Proximity to inlet channel drives spatial variation in sediment carbon across a lagoonal seagrass meadow.

Seagrass meadows can be sinks for organic carbon, but estimates of global organic carbon stocks are complicated by substantial spatial variability in organic carbon burial observed within meadows. To improve estimates of organic carbon burial in seagrass meadows, it is necessary to understand the causes of the spatial heterogeneity. This study investigated relationships between spatial patterns in sediment organic carbon storage and accretion rates, hydrodynamics, and proximity to sources of organic carbon in a current-dominated Zostera marina Linnaeus meadow in Menemsha Pond, Massachusetts, USA.

Epithelial heme oxygenase-1 enhances colonic tumorigenesis by inhibiting ferroptosis.

Colorectal cancer has been linked to chronic colitis and red meat consumption, which can increase colonic iron and heme. Heme oxygenase-1 ( ) metabolizes heme and releases ferrous iron, but its role in colonic tumorigenesis is not well-described. Recent studies suggest that ferroptosis, the iron-dependent form of cell death, protects against colonic tumorigenesis.

Disruption of monocyte-macrophage differentiation and trafficking by a heme analog during active inflammation.

Heme metabolism is a key regulator of inflammatory responses. Cobalt protoporphyrin IX (CoPP) is a heme analog and mimic that potently activates the NRF2/heme oxygenase-1 (HO-1) pathway, especially in monocytes and macrophages. We investigated the influence of CoPP on inflammatory responses using a murine model of colitis.

Mucosal acidosis elicits a unique molecular signature in epithelia and intestinal tissue mediated by GPR31-induced CREB phosphorylation.

Metabolic changes associated with tissue inflammation result in significant extracellular acidosis (EA). Within mucosal tissues, intestinal epithelial cells (IEC) have evolved adaptive strategies to cope with EA through the up-regulation of SLC26A3 to promote pH homeostasis. We hypothesized that EA significantly alters IEC gene expression as an adaptive mechanism to counteract inflammation.

Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage.

During episodes of acute inflammation, polymorphonuclear leukocytes (PMNs) are actively recruited to sites of inflammation or injury where they provide anti-microbial and wound-healing functions. One enzyme crucial for fulfilling these functions is myeloperoxidase (MPO), which generates hypochlorous acid from Cl and hydrogen peroxide. The potential exists, however, that uncontrolled the extracellular generation of hypochlorous acid by MPO can cause bystander tissue damage and inhibit the healing response.

Retaining doctors and reducing burnout through a flexible work initiative in a rural South African training hospital.

Background: South African doctors work up to 60 h per week to ensure 24-h service delivery. Many doctors are physically and emotionally exhausted, neglecting families, self-care, patient empathy and innovative thinking about complex health issues. Exposure to clinical work hours demonstrated a dose effect with burnout, suggesting cause and effect, affecting up to 80% of doctors.

The evolving role of family physicians during the coronavirus disease 2019 crisis: An appreciative reflection.

Ten family physicians and family medicine registrars in a South African semi-rural training complex reflected on the coronavirus disease 2019 (COVID-19) crisis during their quarterly training complex meeting. The crisis has become the disruptor that is placing pressure on the traditional roles of the family physician. The importance of preventative and promotive care in a community-oriented approach, being a capacity builder and leading the health team as a consultant have assumed new meanings.

Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3.

Acute intestinal inflammation includes the early accumulation of neutrophils (PMN). Based on recent evidence that PMN infiltration "imprints" changes in the local tissue environment through local oxygen depletion and the release of adenine nucleotides, we hypothesized that the interaction between transmigrating PMN and intestinal epithelial cells (IECs) results in inflammatory acidification of the tissue. Using newly developed tools, we revealed that active PMN transepithelial migration (TEM) significantly acidifies the local microenvironment, a decrease of nearly 2 pH units.

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer.

Purpose: Despite decreased screening-based detection of clinically insignificant tumors, most diagnosed prostate cancers are still indolent, indicating a need for better strategies for detection of clinically significant disease before treatment. We hypothesized that patients with detectable circulating tumor DNA (ctDNA) were more likely to harbor aggressive disease.

Methods: We applied ultra-low-pass whole-genome sequencing to profile cell-free DNA from 112 patients diagnosed with localized prostate cancer and performed targeted resequencing of plasma DNA for somatic mutations previously identified in matched solid tumor in nine cases.

A Physiologically-Based Pharmacokinetic Model for Targeting Calcitriol-Conjugated Quantum Dots to Inflammatory Breast Cancer Cells.

Quantum dots (QDs) conjugated with 1,25 dihydroxyvitamin D3 (calcitriol) and Mucin-1 (MUC-1) antibodies (SM3) have been found to target inflammatory breast cancer (IBC) tumors and reduce proliferation, migration, and differentiation of these tumors in mice. A physiologically-based pharmacokinetic model has been constructed and optimized to match experimental data for multiple QDs: control QDs, QDs conjugated with calcitriol, and QDs conjugated with both calcitriol and SM3 MUC1 antibodies. The model predicts continuous QD concentration for key tissues in mice distinguished by IBC stage (healthy, early-stage, and late-stage).

A Central Role for Heme Oxygenase-1 in the Control of Intestinal Epithelial Chemokine Expression.

In mucosal inflammatory disorders, the protective influence of heme oxygenase-1 (HO-1) and its metabolic byproducts, carbon monoxide (CO) and biliverdin, is a topic of significant interest. Mechanisms under investigation include the regulation of macrophage function and mucosal cytokine expression. While there is an increasing recognition of the importance of epithelial-derived factors in the maintenance of intestinal mucosal homeostasis, the contribution of intestinal epithelial cell (IEC) HO-1 on inflammatory responses has not previously been investigated.

Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2.

Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation.

Expression of PD-L1 in Hormone-naïve and Treated Prostate Cancer Patients Receiving Neoadjuvant Abiraterone Acetate plus Prednisone and Leuprolide.

Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models.

Gleason Score 7 Prostate Cancers Emerge through Branched Evolution of Clonal Gleason Pattern 3 and 4.

The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations.

Kinetic partitioning during de novo septin filament assembly creates a critical G1 "window of opportunity" for mutant septin function.

Septin proteins form highly conserved cytoskeletal filaments composed of hetero-oligomers with strict subunit stoichiometry. Mutations within one hetero-oligomerization interface (the "G" interface) bias the mutant septin toward conformations that are incompatible with filament assembly, causing disease in humans and, in budding yeast cells, temperature-sensitive defects in cytokinesis. We previously found that, when the amount of other hetero-oligomerization partners is limiting, wild-type and G interface-mutant alleles of a given yeast septin "compete" along parallel but distinct folding pathways for occupancy of a limited number of positions within septin hetero-octamers.

Loss of Wave1 gene defines a subtype of lethal prostate cancer.

Genetic alterations involving TMPRSS2-ERG alterations and deletion of key tumor suppressor genes are associated with development and progression of prostate cancer (PCa). However, less defined are early events that may contribute to the development of high-risk metastatic prostate cancer. Bioinformatic analysis of existing tumor genomic data from PCa patients revealed that WAVE complex gene alterations are associated with a greater likelihood of prostate cancer recurrence.

Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors.

Purpose: The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs.

1,25 Dihydroxyvitamin D3 uptake is localized at caveolae and requires caveolar function.

Vitamin D3 is an essential vitamin that has been extensively studied due to its potential role as therapeutic for many diseases, including breast cancer. Previous research has indicated that calcitriol, the active form of Vitamin D3 has a negative effect on the metastatic ability of Inflammatory Breast Cancer (IBC) cells however the mechanism is not fully understood. The effect of calcitriol on IBC cells starting from cellular uptake must be investigated in order to understand these therapeutic effects.

The kinetics of vitamin D₃ in the osteoblastic cell.

Experimental evidence is presented on the translocation of vitamin D metabolite, 1,25-(OH)₂D₃, from the membrane to the nucleus in osteoblast progenitor cells. A mathematical model permitting traversal of the cytoplasm at either a fixed velocity or by diffusion is formulated in order to determine whether transport along the cytoskeletal tracks is more consistent with the observed spatial-temporal distribution than diffusion, and it is so found. The model includes reactions in the nucleus involving D₃ to form other compounds, such as protegerin, and thus also makes predictions of the concentrations of these compounds in various regions of the cell.

Design of 1,25 dihydroxyvitamin D3 coupled quantum dots, a novel imaging tool.

1,25 dihydroxyvitamin D3 (Calcitriol), one of the active forms of Vitamin D, plays a vital role not only in calcium absorption but also during neuromuscular function and regulation of inflammation. Epidemiological studies suggest a preventive effect of Calcitriol in breast, colon and prostate cancer, however high concentrations of Calcitriol are necessary. Therefore targeted biologically active probes must be designed to determine Calcitriol distribution and dynamics in vitro and in vivo.

Effect of intermittent umbilical cord occlusion on fetal respiratory activity and brain adenosine in late-gestation sheep.

It was hypothesized that intermittent umbilical cord occlusion (UCO) would inhibit ovine fetal breathing movements (FBM) in association with increased cerebral adenosine levels. To test this hypothesis, on two successive days during late gestation (133-134 days; term = 146 days), microdialysis samples were collected from the brains of 10 chronically instrumented fetal sheep during 2-h periods of complete UCO induced every 30 min (Day 1: 2-min UCOs; Day 2: 4-min UCOs). Control fetuses (n = 10) underwent no UCO.