Miracle-dz/UniFAR-FTUs huggingface dataset:
Diacylglycerol Kinase ζ Limits the Generation of Natural Regulatory T Cells

Increasing the activation of extracellular signal–regulated kinase promotes the generation of natural regulatory T cells. ERK Signaling Promotes Treg Cells When T cell precursors (thymocytes) in the thymus receive a strong signal through their T cell receptor (TCR), they develop into natural regulatory T (nTreg) cells. TCR stimulation leads to the activation of phospholipase C–γ1 (PLC-γ1) and the production of the second messenger diacylglycerol (DAG), which, in turn, activates extracellular signal–regulated kinase (ERK) signaling. In one of a pair of papers published this week, Schmidt et al. investigated nTreg cell development in mice deficient in the ζ isoform of DAG kinase (DGKζ), an enzyme that converts DAG to phosphatidic acid, thus inhibiting DAG-dependent signaling. Compared to wild-type mice, DGKζ-deficient mice generated increased numbers of nTreg cells and their precursors. The accumulation of DAG in DGKζ-deficient thymocytes resulted in enhanced ERK activation, as well as of nuclear factor κB, and the authors found a positive correlation between the extent of ERK activation and the numbers of nTreg cells produced in vivo. Together, these data suggest that DGKζ inhibits nTreg cell generation by limiting the extent to which TCR stimulation activates ERK. Natural regulatory T (nTreg) cells are important for maintaining tolerance to self- and foreign antigens, and they are thought to develop from thymocytes that receive strong T cell receptor (TCR)–mediated signals in the thymus. TCR engagement leads to the activation of phospholipase C–γ1, which generates the lipid second messenger diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate. We used mice that lack the ζ isoform of DAG kinase (DGKζ), which metabolizes DAG to terminate its signaling, to enhance TCR-mediated signaling and identify critical signaling events in nTreg cell development. Loss of DGKζ resulted in increased numbers of thymic CD25+Foxp3−CD4+ nTreg cell precursors and Foxp3+CD4+ nTreg cells in a cell-autonomous manner. DGKζ-deficient T cells exhibited increased nuclear translocation of the nuclear factor κB subunit c-Rel, as well as enhanced extracellular signal–regulated kinase (ERK) phosphorylation in response to TCR stimulation, suggesting that these downstream pathways may contribute to nTreg cell development. Indeed, reducing c-Rel abundance or blocking ERK phosphorylation abrogated the increased generation of nTreg cells by DGKζ-deficient thymocytes. The extent of ERK phosphorylation correlated with TCR-mediated acquisition of Foxp3 in immature thymocytes in vitro. Furthermore, the development of nTreg cells was augmented in mice in which ERK activation was selectively enhanced in T cells. Together, these data suggest that DGKζ regulates the development of nTreg cells by limiting the extent of activation of the ERK and c-Rel signaling pathways.
Divergence and Recombination of Clinical Herpes Simplex Virus Type 2 Isolates

ABSTRACT Herpes simplex virus type 2 (HSV-2) infects the genital mucosa and is one of the most common sexually transmitted viruses. Here we sequenced a segment comprising 3.5% of the HSV-2 genome, including genes coding for glycoproteins G, I, and E, from 27 clinical isolates from Tanzania, 10 isolates from Norway, and 10 isolates from Sweden. The sequence variation was low compared to that described for clinical HSV-1 isolates, with an overall similarity of 99.6% between the two most distant HSV-2 isolates. Phylogenetic analysis revealed a divergence into at least two genogroups arbitrarily designated A and B, supported by high bootstrap values and evolutionarily separated at the root. Genogroup A contained isolates collected in Tanzania, and genogroup B contained isolates collected in Tanzania and Scandinavia, implying that the genetic variability of HSV-2 is higher in Tanzania than in Scandinavia. Recombination network analysis and bootscan analysis revealed a complex pattern of phylogenetically conflicting informative sites in the sequence alignments. These signals were present in synonymous and nonsynonymous sites in all three genes and were not accumulated in specific regions, observations arguing against positive selection. Since the PHI test applied solely to synonymous sites revealed a high statistical probability of recombination, we suggest as a novel finding that homologous recombination is, as reported earlier for HSV-1 and varicella-zoster virus, a prominent feature in the evolution of HSV-2.
Immigrant Narratives: Orientalism and Cultural Translation in Arab American and Arab British Literature

Preface Introduction 1 The Rise of Arab-American Literature 2 The Gibran Phenomenon 3 The Emergence of Autobiography 4 The Retreat of Cultural Translation 5 Exilic Memoirs 6 Academic Itineraries 7 Postcolonial Translation 8 Muslim Immigrant Fiction 9 Queering Orientalism Conclusion Works Cited
Protein kinase A induces recruitment of active Na+,K+‐ATPase units to the plasma membrane of rat proximal convoluted tubule cells

1 The aim of this study was to investigate the mechanism of control of Na+,K+‐ATPase activity by the cAMP‐protein kinase A (PKA) pathway in rat proximal convoluted tubules. For this purpose, we studied the in vitro action of exogenous cAMP (10−3 M dibutyryl‐cAMP (db‐cAMP) or 8‐bromo‐cAMP) and endogenous cAMP (direct activation of adenylyl cyclases by 10−5 M forskolin) on Na+,K+‐ATPase activity and membrane trafficking. 2 PKA activation stimulated both the cation transport and hydrolytic activity of Na+,K+‐ATPase by about 40 %. Transport activity stimulation was specific to the PKA signalling pathway since (1) db‐cAMP stimulated the ouabain‐sensitive 86Rb+ uptake in a time‐ and dose‐dependent fashion; (2) this effect was abolished by addition of H‐89 or Rp‐cAMPS, two structurally different PKA inhibitors; and (3) this stimulation was not affected by inhibition of protein kinase C (PKC) by GF109203X. The stimulatory effect of db‐cAMP on the hydrolytic activity of Na+,K+‐ATPase was accounted for by an increased maximal ATPase rate (Vmax) without alteration of the efficiency of the pump, suggesting that cAMP‐PKA pathway was implicated in membrane redistribution control. 3 To test this hypothesis, we used two different approaches: (1) cell surface protein biotinylation and (2) subcellular fractionation. Both approaches confirmed that the cAMP‐PKA pathway was implicated in membrane trafficking regulation. The stimulation of Na+,K+‐ATPase activity by db‐cAMP was associated with an increase (+40 %) in Na+,K+‐ATPase units expressed at the cell surface which was assessed by Western blotting after streptavidin precipitation of biotinylated cell surface proteins. Subcellular fractionation confirmed the increased expression in pump units at the cell surface which was accompanied by a decrease (‐30 %) in pump units located in the subcellular fraction corresponding to early endosomes. 4 In conclusion, PKA stimulates Na+,K+‐ATPase activity, at least in part, by increasing the number of Na+‐K+ pumps in the plasma membrane in proximal convoluted tubule cells.
CC3/TIP30 regulates metabolic adaptation of tumor cells to glucose limitation

CC3/TIP30 is a metastasis and tumor suppressor, with reduced or absent expression in a variety of aggressive tumors. Overexpression of CC3 in tumor cells predisposes them to apoptosis in response to different death signals. We found that silencing of CC3 expression does not increase apoptotic resistance of cells. However, it strongly improves survival of tumor cells in response to glucose limitation. HeLa cells with silenced CC3 survive long-term in low glucose, and, in comparison to control HeLa cells, show superior metabolic adaptation to glucose limitation. First, unlike the parental HeLa cells, HeLa with silenced CC3 activate and maintain high levels of mitochondrial respiration that is critical for their ability to thrive in low glucose. Second, silencing of CC3 leads to higher expression levels of mitochondrial proteins in respiration complexes when cells are continuously cultured in limiting glucose. Third, HeLa cells with silenced CC3 maintain higher levels of c-MYC and the M2 isoform of pyruvate kinase in low glucose, contributing to more efficient glycolysis. Fourth, HeLa cells with silenced CC3 fail to fully activate AMPK in response to glucose limitation. Inhibition of AMPK, either pharmacologic or via siRNA, protects control HeLa cells from death in low glucose. The metabolic flexibility acquired by cells after silencing of CC3 could be directly relevant to the development of metastatic and aggressive human tumors that frequently have low or absent expression of CC3.
Effects of nicotine on intercellular adhesion molecule expression in endothelial cells and integrin expression in neutrophils in vitro.

OBJECTIVE We previously reported that nicotine decreases leukocyte adhesion to uterine vascular endothelial cells in vivo under ischemic conditions in pregnant rabbits. To further investigate the mechanism of decreased leukocyte-endothelial adhesion by nicotine exposure, the effect of nicotine on endothelial cell intercellular adhesion molecule expression and neutrophil integrin expression of CD62L, CD11a, and CD11b were examined. STUDY DESIGN Endothelial cells were isolated from human umbilical cord veins from normal pregnancies in nonsmoking women immediately after delivery. Neutrophils were isolated from healthy nonpregnant and nonsmoking female volunteers. First passage of endothelial cells and fresh isolated neutrophils were exposed to nicotine at different concentrations. Surface adhesion molecule expression of intercellular adhesion molecule on endothelial cells was determined by colorimetric assay. Neutrophil integrin expressions for CD62L, CD11a, and CD11b were determined by flow cytometry. Messenger RNA expression for intercellular adhesion molecule in endothelial cells was examined by reverse transcription-polymerase chain reaction. RESULTS Nicotine at a lower concentration of 0.01 micromol/L had no effect on endothelial cell surface intercellular adhesion molecule expression compared with controls (P =.614). Nicotine at a higher concentration of 10 micromol/L completely inhibited endothelial cell surface intercellular adhesion molecule-1 expression(P <.0001). At concentrations between 0.10 and 10 micromol/L, nicotine inhibited intercellular adhesion molecule expression in a dose-dependent manner. Messenger RNA expression of intercellular adhesion molecule in endothelial cells was not changed after exposure to nicotine. Decreased integrin expressions of CD62L, CD11a, and CD11b were observed on neutrophils after exposure to nicotine. CONCLUSION Nicotine exerts inhibitory effects on both endothelial cell surface intercellular adhesion molecule expression and neutrophil integrin expressions of CD62L, CD11a, and CD11b in vitro. These in vitro effects of nicotine may relate to the clinical observation of reduced incidence of preeclampsia in women that smoke.
Peroxidase-Mediated Mechanisms Are Involved in the Melanocytotoxic and Melanogenesis-Inhibiting Effects of Chemical Agents

Melanogenesis is based on the enzymatic conversion of the amino acid tyrosine, through a series of intermediates, to melanin pigments. The nature of the enzymes involved in the different steps of melanogenesis has been intensely debated. However, it is now believed that tyrosinase is responsible for the conversion of tyrosine to dopa and of dopa to dopaquinone, and that peroxidase accomplishes the oxidative polymerization of the eventually formed indoles to eumelanin pigments. Some very few investigators have also considered a main role for peroxidase in initiating melanogenesis. At present, most different hypotheses are focused on tyrosinase-mediated mechanisms to elucidate the melanocytotoxic and depigmenting activities of chemicals. However, many properties of these agents cannot be explained by such mechanisms. Most of the melanocytotoxic agents (e.g. hydroquinone, catechols, butylated hydroxyanisole) can be converted to cytotoxic species, such as quinones, by the peroxidase-H2O2 system. On the other hand, many of the melanogenesis inhibitors which are not known to inhibit tyrosinase (e.g. glucocorticoids, ascorbic acid, indomethacin) have the capacity to strongly inhibit peroxidase activity. We have proposed that peroxidase-mediated mechanisms, in addition to or in several instances rather than tyrosinase-mediated mechanisms, can explain the melanocytotoxic and depigmenting properties of such agents.
Transcutaneous electrical nerve stimulation after thoracic surgery: systematic review and meta-analysis of 11 randomized trials.

OBJECTIVES To evaluate the effects of transcutaneous electric nerve stimulation (TENS) on pain and pulmonary function during the postoperative period after thoracic surgery by performing a systematic review and meta-analysis of randomized trials. METHODS The search strategy included MEDLINE, PEDro, Cochrane CENTRAL, EMBASE and LILACS, besides a manual search, from inception to August, 2011. Randomized trials were included, comparing TENS associated or not with pharmacological analgesia vs. placebo TENS associated or not with pharmacological analgesia or vs. pharmacological analgesia alone to assess pain (visual analog scale - VAS) and/or pulmonary function represented by forced vital capacity (FVC) in postoperative thoracic surgery patients (pulmonary or cardiac with approach by thoracotomy or sternotomy). RESULTS Of the 2.489 articles identified, 11 studies were included. In the approach by thoracotomy, TENS associated with pharmacological analgesia reduced pain compared to the placebo TENS associated with pharmacological analgesia (VAS -1.29; CI95%: -1.94 to - 0.65). In the approach by sternotomy, TENS associated with pharmacological analgesia also reduced pain compared to the placebo TENS associated with pharmacological analgesia (VAS -1.33; 95%CI: -1.89 to 0.77) and compared to pharmacological analgesia alone (VAS -1.23; 95%CI: -1.79 to -0.67). There was no significant improvement in FVC (0.12 L; 95%CI: -0.27 to 0.51). CONCLUSION TENS associated with pharmacological analgesia provides pain relief compared to the placebo TENS in postoperative thoracic surgery patients both approached by thoracotomy and sternotomy. In the sternotomy it also provides more effective pain relief compared to pharmacological analgesia alone, but has no significant effect on pulmonary function.
Cytogenetic characteristics of B cell chronic lymphocytic leukemia in 275 Chinese patients by fluorescence in situ hybridization: a multicenter study.

BACKGROUND Under conventional cytogenetic (CC) analysis, only 30% - 50% of B cell chronic lymphocytic leukemia (B-CLL) cases show clonal aberrations. Using fluorescence in situ hybridization (FISH), the percentage of patients with abnormalities rises to almost 80%, among them, the most frequent abnormalities were 13q14, 11q22, p53 deletions and trisomy 12. The aim of this study was to explore the incidence of cytogenetic changes in Chinese patients with B-CLL. METHODS We used FISH methods to detect the cytogenetic features in 275 cases of B-CLL from 48 hospitals. The correlation between FISH abnormalities and clinical characteristics such as age, gender, white blood cell count, peripheral hemoglobin (Hb) level, peripheral platelet count (PLT), lactate dehydrogenase (LDH) level, Rai stage, Binet stage, and overall survival was analyzed, and the relationship between them and overall survival was also analyzed to evaluate their prognostic implications. RESULTS Of the 275 patients, genetic aberrations were found in 77.8% using FISH. The frequencies of abnormalities were as follows: 13q deletion (56.4%), trisomy 12 (34.5%), p53 deletion (33.5%) and 11q22 deletion (30.5%). It was obvious that the patients with p53 deletion had lower level of Hb (P = 0.001) and PLT (P = 0.003) when compared to patients without p53 deletion. Significant differences were obtained in the distribution of p53 deletion according to Rai and Binet classification systems (P = 0.016 and 0.008 respectively). Significant differences were also observed when the overall survival was correlated with p53 deletion (P = 0.043), Rai stage (P = 0.006), Binet stage (P = 0.013), Hb level (P = 0.004) and PLT level (P = 0.010). CONCLUSIONS Chinese CLL patients have the similar frequencies of del(13q), trisomy 12, del(11q) and a higher frequency of del(17p) when compared to literatures. Del(17p) is associated with advanced stage and low levels of Hb and PLT. Patients with p53 deletion, or advanced stage probably have poor survival in China.
The Influence of Hair Shave on the Infection Rate in Neurosurgery

Objective: To investigate whether not shaving hair in neurosurgical operations carries an increased infection rate. Methods: Taking advantage of different practices among neurosurgeons in a single institution, we embarked upon a prospective non-randomised study of 100 consecutive neurosurgical procedures involving 90 paediatric patients aged 7 days to 16.8 years. The patients were split into two groups (‘hair shave’ and ‘no hair shave’). The differences with respect to wound complications, positive microbiology on wound culture swabs and wound infection rates were analysed. Other factors considered were the cleansing solution, prophylactic antibiotic regime, duration of the operation, the surgeon’s experience and the patient’s age. Results: The only complications observed were 4 incidences of wound dehiscence (2 in the hair shave and 2 in the no hair shave group) and 3 shunt infections (2 in the hair shave and 1 in the no hair shave group). We did not find any significant difference between the two arms for any of the factors assessed. Age was a significant factor in shunt infection, as all shunt infections were seen in patients aged less than 6 months, regardless of whether the hair was shaved or not (p = 0.024, Fisher’s exact test). Conclusion: This study confirms our clinical experience that no hair shave is a good alternative to the traditional hair shaving approach, allowing patients to enjoy the psychological benefits of undisturbed body image while recovering from major surgery.
Surface marker abnormalities in myelodysplastic syndromes.

BACKGROUND AND OBJECTIVE The myelodysplastic syndromes (MDS) are clonal stem cell disorders associated with a variety of abnormalities of mature and maturing cells, including surface antigen abnormalities. Granulocytes and monocytes function as members of the immune system. Surface antigens serve as biological sensors allowing various cells to interact with different stimuli. Abnormalities of surface antigens may be associated with defective cell function and may indicate a more severe or more advanced stage of the disease. INFORMATION SOURCES The author has a great interest in bone marrow changes in MDS and has several previous publications in this field. In addition, relevant articles published since 1966 were retrieved using Medline of English literature and were included. STATE OF THE ART AND PERSPECTIVES Several surface antigens in MDS have shown abnormal expression either in the intensity of fluorescence or the percentage of positive cells. These abnormalities include increased, decreased or lineage-aberrant expression. Abnormalities of several surface markers have prognostic significance. MDS patients with a low percentage of bone marrow cells expressing CD11b had a higher risk of evolution to acute myeloid leukemia and shorter survival compared to patients with more than 53% of marrow cells expressing CD11b (29 weeks versus 160 weeks). On the other hand, an increased percentage of bone marrow cells expressing early or immature markers, such as CD 13, CD33, CD34 and HLA-DR, has been associated with a worse outcome and with progression to a higher risk MDS or to acute myeloid leukemia. However, there are numerous discrepancies and inconsistencies in the literature when reviewing surface marker changes in MDS. These discrepancies may be related, at least in part, to the presence of an intracellular storage compartment of numerous surface antigens in the granulocytes and monocytes. Because of these storage pools, the techniques of preparing more mature granulocytes and monocytes, such as density gradient separation, and the interpretation of results must be carefully evaluated. Furthermore, various methods have been used to express abnormal results including percentage of positive or negative cells, fluorescent intensity (FI) of individual patients or a group of patients using a mean fluorescent channel (256 or 1024 channel mode), and finally the expression of FI as molecules of equivalent soluble fluorochromes or antibody binding capacities. Several mechanisms may be involved in the abnormal expression of surface antigens in MDS including defective granulopoiesis, defective intracellular storage pool, abnormal membrane of cytoplasmic granules, and the effect of high levels of marrow cytokines such as tumor necrosis factor alpha and transforming growth factor-beta. Standardization of the methods of preparing and studying mature and maturing granulocytes and monocytes in MDS has to be achieved in order to produce comparable results, thus allowing surface marker studies to be utilized as diagnostic and prognostic tools in MDS.
Attempts to physiologically classify human thenar motor units.

1. This study was designed to determine whether human thenar motor units can be classified into types by the same physiological criteria used for other mammalian limb motor units and to consider whether such classification is functionally relevant. 2. Contractile responses of 25 human thenar single motor units were examined when their motor axons were stimulated intraneurally at rates from 1 to 100 Hz and intermittently at 40 Hz in a conventional 2-min fatigue test. Twitch and tetanic forces were measured together with various indexes of contractile rate. 3. Twitch contraction times and subtetanic to maximum tetanic force ratios were both distributed continuously. "Sag" in tension was not evident in unfused force profiles. Thus these units could not be divided into fast and slow types by the use of traditional contractile rate criteria. 4. Most units were fatigue resistant, with force fatigue indexes (FI) ranging from 0.33 to 1.14. None could be classified as fatiguable (FI less than 0.25). Seven units (28%) fell into the fatigue-intermediate (FI = 0.25-0.75) category, whereas 18 units (72%) had FI greater than 0.75, i.e., they were fatigue-resistant units. However, these units could not be classified by conventional FI and contractile rate criteria, because fatigue-resistant and fatigue-intermediate units had similar contractile rates. 5. Additional FI were calculated to describe changes in contractile rate. During the fatigue test, units behaved in one of three ways, showing 1) little change in either force or rate; 2) contractile slowing during the contraction and relaxation phases, with little or no force loss; or 3) both force and rate reduction. (ABSTRACT TRUNCATED AT 250 WORDS)