Tandem Mobility Mass Spectrometry Study of Electrosprayed Tetraheptyl Ammonium Bromide Clusters

Multiply charged electrospray ions from concentrated solutions of Heptyl4N+Br− (designated A+B− hereafter) in formamide are analyzed mass spectrometrically (MS) following mobility selection in ambient air in a differential mobility analyzer (DMA). Most of the sharp mobility peaks seen are identified as (AB)nA+ clusters, with 0 ≤ n ≤ 5. One anomalously abundant and mobile ion is identified as NH4+(AB)4. Six ions in the (AB)n(A+)2 series are also identified, completing and correcting earlier mobility data for singly and doubly charged ions up to masses of almost 9000 Da. The more mobile of two broad humps seen in the mobility spectrum includes m/z values approximately from 2500 up to 12,000 Da. It is formed primarily by multiply charged (AB)n(A+)z clusters with multiple ammonium bromide adducts. Because of overlapping of many peaks of different m/z and charge state z, only a few individual species can be identified by MS alone in this highly congested region. However, the spectral simplification brought about by mobility selection upstream of the MS reveals a series of broad modulations in m/z space, with all ions resolved in the second, third, …sixth modulation being in charge states z = 2, 3, …6, respectively. Extrapolation of this trend beyond the sixth wave fixes the ion charge state (in some cases up to z = 15) and mass (beyond m = 175,000 u). This wavy structure had been previously observed and explained in terms of ion evaporation kinetics from volatile drops, though without mass identification. All observations indicate that the clusters are formed as charged residues, but their charge state is fixed by the Iribarne-Thomson ion evaporation mechanism. Consequently, the measured curve of cluster diameter versus z yields the two parameters governing ion evaporation kinetics. Clusters with z > 1 and electrical mobility Z > 0.495 cm2/V/s are metastable and evaporate a singly charged cluster, probably (AB)2A+, between the DMA and the MS. Plotting the electrical mobilities Z of the clusters in the form (z/Z)1/2 versus m1/3 (both proportional to cluster diameter) collapse the data for all cluster sizes and charge states into one single straight line for Z below 0.495 cm2/V/s. This linear relation reveals a uniform apparent cluster density of 0.935 g/cm3 and an effective hard-sphere diameter of the air molecules of 0.44 nm. An anomalous mobility increase is observed at diameters below 3 nm

The Giardial Arginine Deiminase Participates in Giardia-Host Immunomodulation in a Structure-Dependent Fashion via Toll-like Receptors

Beyond the problem in public health that protist-generated diseases represent, understanding the variety of mechanisms used by these parasites to interact with the human immune system is of biological and medical relevance. Giardia lamblia is an early divergent eukaryotic microorganism showing remarkable pathogenic strategies for evading the immune system of vertebrates. Among various multifunctional proteins in Giardia, arginine deiminase is considered an enzyme that plays multiple regulatory roles during the life cycle of this parasite. One of its most important roles is the crosstalk between the parasite and host. Such a molecular “chat” is mediated in human cells by membrane receptors called Toll-like receptors (TLRs). Here, we studied the importance of the 3D structure of giardial arginine deiminase (GlADI) to immunomodulate the human immune response through TLRs. We demonstrated the direct effect of GlADI on human TLR signaling. We predicted its mode of interaction with TLRs two and four by using the AlphaFold-predicted structure of GlADI and molecular docking. Furthermore, we showed that the immunomodulatory capacity of this virulent factor of Giardia depends on the maintenance of its 3D structure. Finally, we also showed the influence of this enzyme to exert specific responses on infant-like dendritic cells

Childhood conditions influence adult progesterone levels

Background Average profiles of salivary progesterone in women vary significantly at the inter- and intrapopulation level as a function of age and acute energetic conditions related to energy intake, energy expenditure, or a combination of both. In addition to acute stressors, baseline progesterone levels differ among populations. The causes of such chronic differences are not well understood, but it has been hypothesised that they may result from varying tempos of growth and maturation and, by implication, from diverse environmental conditions encountered during childhood and adolescence. Methods and Findings To test this hypothesis, we conducted a migrant study among first- and second-generation Bangladeshi women aged 19–39 who migrated to London, UK at different points in the life-course, women still resident in Bangladesh, and women of European descent living in neighbourhoods similar to those of the migrants in London (total n = 227). Data collected included saliva samples for radioimmunoassay of progesterone, anthropometrics, and information from questionnaires on diet, lifestyle, and health. Results from multiple linear regression, controlled for anthropometric and reproductive variables, show that women who spend their childhood in conditions of low energy expenditure, stable energy intake, good sanitation, low immune challenges, and good health care in the UK have up to 103% higher levels of salivary progesterone and an earlier maturation than women who develop in less optimal conditions in Sylhet, Bangladesh (F9,178 = 5.05, p < 0.001, standard error of the mean = 0.32; adjusted R2 = 0.16). Our results point to the period prior to puberty as a sensitive phase when changes in environmental conditions positively impact developmental tempos such as menarcheal age (F2,81 = 3.21, p = 0.03) and patterns of ovarian function as measured using salivary progesterone (F2,81 = 3.14, p = 0.04). Conclusions This research demonstrates that human females use an extended period of the life cycle prior to reproductive maturation to monitor their environment and to modulate reproductive steroid levels in accordance with projected conditions they might encounter as adults. Given the prolonged investment of human pregnancy and lactation, such plasticity (extending beyond any intrauterine programming) enables a more flexible and finely tuned adjustment to the potential constraints or opportunities of the later adult environment. This research is the first, to our knowledge, to demonstrate a postuterine developmental component to variation in reproductive steroid levels in women

Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer

Human triosephosphate isomerase (HsTIM) is a central glycolytic enzyme and is overexpressed in cancer cells with accelerated glycolysis. Triple-negative breast cancer is highly dependent on glycolysis and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Deamidated HsTIM was recently proposed as a druggable target. Although thiol-reactive drugs affect cell growth in deamidated HsTIM-complemented cells, the role of this protein as a selective target has not been demonstrated. To delve into the usefulness of deamidated HsTIM as a selective target, we assessed its natural accumulation in breast cancer cells. We found that deamidated HsTIM accumulates in breast cancer cells but not in noncancerous cells. The cancer cells are selectively programmed to undergo cell death with thiol-reactive drugs that induced the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo, a thiol-reactive drug effectively inhibits the growth of xenograft tumors with an underlying mechanism involving deamidated HsTIM. Our findings demonstrate the usefulness of deamidated HsTIM as target to develop new therapeutic strategies for the treatment of cancers and other pathologies in which this post translationally modified protein accumulates

Jaw biodynamic data for 24 patients with chronic unilateral temporomandibular disorder

This study assessed 24 adult patients, suffering from severe chronic unilateral pain diagnosed as temporomandibular joint (TMJ) disorder (TMD). The full dentate patients had normal occlusion and had never received an occlusal therapy, i.e., were with natural dental evolution/maturation. The following functional and dynamic factors were assessed: (1) chewing function; (2) TMJ remodeling or the condylar path (CP); and (3) lateral jaw motion or lateral guidance (LG). CPs were assessed using conventional axiography, and LG was assessed by K7 jaw tracking. Seventeen (71%) of the 24 (100%) patients consistently showed a habitual chewing side. The mean (standard deviation [SD]) of the CP angles was 47.90 (9.24) degrees. The mean (SD) of the LG angles was 42.95 (11.78) degrees. Data collection emerged from the conception of a new TMD paradigm where the affected side could be the habitual chewing side, the side with flatter lateral jaw motion or the side with an increased CP angle. These data may lead to improved diagnosis, therapy plans and evolution in TMD patients

Strategies of the Spanish press in the face of the Twitter algorithm change. Analysis of tweets published between 2018-2020

Twitter recently celebrated its 15th anniversary. During this period, the platform has gone through several phases, culminating in a record number of subscribers and profits in 2021. Twitter is a household name all over the world and people know what it can or cannot provide, independent of the future growth that it may experience with new investments and updates. This article aims to verify two interrelated hypotheses, namely: the Spanish press already knows how to optimise the social network Twitter, as three decades have elapsed since its launch; and, secondly, the algorithm modification implemented by Twitter in 2018 has triggered a change in the positioning of the headers studied in this social network. In order to demonstrate both, the object of analysis will be conducted by a mixed approach through quantitative statistical processes (which will study the number of impacts and retweets and likes obtained), and inductive qualitative methods such as semi-structured interviews. This multidisciplinary approach will provide a more complete and in-depth analysis of the phenomenon. The research focuses on the period between 2018 and 2020, and addresses the participation on Twitter of the four main traditional newspapers (El País, La Vanguardia, ABC and El Mundo) as well as four native digital newspapers (20 Minutos, El Español, elDiario.es and El Huffpost). The analysis comprises more than 1.5 million tweets among the eight chosen newspapers.Twitter acaba de celebrar su decimoquinto aniversario. Durante este periodo, la plataforma ha pasado varias fases que han culminado con un récord de suscriptores y beneficios en 2021. El mundo conoce Twitter y sabe qué es lo que puede o no proporcionar, aparte de las posibilidades de crecimiento que pueda experimentar en caso de potenciales inversiones. En el presente artículo se pretende comprobar dos hipótesis interrelacionadas, a saber: la prensa española en castellano ya sabe cómo optimizar la red social Twitter, por haber transcurrido tres lustros desde su puesta en marcha; y, en segundo lugar, el cambio de algoritmo implementado por Twitter en 2018 que ha desencadenado un cambio de posicionamiento de las cabeceras estudiadas en esta red social. Con el propósito de demostrar ambas, se abordará el objeto de análisis desde un enfoque mixto a través de procesos cuantitativos estadísticos (que estudiarán el número de impactos y de retuits y likes obtenidos), y métodos cualitativos inductivos como entrevistas semiestructuradas a los responsables de redes de los medios involucrados. Esta aproximación mixta proporcionará un análisis más completo y profundo sobre el fenómeno. La investigación se centra en el período comprendido entre 2018 y 2020, y aborda la participación en Twitter de cuatro periódicos tradicionales (El País, La Vanguardia, ABC y El Mundo), así como de cuatro periódicos nativos digitales (20 Minutos, El Español, elDiario.es y El Huffpost). El análisis comprende más de 1,5 millones de tuits entre los ocho periódicos elegidos

Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase

Giardiasis represents a latent problem in public health due to the exceptionally pathogenic strategies of the parasite Giardia lamblia for evading the human immune system. Strains resistant to first-line drugs are also a challenge. Therefore, new antigiardial therapies are urgently needed. Here, we tested giardial arginine deiminase (GlADI) as a target against giardiasis. GlADI belongs to an essential pathway in Giardia for the synthesis of ATP, which is absent in humans. In silico docking with six thiol-reactive compounds was performed; four of which are approved drugs for humans. Recombinant GlADI was used in enzyme inhibition assays, and computational in silico predictions and spectroscopic studies were applied to follow the enzyme’s structural disturbance and identify possible effective drugs. Inhibition by modification of cysteines was corroborated using Ellman’s method. The efficacy of these drugs on parasite viability was assayed on Giardia trophozoites, along with the inhibition of the endogenous GlADI. The most potent drug against GlADI was assayed on Giardia encystment. The tested drugs inhibited the recombinant GlADI by modifying its cysteines and, potentially, by altering its 3D structure. Only rabeprazole and omeprazole decreased trophozoite survival by inhibiting endogenous GlADI, while rabeprazole also decreased the Giardia encystment rate. These findings demonstrate the potential of GlADI as a target against giardiasis

Influence of carbon on intraband scattering in Mg(B1-xCx)2

We report data on the Hall coefficient (RH) of the carbon substituted Mg(B1-xCx)2 single crystals with x in the range from 0 to 0.1. The temperature dependences of RH obtained for the substituted crystals differ systematically at low temperatures, but all of them converge to the value of 1.8 x 10^-10 m^3/C at room temperature. The RH(T) data together with results of the thermoelectric power and electrical resistivity measurements are interpreted within a quasi-classical transport approach, where the presence of four different conducting sheets is considered. The main influence of the carbon substitution on the transport properties in the normal state is associated with enhanced scattering rates, rather than modified concentration of charge carriers. Presumably the carbon substitution increases the electron-impurity scattering mainly in the pi band.Comment: 16 pages, 3 figure

Aspectos generales de la metodología para el cálculo del Margen Bruto Estándar 2000

El objetivo de este documento de trabajo es presentar la metodología para el cálculo del Margen Bruto Estándar con periodo de referencia 1999, 2000 y 2001 (MBE 2000) y para el conjunto de categorías agrícolas definidas en el anexo de la Decisión de la Comisión 2003/369/CE. En este documento, dichas categorías vienen recogidas en el cuadro 2 del anexo. Este documento de trabajo se divide en tres secciones. En la sección 1 se presenta el marco metodológico general recogido en la legislación comunitaria, prestando especial interés a la definición de MBE. Las secciones 2 y 3 presentan, de forma resumida, la metodología seguida para el cálculo de los coeficientes MBE 2000 de las categorías de cultivos y ganados respectivamente