Colonic Protein Fermentation and Promotion of Colon Carcinogenesis by Thermolyzed Casein

Thermolyzed casein is known to promote the growth of aberrant crypt foci (ACF) and colon cancer when it is fed to rats that have been initiated with azoxymethane. We speculated that the promotion was a consequence of increased colonic protein fermentation (i.e., that the thermolysis of the casein decreases its digestibility, increases the amount of protein reaching the colon, and increases colonic protein fermentation and that the potentially toxic products of this fermentation promote colon carcinogenesis). We found that the thermolysis of casein reduces its digestibility and increases colonic protein fermentation, as assessed by fecal ammonium and urinary phenol, cresol, and indol-3-ol. Thermolysis of two other proteins, soy and egg white protein, also increases colonic protein fermentation with increased fecal ammonia and urinary phenols, and thermolysis of all three proteins increases the levels of ammonia and butyric, valeric, and i-valeric acids in the cecal contents. We found, however, that the increased protein fermentation observed with thermolysis is not associated with pro-motion of colon carcinogenesis. With casein, the kinetics of protein fermentation with increasing thermolysis time are clearly different from the kinetics of promotion of ACF growth. The formation of the fermentation products was highest when the protein was thermolyzed for one hour, whereas promotion was highest for protein that had been thermolyzed for two or more hours. With soy and egg white, thermolysis increased colonic protein fermentation but did not promote colon carcinogenesis. Thus, although thermolysis of dietary casein increases colonic protein fermentation, products of this fermentation do not appear to be responsible for the promotion of colon carcinogenesis. Indeed, the results suggest that protein fermentation products do not play an important role in colon cancer promotion

Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices

Background The behaviour of tumour cells depends on factors such as genetics and the tumour microenvironment. The latter plays a crucial role in normal mammary gland development and also in breast cancer initiation and progression. Breast cancer tissues tend to be highly desmoplastic and dense matrix as a pre-existing condition poses one of the highest risk factors for cancer development. However, matrix influence on tumour cell gene expression and behaviour such as cell migration is not fully elucidated. Results We generated high-density (HD) matrices that mimicked tumour collagen content of 20 mg/cm3 that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm3. Live-cell imaging showed breast cancer cells utilizing cytoplasmic streaming and cell body contractility for migration within HD matrix. Cell migration was blocked in the presence of both the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugs individually. This suggests roles for ROCK1 and MMP in cell migration are complicated by compensatory mechanisms. ROCK1 expression and protein activity, were significantly upregulated in HD matrix but these were blocked by treatment with a histone deacetylase (HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirect and relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA or DAPT abrogated the inhibition of ROCK1 by MS-275. Conclusion Increased matrix density elevates ROCK1 activity, which aids in cell migration via cell contractility. The upregulation of ROCK1 is epigenetically regulated in an indirect manner involving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1 expression

COVID-19 Misinformation Prophylaxis: Protocol for a Randomized Trial of a Brief Informational Intervention

Background: As the COVID-19 pandemic continues to affect life in the United States, the important role of nonpharmaceutical preventive behaviors (such as wearing a face mask) in reducing the risk of infection has become clear. During the pandemic, researchers have observed the rapid proliferation of misinformed or inconsistent narratives about COVID-19. There is growing evidence that such misinformed narratives are associated with various forms of undesirable behavior (eg, burning down cell towers). Furthermore, individuals’ adherence to recommended COVID-19 preventive guidelines has been inconsistent, and such mandates have engendered opposition and controversy. Recent research suggests the possibility that trust in science and scientists may be an important thread to weave throughout these seemingly disparate components of the modern public health landscape. Thus, this paper describes the protocol for a randomized trial of a brief, digital intervention designed to increase trust in science. Objective: The objective of this study is to examine whether exposure to a curated infographic can increase trust in science, reduce the believability of misinformed narratives, and increase the likelihood to engage in preventive behaviors. Methods: This is a randomized, placebo-controlled, superiority trial comprising 2 parallel groups. A sample of 1000 adults aged ≥18 years who are representative of the population of the United States by gender, race and ethnicity, and age will be randomly assigned (via a 1:1 allocation) to an intervention or a placebo-control arm. The intervention will be a digital infographic with content based on principles of trust in science, developed by a health communications expert. The intervention will then be both pretested and pilot-tested to determine its viability. Study outcomes will include trust in science, a COVID-19 narrative belief latent profile membership, and the likelihood to engage in preventive behaviors, which will be controlled by 8 theoretically selected covariates. Results: This study was funded in August 2020, approved by the Indiana University Institutional Review Board on September 15, 2020, and prospectively registered with ClinicalTrials.gov. Conclusions: COVID-19 misinformation prophylaxis is crucial. This proposed experiment investigates the impact of a brief yet actionable intervention that can be easily disseminated to increase individuals’ trust in science, with the intention of affecting misinformation believability and, consequently, preventive behavioral intentions

TRPV1 promotes opioid analgesia during inflammation

International audienc

Diabetes Mellitus Type 2 as a Risk Factor and Outcome Modifier for Cryptococcosis in HIV Negative, Non-transplant Patients, a Propensity Score Match Analysis

Cryptococcosis is an opportunistic fungal infection of worldwide distribution with significant associated morbidity and mortality. HIV, organ transplantation, malignancy, cirrhosis, sarcoidosis, and immunosuppressive medications are established risk factors for cryptococcosis. Type 2 diabetes mellitus (DM2) has been hypothesized as a risk factor and an outcome modifier for cryptococcosis. We aimed to compare outcomes among HIV-negative, non-transplant (NHNT) patients with and without DM2. We queried a global research network to identify NHNT patients (n = 3280). We performed a propensity score-matched (PSM) analysis comparing clinical outcomes among cryptococcosis patients by DM status. We also characterize adults with cryptococcosis and DM2 as the only risk factor. After PSM, NHNT patients with DM2 were more likely to develop cognitive dysfunction [9% vs. 6%, OR 1.6; 95% CI (1.1–2.3); P = 0.01] but had similar mortality, hospitalization, ICU, and stroke risk after acquiring cryptococcosis when compared to NHNT patients without DM2. Pulmonary cryptococcosis was the most common site of infection. Among 44 cryptococcosis patients with DM2 as the only identifiable risk factor for disease, the annual incidence of cryptococcosis was 0.001%, with a prevalence of 0.002%. DM2 is associated with increased cognitive dysfunction risk in NHNT patients with cryptococcosis. It is rare for DM2 to be the only identified risk factor for developing cryptococcosis. Kidney disease, hyperglycemia, and immune dysfunction can increase the risk of cryptococcosis in patients with DM2

Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrPC), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution

Mexico City Metropolitan Area children chronically exposed to high concentrations of air pollutants exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, innate and adaptive immune responses along with accumulation of misfolded proteins observed in the early stages of Alzheimer and Parkinson's diseases. A complex modulation of serum cytokines and chemokines influences children's brain structural and gray/white matter volumetric responses to air pollution. The search for biomarkers associating systemic and CNS inflammation to brain growth and cognitive deficits in the short term and neurodegeneration in the long-term is our principal aim. We explored and compared a profile of cytokines, chemokines (Multiplexing LASER Bead Technology) and Cellular prion protein (PrP(C)) in normal cerebro-spinal-fluid (CSF) of urban children with high vs. low air pollution exposures. PrP(C) and macrophage inhibitory factor (MIF) were also measured in serum. Samples from 139 children ages 11.91 ± 4.2 years were measured. Highly exposed children exhibited significant increases in CSF MIF (p = 0.002), IL6 (p = 0.006), IL1ra (p = 0.014), IL-2 (p = 0.04), and PrP(C) (p = 0.039) vs. controls. MIF serum concentrations were higher in exposed children (p = 0.009). Our results suggest CSF as a MIF, IL6, IL1Ra, IL-2, and PrP(C) compartment that can possibly differentiate air pollution exposures in children. MIF, a key neuro-immune mediator, is a potential biomarker bridge to identify children with CNS inflammation. Fine tuning of immune-to-brain communication is crucial to neural networks appropriate functioning, thus the short and long term effects of systemic inflammation and dysregulated neural immune responses are of deep concern for millions of exposed children. Defining the linkage and the health consequences of the brain / immune system interactions in the developing brain chronically exposed to air pollutants ought to be of pressing importance for public health

Copper-containing mesoporous bioactive glass promotes angiogenesis in an in vivo zebrafish model

The osteogenic and angiogenic responses of organisms to the ionic products of degradation of bioactive glasses (BGs) are being intensively investigated. The promotion of angiogenesis by copper (Cu) has been known for more than three decades. This element can be incorporated to delivery carriers, such as BGs, and the materials used in biological assays. In this work, Cu-containing mesoporous bioactive glass (MBG) in the SiO2-CaO-P2O5 compositional system was prepared incorporating 5% mol Cu (MBG-5Cu) by replacement of the corresponding amount of Ca. The biological effects of the ionic products of MBG biodegradation were evaluated on a well-known endothelial cell line, the bovine aorta endothelial cells (BAEC), as well as in an in vivo zebrafish (Danio rerio) embryo assay. The results suggest that ionic products of both MBG (Cu free) and MBG-5Cu materials promote angiogenesis. In vitro cell cultures show that the ionic dissolution products of these materials are not toxic and promote BAEC viability and migration. In addition, the in vivo assay indicates that both exposition and microinjection of zebrafish embryos with Cu free MBG material increase vessel number and thickness of the subintestinal venous plexus (SIVP), whereas assays using MBG-5Cu enhance this effect.The authors gratefully acknowledge the financial support provided by the Andalusian Ministry of Economy, Science and Innovation (Proyectos Excelencia Grants no. P10-CTS-6681 and no. P12-CTS-1507) and Spanish Ministry of Economy and Competitivity (BIO2014-56092-R). LBRS acknowledges the CONACYT-Mexico Fellowship PhD Program

EXPORTS North Atlantic eddy tracking

The EXPORTS North Atlantic field campaign (EXPORTS-NA) of May 2021 used a diverse array of ship-based and autonomous platforms to measure and quantify processes leading to carbon export in the open ocean. The success of this field program relied heavily on the ability to make measurements following a Lagrangian trajectory within a coherent, retentive eddy (Sections 1, 2). Identifying an eddy that would remain coherent and retentive over the course of a monthlong deployment was a significant challenge that the EXPORTS team faced. This report details the processes and procedures used by the primarily shore-based eddy tracking team to locate, track, and sample with autonomous assets such an eddy before and during EXPORTS-NA.This field deployment was funded by the NASA Ocean Biology and Biogeochemistry program and the National Science Foundation Biological and Chemical Oceanography programs. Initial gliders deployments were performed by the RRS Discovery and the authors thank the Porcupine Abyssal Plain – Sustained Observatory of the Natural Environment Research Council (NERC, UK), which is principally funded through the Climate Linked Atlantic Sector Science (CLASS) project supported by NERC National Capability funding (NE/R015953/1) and by IFADO (Innovation in the Framework of the Atlantic Deep Ocean) EAPA_165/2016. Technical assistance with glider deployment was provided by Marine Autonomous Robotic Systems (NOC). The authors thank Inia Soto Ramos for assistance in publishing this manuscript through the NASA Technical Memorandum series. This is PMEL contribution number 5372

Age- and sex-dependent role of osteocytic pannexin1 on bone and muscle mass and strength

Pannexins (Panxs), glycoproteins that oligomerize to form hemichannels on the cell membrane, are topologically similar to connexins, but do not form cell-to-cell gap junction channels. There are 3 members of the family, 1-3, with Panx1 being the most abundant. All Panxs are expressed in bone, but their role in bone cell biology is not completely understood. We now report that osteocytic Panx1 deletion (Panx1Δot) alters bone mass and strength in female mice. Bone mineral density after reaching skeletal maturity is higher in female Panx1Δot mice than in control Panx1fl/fl mice. Further, osteocytic Panx1 deletion partially prevented aging effects on cortical bone structure and mechanical properties. Young 4-month-old female Panx1Δot mice exhibited increased lean body mass, even though pannexin levels in skeletal muscle were not affected; whereas no difference in lean body mass was detected in male mice. Furthermore, female Panx1-deficient mice exhibited increased muscle mass without changes in strength, whereas Panx1Δot males showed unchanged muscle mass and decreased in vivo maximum plantarflexion torque, indicating reduced muscle strength. Our results suggest that osteocytic Panx1 deletion increases bone mass in young and old female mice and muscle mass in young female mice, but has deleterious effects on muscle strength only in males

Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis