Leishmania amazonensis promastigotes in 3D Collagen I culture: an in vitro physiological environment for the study of extracellular matrix and host cell interactions

Leishmania amazonensis is the causative agent of American cutaneous leishmaniasis, an important neglected tropical disease. Once Leishmania amazonensis is inoculated into the human host, promastigotes are exposed to the extracellular matrix (ECM) of the dermis. However, little is known about the interaction between the ECM and Leishmania promastigotes. In this study we established L. amazonensis promastigote culture in a three-dimensional (3D) environment mainly composed of Collagen I (COL I). This 3D culture recreates in vitro some aspects of the human host infection site, enabling the study of the interaction mechanisms of L. amazonensis with the host ECM. Promastigotes exhibited “freeze and run” migration in the 3D COL I matrix, which is completely different from the conventional in vitro swimming mode of migration. Moreover, L. amazonensis promastigotes were able to invade, migrate inside, and remodel the 3D COL I matrix. Promastigote trans-matrix invasion and the freeze and run migration mode were also observed when macrophages were present in the matrix. At least two classes of proteases, metallo- and cysteine proteases, are involved in the 3D COL I matrix degradation caused by Leishmania. Treatment with a mixture of protease inhibitors significantly reduced promastigote invasion and migration through this matrix. Together our results demonstrate that L. amazonensis promastigotes release proteases and actively remodel their 3D environment, facilitating their migration. This raises the possibility that promastigotes actively interact with their 3D environment during the search for their cellular “home”—macrophages. Supporting this hypothesis, promastigotes migrated faster than macrophages in a novel 3D co-culture model

Tea drinking and cognitive function in oldest-old Chinese

10.1007/s12603-012-0077-1The Journal of Nutrition, Health & Aging169754-75

Effect of C-2 substitution on the stability of non-traditional cephalosporins in mouse plasma

A systematic study of the stability of a set of cephalosporins in mouse plasma reveals that cephalosporins lacking an acidic moiety at C-2 may be vulnerable to β-lactam cleavage in mouse plasma

GLORIA - A globally representative hyperspectral in situ dataset for optical sensing of water quality

The development of algorithms for remote sensing of water quality (RSWQ) requires a large amount of in situ data to account for the bio-geo-optical diversity of inland and coastal waters. The GLObal Reflectance community dataset for Imaging and optical sensing of Aquatic environments (GLORIA) includes 7,572 curated hyperspectral remote sensing reflectance measurements at 1 nm intervals within the 350 to 900 nm wavelength range. In addition, at least one co-located water quality measurement of chlorophyll a, total suspended solids, absorption by dissolved substances, and Secchi depth, is provided. The data were contributed by researchers affiliated with 59 institutions worldwide and come from 450 different water bodies, making GLORIA the de-facto state of knowledge of in situ coastal and inland aquatic optical diversity. Each measurement is documented with comprehensive methodological details, allowing users to evaluate fitness-for-purpose, and providing a reference for practitioners planning similar measurements. We provide open and free access to this dataset with the goal of enabling scientific and technological advancement towards operational regional and global RSWQ monitoring

Expert elicitation to inform a cost effectiveness analysis of screening for renal cancer: methodological and practical considerations

Background: Population screening for renal cell carcinoma (RCC) using ultrasound has the potential to improve survival outcomes; however a cost-effectiveness analysis (CEA) has yet to be performed. Due to the lack of existing evidence, we performed structured expert elicitation to derive unknown quantities to inform the CEA. Objectives: To elicit the cancer stage distribution (proportion of individuals with each stage of cancer) for different RCC screening scenarios and the annual transition probabilities for undiagnosed disease becoming diagnosed in the NHS. Methods: The study design and reporting adhered to the Reporting Guidelines for the Use of Expert Judgement in Model-Based Economic Evaluations. The elicitation was conducted face-to-face or via telephone between each individual expert and the facilitator, aided by online material. For multinomial data, Connor Mosimann and modified Connor Mosimann distributions were fitted for each expert and for all experts combined using mathematical linear pooling. Results: A total of 24 clinical experts were invited, and 71% participated (7 urologists, 6 oncologists, 4 radiologists). The modified Connor Mosimann distribution provided the best fit for the majority of elicited quantities. Greater uncertainty was noted for the elicited transition probabilities compared to the elicited stage distributions. Conclusion: We performed the first expert elicitation of RCC screening parameters, crucial information which will inform the CEA of screening. Additionally, the elicited quantities may enable future health economic evaluations assessing the value of diagnostic tools and pathways in RCC

In Vitro and in Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas

A newly validated target for tuberculosis treatment is phosphopantetheinyl transferase, an essential enzyme that plays a critical role in the biosynthesis of cellular lipids and virulence factors in Mycobacterium tuberculosis. The structure-activity relationships of a recently disclosed inhibitor, amidinourea (AU) 8918 (1), were explored, focusing on the biochemical potency, determination of whole-cell on-target activity for active compounds, and profiling of selective active congeners. These studies show that the AU moiety in AU 8918 is largely optimized and that potency enhancements are obtained in analogues containing a para-substituted aromatic ring. Preliminary data reveal that while some analogues, including 1, have demonstrated cardiotoxicity (e.g., changes in cardiomyocyte beat rate, amplitude, and peak width) and inhibit Cav1.2 and Nav1.5 ion channels (although not hERG channels), inhibition of the ion channels is largely diminished for some of the para-substituted analogues, such as 5k (p-benzamide) and 5n (p-phenylsulfonamide)

Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a progressive multisystemic disease that increases significantly cardiovascular morbidity and mortality. It is associated with obesity, insulin resistance, beta-cell dysfunction, and hyperglucagonemia, the combination of which typically leads to hyperglycemia. Incretin-based treatment modalities, and in particular glucagon-like peptide 1 (GLP-1) receptor agonists, are able to successfully counteract several of the underlying pathophysiological abnormalities of T2DM. The pancreatic effects of GLP-1 receptor agonists include glucose-lowering effects by stimulating insulin secretion and inhibiting glucagon release in a strictly glucose-dependent manner, increased beta-cell proliferation, and decreased beta-cell apoptosis. GLP-1 receptors are widely expressed throughout human body; thus, GLP-1-based therapies exert pleiotropic and multisystemic effects that extend far beyond pancreatic islets. A large body of experimental and clinical data have suggested a considerable protective role of GLP-1 analogs in the cardiovascular system (decreased blood pressure, improved endothelial and myocardial function, functional recovery of failing and ischemic heart, arterial vasodilatation), kidneys (increased diuresis and natriuresis), gastrointestinal tract (delayed gastric emptying, reduced gastric acid secretion), and central nervous system (appetite suppression, neuroprotective properties). The pharmacologic use of GLP-1 receptor agonists has been shown to reduce bodyweight and systolic blood pressure, and significantly improve glycemic control and lipid profile. Interestingly, weight reduction induced by GLP-1 analogs reflects mainly loss of abdominal visceral fat. The critical issue of whether the emerging positive cardiometabolic effects of GLP-1 analogs can be translated into better clinical outcomes for diabetic patients in terms of long-term hard endpoints, such as cardiovascular morbidity and mortality, remains to be elucidated with prospective, large-scale clinical trials

Ice core chemistry database: an Antarctic compilation of sodium and sulfate records spanning the past 2000 years

Changes in sea ice conditions and atmospheric circulation over the Southern Ocean play an important role in modulating Antarctic climate. However, observations of both sea ice and wind conditions are limited in Antarctica and the Southern Ocean, both temporally and spatially, prior to the satellite era (1970 onwards). Ice core chemistry data can be used to reconstruct changes over annual, decadal, and millennial timescales. To facilitate sea ice and wind reconstructions, the CLIVASH2k (CLimate Variability in Antarctica and the Southern Hemisphere over the past 2000 years) working group has compiled a database of two species, sodium [Na+] and sulfate [SO2− 4 ], commonly measured ionic species. The database (https://doi.org/10.5285/9E0ED16E-F2AB4372-8DF3-FDE7E388C9A7; Thomas et al., 2022) comprises records from 105 Antarctic ice cores, containing records with a maximum age duration of 2000 years. An initial filter has been applied, based on evaluation against sea ice concentration, geopotential height (500 hPa), and surface wind fields to identify sites suitable for reconstructing past sea ice conditions, wind strength, or atmospheric circulation