Miracle-dz/UniFAR-FTUs huggingface dataset:
Membrane targeting of WAVE2 is not sufficient for WAVE2-dependent actin polymerization: a role for IRSp53 in mediating the interaction between Rac and WAVE2

Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous (WAVE) proteins play a major role in Rac-induced actin dynamics, but Rac does not bind directly to WAVE proteins. It has been proposed that either the insulin receptor substrate protein 53 (IRSp53) or a complex of proteins containing Abelson interactor protein 1 (Abi1) mediates the interaction of WAVE2 and Rac. Depletion of endogenous IRSp53 by RNA-mediated interference (RNAi) in a RAW/LR5 macrophage cell line resulted in a significant reduction of Rac1Q61L-induced surface ruffles and colony-stimulating factor 1 (CSF-1)-induced actin polymerization, protrusion and cell migration. However, IRSp53 was not essential for Fcγ-R-mediated phagocytosis, formation of podosomes or for formation of Cdc42V12-induced filopodia. IRSp53 was found to be present in an immunoprecipitable complex with WAVE2 and Abi1 in a Rac1-activation-dependent manner in RAW/LR5 cells in vivo. Importantly, reduction of endogenous IRSp53 or expression of IRSp53 lacking the WAVE2-binding site (IRSp53ΔSH3) resulted in a significant reduction in the association of Rac1 with WAVE2 and Abi1, indicating that the association of Rac1 with WAVE2 and Abi1 is IRSp53 dependent. While it has been proposed that WAVE2 activity is regulated by membrane recruitment, membrane targeting of WAVE2 in RAW/LR5 and Cos-7 cells did not induce actin polymerization or protrusion, suggesting that membrane recruitment was insufficient for regulation of WAVE2. Combined, these data suggest that IRSp53 links Rac1 to WAVE2 in vivo and its function is crucial for production of CSF-1-induced F-actin-rich protrusions and cell migration in macrophages. This study indicates that Rac1, along with IRSp53 and Abi1, is involved in a more complex and tight regulation of WAVE2 than one operating solely through membrane localization.
Metabolic Adjustments to Short-Term Diurnal Temperature Fluctuation in the Rainbow Trout (Oncorhynchus mykiss)

In rainbow trout, warmer temperatures increase metabolic rate, which can be energetically stressful. Diel fluctuations in water temperatures are common in rivers, raising the question of whether fish experience metabolic preconditioning with repeated heat stress. In this study, rainbow trout (Oncorhynchus mykiss Walbaum, 1792) were subjected to three temperature treatments consisting of either a constant exposure to 16°C, a single exposure to 24°C, or three cycles between 16° and 24°C. Metabolic responses were investigated, including patterns of regulation of adenosine monophosphate–activated protein kinase and its substrates, key metabolic enzymes, and several relevant metabolites. In liver and, to a lesser extent, in heart, patterns of signal transduction suggest an increasingly anabolic phenotype with successive heat cycles. Inhibition of Raptor in the heart suggests lowered gross protein synthesis after multiple heat cycles. Fish also showed recovery of glycogen stores and lipid synthesis after multiple thermal cycles, while they maintained baseline plasma glucose levels. The animals showed no evidence of hypoxemia, and our results suggest rainbow trout exposed to repeated thermal cycles were not at risk of metabolic substrate depletion. Collectively, our data indicate that, when exposed to fluctuating but noncritical thermal cycles, rainbow trout may adopt a new metabolic phenotype to sequester readily accessible metabolic substrates in the liver in preparation for more severe or sustained thermal exposures.
Mismatch repair mutations of Escherichia coli K12 enhance transposon excision.

Excision of the prokaryotic transposon Tn10 is a host-mediated process that occurs in the absence of recA function or any transposon-encoded functions. To determine which host functions might play a role in transposon excision, we have isolated 40 mutants of E. coli K12, designated tex, which increase the frequency of Tn10 precise excision. Three of these mutations (texA) have been shown to qualitatively alter RecBC function. We show that 21 additional tex mutations with a mutator phenotype map to five genes previously identified as components of a methylation-directed pathway for repair of base pair mismatches: uvrD, mutH, mutL, mutS and dam. Previously identified alleles of these genes also have a Tex phenotype. --Several other E. coli mutations affecting related functions have been analyzed for their effects on Tn10 excision. Other mutations affecting the frequency of spontaneous mutations (mutT, polA, ung), different excision repair pathways (uvrA, uvrB) or the state of DNA methylation (dcm) have no effect on Tn10 excision. Mutations ssb-113 and mutD5, however, do increase Tn10 excision. --The products of the mismatch correction genes probably function in a coordinated way during DNA repair in vivo. Thus, mutations in these genes might also enhance transposon excision by a single general mechanism. Alternatively, since mutations in each gene have qualitatively and quantitatively different effects on transposon excision, defects in different mismatch repair genes may enhance excision by different mechanisms.
Recognition of spoken words in L2 speech using L1 probabilistic phonotactics: Evidence from Cantonese-English bilinguals

This study investigates whether Cantonese-English bilingual listeners make implicit use of their L1 (Cantonese) probabilistic phonotactic information in recognizing spoken words in L2 (English) speech. Previous research in different languages demonstrated that probabilistic phonotactics could serve as a cue to locate the possible word boundary in continuous speech. The use of these kinds of information in L1 may also be used in L2 listening for fluent bilingual listeners. In the present study, a word-spotting experiment was conducted to answer this empirical question. The results revealed that the Cantonese-English bilingual listeners might not make use of all, but some of, the information of L1 probabilistic phonotactics in recognizing spoken words in L2 speech.
Attachment and the regulation of the right brain

It has been three decades since John Bowlby first presented an over-arching model of early human development in his groundbreaking volume, Attachment. In the present paper I refer back to Bowlby's original charting of the attachment landscape in order to suggest that current research and clinical models need to return to the integration of the psychological and biological underpinnings of the theory. Towards that end, recent contributions from neuroscience are offered to support Bowlby's assertions that attachment is instinctive behavior with a biological function, that emotional processes lie at the foundation of a model of instinctive behavior, and that a biological control system in the brain regulates affectively driven instinctive behavior. This control system can now be identified as the orbitofrontal system and its cortical and subcortical connections. This ‘senior executive of the emotional brain’ acts as a regulatory system, and is expanded in the right hemisphere, which is dominant in human infancy and centrally involved in inhibitory control. Attachment theory is essentially a regulatory theory, and attachment can be defined as the interactive regulation of biological synchronicity between organisms. This model suggests that future directions of attachment research should focus upon the early-forming psychoneurobiological mechanisms that mediate both adaptive and maladaptive regulatory processes. Such studies will have direct applications to the creation of more effective preventive and treatment methodologies.
Four subtypes of protease‐activated receptors, co‐expressed in rat astrocytes, evoke different physiological signaling

Protease‐activated receptors (PARs) are newly identified members of the superfamily of G‐protein‐coupled receptors that initiate cell signaling by the proteolytic activity of extracellular serine proteases. Certain proteases are believed to be involved in development and repair processes and most likely regulate multiple functions of the CNS by activating PARs. Three members of this family (PAR‐1, PAR‐3, and PAR‐4) are considered thrombin receptors, whereas PAR‐2 is activated by trypsin. In the present study, using reverse transcription‐polymerase chain reaction (RT‐PCR), immunocytochemistry, and Ca2+ mobilization studies, we demonstrate that PAR‐1, PAR‐2, PAR‐3, and PAR‐4 are functionally co‐expressed in cultured rat astrocytes. Short‐term stimulation of astrocytes with thrombin, trypsin, and peptides corresponding to the tethered ligand domains of PAR‐1, PAR‐2, PAR‐3, and PAR‐4 induced a transient rise of [Ca2+]i in cultured astrocytes. In studying calcium signaling, based on receptor desensitization, and using an antagonist of thrombin receptor PAR‐1, we provide evidence that the thrombin‐induced [Ca2+]i response in astrocytes in addition to PAR‐1 stimulation, involves also stimulation of PAR‐3 and PAR‐4. Trypsin, in addition to PAR‐2, can also activate PAR‐1 and PAR‐4. Furthermore we find that activation of PAR‐1, and PAR‐2 induces proliferation of astrocytes while PAR‐4 activation exerts toxic effects. This study is the first to show that (1) cultured astrocytes functionally express PAR‐3 and PAR‐4 together with PAR‐1 and PAR‐2; (2) PAR‐3‐activating peptide (TFRGAP) is effective in eliciting Ca2+ signaling; and (3) activation of different PARs leads to distinct downstream effects. GLIA 37:53–63, 2002. © 2002 Wiley‐Liss, Inc.
A large software vendor's view on Cyber Physical Systems

The rise of Cyber Physical Systems (CPS) brings a new level of complexity into the world of software and systems development and operations. Dynamic dependencies and changes throughout the product lifecycle necessarily impact system performance. At the same time, these new, highly automated systems require exceptional reliability and usability. From a software vendor’s view, experiences with enterprise systems can be extrapolated and transformed into a new model of system operations, where product and service merge to form one common business model. A software vendor must overcome the challenge of ensuring sustainability in a rapidly changing technical environment. The paper shows how this and other challenges can be addressed from a vendor’s view. It explores how a product portfolio for connected systems can be designed, which capabilities need to be covered, and how systems should be delimited to guarantee robustness and flexibility. Finally it describes the demand for new public architecture concepts that should be covered by academic research.
A New Optical-Geometrical Illusion

We describe and attempt to explain a new and unusual optical-geometrical illusion with three levels of distortion. The illusory figure is made up of three juxtaposed bands of the same width, which, when appropriately juxtaposed, appear to be of different widths. We hypothesised that the effect would depend on the combined action of various factors: (i) the band shapes and their reciprocal spatial position; (ii) the degree of coincidence of the sides of the juxtaposed bands; and (iii) the inability of the perceptual system to account for all the projective transformations. An experiment was conducted in which the shape of three stimuli was manipulated through affine transformation as well as variation of side lengths. The participants' task was to evaluate the width of the bands. The results revealed a robust and stable illusory effect; the factors that seem to influence the illusion most are band shape and conjoining side lengths.
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.

BACKGROUND In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. METHODS In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. The trial was stopped after a mean follow-up of 21 months. RESULTS Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). The median times to the first crisis (3.0 vs. 1.5 months, P = 0.01) and the second crisis (8.8 vs. 4.6 months, P < 0.001) were longer with hydroxyurea treatment. Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P < 0.001), and fewer underwent transfusions (48 vs. 73, P = 0.001). At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. Treatment with hydroxyurea did not cause any important adverse effects. CONCLUSIONS Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.
Endpoints of Resuscitation of Critically Injured Patients: Normal or Supranormal?: A Prospective Randomized Trial

ObjectiveTo evaluate the effect of early optimization in the survival of severely injured patients. Summary Background DataIt is unclear whether supranormal (“optimal”) hemodynamic values should serve as endpoints of resuscitation or simply as markers of the physiologic reserve of critically injured patients. The failure of optimization to produce improved survival in some randomized controlled trials may be associated with delays in starting the attempt to reach optimal goals. There are limited controlled data on trauma patients. MethodsSeventy-five consecutive severely injured patients with shock resulting from bleeding and without major intracranial or spinal cord trauma were randomized to resuscitation, starting immediately after admission, to either normal values of systolic blood pressure, urine output, base deficit, hemoglobin, and cardiac index (control group, 35 patients) or optimal values (cardiac index >4.5 L/min/m2, ratio of transcutaneous oxygen tension to fractional inspired oxygen >200, oxygen delivery index >600 mL/min/m2, and oxygen consumption index >170 mL/min/m2; optimal group, 40 patients). Initial cardiac output monitoring was done noninvasively by bioimpedance and, subsequently, invasively by thermodilution. Crystalloids, colloids, blood, inotropes, and vasopressors were used by predetermined algorithms. ResultsOptimal values were reached intentionally by 70% of the optimal patients and spontaneously by 40% of the control patients. There was no difference in rates of death (15% optimal vs. 11% control), organ failure, sepsis, or the length of intensive care unit or hospital stay between the two groups. Patients from both groups who achieved optimal values had better outcomes than patients who did not. The death rate was 0% among patients who achieved optimal values compared with 30% among patients who did not. Age younger than 40 years was the only independent predictive factor of the ability to reach optimal values. ConclusionsSeverely injured patients who can achieve optimal hemodynamic values are more likely to survive than those who cannot, regardless of the resuscitation technique. In this study, attempts at early optimization did not improve the outcome of the examined subgroup of severely injured patients.
Uterine artery embolization of large fibroids: comparative study of procedure with and without pretreatment gonadotropin-releasing hormone agonists.

OBJECTIVE The purpose of this study was to evaluate the safety of pretreatment with gonadotropin-releasing hormone (GnRH) agonists before uterine artery embolization (UAE) of large fibroids. MATERIALS AND METHODS The cases of 40 patients with large fibroids (≥ 10 cm) were retrospectively analyzed. Among the 40 patients, 28 (control group) underwent UAE without pretreatment with GnRH agonists, and 12 (GnRH group) received GnRH agonists 1-5 times before UAE. MRI was used to assess necrosis of large fibroids and their volumes in both groups within 3 months after UAE. RESULTS Complete necrosis of large fibroids after UAE was achieved in 39 of 40 patients (97.5%). Only one patient, who was in the control group, had incomplete necrosis of the predominant fibroid. When GnRH agonists were administered before UAE, the mean volume reduction rate of fibroids was 36.3%. The final mean volume reduction rates of the predominant fibroids and the uterus after UAE in the GnRH group were 56.5% (range, 38-79%) and 50.8% (range, 35-72%), significantly higher than the volume reduction rates of 35.1% (range, 7-65%) and 34.9% (range, 16-54%) in the control group (p < 0.001). Grade D complications were not seen in the GnRH group but occurred in four patients in the control group. CONCLUSION Pretreatment with GnRH agonists before UAE of large fibroids was safe for patients with large fibroids and did not prevent performance of UAE.
A Repertoire of MicroRNAs Regulates Cancer Cell Starvation by Targeting Phospholipase D in a Feedback Loop That Operates Maximally in Cancer Cells

ABSTRACT We report a negative feedback loop between the signaling protein phospholipase D (PLD), phosphatidic acid (PA), and a specific set of microRNAs (miRNAs) during nutrient starvation of breast cancer cells. We show that PLD expression is increased in four breast cancer cell lines and that hypoxia, cell overcrowding, and nutrient starvation for 3 to 6 h increase expression even further. However, after prolonged (>12-h) starvation, PLD levels return to basal or lower levels. The mechanism for this is as follows. First, during initial starvation, an elevated PA (the product of PLD enzymatic activity) activates mTOR and S6K, known to inhibit apoptosis, and enhances cell migration especially in post-epithelial-to-mesenchymal transition (post-EMT) cancer cells. Second, continued PA production in later starvation induces expression of PLD-targeting microRNA 203 (miR-203), miR-887, miR-3619-5p, and miR-182, which reduce PLD translation. We provide direct evidence for a feedback loop, whereby PLD induction upon starvation leads to PA, which induces expression of miRNAs, which in turn inhibits PLD2 translation. The physiological relevance for breast cancer cells is that as PA can activate cell invasion, then, due to the negative feedback, it can deprive mTOR and S6K of their natural activator. It can further prevent inhibition of apoptosis and allow cells to survive nutrient deprivation, which normal cells cannot do.
An Exploratory Study of Perceived Discrimination and Homesickness: A Comparison of International Students and American Students

The authors examined group differences in perceived discrimination and homesickness in a sample of 439 college students (198 international and 241 U.S. students) from 2 campuses of the same university. Within the international student group, the authors also examined relationships between homesickness, discrimination, age, English proficiency, and years of residence in the United States. Results indicated that international students experienced higher levels of discrimination and homesickness than did U.S. students. Age, English proficiency, and perceived discrimination predicted homesickness among the international students. Younger students, students with lower levels of English proficiency, and students with higher levels of perceived discrimination reported having higher levels of homesickness. Also, years of residence and race or ethnicity predicted international students' level of perceived discrimination. Being a European international student predicted lower levels of perceived discrimination than did being an international student from other regions of the world. The authors discuss implications for higher-education institutions and counseling personnel.
Clinical and mechanistic drivers of acute traumatic coagulopathy

BACKGROUND Acute traumatic coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity, and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma. METHODS Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data. RESULTS There were 1,198 patients with laboratory results, of whom 41.6% were coagulopathic. Using international normalized ratio of 1.3 or greater, 41.6% of patients (448) were coagulopathic, while 20.5% (214) were coagulopathic using partial thromboplastin time of 35 or greater. Coagulopathy was primarily associated with a combination of an Injury Severity Score (ISS) of greater than 15 and a base deficit (BD) of less than −6 (p < 0.05). Regression modeling for international normalized ratio–based coagulopathy shows that prehospital crystalloid (odds ratio [OR], 1.05), ISS (OR, 1.03), Glasgow Coma Scale (GCS) score (OR, 0.93), heart rate (OR, 1.08), systolic blood pressure (OR, 0.96), BD (OR, 0.92), and temperature (OR, 0.84) were significant predictors of coagulopathy (all p < 0.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all p < 0.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p < 0.04). Similar results were found for partial thromboplastin time–defined coagulopathy. CONCLUSION ATC is associated with the depletion of factors I, II, V, VII, VIII, IX, and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of ATC and the effects of resuscitation can guide factor-guided resuscitation and correction of coagulopathy after injury. LEVEL OF EVIDENCE Epidemiologic/prognostic study, level IV.