Epithelial-mesenchymal transition (EMT) generating cells with stem cell characteristics have been reported to be associated with chemoradioresistance in cultured cells. However, EMT and stem cell properties in ATC have not been fully investigated. In this study, we retrieved 2 thyroidectomy specimens of ATC with coexisting well differentiated thyroid carcinomas (DTCs) including one papillary carcinoma (PTC) and one follicular carcinoma (FTC). We used immunohistochemistry to examine the expression of stem cell markers (nestin, CD133 and CD44) and a marker for EMT (E-cadherin). Intense expressions of nestin, CD133 and CD44, and no expression of E-cadherin were observed in both ATCs. In contrast, the PTC and FTC, and non-neoplastic thyroid tissue in both cases were negative for nestin and positive for E-cadherin. The expressions of CD133 and CD44 were variable in the PTC, FTC, and non-neoplastic thyroid tissue and were at a lower level of expression of these markers in the overall pattern. The results confirmed EMT, demonstrated the stem cell phenotype in ATC, and revealed the difference in expression of these markers between ATC and DTCs/non-neoplastic thyroid tissue. Nestin may be the most specific marker for stemness in ATC by immunohistochemial staining. The results warrant future studies on a large series of cases in order to gain the understanding of the tumor biology and to provide molecular basis for restoring the sensitivities to clinical therapies.
Teaching enquiry with mysteries incorporated: The benefits of involving pre-service teachers

TEMI, Teaching Enquiry with Mysteries Incorporated, is an EU-funded FP7 Science in Society project running from 2013 to 2016. The project aims to encourage science teachers to develop an understanding of inquiry-based learning as well as developing an understanding of the benefits of utilising such approaches in one’s classroom. Drawing on the 5E learning cycle, TEMI aims to engage pupils in core scientific concepts through the integration of mysteries and discrepant events in science lessons. This current discussion paper explores the approaches taken by the UL project team, one of the partners in the project, to bring about change in Irish second-level science teaching, as part of the TEMI project. In particular, it focuses on the unique aspect of this institution’s approach, which is the involvement of pre-service science teachers (PSST’s) in the project. The role of PSSTs in the project is explored under three main headings: “TEMI and the PSST as researcher”, “TEMI and professional learning communities” and “TEMI and PSST’s collaboration with co-operating teachers”. The paper concludes with a discussion on the benefits of involving PSSTs in the TEMI project.
Role of Corticotropin Releasing Factor Binding Protein in the stress system: a strange case of Dr. Jekyll and Mr. Hyde in the stress system?:

The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP). Extensive literature suggests a role of CRF in alcohol use disorder (AUD). Less is known on the specific role, if any, of CRFBP in AUD. In this review, we summarize recent interdisciplinary efforts towards identifying the contribution of CRFBP in mediating CRF activation. The role of CRFBP in alcohol-related behaviors has been evaluated with the ultimate goal of designing effective novel therapeutic strategies for AUD. A series of in vitro, in vivo, ex vivo and genetic studies presented here provide initial evidence that CRFBP may possess both inhibitory and excitatory roles and support the original hypothesis that it represents a novel pharmacological target for the treatment of AUD. This report summarizes the proceedings of one of the talks at the Young Investigator Award symposium at the Alcoholism and Stress: A Framework for Future Treatment Strategies Conference, Volterra, Italy.
Antigen-specific inhibition of high avidity CTL target lysis by low avidity CTL via trogocytosis: a novel mechanism of immune regulation

Current vaccine conditions predominantly elicit low avidity cytotoxic T-lymphocytes (CTLs), which are non-tumor-cytolytic but indistinguishable by tetramer staining or Enzyme-Linked ImmunoSpot from high avidity CTLs. Using CTL clones of high or low avidity for melanoma antigens, we show that low avidity CTLs can inhibit tumor lysis by high avidity CTLs in an antigen-specific manner. This phenomenon operates in vivo: high avidity CTLs control tumor growth in animals, but not in combination with low avidity CTLs specific for the same antigen. The mechanism involves stripping of specific peptide-major histocompatibility complexes (pMHC) via trogocytosis by low avidity melanoma-specific CTLs without degranulation, leading to insufficient levels of specific pMHC on target cell surface to trigger lysis by high avidity CTLs. As such, peptide repertoire on the cell surface is dynamic and continually shaped by interactions with T cells. These results describe immune regulation by low avidity T cells and have implications for vaccine design.
Phosphorylation Coupled with the Oxidation of a-Ketoglutarate by Heart-Muscle Sarcosomes

replace phosphate both in the extraction of the mitochondria and in the reaction medium. 4. The reaction is dependent on the presence of oxygen, but this may be reduced to a tension of 0 5% without any effect on the reaction velocity. Experiments with cyanide, azide and carbon monoxide suggest that the cytochrome system is involved. 5. 2:4-Dinitrophenol in high concentrations does not, but adenosine triphosphate (1 x 10-3M) does inhibit the reaction. There is no evidence to suggest the necessity for the participation of compounds containing high-energy phosphate bonds in the formation ofascorbic acid from galactono-y-lactone. 6. The enzymic activity of rmitochondria prepared from peas increased rapidly in the early stages of germination.
Mendelian Randomization Analysis Identifies Body Mass Index and Fasting Insulin as Potential Causal Risk Factors for Pancreatic Cancer Risk

In this issue of the Journal, Carreras-Torres and colleagues present evidence for a potential causal role of body mass index (BMI) and fasting insulin with risk of pancreatic cancer in 7110 cases and 7264 controls (1). Specifically, genetically increased levels of BMI and fasting insulin were associated with an increased risk of pancreatic cancer; the association with fasting insulin was limited to men. No evidence of a causal association was observed for type II diabetes, fasting glucose, glucose at two hours postchallenge, height, waist-to-hip circumference ratio, and four lipids (eg, total cholesterol, high- and low-density lipo-protein cholesterol, and triglycerides). Pancreatic
Strain Variation and disease severity in congenital CMV infection – in search of a viral marker

Synopsis The wide spectrum of congenital CMV disease and known differences in the biology and in vitro growth of CMV strains continue to drive studies in search for specific viral genetic determinants that may predict severity of congenital CMV disease. Several CMV genes have been studied in detail in congenitally-infected children, but the complexity of the viral genome and differences in the definition of symptomatic disease vs. asymptomatic CMV infection continue to raise questions related to what constitutes a pathogenic CMV strain. In addition, the prevalence and role of multiple CMV strains as opposed to infection with a single strain in disease severity is debated. Although the new era of highly-sensitive next generation sequencing assays may provide detailed information on multiple genetic loci, strict criteria for differentiating between strains will be required. Identifying a viral marker (or combination of markers) for prediction of disease outcome could have a major impact on pre-natal diagnosis and vaccine development. Large, well-controlled studies with long-term follow-up and use of standardized high stringency molecular techniques will be required to move the field forward. Genetic variation of host genes may play an adjunctive role in the outcome of congenital CMV disease.