Miracle-dz/UniFAR-FTUs huggingface dataset:
Expression, Regulation, and Function of the Calmodulin Accessory Protein PCP4/PEP-19 in Myometrium

Objective: Calmodulin (CaM) plays a key role in the orchestration of Ca2+ signaling events, and its regulation is considered an important component of cellular homeostasis. The control of uterine smooth muscle function is largely dependent on the regulation of Ca2+ and CaM signaling. The objective of this study was to investigate the expression, function, and regulation of CaM regulatory proteins in myometrium during pregnancy. Study Design: Myometrium was obtained from nonpregnant women and 4 groups of pregnant women at the time their primary cesarean delivery: (i) preterm not in labor, (ii) preterm in labor with clinical and/or histological diagnosis of chorioamnionitis, (3) term not in labor; and (4) term in labor. The effect of perinatal inflammation on pcp4/pep-19 expression was evaluated in a mouse model of Ureaplasma parvum-induced chorioamnionitis. Human myometrial cells stably expressing wild-type and mutant forms of PCP4/PEP-19 were used in the evaluation of agonist-induced intracellular Ca2+ mobilization. Results: Compared to other CaM regulatory proteins, PCP4/PEP-19 transcripts were more abundant in human myometrium. The expression of PCP4/PEP-19 was lowest in myometrium of women with preterm pregnancy and chorioamnionitis. In the mouse uterus, pcp4/pep-19 expression was lower in late compared to mid-gestation and decreased in mice injected intra-amniotic with Ureaplasma parvum. In myometrial smooth muscle cells, tumor necrosis factor alpha and progesterone decreased and PCP4/PEP-19 promoter activity increased. Finally, the overexpression of PCP4/PEP-19 reduced agonist-induced intracellular Ca2+ levels in myometrial cells. Conclusion: The decreased expression of PCP4/PEP-19 in myometrium contributes to a loss of quiescence in response to infection-induced inflammation at preterm pregnancy.
The Algicidal Bacterium Kordia algicida Shapes a Natural Plankton Community

Plankton communities change on a seasonal basis in temperate systems, with distinct succession patterns; this is mainly due to algal species that have their optimal timing relative to environmental conditions. We know that bacterial populations are also instrumental in the decay and termination of phytoplankton blooms. Here, we describe algicidal bacteria as modulators of this important species succession. Upon treatment of a natural plankton consortium with an algicidal bacterium, we observed a strong shift in the phytoplankton community structure, compared to controls, resulting in formation of a succeeding Phaeocystis bloom. Blooms of this alga have a substantial impact on global biogeochemical and ecological cycles, as they are responsible for a substantial proportion of primary production during spring in the North Sea. We propose that one of the key factors influencing such community shifts may be algicidal bacteria. ABSTRACT Plankton communities consist of complex microbial consortia that change over time. These fluctuations can be only partially explained by limiting resources. Biotic factors such as herbivores and pathogens also contribute to the control of algal blooms. Here we address the effects of algicidal bacteria on a natural plankton community in an indoor enclosure experiment. The algicidal bacteria, introduced into plankton taken directly from the North Sea during a diatom bloom, caused the rapid decline of the bloom-forming Chaetoceros socialis within only 1 day. The haptophyte Phaeocystis, in contrast, is resistant to the lytic bacteria and could benefit from the removal of the competitor, as indicated by an onset of a bloom in the treated enclosures. This cascading effect caused by the bacterial pathogen accelerated the succession of Phaeocystis, which bloomed with a delay of only several weeks in the in situ waters at Helgoland Roads in the North Sea. The algicidal bacteria can thus modulate the community within the limits of the abiotic and biotic conditions of the local environment. Implications of our findings for plankton ecosystem functioning are discussed. IMPORTANCE Plankton communities change on a seasonal basis in temperate systems, with distinct succession patterns; this is mainly due to algal species that have their optimal timing relative to environmental conditions. We know that bacterial populations are also instrumental in the decay and termination of phytoplankton blooms. Here, we describe algicidal bacteria as modulators of this important species succession. Upon treatment of a natural plankton consortium with an algicidal bacterium, we observed a strong shift in the phytoplankton community structure, compared to controls, resulting in formation of a succeeding Phaeocystis bloom. Blooms of this alga have a substantial impact on global biogeochemical and ecological cycles, as they are responsible for a substantial proportion of primary production during spring in the North Sea. We propose that one of the key factors influencing such community shifts may be algicidal bacteria.
Does fMRI repetition suppression reveal mirror neuron activity in the human brain? Insights from univariate and multivariate analysis

Mirror neurons (MN) have been proposed as the neural substrate for a wide range of clinical, social and cognitive phenomena. Over the last decade, a commonly used tool for investigating MN activity in the human brain has been functional magnetic resonance (fMRI) repetition suppression (RS) paradigms. However, the available evidence is mixed, largely owing to inconsistent application of the methodological criteria necessary to infer MN properties. This raises concerns about the degree to which one can infer the presence (or absence) of MN activity from earlier accounts that adopted RS paradigms. We aimed to clarify this issue using a well‐validated fMRI RS paradigm and tested for mirror properties by rigorously applying the widely accepted criteria necessary to demonstrate MN activity using traditional univariate techniques and Multivariate Pattern Analysis (MVPA). While univariate whole brain analysis in healthy adults showed uni‐modal RS effects within the supplementary motor area, no evidence for cross‐modal RS effects consistent with mirror neuron activity was found. MVPA on the other hand revealed a region along the anterior intraparietal sulcus that met the criteria for MN activity. Taken together, these results clarify disparate evidence from earlier RS studies, highlighting that traditional univariate analysis of RS data may not be sensitive for detecting MN activity when rigorously applying the requisite criteria. In light of these findings, we recommend that short of increasing sample sizes substantially, future studies using RS paradigms to investigate MNs across the human brain consider the use of MVPA.
Intravenous administration of multipotent stromal cells and bone allograft modification to enhance allograft healing.

Aim: This study investigated a coordinated strategy of revitalizing bone allograft with circulating multipotent stromal cells (MSCs). Materials & methods: After chemotactic and releasing assessments, stromal cell-derived factor 1 and platelet-derived growth factor BB in copolymers were coated on the bone allograft (AlloS-P). Allograft coated with copolymers alone (Allo), as controls, or AlloS-P was implanted into the femur of athymic mice, which received intravenous injections of human MSCs or saline at weeks 1, 2 and 3. Results: At week 8, the total callus volume (both cartilaginous and bony callus) around the allograft was the largest in the AlloS-P + MSC group (p < 0.05). Conclusion: Coating bone allograft with stromal cell-derived factor 1 and platelet-derived growth factor BB and intravenous injections of MSCs improved allograft incorporation.
Continuous Glycoprotein-130-Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction

Background— In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130Y757F mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction. Methods and Results— The cardiomyocyte-restricted &agr;-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130Y757F mutant cardiomyocytes (&agr;MHC-Cretg/−;gp130fl/Y757F [Y757F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y757F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y757F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y757F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3flox/+) restricted to cardiomyocytes in Y757F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction. Conclusion— Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.
Nuclear import of the DSCAM‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

DSCAM and DSCAML1 are immunoglobulin and cell adhesion‐type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self‐avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high‐throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifically and directly interact with IPO5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ‐secretase‐dependent cleavage, and both the DSCAM and DSCAML1 ICDs efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML1 ICDs alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain‐of‐function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full‐length DSCAM or the DSCAM ICD, but not the DSCAML1 ICD, significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane‐to‐nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome.
The association between problematic online gaming and perceived stress: The moderating effect of psychological resilience

Background and aims Vulnerability to stress appears to be a potential predisposing factor for developing specific internet-use disorders, such as Internet Gaming Disorder (IGD). Studies investigating the protective effect of psychological resilience against the impact of perceived stress on IGD and weekly gameplay have yet to be reported in the existing literature. The aim of this study was to examine the potential moderating relationships between perceived stress and online gaming (more specifically operationalized as IGD and weekly gameplay) with psychological resilience. Methods An online survey was administered to 605 participants (males = 82%, Mage = 24.01 years, SDage = 6.11). A multivariate multiple regression model was applied to test for the possible contribution of perceived stress and psychological resilience to weekly gameplay and IGD. Results Perceived stress was associated with higher scores of IGD, whereas psychological resilience was related to lower scores of IGD. In addition, the combination of having higher perceived stress and lower level of psychological resilience was associated with a particularly high hours of gameplay per week. Discussion and conclusions These findings further support the importance of personal traits (perceived stress and psychological resilience) in online gaming (IGD severity and weekly gameplay), and also emphasize the unique moderating relationship between perceived stress and weekly gameplay with lack of resilience. Enhancing psychological resilience to decrease the likelihood of online gamers who experience higher level of stress from spending more hours per week gaming is recommended.
TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells

Purpose: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. Experimental Design: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined. Results: Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. Conclusions: Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804–13. ©2016 AACR. See related commentary by Zenarruzabeitia et al., p. 615
Self-efficacy predicts response to cognitive rehabilitation in military service members with post-concussive symptoms

ABSTRACT This study examined whether self-efficacy differentiated treatment responders from non-responders in a trial of cognitive rehabilitation (CR) for postconcussive symptoms. 126 service members with mild TBI seen on average 9.5 months since injury completed one of four cognitive rehabilitation treatments for 6 weeks. The four treatment arms were: (1) Psychoeducation control, (2) Self-administered computerized CR, (3) Interdisciplinary CR, and (4) Interdisciplinary CR integrated with CBT. Outcome was assessed across time (baseline, and 6, 12, and 18 weeks post-treatment) for three domains: psychological (Symptom Checklist–90-Revised; SCL-90-R), cognitive (Paced Auditory Serial Addition Test; PASAT), and functional/behavioural (Key Behaviors Change Inventory; KBCI). Mixed model ANOVAs tested for self-efficacy differences across time in treatment responders versus non-responders, as defined by reliable change indices. A significant interaction was found on the SCL-90 such that responders had increasing self-efficacy with respect to psychological symptoms across four time points, whereas non-responders’ self-efficacy did not change. Perceived self-efficacy at the beginning of treatment was associated with treatment engagement within the psychological domain for responders only, suggesting a mediating role in treatment outcome. Overall, results suggest that increasing patients’ level of self-efficacy may be important for successful treatment of psychological distress in those with remote concussion.
Effect of a lateral gravitational field on the nonaxisymmetric equilibrium shapes of liquid bridges held between eccentric disks and of volumes equal to those of cylinders

Bifurcation diagrams of nonaxisymmetric cylindrical volume liquid bridges held between nonconcentric circular disks subject to a lateral gravitational force are found by solving the Young-Laplace equation for the interface by a finite difference method. In the absence of lateral gravity, the primary family of liquid bridges that starts with the cylinder when the eccentricity of the disks, e, is zero first loses stability at a subcritical bifurcation point as e increases. Further loss of stability is experienced by the already unstable primary family as a turning point is encountered at yet higher values of the eccentricity. However, the introduction of lateral gravity gl changes entirely the structure of the solutions in that instability always occurs at a turning point with respect to e no matter how small the magnitude of gl. The stability limits calculated are compared with the ones obtained using asymptotic techniques by taking as base solution the cylinder of slenderness Λ=π.
The AAA+ ATPase/ubiquitin ligase mysterin stabilizes cytoplasmic lipid droplets

Mysterin, also known as RNF213, is an intracellular protein that forms large toroidal oligomers. Mysterin was originally identified in genetic studies of moyamoya disease (MMD), a rare cerebrovascular disorder of unknown etiology. While mysterin is known to exert ubiquitin ligase and putative mechanical ATPase activities with a RING finger domain and two adjacent AAA+ modules, its biological role is poorly understood. Here, we report that mysterin is targeted to lipid droplets (LDs), ubiquitous organelles specialized for neutral lipid storage, and markedly increases their abundance in cells. This effect was exerted primarily through specific elimination of adipose triglyceride lipase (ATGL) from LDs. The ubiquitin ligase and ATPase activities of mysterin were both important for its proper LD targeting. Notably, MMD-related mutations in the ubiquitin ligase domain of mysterin significantly impaired its fat-stabilizing activity. Our findings identify a unique new regulator of cytoplasmic LDs and suggest a potential link between the pathogenesis of MMD and fat metabolism.
Synthetic genome defenses against selfish DNA elements stabilize engineered bacteria against evolutionary failure

Mobile genetic elements drive evolution by disrupting genes and rearranging genomes. Eukaryotes have evolved epigenetic mechanisms, including DNA methylation and RNA interference, that silence mobile elements and thereby preserve the integrity of their genomes. We created an artificial reprogrammable epigenetic system based on CRISPR interference to give engineered bacteria a similar line of defense against transposons and other selfish elements in their genomes. We demonstrate that this CRISPR interference against mobile elements (CRISPRi-ME) approach can be used to simultaneously repress two different transposon families in Escherichia coli, thereby increasing the evolutionary stability of costly protein expression. We further show that silencing a transposon in Acinetobacter baylyi ADP1 reduces mutation rates by a factor of five, nearly as much as deleting all copies of this element from its genome. By deploying CRISPRi-ME on a broad-host-range vector we have created a generalizable platform for stabilizing the genomes of engineered bacterial cells for applications in metabolic engineering and synthetic biology. Significance Engineered cells often cease to function or lose productivity when mutations arise in their genomes. Mobile DNA elements, such as transposons, are major sources of these inactivating mutations. Eukaryotic genomes have evolved flexible epigenetic defenses against mobile DNA that help them to maintain genome integrity, but bacteria do not possess comparable silencing systems. We developed a synthetic control system based on CRISPR interference that can be used to give bacterial cells a reprogrammable line of defense against selfish DNA elements in their genomes. We show that this system effectively represses multicopy transposons and multiple families of transposons. Limiting selfish DNA proliferation within a genome in this way improves the reliability of genetically engineered functions in replicating bacterial cell populations.
MRI of Rectal Cancer: Tumor Staging, Imaging Techniques, and Management.

Rectal cancer is prone to local recurrence and systemic metastasis. However, owing to improvements in TNM staging and treatment, including a more widespread use of rectal MRI and increased radiologist awareness of the key rectal cancer TNM staging features, the mortality rate of rectal cancer has been declining over the past few decades in adults over 50 years of age. Currently, rectal MRI plays a key role in the pre- and posttreatment evaluation of rectal cancer, assisting the multidisciplinary team in tailoring the most appropriate treatment option. The benefits achieved with rectal MRI are strictly dependent on obtaining good-quality images, which is important for the characterization of the main anatomic structures and their relationship with the tumor. In primary staging, rectal MRI helps the radiologist (a) describe the tumor location and morphology, (b) provide its T and N categories, (c) detect the presence of extramural vascular invasion, and (d) identify its relationship with surrounding structures, including the sphincter complex and involvement of the mesorectal fascia. These features help diagnose locally advanced rectal tumors (categories T3c-d, T4, N1, and N2), for which neoadjuvant chemoradiotherapy (CRT) is indicated. In restaging after neoadjuvant CRT, in addition to reassessing the features noted during primary staging, rectal MRI can help in the assessment of treatment response, especially with the emergence of nonsurgical approaches such as "watch and wait. " ©RSNA, 2019.