Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing

Stereochemistry of Endogenous Palmitic Acid Ester of 9‑Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation

Lipids have fundamental roles in the structure, energetics, and signaling of cells and organisms. The recent discovery of fatty acid esters of hydroxy fatty acids (FAHFAs), lipids with potent antidiabetic and anti-inflammatory activities, indicates that our understanding of the composition of lipidome and the function of lipids is incomplete. The ability to synthesize and test FAHFAs was critical in elucidating the roles of these lipids, but these studies were performed with racemic mixtures, and the role of stereochemistry remains unexplored. Here, we synthesized the R- and S- palmitic acid ester of 9-hydroxystearic acid (R-9-PAHSA, S-9-PAHSA). Access to highly enantioenriched PAHSAs enabled the development of a liquid chromatography-mass spectrometry (LC-MS) method to separate and quantify R- and S-9-PAHSA, and this approach identified R-9-PAHSA as the predominant stereoisomer that accumulates in adipose tissues from transgenic mice where FAHFAs were first discovered. Furthermore, biochemical analysis of 9-PAHSA biosynthesis and degradation indicate that the enzymes and pathways for PAHSA production are stereospecific, with cell lines favoring the production of R-9-PAHSA and carboxyl ester lipase (CEL), a PAHSA degradative enzyme, selectively hydrolyzing S-9-PAHSA. These studies highlight the role of stereochemistry in the production and degradation of PAHSAs and define the endogenous stereochemistry of 9-PAHSA in adipose tissue. This information will be useful in the identification and characterization of the pathway responsible for PAHSA biosynthesis, and access to enantiopure PAHSAs will elucidate the role of stereochemistry in PAHSA activity and metabolism in vivo

Energy scales of Lu(1-x)Yb(x)Rh2Si2 by means of thermopower investigations

We present the thermopower S(T) and the resistivity rho(T) of Lu(1-x)Yb(x)Rh2Si2 in the temperature range 3 K < T < 300 K. S(T) is found to change from two minima for dilute systems (x < 0.5) to a single large minimum in pure YbRh2Si2. A similar behavior has also been found for the magnetic contribution to the resistivity rho_mag(T). The appearance of the low-T extrema in S(T) and rho_mag(T) is attributed to the lowering of the Kondo scale with decreasing x. The evolution of the characteristic energy scales for both the Kondo effect and the crystal electric field splitting are deduced. An extrapolation allows to estimate the Kondo temperature of YbRh2Si2 to 29 K.Comment: 15 pages, 4 figures, accepted in Phys. Rev.

Diagnostic Approach of Hypersensitivity Reactions to Cefazolin in a Large Prospective Cohort.

*Bogas G and Doña I should be considered joint first author. *Moreno E, Laguna JJ and Torres MJ should be considered joint senior author.https://www.elsevier.com/about/policies-and-standards/sharing#2-preprint: "Authors can share their preprint anywhere at any time."Introduction: Cefazolin is a common trigger of perioperative anaphylaxis. The diagnostic approach is controversial as the optimal concentration for skin testing is uncertain, drug provocation tests (DPTs) are contraindicated in severe reactions, and in vitro tests are not thoroughly validated. We aimed to characterise a large number of patients reporting cefazolin allergic reactions, and to analyse in vivo and in vitro tests’ diagnostic role. Methods: We prospectively evaluated patients with suspicion of allergic reactions to cefazolin by clinical history, skin tests (STs), and, if negative, DPT. In a subgroup of patients (both allergic and non-allergic), basophil activation test (BAT) and radioallergosorbent test (RAST) were also done. Results: From 184 evaluated patients, 41.3% were confirmed as allergic, 48.9% as non-allergic, and in 9.8% diagnosis was not confirmed. All reactions were immediate, besides, all cases reporting anaphylactic shock and most patients reporting anaphylaxis were confirmed as allergic (p<0.001); 52.6% of allergic cases were confirmed by STs, 28.9% by DPT, and 18.4% by clinical history. All subjects manifesting exanthemas and generalised pruritus were non-allergic. BAT sensitivity was 66.7% when combining CD63 and CD203c as activation markers. Six out of eight patients with negative STs and positive DPT had a positive BAT. Conclusions: Allergic patients to cefazolin often reported severe immediate-type reactions. STs allowed diagnosing half of patients. Unfortunately, DPT could not be performed in all cases due to reaction severity, being BAT a promising diagnostic tool. Further researches are needed to clarify the underlying mechanisms, especially in patients with severe reactions

Palmitic Acid Hydroxystearic Acids Activate GPR40, Which Is Involved in Their Beneficial Effects on Glucose Homeostasis.

Palmitic acid hydroxystearic acids (PAHSAs) are endogenous lipids with anti-diabetic and anti-inflammatory effects. PAHSA levels are reduced in serum and adipose tissue of insulin-resistant people and high-fat diet (HFD)-fed mice. Here, we investigated whether chronic PAHSA treatment enhances insulin sensitivity and which receptors mediate PAHSA effects. Chronic PAHSA administration in chow- and HFD-fed mice raises serum and tissue PAHSA levels ∼1.4- to 3-fold. This improves insulin sensitivity and glucose tolerance without altering body weight. PAHSA administration in chow-fed, but not HFD-fed, mice augments insulin and glucagon-like peptide (GLP-1) secretion. PAHSAs are selective agonists for GPR40, increasing Ca+2 flux, but not intracellular cyclic AMP. Blocking GPR40 reverses improvements in glucose tolerance and insulin sensitivity in PAHSA-treated chow- and HFD-fed mice and directly inhibits PAHSA augmentation of glucose-stimulated insulin secretion in human islets. In contrast, GLP-1 receptor blockade in PAHSA-treated chow-fed mice reduces PAHSA effects on glucose tolerance, but not on insulin sensitivity. Thus, PAHSAs activate GPR40, which is involved in their beneficial metabolic effects.Supported by NIH grants R01 DK43051, P30 DK57521 (B.B.K.), and R01 DK106210 (B.B.K. and A. Saghatelian); a grant from the JPB Foundation (B.B.K.); and T32DK07516 (B.B.K. and J.L.)

Perception of the risk of adverse reactions to analgesics: Differences between medical students and residents

Low permeability of many wood species due to their anatomical properties causes problems during timber drying as well as impregnating with preservatives and resins. Microwave (MW) treatment influences heartwood permeability and improves preservative uptake and distribution. In the present study, microwave treatment of chir pine (Pinus roxburghii) wood was done at 2,45 GHz frequency at different level of intensity and radiation time. The gas permeability of chir pine wood was measured in an in-house built apparatus. Preservative uptake was tested using acid copper chromate (ACC) preservative by a dipping process. The effect of radiation intensity and time on preservative uptake and air permeability were studied. The results revealed remarkable increase in longitudinal woodair permeability and preservative uptake with the increase of intensity and time of treatment. The results indicate that this technology can be tested and applied on pilot scale for application in wood preservation industry

Prediction of cardiovascular events in rheumatoid arthritis using risk age calculations: evaluation of concordance across risk age models

Background: In younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics. Methods: RA patients aged 30?70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusión criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up. Results: A total of 1974 patients were included in the main analyses, and 144 events were observed during followup, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15?32% of patients. C-statistics ranged 0.68?0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results. Conclusions: The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive

Evaluación geológica y geodinámica en la quebrada Chicón: aluvión del 17 de octubre del 2010 que afectó Urubamba-Cusco

En la quebrada Chicón del distrito de Urubamba, provincia de Urubamba, el día domingo 17 de Octubre del 2010 alrededor de las 23.35 hrs ocurrió un proceso de movimiento en masa. En el nevado Chicón (5530 msnm) el desprendimiento de un bloque de hielo (de aproximadamente 100 x 30m) provocó el rebalse de una pequeña laguna localizada a 4870 msnm. Este rebalse incrementó el caudal de un pequeño riachuelo que nace de esta laguna y la conecta con la laguna Pucacocha, a 4670 msnm. La laguna Pucacocha también rebalsó luego de superar su capacidad. Es a partir de la desembocadura de esta laguna, el que coincide con el cambio brusco de pendiente, que las aguas rebalsadas empiezan a erosionar el material morrénico, los cuales se hallan colgados en la ladera de pendiente muy alta (> 60º). La erosión de este material, por la gran cantidad de agua, originó un flujo de detritos (aluvión) que descendió por la Ladera Norte hasta la quebrada Occororuyoc donde se depositó gran parte del volumen aluviónico. Sin embargo, la parte liquida con sedimentos finos siguió su camino por la quebrada hasta alcanzar la quebrada de Chicón, donde producto de nuevas erosiones da lugar a otros aluviones menores que llegan hasta la ciudad de Urubamba donde destruyen numerosas viviendas en las localidades de Yanacona, Chichubamba y San Isidro de Chicón. En Urubamba afectó principalmente la Av. Ramón Castlla, el Jr. Arica y las calles transversales a estas, llegando incluso a una esquina de la Plaza de Armas. Este fenómeno afectó unas 300 viviendas, destruyó tierras de cultivo, y dejó más de 1,200 damnificados