Typical antipsychotics can cause disabling side effects. Specifically, antagonism of D2R signaling by the typical antipsychotic haloperidol induces parkinsonism in humans and catalepsy in rodents. ...Striatal dopamine D2 receptors (D2R) are major regulators of motor activity through their signaling on striatal projection neurons and interneurons. We show that D2R signaling on cholinergic interneurons contributes to an in vitro pause in firing of these otherwise tonically active neurons and to the striatal dopamine/acetylcholine balance. The selective ablation of D2R from cholinergic neurons allows discrimination between the motor-reducing and cataleptic effects of antipsychotics. The cataleptic effect of antipsychotics is triggered by blockade of D2R on cholinergic interneurons and the consequent increase of acetylcholine signaling on striatal projection neurons. These studies illuminate the critical role of D2R-mediated signaling in regulating the activity of striatal cholinergic interneurons and the mechanisms of typical antipsychotic side effects.
•D2R signaling directs the striatal dopamine/acetylcholine balance•D2R signaling controls the in vitro “pause” of striatal cholinergic interneurons•Antipsychotic-induced catalepsy depends on D2R blockade on cholinergic interneurons•Acetylcholine signaling on medium spiny neurons induces catalepsy
A functional reciprocal interaction between dopamine and acetylcholine is critical to contain and regulate acetylcholine signaling in the striatum. Genetic deletion of D2 receptors on striatal cholinergic interneurons reduced the in vitro pause response, with consequences on striatal medium spiny neurons and motor activity. We reveal that acetylcholine operates as a trigger of catalepsy generated by typical antipsychotics such as haloperidol.
Objetivo. Determinar la circulación del virus del Oeste del Nilo (VON) en caballos del oriente de Yucatán, México. Materiales y métodos. Por conveniencia se estudiaron 184 caballos localizados en 23 ...unidades de producción de los municipios de Tizimín y Panabá, Yucatán. De cada caballo se obtuvo una muestra de suero sanguíneo, la cual fue evaluada con un ensayo de inmunoabsorción enzimática de captura (MAC-ELISA) para detectar inmunoglobulinas de clase M (IgM) específicas contra VON. Adicionalmente, los sueros seroreactores y los sospechosos fueron analizados con una reacción en cadena de la polimerasa por retrotranscripción (RT-PCR) para detectar ARN viral. Resultados. Ocho caballos estudiados fueron seroreactores en la ELISA-MAC (4.3%, 8/184) y dos fueron sospechosos (1.1%, 2/184). Todos estos sueros fueron negativos a la RT-PCR. Conclusiones. La detección de IgM específicas contra VON en los caballos estudiados, demuestra infecciones recientes e indica la circulación del virus en el oriente de Yucatán.
Echinoderms comprise a group of animals with impressive regenerative capabilities. They can replace complex internal organs following injury or autotomy. In holothurians or sea cucumbers, cellular ...processes of intestinal regeneration have been extensively studied. The molecular machinery behind this faculty, however, remains to be understood. Here we assembled and annotated a de novo transcriptome using RNA-seq data consisting of regenerating and non-regenerating intestinal tissues from the sea cucumber Holothuria glaberrima. Comparisons of differential expression were made using the mesentery as a reference against 24 h and 3 days regenerating intestine, revealing a large number of differentially expressed transcripts. Gene ontology and pathway enrichment analysis showed evidence of increasing transcriptional activity. Further analysis of transcripts associated with transcription factors revealed diverse expression patterns with mechanisms involving developmental and cancer-related activity that could be related to the regenerative process. Our study demonstrates the broad and diversified gene expression profile during the early stages of the process using the mesentery as the focal point of intestinal regeneration. It also establishes the genes that are the most important candidates in the cellular processes that underlie regenerative responses.
Data-Driven (DD) computing is an emerging field of Computational Mechanics, motivated by recent technological advances in experimental measurements, the development of highly predictive computational ...models, advances in data storage and data processing, which enable the transition from a material data-scarce to a material data-rich era. The predictive capability of DD simulations is contingent on the quality of the material data set, i.e. its ability to closely sample all the strain–stress states in the phase space of a given mechanical problem. In this study, we develop a methodology for increasing the quality of an existing material data set through iterative expansions. Leveraging the formulation of the problems treated with the DD paradigm as distance minimization problems, we identify regions in phase space with poor data coverage, and target them with additional experiments or lower-scale simulations. The DD solution informs the additional experiments so that they can provide better coverage of the phase space of a given application.
We first illustrate the convergence properties of the approach through a DD finite element simulation of a linear elastic cylinder under triaxial compression. The same numerical experiment is then performed on a specimen of Hostun sand, a material with complex history-dependent behavior. Data sampling is performed with Level-Set Discrete Element Method (LS-DEM) calculations of unit cells representative of this granular material, subjected to loading paths determined by the proposed method. It is shown that this adaptive expansion of the data set, tailored for a particular application, leads to convergent and accurate DD predictions, without the computational cost of using large databases with potentially redundant or low-quality data.
Chronic right ventricular apical pacing (RVAP) has been associated with negative hemodynamic and clinical effects. The aim of the present study was to compare RVAP with right ventricular septal ...pacing (RVSP) in terms of echocardiographic features and clinical outcomes. A total of 93 patients without structural heart disease and with an indication for a permanent pacemaker were randomly assigned to receive a screw-in lead either in the RV apex (n = 46) or in the RV mid-septum (n = 47). The patients were divided into 3 subgroups according to the percentage of ventricular pacing: control group (n = 21, percentage of ventricular pacing ≤10%), RVAP group (n = 28), or RVSP group (n = 32; both latter groups had a percentage of ventricular pacing >10%). The RVAP group had more intraventricular dyssynchrony and a trend toward a worse left ventricular ejection fraction compared to the RVSP and control groups at 12 months of follow-up (maximal delay to peak systolic velocity between any of the 6 left ventricular basal segments was 57.8 ± 38.2, 35.5 ± 20.6, and 36.5 ± 17.8 ms for RVAP, RVSP, and control group, respectively; p = 0.006; mean left ventricular ejection fraction 62.9 ± 7.9%, 66.5 ± 7.2%, and 66.6 ± 7.2%, respectively, p = 0.14). Up to 48.1% of the RVAP patients showed significant intraventricular dyssynchrony compared to 19.4% of the RVSP patients and 23.8% of the controls (p = 0.04). However, no overt clinical benefits from RVSP were found. In conclusion, RVAP was associated with increased dyssynchrony compared to the RVSP and control patients. RVSP could represent an alternative pacing site in selected patients to reduce the harmful effects of traditional RVAP.
Maternal serum concentrations of folate, homocysteine, and vitamin B12 have been associated with pre-eclampsia. Nevertheless, reported studies involve limited number of cases to reliably assess the ...nature of these associations. Our aim was to examine the relation of these three biomarkers with pre-eclampsia risk in a large Colombian population.
Design: A case-control study. Setting: Cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight different Colombian cities between 2000 and 2012. Population or Sample: 2978 cases and 4096 controls were studied. Maternal serum concentrations of folate, homocysteine, and vitamin B12 were determined in 1148 (43.6%) cases and 1300 (31.7%) controls. Also, self-reported folic acid supplementation was recorded for 2563 (84%) cases and 3155 (84%) controls. Analysis: Adjusted odds ratios (OR) for pre-eclampsia were estimated for one standard deviation (1SD) increase in log-transformed biomarkers. Furthermore, we conducted analyses to compare women that reported taking folic acid supplementation for different periods during pregnancy. Main Outcomes Measures: Odds ratio for pre-eclampsia.
After adjusting for potential confounders in logistic regression models, the OR for pre-eclampsia was 0.80 (95% CI: 0.72, 0.90) for 1SD increase in log-folate, 1.16 (95%CI: 1.05, 1.27) for 1SD increase in log-homocysteine, and 1.10 (95%CI: 0.99, 1.22) for 1SD increase in log-vitamin B12. No interactions among the biomarkers were identified. Women who self-reported consumption of folic acid (1 mg/day) throughout their pregnancy had an adjusted OR for pre-eclampsia of 0.86 (95%CI: 0.67, 1.09) compared to women that reported no consumption of folic acid at any point during pregnancy.
Maternal serum concentrations of folate were associated as a protective factor for pre-eclampsia while concentrations of homocysteine were associated as a risk factor. No association between maternal vitamin B12 concentrations and preeclampsia was found.
Novel four-coordinated boron complexes (1–5) were synthesized via a reaction between BF3·CH3OH and benzimidazole–phenolate ligands (L1–L5), which are N,O-donors. These complexes exhibit intense blue ...emission in the solution and solid states accompanied by notable fluorescence quantum yields (ΦF). The study of the structure–property relation, through theoretical and experimental approaches, revealed a distinctive trend where compounds incorporating electron-donating substituents (methyl and ethoxy groups) in the phenolate moiety manifest shifts in emission wavelengths across the blue spectrum, concomitant with an increase in ΦF. Furthermore, the incorporation of an aromatic ring into the benzimidazole moiety considerably intensifies the rate of radiative relaxation from excited states. Notably, in the solid phase, either as a crystalline powder or loaded into polymer films, these modified complexes maintain or even surpass ΦF values observed in molecular solutions, ranging from 0.18 to 0.57, depending on the substitution. This characteristic makes these compounds attractive for applications in optoelectronics. All of the compounds were characterized using 1H, 13C, 11B, and 19F NMR, elemental analysis, and the molecular structures were corroborated through single-crystal X-ray diffraction analysis. Computational calculations via time-dependent density functional theory further elucidate the tunability of optical bandgaps through group substitution on ligands, aligning well with experimental observations.
This paper presents a model-free data-driven framework for breakage mechanics. In contrast with continuum breakage mechanics, the de facto approach for the macroscopic analysis of crushable granular ...media, the present framework does not require the definition of constitutive models and phenomenological assumptions, relying on material behavior that is known only through empirical data. For this purpose, we revisit the recent developments in model-free data-driven computing for history-dependent materials and extend the main ideas to materials with particle breakage. A systematic construction of the modeling framework is presented, starting from the closed-form representation of continuum breakage mechanics and arriving at alternative model-free representations. The predictive ability of the data-driven framework is highlighted and contrasted with continuum breakage mechanics on different boundary value problems. Moreover, an application to a real experimental test in crushable sand is presented, where the data is furnished by high-fidelity grain-scale simulations, indicating that the proposed framework provides an accurate prediction of the mechanics of crushable materials including the state of comminution.
The ring-opening polymerization (ROP) of l-lactide (l-LA) was induced by the catalytic action of bismuth subsalicylate (BiSS) using linear aliphatic diols HO(CH
)
OH, where
= 2, 3, 4, 5, 6, and 8 as ...initiators and chain transfer agents. The theoretical and experimental degree of polymerization (DP) in all samples of α,ω-hydroxy telechelic poly(l-lactide) (HOPLLAOH) had a good agreement in all samples, an effect attributed to the interaction of BiSS with HO(CH
)
OH inducing a transfer reaction. HOPLLAOH was synthesized and characterized by a range of analytical techniques, confirming the insertion of methylene groups from the initiator into the main chain of the polyester. The glass-transition temperature (
) of HOPLLAOH was found to be proportional to the number of methylene groups present in the diol. Various parameters regarding the ROP of l-LA were studied, such as temperature, time of reaction, amount of catalyst, and the nature of the diols. A kinetic study of the reaction allowed the determination of the rate constants (
) and activation energy (
). A mechanism of initiation is proposed based on a computational study using density functional theory (DFT), evidencing the role of the alkyl diol as an initiator, producing an alkoxide (Bi-OROH). This species then acts as a nucleophile, attacking the carbonyl group, inducing its insertion, and ultimately completing the ring-opening of l-LA.
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