A Rheological Study of the Association and Dynamics of MUC5AC Gels.

The details of how a mucus hydrogel forms from its primary structural component, mucin polymers, remain incompletely resolved. To explore this, we use a combination of macrorheology and single-particle tracking to investigate the bulk and microscopic mechanical properties of reconstituted MUC5AC mucin gels. We find that analyses of thermal fluctuations on the length scale of the micrometer-sized particles are not predictive of the linear viscoelastic response of the mucin gels, and that taken together, the results from both techniques help to provide complementary insight into the structure of the network.

Lithium reduces the span of G protein-activated K (GIRK) channel inhibition in hippocampal neurons.

Objectives: Lithium (Li ) is one of the most widely used treatments for bipolar disorder (BD). However, the molecular and neuronal basis of BD, as well as the mechanisms of Li actions are poorly understood. Cellular and biochemical studies identified G proteins as being among the cellular targets for Li action, while genetic studies indicated an association with the KCNJ3 gene, which encodes the G protein-activated inwardly rectifying K (GIRK) channels.

Molecular structure of bottlebrush polymers in melts.

Bottlebrushes are fascinating macromolecules that display an intriguing combination of molecular and particulate features having vital implications in both living and synthetic systems, such as cartilage and ultrasoft elastomers. However, the progress in practical applications is impeded by the lack of knowledge about the hierarchic organization of both individual bottlebrushes and their assemblies. We delineate fundamental correlations between molecular architecture, mesoscopic conformation, and macroscopic properties of polymer melts.

Molecular and functional genetics of the proopiomelanocortin gene, food intake regulation and obesity.

A specter is haunting the world, the specter of obesity. During the last decade, this pandemia has skyrocketed threatening children, adolescents and lower income families worldwide. Although driven by an increase in the consumption of ultraprocessed edibles of poor nutritional value, the obesogenic changes in contemporary human lifestyle affect people differently, revealing that some individuals are more prone to develop increased adiposity.

Platelets subvert T cell immunity against cancer via GARP-TGFβ axis.

Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We show that genetic targeting of platelets enhances adoptive T cell therapy of cancer.

Lactic Acidosis as Presenting Symptom of Thiamine Deficiency in Children with Hematologic Malignancy.

Thiamine is an essential component of cellular metabolism and its deficiency results in potentially life-threatening events and profound lactic acidosis through anaerobic metabolism. Acute decompensation in thiamine-deficient patients may manifest as neurologic or cardiovascular changes, with severe lactic acidosis as the presenting symptom. We describe two hematological pediatric patients with thiamine deficiency and hemodynamic instability who improved following thiamine supplements.

PERK induces resistance to cell death elicited by endoplasmic reticulum stress and chemotherapy.

Background: Nutrient deprivation, hypoxia, radiotherapy and chemotherapy induce endoplasmic reticulum (ER) stress, which activates the so-called unfolded protein response (UPR). Extensive and acute ER stress directs the UPR towards activation of death-triggering pathways. Cancer cells are selected to resist mild and prolonged ER stress by activating pro-survival UPR.

Single-stranded nucleic acid elasticity arises from internal electrostatic tension.

Understanding of the conformational ensemble of flexible polyelectrolytes, such as single-stranded nucleic acids (ssNAs), is complicated by the interplay of chain backbone entropy and salt-dependent electrostatic repulsions. Molecular elasticity measurements are sensitive probes of the statistical conformation of polymers and have elucidated ssNA conformation at low force, where electrostatic repulsion leads to a strong excluded volume effect, and at high force, where details of the backbone structure become important. Here, we report measurements of ssDNA and ssRNA elasticity in the intermediate-force regime, corresponding to 5- to 100-pN forces and 50-85% extension.

β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity.

ICOS costimulation generates Th17 cells with durable memory responses to tumor. Herein, we found that ICOS induces PI3K/p110δ/Akt and Wnt/β-catenin pathways in Th17 cells. Coinhibiting PI3Kδ and β-catenin altered the biological fate of Th17 cells.

Nanoparticle Motion in Entangled Melts of Linear and Nonconcatenated Ring Polymers.

The motion of nanoparticles (NPs) in entangled melts of linear polymers and nonconcatenated ring polymers are compared by large-scale molecular dynamics simulations. The comparison provides a paradigm for the effects of polymer architecture on the dynamical coupling between NPs and polymers in nanocomposites. Strongly suppressed motion of NPs with diameter larger than the entanglement spacing is observed in a melt of linear polymers before the onset of Fickian NP diffusion.

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer.

Background: Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).

Methods: We generated autologous DCs from the peripheral blood of HLA-A2 patients with PC.

C/EBPβ LIP augments cell death by inducing osteoglycin.

Many types of tumor cell are devoid of the extracellular matrix proteoglycan osteoglycin (Ogn), but its role in tumor biology is poorly studied. Here we show that RNAi of Ogn attenuates stress-triggered cell death, whereas its overexpression increases cell death. We found that the transcription factor C/EBPβ regulates the expression of Ogn.

[Epigenetics 2.0: The multiple faces of the genome].

Epigenetics is the branch of genetics that studies the dynamic relationship between stable genotypes and varying phenotypes. To this end, epigenetics aims to discover the molecular mechanisms that explain how different nutrients and hormones, environmental changes, and emotional, social and cognitive experiences modify gene expression and behaviors, even permanently so. Psychiatry has learned that diseases with strong genetic predisposition, such as schizophrenia, show a concordance of around 50% between monozygotic twins, thus evidencing the importance of the genetic background and the presence of environmental variables that stimulate or block phenotypic development.

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

Adoptive cellular therapy (ACT) with the Th17 subset of CD4 T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells.

Inappropriate Shocks and Power Delivery Using Adult Automatic External Defibrillator Pads in a Pediatric Patient.

The use of automatic external defibrillators (AEDs) during pulseless resuscitations is considered safe and reliable, and was established as part of the guidelines in out-of-hospital events. Based on extensive studies, the use of the standard AED is now indicated in every age group with a preference of pediatric pad application for small children and babies. If unavailable, adult pads are recommended.

Public provision of postsecondary education for transition-age youth with mental health conditions.

Objective: We examine the role of state vocational rehabilitation (VR) agencies (SVRA) in providing postsecondary education support to transition-age youth with and without mental health conditions (MHC) to provide insights into who receives such supports and the association between the receipt of postsecondary education support and successful VR exits.

Method: We used data from SVRA administrative records (fiscal years 2002 through 2013) for a secondary analytical approach that relied on descriptive and regression methods, resulting in the identification of 436,883 VR youth clients who applied from 2002 to 2004. Linear regression models examined the relationships between youth demographic and service characteristics and each of 4 binary outcomes derived from the administrative records: (1) receipt of VR services, (2) receipt of college support (conditional on receiving services), (3) receipt of vocational training support (conditional on receiving services), and (4) exiting with employment.

Flory theory of randomly branched polymers.

Randomly branched polymer chains (or trees) are a classical subject of polymer physics with connections to the theory of magnetic systems, percolation and critical phenomena. More recently, the model has been reconsidered for RNA, supercoiled DNA and the crumpling of topologically-constrained polymers. While solvable in the ideal case, little is known exactly about randomly branched polymers with volume interactions.

Key role of the dopamine D receptor in the modulation of corticostriatal glutamatergic neurotransmission.

Polymorphic variants of the dopamine D receptor gene () have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D receptor and the functional differences of the products of polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D receptor with the long intracellular domain of a human polymorphic variant associated with attention deficit hyperactivity disorder (ADHD).

Strong, Tough, Stretchable, and Self-Adhesive Hydrogels from Intrinsically Unstructured Proteins.

Strong, tough, stretchable, and self-adhesive hydrogels are designed with intrinsically unstructured proteins. The extraordinary mechanical properties exhibited by these materials are enabled by an integration of toughening mechanisms that maintain high elasticity and dissipate mechanical energy within the protein networks.

Basal Ganglia Dysfunction Contributes to Physical Inactivity in Obesity.

Obesity is associated with physical inactivity, which exacerbates the health consequences of weight gain. However, the mechanisms that mediate this association are unknown. We hypothesized that deficits in dopamine signaling contribute to physical inactivity in obesity.

Polydrug use among urban adolescent cigarette smokers.

Purpose: Adolescent smokers are at increased risk for polydrug use, which is associated with more consequences than use of a single drug. Here we classified subgroups of polydrug use among urban adolescent cigarette-smokers; described the sociodemographic, smoking, and depression correlates; and identified three-year outcomes associated with subgroup membership.

Methods: Adolescent cigarette smokers (N=176; M=16.

Association of rare missense variants in the second intracellular loop of Na1.7 sodium channels with familial autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases.