Miracle-dz/UniFAR-FTUs huggingface dataset:
Activation of sphingosine‐1‐phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration

Sphingosine‐1‐phosphate (S1P) acts as an extracellular ligand for a family of G‐protein coupled receptors that are crucial in cell migration. S1P5 is exclusively expressed in oligodendrocytes and oligodendrocyte precursor cells (OPCs), which migrate considerable distances during brain development. The current studies suggest a physiological role for S1P and S1P5 in regulation of OPC migration. mRNA expression levels of S1P2 and S1P5 are comparable in OPCs, but S1P binding specifically to the S1P5 receptor blocked OPC migration (IC50 = 29 nM). Thus, knocking down S1P5 using siRNA prevented the S1P‐induced decrease in OPC migration, whereas knocking down S1P2 did not have any effect. S1P‐induced modulation of OPC migration was insensitive to pertussis toxin, suggesting that S1P5‐initiated signaling is not mediated by the Gαi‐protein coupled pathway. Furthermore, S1P5 appears to engage the Gα12/13 protein coupled Rho/ROCK signaling pathway to impede OPC migration. To modulate OPC motility, extracellular S1P could be derived from the export of intracellular S1P generated in response to glutamate treatment of OPCs. These studies suggest that S1P could be a part of the neuron‐oligodendroglial communication network regulating OPC migration and may provide directional guidance cues for migrating OPCs in the developing brain. —Novgorodov A. S. , El‐Alwani, M. , Bielawski, J., Obeid, L. M. , Gudz T. I. Activation of sphingosine‐1‐phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J. 21, 1503–1514 (2007)
Differential Expression of RUNX Genes in Human Esophageal Squamous Cell Carcinoma: Downregulation of RUNX3 Worsens Patient Prognosis

Background: The RUNX proteins are a family of transcriptional factors that have essential functions during embryogenesis and development, whereas deregulation in expression of RUNXs is often linked to tumor formation. To date, there has been no study describing the precise expression, prognostic impact and methylation status of RUNXs in esophageal squamous cell carcinoma. Methods: Resected specimens from 61 patients with esophageal SCC were used to identify the expression of RUNX1, RUNX2 and RUNX3 by real-time RT-PCR. Localization of mRNA was done by in situ hybridization, expression of Smad4 was evaluated by immunohistochemistry, and the methylation status of RUNX3 was analyzed by methylation-specific PCR. Results: RUNX3 had a significant impact on patient prognosis with worse survival in the RUNX3-negative group. In early tumors (T1/T2), the prevalence of lymph vessel invasion and the number of metastatic lymph nodes were significantly higher in RUNX3-negative tumors. Furthermore, RUNX3 became a strong prognostic factor only in Smad4-positive tumors. Also, the methylation status of the RUNX3 promoter had a significant correlation with the loss of RUNX3 expression. Conclusion: Downregulation of RUNX3 may play a role in disease progression of esophageal SCC, and hypermethylation of the promoter region might be one of the crucial pathways to silence RUNX3 gene.
Development of Smallpox Vaccine Candidates with Integrated Interleukin-15 That Demonstrate Superior Immunogenicity, Efficacy, and Safety in Mice

ABSTRACT The potential use of variola virus, the etiological agent of smallpox, as a bioterror agent has heightened the interest in the reinitiation of smallpox vaccination. However, the currently licensed Dryvax vaccine, despite its documented efficacy in eradicating smallpox, is not optimal for the vaccination of contemporary populations with large numbers of individuals with immunodeficiencies because of severe adverse effects that can occur in such individuals. Therefore, the development of safer smallpox vaccines that can match the immunogenicity and efficacy of Dryvax for the vaccination of contemporary populations remains a priority. Using the Wyeth strain of vaccinia virus derived from the Dryvax vaccine, we generated a recombinant Wyeth interleukin-15 (IL-15) with integrated IL-15, a cytokine with potent immunostimulatory functions. The integration of IL-15 into the Wyeth strain resulted in a >1,000-fold reduction in lethality of vaccinated athymic nude mice and induced severalfold-higher cellular and humoral immune responses in wild-type mice that persisted longer than those induced by the parental Wyeth strain. The superior efficacy of Wyeth IL-15 was further demonstrated by the ability of vaccinated mice to fully survive a lethal intranasal challenge of virulent vaccinia virus even 10 months after vaccination, whereas all mice vaccinated with parental Wyeth strain succumbed. By integrating IL-15 into modified vaccinia virus Ankara (MVA), a virus currently under consideration as a substitute for the Dryvax vaccine, we developed a second vaccine candidate (MVA IL-15) with greater immunogenicity and efficacy than Dryvax. Thus, Wyeth IL-15 and MVA IL-15 viruses hold promise as more-efficacious and safe alternatives to the Dryvax vaccine.
A Diagnostic Accuracy Meta-analysis of Endoanal Ultrasound and MRI for Perianal Fistula Assessment

BACKGROUND: Imaging modalities such as endoanal ultrasound or MRI can be useful preoperative adjuncts before the appropriate surgical intervention for perianal fistulas. OBJECTIVES: We present a systematic review of published literature comparing endoanal ultrasound with MRI for the assessment of idiopathic and Crohn’s perianal fistulas. DESIGN: A meta-analysis was performed to obtain pooled values for specificity and sensitivity. SETTINGS: Electronic databases were searched from January 1970 to October 2010 for published studies. PATIENTS AND INTERVENTIONS: Four studies were used in our analysis. There were 241 fistulas in the ultrasound group and 240 in the magnetic resonance group. RESULTS: The combined sensitivity and specificity of magnetic resonance for fistula detection were 0.87 (95% CI: 0.63-0.96) and 0.69 (95% CI: 0.51-0.82). There was a high degree of heterogeneity between studies reporting on MRI sensitivity (df = 3, I2 = 93%). This compares to a sensitivity and specificity for endoanal ultrasound of 0.87 (95% CI: 0.70-0.95) and 0.43 (95% CI: 0.21-0.69). There was a high degree of heterogeneity between studies reporting on endoanal ultrasound sensitivity (df = 3, I2 = 92%). CONCLUSIONS: From the available literature, the summarized performance characteristics for MRI and endoanal ultrasound demonstrate comparable sensitivities at detecting perianal fistulas, although the specificity for MRI was higher than that for endoanal ultrasound. Both specificity values are considered to be diagnostically poor, however. The high degree of data heterogeneity and the shortage of applicable studies precludes any firm conclusions being made for clinical practice. Future trials with improved study design (including prospective data collection and consideration of verification bias) may help to further clarify the role of MRI in the assessment and treatment response monitoring of perianal fistulas (particularly in patients with Crohn’s disease).
Identification of cardiovascular lineage descendants at single-cell resolution

The transcriptional profiles of cardiac cells derived from murine embryos and from mouse embryonic stem cells (mESCs) have primarily been studied within a cell population. However, the characterization of gene expression in these cells at a single-cell level might demonstrate unique variations that cannot be appreciated within a cell pool. In this study, we aimed to establish a single-cell quantitative PCR platform and perform side-by-side comparison between cardiac progenitor cells (CPCs) and cardiomyocytes (CMs) derived from mESCs and mouse embryos. We first generated a reference map for cardiovascular single cells through quantifying lineage-defining genes for CPCs, CMs, smooth muscle cells (SMCs), endothelial cells (EDCs), fibroblasts and mESCs. This panel was then applied against single embryonic day 10.5 heart cells to demonstrate its ability to identify each endocardial cell and chamber-specific CM. In addition, we compared the gene expression profile of embryo- and mESC-derived CPCs and CMs at different developmental stages and showed that mESC-derived CMs are phenotypically similar to embryo-derived CMs up to the neonatal stage. Furthermore, we showed that single-cell expression assays coupled with time-lapse microscopy can resolve the identity and the lineage relationships between progenies of single cultured CPCs. With this approach, we found that mESC-derived Nkx2-5+ CPCs preferentially become SMCs or CMs, whereas single embryo-derived Nkx2-5+ CPCs represent two phenotypically distinct subpopulations that can become either EDCs or CMs. These results demonstrate that multiplex gene expression analysis in single cells is a powerful tool for examining the unique behaviors of individual embryo- or mESC-derived cardiac cells. Highlighted article: Multiplex gene expression analysis on single cardiac lineage cells provides a high-resolution view of cardiac fate choice in the mouse embryo and during stem cell differentiation.
Biobehavioral Mechanisms of Mindfulness as a Treatment for Chronic Stress: An RDoC Perspective

Mindfulness-based interventions have been heralded as promising means of alleviating chronic stress. While meta-analyses indicate that mindfulness-based interventions significantly reduce global measures of stress, how mindfulness-based interventions modulate the specific mechanisms underpinning chronic stress as operationalized by the National Institute of Mental Health research domain criteria (RDoC) of sustained threat has not yet been detailed in the literature. To address this knowledge gap, this article aims to (1) review evidence that mindfulness-based interventions ameliorate each of the 10 elements of behavioral dysregulation characterizing sustained threat via an array of mindful counter-regulatory strategies; (2) review evidence that mindfulness-based interventions modify biological domains implicated in sustained threat, such as the hypothalamic–pituitary–adrenal axis, as well as brain circuits involved in attentional function, limbic reactivity, habit behavior, and the default mode network; and (3) integrate these findings into a novel conceptual framework of mindful self-regulation in the face of stress—the Mindfulness-to-Meaning Theory. Taken together, the extant body of scientific evidence suggests that the practice of mindfulness enhances a range biobehavioral factors implicated in adaptive stress coping and induces self-referential plasticity, leading to the ability to find meaning in adversity. These mechanistic findings can inform the treatment development process to optimize the next generation of mindfulness-based interventions for greater therapeutic efficacy.
Inverse electrostatic effect: electrostatic repulsion in the unfolded state stabilizes a leucine zipper.

The pH-dependent stability of a protein is strongly affected by electrostatic interactions between ionizable residues in the folded as well as unfolded state. Here we characterize the individual contributions of charged Glu and His residues to stability and determine the NMR structure of the designed, heterodimeric leucine zipper AB consisting of an acidic A chain and a basic B chain. Thermodynamic parameters are compared with those of the homologous leucine zipper AB(SS) in which the A and B chains are disulfide-linked. NMR structures of AB based on (1)H NMR data collected at 600 MHz converge, and formation of the same six interchain salt bridges found previously in disulfide-linked AB(SS) [Marti, D. N. , and Bosshard, H. R. (2003) J. Mol. Biol. 330, 621-637] is indicated. While the structures of AB and AB(SS) are very similar, their pH-dependent relative stabilities are strikingly different. The stability of AB peaks at pH approximately 4.5 and is higher at pH 8 than at pH 2. In contrast, AB(SS) is most stable at acidic pH where no interhelical salt bridges are formed. The different energetic contributions of charged Glu and His residues to stability of the two coiled coil structures were evaluated from pK(a) shifts induced by folding. The six charged Glu residues involved in salt bridges stabilize leucine zipper AB by 4.5 kJ/mol yet destabilize disulfide-linked AB(SS) by -1.1 kJ/mol. Two non-ion-paired Glu charges destabilize AB by only -1.8 kJ/mol but AB(SS) by -5.6 kJ/mol. The higher relative stability of AB at neutral pH is not caused by more favorable electrostatic interactions in the folded leucine zipper. It is due mainly to unfavorable electrostatic interactions in the unfolded A and B chains and may therefore be called an inverse electrostatic effect. This study illustrates the importance of residual interactions in the unfolded state and how the energetics of the unfolded state affect the stability of the folded protein.
Impaired Systemic Vascular Endothelial Function in Patients with Branch Retinal Vein Occlusion

Purpose: To evaluate systemic endothelial function in patients with branch retinal vein occlusion (BRVO). Methods: Twenty-seven patients with BRVO (BRVO group, 8 men, 19 women; mean age, 65.4 ± 1.3), 10 patients with systemic hypertension and no other systemic or ocular disease (hypertension group, 6 men, 4 women; mean age, 70.4 ± 2.2), and 10 healthy volunteers (healthy group, 3 men, 7 women; mean age, 63.8 ± 2.1) were enrolled. We excluded patients with diabetes mellitus and current smokers. Using high-resolution ultrasonographic imaging, we evaluated the brachial artery (mm) to evaluate the flow-mediated vasodilation (FMD) by measuring the diameter of the brachial artery during reperfusion after arterial occlusion. Results: There were no significant differences among the three groups in age (p = 0.98), sex (p = 0.21), or the baseline diameter of the brachial artery (p = 0.11). The group-averaged FMD value decreased significantly in the BRVO group (4.6 ± 0.4%) compared to the hypertension group (8.0 ± 0.8%, p < 0.01) and the healthy group (6.9 ± 0.6%, p < 0.05). Multiple logistic regression analysis identified lower FMD as an independent risk factor for BRVO. Conclusions: The results suggested that BRVO is associated with generalized endothelial dysfunction and that impaired systemic endothelial function may be associated with BRVO.
Familial aggregation of body mass index and subcutaneous fat measures in the longitudinal Québec family study

Family resemblance for several measures of body fat and fat distribution was explored in the longitudinal Québec Family Study (QFS), including an overall measure of adiposity (body mass index, BMI), total subcutaneous fat (the sum of 6 skinfolds, SF6), and subcutaneous fat distribution (the trunk to extremity ratio, TER). Repeated measures were taken twice approximately 12 years apart. A longitudinal familial correlation model was used to assess familial resemblance at each of times 1, 2, and cross‐time, and a univariate model was used for the change score. The change score was assumed to index the degree to which different familial factors impacted on the longitudinal resemblance, while the cross‐time comparisons indexed similar familial factors across time. For BMI, the maximal heritability was 44 and 36% at times 1 and 2, respectively, 37% for the change score, and 33–43% for the cross‐time comparison. While the etiology of the BMI familial effect at times 1, 2, and cross‐time was assumed to be primarily polygenic, that for the change score was a function of cohort effects (environmental). For SF6, the maximal heritability (primarily genetic) was low at time 1 and for the change score (16%), but was nonsignificant at time 2 and cross‐time. For TER, the maximal heritabilities were significant for each of times 1 (42%), 2 (40%), change score (59%), and cross‐time comparisons (35–36%). In summary, simple univariate familial correlation analysis of the change scores and bivariate analysis of the longitudinal measures are useful in delineating the underlying factors leading to both change and stability across time. Genet. Epidemiol. 16:316–334, 1999. © 1999 Wiley‐Liss, Inc.
Familial cardioneuromyopathy with hyaline masses and nemaline rods: A novel phenotype

Two siblings (patients 1 and 2) had adult‐onset muscle weakness that was greater distally than proximally, as well as respiratory insufficiency, cardiomyopathy, and cervical spine anomalies. Electromyography studies indicated myopathy and findings consistent with neuropathy in both. In the deltoid muscle of patient 1 and the anterior tibial muscle of patient 2, myriad type 1 fibers harbored large, irregularly polygonal, and mostly central hyaline masses, small vacuoles, and nemaline rods flanking the hyaline masses or congregated under the sarcolemma. The hyaline masses are intensely congophilic; react strongly for desmin, αB‐crystallin, α1‐antichymotrypsin, and ubiquitin and variably for gelsolin and dystrophin; and are devoid of α‐actinin, nebulin, titin, and slow myosin. The presence of ubiquitin, gelsolin, and fragmented filaments, and the absence of nebulin, titin, α‐actinin, and slow myosin in the hyaline masses, signal nonlysosomal protein degradation. Ultrastructurally, the hyaline masses are composed of intermediate‐density amorphous material intermingled with fragmented filaments and irregularly branching, pleomorphic, highly electron‐dense material, resembling the hyaline structures of myofibrillar myopathy. We conclude that the pathological process in this syndrome is one that induces destruction of myofibrillar components, resulting in aggregation of the degraded residues in hyaline masses, and causes replication of Z disks, resulting in formation of nemaline rods.
Chemical and immunological characterizations of equine infectious anemia virus gag-encoded proteins

The viral core proteins (p15, p26, p11, and p9) of equine infectious anemia virus (EIAV) (Wyoming strain) were purified by reverse-phase high-pressure liquid chromatography. Each purified protein was analyzed for amino acid content, N-terminal amino acid sequence, C-terminal amino acid sequence, and phosphoamino acid content. The results of N- and C-terminal amino acid sequence analysis of each gag protein, taken together with the nucleotide sequence of the EIAV gag gene (R. M. Stephens, J. W. Casey, and N. R. Rice, Science 231:589-594, 1986), show that the order of the proteins in the precursor is p15-p26-*-p11-p9, where a pentapeptide also found in the virus is represented by the asterisk. The data are in complete agreement with the predicted structure of the gag polyprotein and show the peptide bonds cleaved during proteolytic processing. The N-terminus of p15 is blocked to Edman degradation. The p11 protein is identical to the nucleic acid-binding protein of EIAV previously isolated (C. W. Long, L. E. Henderson, and S. Oroszlan, Virology 104:491-496, 1980). High-titer rabbit antiserum was prepared against each purified protein. These antisera were used to detect the putative gag precursor (Pr55gag) and intermediate cleavage products designated Pr49 (p15-p26-*-p11), Pr40 (p15-p26), and Pr35 (p26-*-p11) in the virus and in virus-infected cells. High-titer antisera to EIAV p15 and p26 showed cross-reactivity with the homologous protein of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus.
Education and Cognitive Ability as Direct, Mediating, or Spurious Influences on Female Age at First Birth: Behavior Genetic Models Fit to Danish Twin Data1

The authors study education and cognitive ability as predictors of female age at first birth (AFB), using monozygotic and dizygotic female twin pairs from the Middle‐Aged Danish Twin survey. Using mediated regression, they replicate findings linking education (and not cognitive ability) to AFB. But in a behavior genetic model, both relationships are absorbed within a latent variable measuring the shared family environment. Two interpretations are relevant. First, variance in AFB emerges from differences between families, not differences between sisters within the same family. Second, even in a natural laboratory sensitive to genetic variance in female fertility—during demographic transition—the variance in AFB was nongenetic, located instead within the shared environment.
The relationship between subcortical brain volume and striatal dopamine D2/3 receptor availability in healthy humans assessed with [11C]‐raclopride and [11C]‐(+)‐PHNO PET

Abnormalities in dopamine (DA) and brain morphology are observed in several neuropsychiatric disorders. However, it is not fully understood how these abnormalities may relate to one another. For such in vivo findings to be used as biomarkers for neuropsychiatric disease, it must be understood how variability in DA relates to brain structure under healthy conditions. We explored how the availability of striatal DA D2/3 receptors (D2/3R) is related to the volume of subcortical brain structures in a sample of healthy humans. Differences in D2/3R availability measured with an antagonist radiotracer ([11C]‐raclopride) versus an agonist radiotracer ([11C]‐(+)‐PHNO) were examined.
Management of acute maxillary sinusitis in Finnish primary care Results from the nationwide MIKSTRA study

Objectives – To study the management of acute maxillary sinusitis (AMS) in Finnish primary care and to compare it both to recommendations in national guidelines and to the management of other upper respiratory tract infections (URTI). Design – A cross-sectional multi-centre epidemiological survey. Setting – Thirty primary care health centres in Finland. Subjects – 7284 patients with symptoms of possible acute rhinosinusitis during one week in both November 1998 and November 1999. Main outcome measure – Symptoms and their duration, use of diagnostic tools, choice of antibiotics, patient outcomes. Results – A total of 1601 patients were diagnosed as having AMS (12% of all patients with infectious disease). In 45% of cases the differentiation between AMS and URTI was based on clinical examination alone. Sinus ultrasound was the most common diagnostic tool used (38%). Sinus radiography or blood tests (CRP or leukocytes) were both studied in 8% of cases. AMS was diagnosed and treated with antibiotics also in the early stages of URTI when viruses are the most likely explanation. In total, 83% of patients with AMS received a prescription for antibiotics; the most common choice was amoxycillin (37%), doxycycline was used in 29% of cases, and macrolides in 15%. Conclusions – Antibiotics are prescribed for AMS 2 to 5 times more often than true disease incidence would suggest in Finland. The choice of antibiotics follows the guideline recommendations; however, use of macrolides is higher than recommended. Physicians feel strong pressure from patients to prescribe antibiotics for AMS. Primary care physicians need better support in the accurate diagnosis of AMS.