Hyperlipidemia-induced hematopoiesis is repressed by MLKL in endothelial cells of the splenic niche.

Dysregulation of the hematopoietic niche during hyperlipidemia facilitates pathologic leukocyte production, driving atherogenesis. Although definitive hematopoiesis occurs primarily in the bone marrow, during atherosclerosis this also occurs in the spleen. Cells of the bone marrow niche, particularly endothelial cells, have been studied in atherosclerosis, although little is known about how splenic endothelial cells respond to the atherogenic environment.

Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

Objective: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis.

Dynamic relationships among pathways producing hydrocarbons and fatty acids of maize silk cuticular waxes.

The hydrophobic cuticle is the first line of defense between aerial portions of plants and the external environment. On maize (Zea mays L.) silks, the cuticular cutin matrix is infused with cuticular waxes, consisting of a homologous series of very long-chain fatty acids (VLCFAs), aldehydes, and hydrocarbons.

Allosteric communication in the gating mechanism for controlled protein degradation by the bacterial ClpP peptidase.

Proteolysis is essential for the control of metabolic pathways and the cell cycle. Bacterial caseinolytic proteases (Clp) use peptidase components, such as ClpP, to degrade defective substrate proteins and to regulate cellular levels of stress-response proteins. To ensure selective degradation, access to the proteolytic chamber of the double-ring ClpP tetradecamer is controlled by a critical gating mechanism of the two axial pores.

Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift.

Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (B) and find that many B cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, B cells may exit the lymph node to enter distant tissues, while some B cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC.

Tolerability of palbociclib in younger and older patients with advanced breast cancer.

Introduction: Palbociclib is a small-molecule cyclin-dependent kinase 4/6 inhibitor used to treat hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. Patient-specific factors impacting dose reductions or discontinuations are unknown.

Methods: The primary objective was to evaluate the association of age (<60 vs.

Impact of Oncology Pharmacists on the Knowledge, Attitude, and Practices of Clinicians to Enhance Patient Engagement of Self-Administered Oral Oncolytics.

Oncology clinical pharmacists are uniquely positioned to make interventions to impact the knowledge, attitudes, and practices of clinicians as well as patient activation and engagement. To accomplish this goal, pharmacists can target health system-related, provider-related, and patient-related factors to enhance patient-centered care and drive behavioral health changes. Interventions that pharmacists must tackle include educating team members and patients on the medication acquisition process, communicating urgency of treatment, optimizing workflows, facilitating guideline recommendations, preventing, and managing treatment toxicities, and promoting patient self-advocacy through education and shared decision-making.

A Pharmacist-Led Oral Chemotherapy Program's Impact on Chronic Myeloid Leukemia Patient Satisfaction, Adherence, and Outcomes.

Patients with chronic myeloid leukemia (CML) can be treated with oral tyrosine kinase inhibitors (TKIs). Pharmacist-led oral chemotherapy programs (POCPs) can improve TKI adherence rates, but evaluation of patient satisfaction with such programs is rare. The purpose of this analysis was to compare the satisfaction of patients with CML taking TKIs enrolled in a POCP program with that of those not enrolled.

A multigenotype maize silk expression atlas reveals how exposure-related stresses are mitigated following emergence from husk leaves.

The extraordinarily long stigmatic silks of corn (Zea mays L.) are critical for grain production but the biology of their growth and emergence from husk leaves has remained underexplored. Accordingly, gene expression was assayed for inbreds 'B73' and 'Mo17' across five contiguous silk sections.

Formulation and Bioequivalence Testing of Fixed-Dose Combination Orally Disintegrating Tablets for the Treatment of Tuberculosis in the Paediatric Population.

Tuberculosis (TB) is believed to affect around 10 million people worldwide. Treatment for TB includes isoniazid and rifampicin, with fixed-dose combination (FDC) recommended for improved patient compliance. Similarly, orally disintegrating tablets (ODTs) are an increasingly popular dosage form that aid compliance since they do not require swallowing.

Perspectives on neuropsychology and clinical care in paediatric and adolescent medicine.

As a child and adolescent neuropsychology service based within a paediatric psychology team at a large teaching hospital, we meet children and young people across the age range who experience cognitive impairment as a result of long-term health conditions or traumatic brain injury. We have a remit of providing a neuropsychological assessment and report. Typically, a neuropsychology report includes recommendations for home and for school.

Loss of MLKL (Mixed Lineage Kinase Domain-Like Protein) Decreases Necrotic Core but Increases Macrophage Lipid Accumulation in Atherosclerosis.

Objectives: During the advancement of atherosclerosis, plaque cellularity is governed by the influx of monocyte-derived macrophages and their turnover via apoptotic and nonapoptotic forms of cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, of plaque macrophages contribute to necrotic core formation. Knockdown or inhibition of the necrosome components RIPK1 (receptor-interacting protein kinase 1) and RIPK3 (receptor-interacting protein kinase 3) slow atherogenesis, and activation of the terminal step of necroptosis, MLKL (mixed lineage kinase domain-like protein), has been demonstrated in advanced human atherosclerotic plaques.

Genetic and environmental variation impact the cuticular hydrocarbon metabolome on the stigmatic surfaces of maize.

Background: Simple non-isoprenoid hydrocarbons accumulate in discrete regions of the biosphere, including within bacteria and algae as a carbon and/or energy store, and the cuticles of plants and insects, where they may protect against environmental stresses. The extracellular cuticular surfaces of the stigmatic silks of maize are rich in linear hydrocarbons and therefore provide a convenient system to study the biological origins and functions of these unique metabolites.

Results: To test the hypotheses that genetics and environment influence the accumulation of surface hydrocarbons on silks and to examine the breadth of metabolome compositions across diverse germplasm, cuticular hydrocarbons were analyzed on husk-encased silks and silks that emerged from the husk leaves from 32 genetically diverse maize inbred lines, most of which are commonly utilized in genetics experiments.

Meiotic crossovers characterized by haplotype-specific chromosome painting in maize.

Meiotic crossovers (COs) play a critical role in generating genetic variation and maintaining faithful segregation of homologous chromosomes during meiosis. We develop a haplotype-specific fluorescence in situ hybridization (FISH) technique that allows visualization of COs directly on metaphase chromosomes. Oligonucleotides (oligos) specific to chromosome 10 of maize inbreds B73 and Mo17, respectively, are synthesized and labeled as FISH probes.

Phenotypically distinct neutrophils patrol uninfected human and mouse lymph nodes.

Neutrophils play a key role in innate immunity. As the dominant circulating phagocyte, they are rapidly recruited from the bloodstream to sites of infection or injury to internalize and destroy microbes. More recently, neutrophils have been identified in uninfected organs, challenging the classical view of their function.

Anti-commensal IgG Drives Intestinal Inflammation and Type 17 Immunity in Ulcerative Colitis.

Inflammatory bowel disease is a chronic, relapsing condition with two subtypes, Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies (GWASs) in UC implicate a FCGR2A variant that alters the binding affinity of the antibody receptor it encodes, FcγRIIA, for immunoglobulin G (IgG). Here, we aimed to understand the mechanisms whereby changes in FcγRIIA affinity would affect inflammation in an IgA-dominated organ.

Quality by Design (QbD) based process optimisation to develop functionalised particles with modified release properties using novel dry particle coating technique.

Quality by Design (QbD), a current trend employed to develop and optimise various critical pharmaceutical processes, is a systematic approach based on the ethos that quality should be designed into the product itself, not just end tested after manufacture. The present work details a step-wise application of QbD principles to optimise process parameters for production of particles with modified functionalities, using dry particle coating technology. Initial risk assessment identified speed, air pressure, processing time and batch size (independent factors) as having high-to-medium impact on the dry coating process.

Colonic delivery of indometacin loaded PGA-co-PDL microparticles coated with Eudragit L100-55 from fast disintegrating tablets.

The aim of this work was to investigate the efficient targeting and delivery of indometacin (IND), as a model anti-inflammatory drug to the colon for treatment of inflammatory bowel disease. We prepared fast disintegrating tablets (FDT) containing IND encapsulated within poly(glycerol-adipate-co-ɷ-pentadecalactone), PGA-co-PDL, microparticles and coated with Eudragit L100-55 at different ratios (1:1.5, 1:1, 1:0.

Renal Sodium Gradient Orchestrates a Dynamic Antibacterial Defense Zone.

Lower urinary tract infections are among the most common human bacterial infections, but extension to the kidneys is rare. This has been attributed to mechanical forces, such as urine flow, that prevent the ascent of bladder microbes. Here, we show that the regional hypersalinity, required for the kidney's urine-concentrating function, instructs epithelial cells to produce chemokines that localize monocyte-derived mononuclear phagocytes (MNPs) to the medulla.

Two-stage reimplantation for the treatment of deep infection after shoulder arthroplasty.

Background: Two-stage reimplantation is the most common treatment modality considered for periprosthetic shoulder infection (PSI). Most studies to date have reported on a relatively small number of shoulders. The purpose of this study was to determine the outcome of 2-stage reimplantation for PSI in terms of both eradication of infection and restoration of function.

The hospital cost of two-stage reimplantation for deep infection after shoulder arthroplasty.

Background: The cost of treating infection after hip and knee arthroplasty is well documented in the literature. The purpose of this study was to determine the cost of two-stage reimplantation for deep infection after shoulder arthroplasty.

Methods: Between 2003 and 2012, 57 shoulders (56 patients) underwent a two-stage reimplantation for deep periprosthetic shoulder infection; implants placed at reimplantation included anatomic total shoulder arthroplasty (a-TSA) in 58%, reverse total shoulder arthroplasty (r-TSA) in 40%, and hemiarthroplasty (HA) in 2%.

Fixed-dose combination orally disintegrating tablets to treat cardiovascular disease: formulation, in vitro characterization and physiologically based pharmacokinetic modeling to assess bioavailability.

Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong.