Miracle-dz/UniFAR-FTUs huggingface dataset:
Proline-rich Tyrosine Kinase 2 (Pyk2) Mediates Vascular Endothelial-Cadherin-based Cell-Cell Adhesion by Regulating β-Catenin Tyrosine Phosphorylation*

Vascular endothelial-cadherin (VE-cadherin) controls endothelial cell-cell adhesion and preserves endothelial integrity. In order to maintain endothelial barrier function, VE-cadherin function is tightly regulated through mechanisms that involve protein phosphorylation and cytoskeletal dynamics. Here, we show that loss of VE-cadherin function results in intercellular gap formation and a drop in electrical resistance of monolayers of primary human endothelial cells. Detailed analysis revealed that loss of endothelial cell-cell adhesion, induced by VE-cadherin-blocking antibodies, is preceded by and dependent on a rapid activation of Rac1 and increased production of reactive oxygen species. Moreover, VE-cadherin-associated β-catenin is tyrosine-phosphorylated upon loss of cell-cell contact. Finally, the redox-sensitive proline-rich tyrosine kinase 2 (Pyk2) is activated and recruited to cell-cell junctions following the loss of VE-cadherin homotypic adhesion. Conversely, the inhibition of Pyk2 activity in endothelial cells by the expression of CRNK (CADTK/CAKβ-related non-kinase), an N-terminal deletion mutant that acts in a dominant negative fashion, not only abolishes the increase in β-catenin tyrosine phosphorylation but also prevents the loss of endothelial cell-cell contact. These results implicate Pyk2 in the reduced cell-cell adhesion induced by the Rac-mediated production of ROS through the tyrosine phosphorylation of β-catenin. This signaling is initiated upon loss of VE-cadherin function and is important for our insight in the modulation of endothelial integrity.
Retrograde labeling of rat dorsolateral septal nucleus neurons following intraseptal injections of WGA‐HRP

Projection neurons in the rat dorsolateral septal nucleus (DLSN) were retrogradely labeled following intraseptal injection of wheat germ agglutinin conjugated horseradish peroxidase (WGA‐HRP). Injections of WGA‐HRP centered in the medial septum (MS) and parts of the intermediate and ventrolateral subdivisions of the lateral septum retrogradely labeled only a few centrally scattered multipolar‐shaped neurons. In contrast, injections placed in the nucleus of the diagonal band of Broca (DBB) consistently resulted in labeling of DLSN neurons of all sizes and shapes. Large injections in rostral DBB appeared to retrogradely label every DLSN neuron, while similar injections in caudal DBB only labeled neurons in restricted regions of the nucleus. A collection of small cells forming the ventricular border of caudal DLSN and a group of larger cells situated in the dorsolateral tip of rostral DLSN were consistently labeled following each DBB injection. The pattern of retrogradely labeled neurons in the DLSN appeared in a complementary fashion to that seen in the other lateral septal nuclei. Our findings support the conclusion that the DLSN is a morphologically heterogeneous nucleus consisting almost entirely of projection neurons. The pattern of retrograde labeling in the lateral septum suggests that these projection neurons may be topographically organized since distinct subpopulations of cells were labeled following different injections in the MS/DBB complex. © 1996 Wiley‐Liss, Inc.
Relationship between serum isoflavone levels and disability-free survival among community-dwelling elderly individuals: nested case-control study of the Tsurugaya project.

BACKGROUND The longer healthy life expectancy observed in Japan may be partly attributed to the Japanese diet. The researchers sought to examine whether serum isoflavone levels are associated with disability and death. METHODS The researchers used a nested case-control study to compare serum isoflavones (daidzein, genistein, glycitein, and equol) levels between 165 participants that died or were certificated as disabled (cases) and 177 controls. Disability was defined by certification of long-term care insurance. Conditional logistic regression models were used to calculate the risk of isoflavones for the composite outcome. RESULTS The proportion of cases was lower in the group with the highest levels of equol (34/91, 37%) compared with equol nonproducers (84/161, 52%). The risk of disability or death among equol producers remained reduced after adjusting for age and sex (odds ratio: 0.55, 95% confidence interval: 0.33-0.93). In a multivariate model, this risk was also unchanged (odds ratio: 0.51, 95% confidence interval: 0.27-0.96). There were no significant associations between daidzein, genistein, and glycitein with the composite endpoint. CONCLUSIONS Higher serum equol levels, but not any other isoflavones, were inversely associated with the composite endpoint of disability and death. Although it cannot be concluded that equol per se has preventive effects on disability or death, higher equol levels appear associated with better health.
Tail regeneration and other phenomena of wound healing and tissue restoration in lizards

ABSTRACT Wound healing is a fundamental evolutionary adaptation with two possible outcomes: scar formation or reparative regeneration. Scars participate in re-forming the barrier with the external environment and restoring homeostasis to injured tissues, but are well understood to represent dysfunctional replacements. In contrast, reparative regeneration is a tissue-specific program that near-perfectly replicates that which was lost or damaged. Although regeneration is best known from salamanders (including newts and axolotls) and zebrafish, it is unexpectedly widespread among vertebrates. For example, mice and humans can replace their digit tips, while many lizards can spontaneously regenerate almost their entire tail. Whereas the phenomenon of lizard tail regeneration has long been recognized, many details of this process remain poorly understood. All of this is beginning to change. This Review provides a comparative perspective on mechanisms of wound healing and regeneration, with a focus on lizards as an emerging model. Not only are lizards able to regrow cartilage and the spinal cord following tail loss, some species can also regenerate tissues after full-thickness skin wounds to the body, transections of the optic nerve and even lesions to parts of the brain. Current investigations are advancing our understanding of the biological requirements for successful tissue and organ repair, with obvious implications for biomedical sciences and regenerative medicine. Summary: We highlight how lizards can inform, enhance and expand our understanding of the biology of regeneration.
The TRAPP Complex: Insights into its Architecture and Function

Vesicle‐mediated transport is a process carried out by virtually every cell and is required for the proper targeting and secretion of proteins. As such, there are numerous players involved to ensure that the proteins are properly localized. Overall, transport requires vesicle budding, recognition of the vesicle by the target membrane and fusion of the vesicle with the target membrane resulting in delivery of its contents. The initial interaction between the vesicle and the target membrane has been referred to as tethering. Because this is the first contact between the two membranes, tethering is critical to ensuring that specificity is achieved. It is therefore not surprising that there are numerous ‘tethering factors’ involved ranging from multisubunit complexes, coiled‐coil proteins and Rab guanosine triphosphatases. Of the multisubunit tethering complexes, one of the best studied at the molecular level is the evolutionarily conserved TRAPP complex. There are two forms of this complex: TRAPP I and TRAPP II. In yeast, these complexes function in a number of processes including endoplasmic reticulum‐to‐Golgi transport (TRAPP I) and an ill‐defined step at the trans Golgi (TRAPP II). Because the complex was first reported in 1998 (1), there has been a decade of studies that have clarified some aspects of its function but have also raised further questions. In this review, we will discuss recent advances in our understanding of yeast and mammalian TRAPP at the structural and functional levels and its role in disease while trying to resolve some apparent discrepancies and highlighting areas for future study.
Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count

Objective:To assess the absolute rate of AIDS and death in antiretroviral therapy (ART)-naive patients with a high CD4 cell count. Such information would be helpful in the design of a trial investigating early initiation of ART. Design:Analysis of data from an ongoing HIV cohort study. Methods:The rate of (severe) AIDS or death and death alone was evaluated in ART-naive patients according to the current CD4 cell count, focusing on CD4 cell counts ≥ 350 cells/μl among patients in the UK CHIC Study. Results:In a total of 30 313 person-years of follow-up, there were 1557 AIDS or death events. The rate of AIDS or death in persons with most recent CD4 cell count 350–499, 500–649 and > 650 cells/μl was 2.49, 1.54 and 0.96 per 100 person-years, respectively. The rate ratio for those with CD4 cell count 500–649 cells/μl compared with those with CD4 cell count ≥ 650 cells/μl was 1.55 [95% confidence interval (CI), 1.11–2.17; P = 0.01]. In a Poisson regression model based on person years with CD4 cell count ≥ 350 cells/μl, there was a strong effect of CD4 cell count on rate of AIDS or death (rate ratio, 0.84; 95% CI, 0.76–0.93; P = 0.001), independent of viral load and age. Conclusions:The trend of decreasing rate of AIDS and death with higher CD4 cell count is present throughout the CD4 cell count ≥ 350 cells/μl range in ART-naive people.
Neurofibromin GTPase-activating Protein-related Domains Restore Normal Growth in Nf1−/− Cells*

Members of the Ras superfamily of signaling proteins modulate fundamental cellular processes by cycling between an active GTP-bound conformation and an inactive GDP-bound form. Neurofibromin, the protein product of the NF1 tumor suppressor gene, and p120GAP are GTPase-activating proteins (GAPs) for p21Ras (Ras) and negatively regulate output by accelerating GTP hydrolysis on Ras. Neurofibromin and p120GAP differ markedly outside of their conserved GAP-related domains (GRDs), and it is therefore unknown if the respective GRDs contribute functional specificity. To address this question, we expressed the GRDs of neurofibromin and p120GAP in primary cells from Nf1 mutant mice in vitro and in vivo. Here we show that expression of neurofibromin GRD, but not the p120GAP GRD, restores normal growth and cytokine signaling in three lineages of primaryNf1-deficient cells that have been implicated in the pathogenesis of neurofibromatosis type 1 (NF1). Furthermore, utilizing a GAP-inactive mutant NF1 GRD identified in a family with NF1, we demonstrate that growth restoration is a function ofNF1 GRD GAP activity on p21Ras. Thus, the GRDs of neurofibromin and p120GAP specify nonoverlapping functions in multiple primary cell types.
Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells

A novel mechanism is found by which Drosophila male germline stem cells (GSCs) slow their cell cycle under limited nutrient conditions. Upon culturing in poor media, GSCs misorient their centrosomes with respect to the stem cell niche, activating the centrosome orientation checkpoint and leading to slowdown of the cell cycle.
Neuropsychological test performance in African-American* and white patients with Alzheimer's disease

Little information exists on the performance of black versus white patients with Alzheimer's disease on neuropsychological tests for dementia.In this study, we compared performance on the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuropsychological battery between white (n equals 830) and black (n equals 158) patients with Alzheimer's disease enrolled in the CERAD study at 23 university medical centers in the United States. The black patients were older, had fewer years of formal education, and were more impaired in their activities of daily living than were the white patients. After controlling for these characteristics and for duration of the disease and severity of dementia, there were differences in the performance of black and white patients on several of the cognitive measures. Black patients scored lower than whites on tests of visual naming and constructional praxis and on the Mini-Mental State Examination. There were no statistical differences in performance on tests of fluency and word list memory. These findings suggest that cultural or experiential differences may modify performance on specific neuropsychological tests. These factors, in addition to age and educational background, should be considered when interpreting performance on neuropsychological tests in elderly black patients with dementia. NEUROLOGY 1995;45: 2207-2211
Nuage hypermassif, chocs et efficacité de formation stellaire

Les etoiles massives, de type O ou B, sont d'une importance capitale pour le budget energetique des galaxies et l'enrichissement du milieu interstellaire. Neanmoins, leur formation, contrairement a celle des etoiles de type solaire reste sujet a debats, sinon une enigme. Les toutes premieres etapes de la formation des etoiles massives ainsi que la formation de leur nuage parent sont des themes qui stimulent une grande activite sur les plans theorique et observationnel depuis une decennie. Il semble maintenant acquis que les etoiles massives naissent dans des cœurs denses massifs, qui se forment au travers de processus dynamiques, tels que les flots de gaz collisionnels. Au cours de ma these, j'ai mene une etude approfondie de la formation des cœurs denses et des etoiles massives au sein de la structure hypermassive W43-MM1, localisee a 6~kpc du soleil. Dans un premier temps, j'ai montre une correlation directe entre l'efficacite a former des etoiles et la densite volumique des nuages moleculaires, en decalage avec un certain nombre d'etudes precedentes. En effet, la distribution spatiale et de masse des cœurs denses massifs en formation au sein de W43-MM1 suggere que ce filament hypermassif est en phase de flambee de formation d'etoiles, flambee d'autant plus grande que l'on se rapproche de son cœur. J'ai compare ces resultats observationnels aux modeles numeriques et analytiques d'efficacite de formation stellaire les plus recents. Cette confrontation permet non seulement d'apporter de nouvelles contraintes sur la formation des filaments hypermassifs, mais suggere aussi que la comprehension de la formation d'etoiles dans les nuages hypermassifs necessite une description fine de la structure de ces objets exceptionnels. En second lieu, ayant montre que la formation des etoiles massives est fortement dependante des proprietes des filaments qui les forment, je me suis naturellement interesse aux processus de formation de ces filaments, grâce a une etude de leur dynamique globale. Plus precisement, j'ai utilise un traceur de chocs (la molecule de SiO) pour discerner les chocs dus aux processus locaux de formation des etoiles (jets et flots bipolaires), des chocs dus aux processus permettant la formation du nuage. J'ai ainsi pu, via une etude sans precedent alliant observations et modelisation de chocs dans une region formant de nombreuses etoiles, montrer l'existence de chocs a basse vitesse, premiere signature directe de la formation du nuage moleculaire dans lequel les etoiles massives se forment. Ces resultats constituent une etape importante reliant, via des processus dynamiques, la formation des nuages moleculaires a la formation des etoiles massives.
Prospective Study of Lidocaine, Bupivacaine, and Epinephrine Levels and Blood Loss in Patients Undergoing Liposuction and Abdominoplasty

Background: Bupivacaine levels have not been measured in cosmetic surgery patients to establish safety. Blood loss has been underestimated using the small volumes present in the aspirate. The proportion of wetting solution removed by liposuction has not been reliably ascertained. Methods: To remedy these deficiencies, a prospective study was undertaken among 322 consecutive patients presenting for superwet ultrasonic liposuction and/or abdominoplasty, and other combined procedures, using infusions containing 0.05% lidocaine (liposuction) and/or 0.025% bupivacaine (abdominoplasty) with 1:500,000 epinephrine. Plasma levels of lidocaine, bupivacaine, and epinephrine were studied in a subset of 76 consecutive patients, including hourly intraoperative samples in 39 consecutive patients. Anesthetic levels were also measured in 12 consecutive patients during the 24-hour period after infusion. Results: The maximum lidocaine dose was 3243 mg and the maximum level was 2.10 &mgr;g/ml. The maximum bupivacaine dose was 550 mg and the maximum level was 0.81 &mgr;g/ml. No clinical toxicity was encountered. Estimated blood loss from liposuction was 217.5 cc + 187 cc/liter of aspirate (r = 0.65). Abdominoplasty added 290 cc of blood loss, on average. The mean proportion of wetting solution removed by liposuction was 9.8 percent. Conclusions: Bupivacaine may be safely used in cosmetic surgery. A concentration of 1:500,000 epinephrine is safe and effective when administered as part of a wetting solution that is limited to less than 5 liters. Estimated blood loss is higher than previous estimates based on lipocrits. Combination procedures are safe.
Ultrastructural and immunocytochemical study of the pulmonary intravascular macrophages of Escherichia coli lipopolysaccharide‐treated sheep

Pulmonary intravascular macrophages (PIMs) of sheep, cattle, goats, and horses have a novel heparin‐sensitive chain of globules, called a surface coat, on their plasma membrane. The globules are arranged at a distance of 32‐39 nm from the plasma membrane of PIMs. Intravascular nonbiological tracer particles complex with these globules prior to their endocytosis by the PIMs.
APC, K-ras, and p53 Gene Mutations in Colorectal Cancer Patients: Correlation to Clinicopathologic Features and Postoperative Surveillance

Current researches have proposed a genetic model for colorectal cancer (CRC), in which the sequential accumulation of mutations in specific cancer-related genes, including adenomatous polyposis coli (APC), K-ras, and p53, drives the transition from normal epithelium through increasing adenomatous dysplasia to colorectal cancer. To identify patients with an increased risk of tumor recurrence or metastasis and evaluate the prognostic values of APC, K-ras, and p53 gene mutations, we investigated the frequency of these three mutated genes in tumors and sera of CRC patients. APC, K-ras, and p53 gene mutations in primary tumor tissues and their paired preoperative serum samples of 118 CRC patients were detected by using polymerase chain reaction– single strand conformation polymorphism (PCR-SSCP) analysis, followed by direct DNA sequencing of the PCR-amplified genomic DNA. Subsequently, serum molecular markers were analyzed for their correlation with patients’ clinicopathologic features and presence of postoperative recurrence/metastasis. We did not observe any significant difference in the association of APC or K-ras or p53 gene mutations in primary tumors with patients’ demographic data (all were P > 0.05). In contrast, both serum APC and p53 molecular markers were closely correlated with lymph node metastasis and TNM stage (both P < 0.05). Moreover, the serum overall molecular markers (at least one of the three markers) were prominently associated with depth of tumor invasion (P = 0.033), lymph node metastasis (P < 0.001), and TNM stage (P < 0.001). In addition, a significantly higher postoperative metastasis/recurrence rate in patients positive for overall molecular markers compared to those negative for these molecular markers were also demonstrated (P < 0.001). APC and K-ras molecular markers were more frequently observed in patients with locoregional metastasis (both P < 0.05), while p53 molecular marker was usually detected in the cases of peritoneal metastasis (P = 0.004). Our findings suggest that serum molecular markers are potentially useful in the determination of colorectal cancer patients harboring gene mutations at high risk of metastasis. Serial analysis is warranted in order to assess their long-term prognostic significance and the therapeutic implications.
Diagnostic value of interleukin-1alpha, interleukin-6, and tumor necrosis factor in pleural effusions.

STUDY OBJECTIVES Interleukin (IL)-1alpha, IL-6, and tumor necrosis factor (TNF)-alpha were measured in pleural fluid from 57 patients with pleural effusion in order to evaluate the diagnostic utility of these cytokines. We studied 20 patients with malignant pleural effusion, 11 patients with parapneumonic pleural effusion, 9 patients with tuberculous pleural effusion, and 17 patients with transudative pleural effusion. Cytokines were measured by radioimmunoassay. SETTING University tertiary hospital. RESULTS The mean values of the three cytokines measured in pleural fluid or in serum were significantly higher in patients with exudates than with transudates (p < 0.05). The ratio of IL-6 in pleural fluid to serum was significantly higher in exudates than in transudates (p < 0.05). The level of IL-6 in pleural fluid was significantly higher in tuberculous than malignant (p < 0.007) or parapneumonic pleural effusions (p < 0.04). No significant difference between the three types of exudates was found in pleural fluid levels of IL-1alpha or TNF-alpha. CONCLUSIONS Serum levels of IL-1alpha, TNF-alpha, and in particular IL-6 can distinguish exudates from transudates, while pleural fluid IL-6 levels could be useful as an additional marker in the differential diagnosis of tuberculous, malignant, and parapneumonic exudates. Finally, our results suggest that there is local cytokine production in exudative pleural effusions.
Human Immunodeficiency Virus Infection and Risk of Venous Thromboembolism

Background:The incidence of venous thromboembolism (VTE) in HIV-infected patients is uncertain, and the impact of protease inhibitors on the incidence of VTE is also uncertain, yet important to know to create a database for providing opinion regarding prophylaxis for the prevention of VTE. Methods:Data from the National Hospital Discharge Survey (NHDS) were analyzed from 1990 through 2005. International Classification of Diseases, Ninth Revision, and Clinical Modification (ICD-9-CM) codes were used to identify illnesses. Results:Among 2,429,000 patients older than 18 years hospitalized with HIV infection, the incidence of pulmonary embolism (PE) was 0.4%, deep venous thrombosis (DVT) 1.4%, and VTE 1.7%. The relative risks compared with all hospitalized non-HIV patients of PE, DVT, and VTE were 0.91, 1.26, and 1.21. The incidence of VTE from 1990 to 1996 was 17,000 of 1,198,000 (1.4%) and after 1996 it was 25,000 of 1,230,000 (2.0) (P < 0.0001) (relative risk = 1.43). Among hospitalized patients who did not have HIV, the relative risk comparing incidences after 1996 with incidences before was 1.22. Conclusion:The incidence of VTE in patients with HIV infection was higher than in non-HIV patients. The incidence of VTE in patients with HIV in the postprotease inhibitor era (after 1996) was higher than in HIV patients before 1996, but the incidence was also higher in non-HIV patients after 1996. The higher incidence since 1996 is small, probably not clinically significant, and not necessarily because of protease inhibitors.