Evaluation of resurgence following differential reinforcement of alternative behavior with and without extinction in a human operant model.

One of the most common treatments for severe challenging behavior involves placing the challenging behavior on extinction and differentially reinforcing an alternative response (DRA). However, extinction is not always feasible and may be unsafe or impractical to implement in some circumstances. Thus, implementing a DRA without extinction intervention may be necessary for some cases.

Tigilanol Tiglate-Induced Changes in Secretome Profiles Alter C-Met Phosphorylation and Cell Surface Protein Expression in H357 Head and Neck Cancer Cells.

Tigilanol tiglate (TT, also known as EBC-46) is a novel, plant-derived diterpene ester possessing anticancer and wound-healing properties. Here, we show that TT-evoked PKC-dependent S phosphorylation of the tyrosine kinase MET leads to subsequent degradation of tyrosine phosphorylated p-Y and p-Y MET species. PKC inhibition with BIM-1 blocked S phosphorylation of MET and led to MET cell surface accumulation.

Intraphagosomal Free Ca Changes during Phagocytosis.

Phagocytosis (and endocytosis) is an unusual cellular process that results in the formation of a novel subcellular organelle, the phagosome. This phagosome contains not only the internalised target of phagocytosis but also the external medium, creating a new border between extracellular and intracellular environments. The boundary at the plasma membrane is, of course, tightly controlled and exploited in ionic cell signalling events.

Mesenchymal Transglutaminase 2 Activates Epithelial ADAM17: Link to G-Protein-Coupled Receptor 56 (ADGRG1) Signalling.

A wound healing model was developed to elucidate the role of mesenchymal-matrix-associated transglutaminase 2 (TG2) in keratinocyte re-epithelialisation. TG2 drives keratinocyte migratory responses by activation of disintegrin and metalloproteinase 17 (ADAM17). We demonstrate that epidermal growth factor (EGF) receptor ligand shedding leads to EGFR-transactivation and subsequent rapid keratinocyte migration on TG2-positive ECM.

Studying moral distress and moral injury among inpatient and outpatient healthcare professionals during the COVID-19 pandemic.

COVID-19 increased moral distress (MD) and moral injury (MI) among healthcare professionals (HCPs). The purpose of this study was to examine MD and MI among inpatient and outpatient HCPs during March of 2022.The study sought to examine (1) the relationship between MD and MI; (2) the relationship between MD/MI and pandemic-related burnout and resilience; and (3) the degree to which HCPs experienced pandemic-related MD and MI based on background characteristics.

Categorical Updating in a Bayesian Propensity Problem.

We present three experiments using a novel problem in which participants update their estimates of propensities when faced with an uncertain new instance. We examine this using two different causal structures (common cause/common effect) and two different scenarios (agent-based/mechanical). In the first, participants must update their estimate of the propensity for two warring nations to successfully explode missiles after being told of a new explosion on the border between both nations.

Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus.

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus.

Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1).

Background & Aims: Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity.

How Reproducible are Surface Areas Calculated from the BET Equation?

Porosity and surface area analysis play a prominent role in modern materials science. At the heart of this sits the Brunauer-Emmett-Teller (BET) theory, which has been a remarkably successful contribution to the field of materials science. The BET method was developed in the 1930s for open surfaces but is now the most widely used metric for the estimation of surface areas of micro- and mesoporous materials.

Therapeutic potential of deuterium-stabilized (R)-pioglitazone-PXL065-for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) results from ABCD1 gene mutations which impair Very Long Chain Fatty Acids (VLCFA; C26:0 and C24:0) peroxisomal import and β-oxidation, leading to accumulation in plasma and tissues. Excess VLCFA drives impaired cellular functions (e.g.

Polymeric Fiber Sorbents Embedded with Porous Organic Cages.

The synthesis and functionalization of porous organic cages (POCs) for separation have attracted growing interest over the past decade. However, the potential of solid-phase POCs for practical, large-scale separations will require incorporation into appropriate gas-solid or liquid-solid contactors. Contactors with more effective mass transfer properties and lower pressure drops than pelletized systems are preferred.

Caring for Patients With Dementia at End of Life.

Care of the dementia patient continues to be challenging. It is a terminal condition that many times goes undiagnosed leading to improper evidence-based interventions. Healthcare professionals (HCPs) should initiate goals of care conversations early with patients and their families in order to align treatment preferences.

Deuterium-Stabilized ()-Pioglitazone (PXL065) Is Responsible for Pioglitazone Efficacy in NASH yet Exhibits Little to No PPARγ Activity.

The antidiabetic drug pioglitazone is, to date, the most efficacious oral drug recommended off-label for the treatment of nondiabetic or diabetic patients with biopsy-proven nonalcoholic steatohepatitis (NASH). However, weight gain and edema side effects have limited its use for NASH. Pioglitazone is a mixture of two stereoisomers (()-pioglitazone and ()-pioglitazone) that interconvert and .

Treatment of Chondroblastoma with Denosumab: A Case Report with a Correlative Analysis of Effect on the RANK Signaling Pathway.

Case: A 15-year-old boy with chondroblastoma of the right hemipelvis presented with significant periacetabular bone destruction. Neoadjuvant denosumab treatment facilitated initial joint preserving surgery. Unfortunately, he experienced 2 local recurrences and underwent wide surgical resection 2 years after his initial diagnosis.

Data-driven parcellation and graph theory analyses to study adolescent mood and anxiety symptoms.

Adolescence is a period of rapid brain development when psychiatric symptoms often first emerge. Studying adolescents may therefore facilitate the identification of neural alterations early in the course of psychiatric conditions. Here, we sought to utilize new, high-quality brain parcellations and data-driven graph theory approaches to characterize associations between resting-state networks and the severity of depression, anxiety, and anhedonia symptoms-salient features across psychiatric conditions.

Propensities and Second Order Uncertainty: A Modified Taxi Cab Problem.

The study of people's ability to engage in causal probabilistic reasoning has typically used fixed-point estimates for key figures. For example, in the classic taxi-cab problem, where a witness provides evidence on which of two cab companies (the more common 'green'/less common 'blue') were responsible for a hit and run incident, solvers are told the witness's ability to judge cab color is 80%. In reality, there is likely to be some uncertainty around this estimate (perhaps we tested the witness and they were correct 4/5 times), known as second-order uncertainty, producing a distribution rather than a fixed probability.

Deuterium-Enabled Chiral Switching (DECS) Yields Chirally Pure Drugs from Chemically Interconverting Racemates.

Separation of the preferred enantiomer from racemic mixtures, i.e. "chiral switching," often improves efficacy and reduces toxicity.

Palliative Care and Rapid Emergency Screening Tool and the Palliative Performance Scale to Predict Survival of Older Adults Admitted to the Hospital From the Emergency Department.

Background: The Palliative Care and Rapid Emergency Screening (P-CaRES) tool has been validated to identify patients in the emergency department (ED) with unmet palliative care needs, but no prognostic data have been published. The Palliative Performance Scale (PPS) has been validated to predict survival based on performance status and separately has been shown to predict survival among adults admitted to the hospital from the ED.

Objective: To concurrently validate the 6-month prognostic utility of P-CaRES with a replication of prior studies that demonstrated the prognostic utility of the PPS among adults admitted to the hospital from the ED.

Cell surface topography controls phagocytosis and cell spreading: The membrane reservoir in neutrophils.

Neutrophils exhibit rapid cell spreading and phagocytosis, both requiring a large apparent increase in the cell surface area. The wrinkled surface topography of these cells may provide the membrane reservoir for this. Here, the effects of manipulation of the neutrophil cell surface topography on phagocytosis and cell spreading were established.

Calpain Activation by Ca and Its Role in Phagocytosis.

Although the cytosolic Ca signalling event in phagocytosis is well established, and the mechanism for generating such signals also understood, the target for the Ca signal and how this relates to the phagocytic outcome is less clear. In this chapter, we present the evidence for a role of the Ca activated protease, calpain, in phagocytosis. The abundant evidence for Ca changes and calpain activation during cell shape changes is extended to include the specific cell shape change which accompanies phagocytosis.

Membrane Tension and the Role of Ezrin During Phagocytosis.

During phagocytosis, there is an apparent expansion of the plasma membrane to accommodate the target within a phagosome. This is accompanied (or driven by) a change in membrane tension. It is proposed that the wrinkled topography of the phagocyte surface, by un-wrinkling, provides the additional available membrane and that this explains the changes in membrane tension.

Widening Access to Bayesian Problem Solving.

Bayesian reasoning and decision making is widely considered normative because it minimizes prediction error in a coherent way. However, it is often difficult to apply Bayesian principles to complex real world problems, which typically have many unknowns and interconnected variables. Bayesian network modeling techniques make it possible to model such problems and obtain precise predictions about the causal impact that changing the value of one variable may have on the values of other variables connected to it.

Optical Methods for the Measurement and Manipulation of Cytosolic Calcium Signals in Neutrophils.

The measurement and manipulation of cytosolic free Ca of neutrophils is crucial for investigating the mechanisms within living neutrophils which generate Ca signals and the cellular responses triggered by them. Optical methods for this are the most applicable for neutrophils, and are discussed here, especially the use of fluorescent indicators of Ca and photoactivation of reagents involved in Ca signaling. Both of these synthetic agents can be loaded into neutrophils as lipid-soluble esters or can be microinjected into the cell.

Microinjection and Micropipette-Controlled Phagocytosis Methods for Neutrophils.

The ability to microinject substances into the cytosol of living neutrophils opens the possibility of manipulating the chemistry within the cell and also of monitoring changes using indicators which otherwise cannot be introduced into the cell. However, neutrophils cannot be microinjected by the conventional glass pipette insertion method. Here we outline two techniques which work well with neutrophils, namely, SLAM (Simple Lipid-Assisted Microinjection) and electromicroinjection.

Improving Cancer Drug Discovery by Studying Cancer across the Tree of Life.

Despite a considerable expenditure of time and resources and significant advances in experimental models of disease, cancer research continues to suffer from extremely low success rates in translating preclinical discoveries into clinical practice. The continued failure of cancer drug development, particularly late in the course of human testing, not only impacts patient outcomes, but also drives up the cost for those therapies that do succeed. It is clear that a paradigm shift is necessary if improvements in this process are to occur.