Miracle-dz/UniFAR-FTUs huggingface dataset:
Signaling by the Matrix Proteoglycan Decorin Controls Inflammation and Cancer Through PDCD4 and MicroRNA-21

A component of the extracellular matrix promotes inflammatory responses in sepsis and in tumors. Boosting Inflammation Components of the extracellular matrix have structural roles, but various stresses can induce the release of soluble fragments of these components that can participate in signaling pathways. Merline et al. showed that the soluble form of the proteoglycan decorin promoted inflammatory activity by attenuating the release of anti-inflammatory factors and by activating receptors that trigger the production of proinflammatory mediators. Septic patients showed increased plasma concentrations of decorin, and mice lacking decorin showed increased production of anti-inflammatory factors and decreased production of proinflammatory factors during sepsis. Injecting established tumors in mice with an adenovirus expressing decorin resulted in reduced tumor growth. Thus, treatments that decrease decorin abundance could be used to calm inflammation during sepsis, whereas those that increase decorin abundance might be of clinical use in reducing tumor growth. The mechanisms linking immune responses and inflammation with tumor development are not well understood. Here, we show that the soluble form of the extracellular matrix proteoglycan decorin controls inflammation and tumor growth through PDCD4 (programmed cell death 4) and miR-21 (microRNA-21) by two mechanisms. First, decorin acted as an endogenous ligand of Toll-like receptors 2 and 4 and stimulated production of proinflammatory molecules, including PDCD4, in macrophages. Second, decorin prevented translational repression of PDCD4 by decreasing the activity of transforming growth factor–β1 and the abundance of oncogenic miR-21, a translational inhibitor of PDCD4. Moreover, increased PDCD4 abundance led to decreased release of the anti-inflammatory cytokine interleukin-10, thereby making the cytokine profile more proinflammatory. This pathway operates in both pathogen-mediated and sterile inflammation, as shown here for sepsis and growth retardation of established tumor xenografts, respectively. Decorin was an early response gene evoked by septic inflammation, and protein concentrations of decorin were increased in the plasma of septic patients and mice. In cancer, decorin reduced the abundance of anti-inflammatory molecules and increased that of proinflammatory molecules, thereby shifting the immune response to a proinflammatory state associated with reduced tumor growth. Thus, by stimulating proinflammatory PDCD4 and decreasing the abundance of miR-21, decorin signaling boosts inflammatory activity in sepsis and suppresses tumor growth.
Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for the treatment of metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) in patients failing previous TKI therapy. The T790M mutation is an acquired resistance mechanism found in over half of patients with NSCLC progressing on first-generation TKIs. First- and second-generation TKIs do not inhibit the T790M mutation at clinically relevant concentrations. Osimertinib is selective for mutated forms of EGFR, including the TKI-sensitizing mutations L858R and exon 19 deletions, as well as the acquired T790M resistance mutation. In a trial comparing osimertinib to platinum doublet therapy among patients with the T790M mutation progressing on first-line TKI therapy, median progression-free survival was significantly longer in patients receiving osimertinib. Osimertinib has a favorable safety profile compared to platinum-doublet chemotherapy. Common adverse events include diarrhea, skin rash, dry skin, and paronychia; however, because it spares wild-type EGFR, these toxicities appear to occur with less frequency and severity compared to other TKIs. Serious, but rare, adverse events include pneumonitis, interstitial lung disease-like events, QT interval prolongation, and reduced ejection fraction. Osimertinib has the unique ability to distribute readily into brain tissue compared with other TKIs, giving it a potential role in the treatment and/or prevention of CNS metastases; future studies are warranted in this area. An ongoing study evaluating osimertinib versus first-generation TKIs as first-line treatment for patients with EGFR mutation-positive NSCLC may help to define the role of osimertinib as front-line therapy.
Protein Kinase CK2 Triggers Cytosolic Zinc Signaling Pathways by Phosphorylation of Zinc Channel ZIP7

Phosphorylation of the zinc channel ZIP7 releases zinc from the endoplasmic reticulum and promotes signals associated with proliferation and migration. Regulating Zinc Signals Zinc, which has emerged as a second messenger, is released from intracellular stores, leading to activation of tyrosine kinases and thereby to stimulation of pathways involved in cell proliferation and migration. Here, Taylor et al. uncover evidence implicating the kinase CK2, which plays a prominent role in cell proliferation, in this process through its association with and phosphorylation of the endoplasmic reticulum–resident zinc channel ZIP7. Inhibition of CK2 attenuated zinc release from the endoplasmic reticulum and downstream signals. A functional mutation of ZIP7 that interfered with CK2-ZIP7 interactions prevented ZIP7-mediated zinc signals, decreased downstream signaling events, and attenuated ZIP7-mediated cell migration. Thus, the authors conclude that CK2 plays a crucial role in the activation of ZIP7 and thereby in mediating zinc signals. The transition element zinc, which has recently been identified as an intracellular second messenger, has been implicated in various signaling pathways, including those leading to cell proliferation. Zinc channels of the ZIP (ZRT1- and IRT1-like protein) family [also known as solute carrier family 39A (SLC39A)] transiently increase the cytosolic free zinc (Zn2+) concentration in response to extracellular signals. We show that phosphorylation of evolutionarily conserved residues in endoplasmic reticulum zinc channel ZIP7 is associated with the gated release of Zn2+ from intracellular stores, leading to activation of tyrosine kinases and the phosphorylation of AKT and extracellular signal–regulated kinases 1 and 2. Through pharmacological manipulation, proximity ligation assay, and mutagenesis, we identified protein kinase CK2 as the kinase responsible for ZIP7 activation. Together, the present results show that transition element channels in eukaryotes can be activated posttranslationally by phosphorylation, as part of a cell signaling cascade. Our study links the regulated release of zinc from intracellular stores to phosphorylation of kinases involved in proliferative responses and cell migration, suggesting a functional role for ZIP7 and zinc signals in these events. The connection with proliferation and migration, as well as the activation of ZIP7 by CK2, a kinase that is antiapoptotic and promotes cell division, suggests that ZIP7 may provide a target for anticancer drug development.
Chemoattractant Signaling in Dictyostelium: Adaptation and Amplification

Dictyostelium cells sense and interpret gradients by combining an incoherent feedforward loop and an amplification step. The social amoebae Dictyostelium discoideum has long proved a powerful model organism for studying how cells sense and interpret chemoattractant gradients. Because of the rich behavior observed in its response to chemoattractants, as well as the complex nature of the signaling pathways involved, this research has attracted and benefited from the use of theoretical models. Recent quantitative experiments provide support for a popular model: the local excitation, global inhibition mechanism of gradient sensing. Here, I discuss these findings and suggest some important open problems.
An Interaction Between BZR1 and DELLAs Mediates Direct Signaling Crosstalk Between Brassinosteroids and Gibberellins in Arabidopsis

Crosstalk between two signaling pathways that control plant growth occurs through the DELLA family of transcription factors. Integrating Growth Signals Brassinosteroids (BRs) and gibberellins (GAs) are plant hormones that promote cell elongation and plant growth. Li et al. found that proteins of the DELLA family, which are negative regulators of GA signaling, also inhibited the activity of the transcription factors that mediate BR signaling, BZR1, and the related protein BES1, thus establishing DELLAs as points of crosstalk between these two pathways. The DELLA protein RGA interacted with BZR1, and DELLAs and BZR1 were functionally antagonistic. Manipulation of GA signaling indicated that DELLAs may reduce the abundance of protein phosphatase 2A, thereby promoting the accumulation of the phosphorylated and inactive form of BRZ1. Thus, these results indicated that crosstalk between the BR and the GA signaling pathways occurs through the DELLA family of proteins. Plant growth and development are coordinated by several groups of small-molecule hormones, including brassinosteroids (BRs) and gibberellins (GAs). Physiological and molecular studies have suggested the existence of crosstalk between BR and GA signaling. We report that BZR1, a key transcription factor activated by BR signaling, interacts in vitro and in vivo with REPRESSOR OF ga1-3 (RGA), a member of the DELLA family of transcriptional regulators that inhibits the GA signaling pathway in Arabidopsis thaliana. Genetic analyses of plants with mutations in the genes encoding RGA and BZR1 revealed that RGA suppressed root and hypocotyl elongation of the gain-of-function mutant bzr1-1D. Ectopic expression of proteins of the DELLA family reduced the abundance and transcriptional activity of BZR1. Reporter gene analyses further indicated that BZR1 and RGA antagonize each other’s transcriptional activity. Our data indicated that BZR1 and RGA served as positive and negative regulators, respectively, of both the BR and the GA signaling pathways and establish DELLAs as mediators of signaling crosstalk between BRs and GAs in controlling cell elongation and regulation of plant growth.
Support Vector Machine with the Fuzzy Hybrid Kernel for Protein Subcellular Localization Classification

In the paper, we present a fuzzy hybrid kernel that combines several conventional kernels by using the TSK model. The major technical merit is to make a more reliable kernel fusing different kernels. Support vector machine (SVM) with the fuzzy hybrid kernel is employed for protein subcellular localization classification. Experimental results indicate that SVM with the new fuzzy hybrid kernel is better than those with conventional kernels
Do Pancreatic β Cells “Taste” Nutrients to Secrete Insulin?

The role of β cell taste receptors in the control of insulin secretion is unclear. Insulin secretion from pancreatic β cells is controlled by nutrients, hormones, and neurotransmitters. Unlike the latter, which work through classic receptors, glucose and most other nutrients do not interact with membrane receptors but must be metabolized by β cells to induce insulin secretion. Studies have revealed the presence of umami and sweet taste receptors and their downstream effectors in β cells. That the receptors are functional was established by the effects of fructose and artificial sweeteners, which induced signals similar to those produced in taste buds of the tongue. These signals mediated an increase in insulin secretion in the presence of glucose. However, the physiological implications of these pathways in insulin secretion are unclear because of the large differences between plasma concentrations of fructose or sweeteners and their effective concentrations in vitro.
Revisiting the Nucleolus: From Marker to Dynamic Integrator of Cancer Signaling

Deregulations in ribosome biogenesis contribute to tumorigenesis and could be targeted to treat cancer. Key signaling pathways (such as phosphoinositide 3-kinase, Myc, and RAS) act as sensors of energy, stress, and nutrient availability and integrate these inputs to directly control ribosome production and gene expression at the translational level. This activity is normally directly coupled to cell growth, division, and survival. However, it remains poorly understood the extent to which changes in ribosome number and nucleolar integrity downstream of these key signaling pathways contribute to their oncogenic activity. Emerging studies provide interesting insight into how deregulations in RNA polymerase I activity may lead to tumorigenesis and suggest that new drugs targeting ribosomal DNA transcription may hold great promise for the treatment of cancer.
Childbirth expectations and experiences and associations with mothers’ attitudes to pregnancy, the child and motherhood

Objective: The aim of this study was to investigate whether a woman’s childbirth experience could be predicted by Raphael‐Leff’s model of antenatal views of pregnancy and motherhood (the Facilitator, Regulator, Reciprocator, and Conflicted or Bipolar mother). Design and methods: In a monocentric prospective observational cohort study, 298 expecting mothers completed a booklet with questionnaires (including the Facilitator scale, Regulator scale, and Salmon Item List) at 30–36 gestational weeks (T1). A follow‐up booklet was completed at 8–12 weeks postpartum (T2). Obstetric outcome was retrieved from the electronic patient files. Results: At T2, women reported less distress and less difficulty than they had expected at T1. Women tending to the Facilitator orientation expected more fulfilment and less distress, whereas women tending to the Regulator orientation expected less fulfilment and more distress. Similar associations were found for the actual childbirth experience. However, the significance of the contribution to the childbirth experience disappeared when controlled for obstetric history, maternal expectations, and obstetric and neonatal outcome. In addition, primiparious women tending to the Facilitator orientation reported less intrapartum feelings of fulfilment when they had an assisted delivery. Conclusion: The maternal orientations contribute, to some extent, to the understanding of the variations in the childbirth experience.
Medical Parole and Aging Prisoners: A Qualitative Study

The population of geriatric prisoners in the United States will reach unprecedented levels in the coming decades. Geriatric prisoners are at increased risk for deteriorating health and experience the onset of disease earlier than the aging population at large. Medical parole is an underutilized program that allows aging prisoners to transition to community-based health care. This article presents original key informant interview data and analysis of the perceptions of medical parole. Three dominant themes emerged: (1) drugs and nonviolent crimes; (2) politics, costs, and consequences; and (3) quality of health care and sense of security in prison. Participants rejected the possibility that medical care provided is below the clinical standard or is the cause of geriatric prisoners’ deteriorating health and consistently implied that medical care at this prison is better than most Americans receive. Participants perceived their careers more as contributions to public health than criminal justice.
The regulatory subunits of PI3Kγ control distinct neutrophil responses

Migration of neutrophils to sites of infection and their generation of reactive oxygen species depend on different regulatory subunits of PI3Kγ. Not All PIP3 Is Equal Neutrophils are immune cells that migrate to sites of infection and generate reactive oxygen species (ROS) to kill pathogens. Both functions depend on the heterodimeric kinase PI3Kγ, which consists of the catalytic p110γ subunit and either a p101 or p84 regulatory subunit. PI3Kγ generates the phospholipid PIP3, which is required for the activation of downstream effectors. Deladeriere et al. generated p84-deficient mice and found that their neutrophils had defects in GPCR-dependent PIP3 generation, which were similar to those of previously described p101-deficient neutrophils. However, unlike loss of p101, which impairs migration, loss of p84 resulted in reduced ROS generation without affecting neutrophil migration. These results suggest that, although the p84 and p101 subunits similarly promote PIP3 production, they enable PI3Kγ signaling to mediate distinct neutrophil functions. Neutrophils, which migrate toward inflamed sites and kill pathogens by producing reactive oxygen species (ROS), are important in the defense against bacterial and fungal pathogens, but their inappropriate regulation causes various chronic inflammatory diseases. Phosphoinositide 3-kinase γ (PI3Kγ) functions downstream of proinflammatory G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) in neutrophils and is a therapeutic target. In neutrophils, PI3Kγ consists of a p110γ catalytic subunit, which is activated by the guanosine triphosphatase Ras, and either a p84 or p101 regulatory subunit. Loss or inhibition of p110γ or expression of a Ras-insensitive variant p110γ (p110γDASAA/DASAA) impairs PIP3 production, Akt phosphorylation, migration, and ROS formation in response to GPCR activation. The p101 subunit binds to, and mediates PI3Kγ activation by, G protein βγ subunits, and p101−/− neutrophils have a similar phenotype to that of p110γ−/− neutrophils, except that ROS responses are normal. We found that p84−/− neutrophils displayed reduced GPCR-stimulated PIP3 and Akt signaling, which was indistinguishable from that of p101−/− neutrophils. However, p84−/− neutrophils produced less ROS and exhibited normal migration in response to GPCR stimulation. These data suggest that p84-containing PI3Kγ controls GPCR-dependent ROS production. Thus, the PI3Kγ regulatory subunits enable PI3Kγ to mediate distinct neutrophil responses, which may occur by targeting PIP3 signaling into spatially distinct domains.
Building a Tobacco Cessation Telehealth Care Management Program for Veterans With Posttraumatic Stress Disorder

BACKGROUND: Veterans with posttraumatic stress disorder (PTSD) have high rates of smoking. Motivational interviewing (MI) enhances readiness for change. OBJECTIVE: To test the feasibility and fidelity of home telehealth care management strategy to improve quit rates. DESIGN: A telehealth device delivered a cessation curriculum while a nurse supported veterans through weekly MI telephone calls. Treatment fidelity was evaluated. Outcomes measures included changes in smoking behaviors, stage of change, dose effect, and participant satisfaction with intervention. RESULTS: There was a correlation (r = −.677; p = .03) at the end of treatment between readiness to change and number of cigarettes smoked per day. As 11 participants progressed along stages of change, they smoked fewer cigarettes per day. Two (20%) quit smoking. The nurse adhered to MI principles. Participants were highly satisfied and 100% felt curriculum delivered new information and respected choices. CONCLUSIONS: It was feasible to deliver the home telehealth care management intervention with high treatment fidelity. Participants were motivated to change smoking behaviors.
A Pilot Randomized Control Trial

OBJECTIVE: People with multiple and persistent mental and physical health problems have high rates of transition failures when transferring from a hospital level of care to home. The transitional care model (TCM) is evidence-based and demonstrated to improve posthospital outcomes for elderly with physical health conditions, but it has not been studied in the population with serious mental illness. METHOD: Using a randomized controlled design, 40 inpatients from two general hospital psychiatric units were recruited and randomly assigned to an intervention group (n = 20) that received the TCM intervention that was delivered by a psychiatric nurse practitioner for 90 days posthospitalization, or a control group (n = 20) that received usual care. Outcomes were as follows: service utilization, health-related quality of life, and continuity of care. RESULTS: The intervention group showed higher medical and psychiatric rehospitalization than the control group (p = .054). Emergency room use was lower for intervention group but not statistically significant. Continuity of care with primary care appointments were significantly higher for the intervention group (p = .023). The intervention group’s general health improved but was not statistically significant compared with controls. CONCLUSIONS: A transitional care intervention is recommended; however, the model needs to be modified from a single nurse to a multidisciplinary team with expertise from a psychiatric nurse practitioner, a social worker, and a peer support specialist. A team approach can best manage the complex physical/mental health conditions and complicated social needs of the population with serious mental illness.
Hypertriglyceridemia Deteriorates Coronary Flow Reserve Even if There is no Coronary Stenosis: Real-Time Myocardial Contrast Echocardiographic Study

Background. It is reported that hyperlipidemia may deteriorate the coronary circulation by itself. The aim is to examine the effect of acute hypertriglyceridemia on myocardial perfusion using real-time myocardial contrast echocardiography (MCE). Methods. Hypertriglyceridemia was induced by infusion of fat emulsion (Intralipos) in 7 open-chest dogs. The coronary flow was measured by a flow meter, and its reserve (CFR) was determined by adenosine triphosphate (ATP) injection. MCE was examined using SIEMENS Sequoia-512 during infusion of Definity®. The replenishment curve was obtained to measure the A and β value in the equation of y=A(1-e-βt). Results. The β value did not change by hyperlipidemia, however, its increment by ATP decreased significantly at hyperlipidemia. The β value after ATP decreased concomitantly with the increase of both serum triglyceride level and blood viscosity. However, the A value was not affected by either serum triglyceride or viscosity.Conclusions. Hypertriglyceridemia makes blood viscous followed by high shear stress in the resistant vessels. Although myocardial resistant vessels are dilated for its compensatory response, exaggeration of blood flow speed in the capillaries after ATP is impaired due to high viscosity of hyperlipidemia.
Parent and Family Processes Related to ADHD Management in Ethnically Diverse Youth

BACKGROUND: Previous research has shown major disparities in attention deficit hyperactivity disorder (ADHD) for diverse youth across America. We do not fully understand, however, how parent and family processes are related to the identification, care-seeking approaches, treatment preferences, and engagement with care systems and services for youth with ADHD. OBJECTIVES: The present study aimed to explore parent and family processes related to the management of ADHD in racially and ethnically diverse youth. DESIGN: This integrative review was structured with the methodology proposed by Whittemore and Knafl. RESULTS: Three major electronic databases yielded a final sample of 32 articles (24 quantitative, 6 qualitative, and 2 mixed methods). Nine themes emerged within three overarching meta-themes. CONCLUSIONS: Understanding the unique perspectives of families from diverse backgrounds is essential for clinicians, researchers, and policymakers, who are dedicated to understanding racial and ethnic perspectives and developing ecologically appropriate and family-based interventions for youth with ADHD.