Kumarmcdaniel9017

Regulated thin filaments (RTFs) tightly control striated muscle contraction through calcium binding to troponin, which enables tropomyosin to expose myosin-binding sites on actin. Myosin binding holds tropomyosin in an open position, exposing more myosin-binding sites on actin, leading to cooperative activation. At lower calcium levels, troponin and tropomyosin turn off the thin filament; however, this is antagonised by the high local concentration of myosin, questioning how the thin filament relaxes. To provide molecular details of deactivation, we used single-molecule imaging of green fluorescent protein (GFP)-tagged myosin-S1 (S1-GFP) to follow the activation of RTF tightropes. In sub-maximal activation conditions, RTFs are not fully active, enabling direct observation of deactivation in real time. We observed that myosin binding occurs in a stochastic step-wise fashion; however, an unexpectedly large probability of multiple contemporaneous detachments is observed. This suggests that deactivation of the thin filament is a coordinated active process.Accumulating evidence has shown transcranial low-intensity ultrasound can be potentially a non-invasive neural modulation tool to treat brain diseases. However, the underlying mechanism remains elusive and the majority of studies on animal models applying rather high-intensity ultrasound that cannot be safely used in humans. Here, we showed low-intensity ultrasound was able to activate neurons in the mouse brain and repeated ultrasound stimulation resulted in adult neurogenesis in specific brain regions. In vitro calcium imaging studies showed that a specific ultrasound stimulation mode, which combined with both ultrasound-induced pressure and acoustic streaming mechanotransduction, is required to activate cultured cortical neurons. ASIC1a and cytoskeletal proteins were involved in the low-intensity ultrasound-mediated mechanotransduction and cultured neuron activation, which was inhibited by ASIC1a blockade and cytoskeleton-modified agents. In contrast, the inhibition of mechanical-sensitive channels involved in bilayer-model mechanotransduction like Piezo or TRP proteins did not repress the ultrasound-mediated neuronal activation as efficiently. The ASIC1a-mediated ultrasound effects in mouse brain such as immediate response of ERK phosphorylation and DCX marked neurogenesis were statistically significantly compromised by ASIC1a gene deletion. Collated data suggest that ASIC1a is the molecular determinant involved in the mechano-signaling of low-intensity ultrasound that modulates neural activation in mouse brain.Brain abnormalities in the reading network have been repeatedly reported in individuals with developmental dyslexia (DD); however, it is still not totally understood where the structural and functional abnormalities are consistent/inconsistent across languages. In the current multimodal meta-analysis, we found convergent structural and functional alterations in the left superior temporal gyrus across languages, suggesting a neural signature of DD. We found greater reduction in grey matter volume and brain activation in the left inferior frontal gyrus in morpho-syllabic languages (e.g. Chinese) than in alphabetic languages, and greater reduction in brain activation in the left middle temporal gyrus and fusiform gyrus in alphabetic languages than in morpho-syllabic languages. These language differences are explained as consequences of being DD while learning a specific language. In addition, we also found brain regions that showed increased grey matter volume and brain activation, presumably suggesting compensations and brain regions that showed inconsistent alterations in brain structure and function. Our study provides important insights about the etiology of DD from a cross-linguistic perspective with considerations of consistency/inconsistency between structural and functional alterations.Transient receptor potential melastatin 7 (TRPM7) contributes to a variety of physiological and pathological processes in many tissues and cells. With a widespread distribution in the nervous system, TRPM7 is involved in animal behaviors and neuronal death induced by ischemia. However, the physiological role of TRPM7 in central nervous system (CNS) neuron remains unclear. Here, we identify endocytic defects in neuroendocrine cells and neurons from TRPM7 knockout (KO) mice, indicating a role of TRPM7 in synaptic vesicle endocytosis. Our experiments further pinpoint the importance of TRPM7 as an ion channel in synaptic vesicle endocytosis. Ca2+ imaging detects a defect in presynaptic Ca2+ dynamics in TRPM7 KO neuron, suggesting an importance of Ca2+ influx via TRPM7 in synaptic vesicle endocytosis. Moreover, the short-term depression is enhanced in both excitatory and inhibitory synaptic transmissions from TRPM7 KO mice. Taken together, our data suggests that Ca2+ influx via TRPM7 may be critical for short-term plasticity of synaptic strength by regulating synaptic vesicle endocytosis in neurons.The force-induced unfolding and refolding of proteins is speculated to be a key mechanism in the sensing and transduction of mechanical signals in the living cell. Yet, little evidence has been gathered for its existence in vivo. Prominently, stretch-induced unfolding is postulated to be the activation mechanism of the twitchin/titin family of autoinhibited sarcomeric kinases linked to the mechanical stress response of muscle. To test the occurrence of mechanical kinase activation in living working muscle, we generated transgenic C. elegans expressing twitchin containing FRET moieties flanking the kinase domain and developed a quantitative technique for extracting FRET signals in freely moving C. elegans, using tracking and simultaneous imaging of animals in three channels (donor fluorescence, acceptor fluorescence, and transmitted light). Computer vision algorithms were used to extract fluorescence signals and muscle contraction states in each frame, in order to obtain fluorescence and body curvature measurements with spatial and temporal precision in vivo. The data revealed statistically significant periodic changes in FRET signals during muscle activity, consistent with a periodic change in the conformation of twitchin kinase. We conclude that stretch-unfolding of twitchin kinase occurs in the active muscle, whereby mechanical activity titrates the signalling pathway of this cytoskeletal kinase. We anticipate that the methods we have developed here could be applied to obtaining in vivo evidence for force-induced conformational changes or elastic behavior of other proteins not only in C. elegans but in other animals in which there is optical transparency (e.g zebrafish).

Artemisinin-based treatment in malaria patients with abnormal hemoglobin may be ineffective because of their genetic particularity, which could lead to resistance. The main purpose of this study was to assess the effect of artemisinin derivatives on in vivo parasite clearance according to erythrocyte variants. In vivo response was investigated through retrospective data obtained over a 42-day artemether-lumefantrine/artesunate amodiaquine efficacy protocol conducted from 2012 to 2016.

A total of 770 patients in Côte d'Ivoire attending the hospitals of Anonkoua-koute (Abidjan), Petit Paris (Korhogo), Libreville (Man), Dar es salam (Bouaké), Ayamé and Yamoussoukro with acute uncomplicated falciparum malaria were selected for successful hemoglobin typing. HbAS, HbSS, HbAC, and HbSC genotypes were found. Parasite clearance time was obtained for 414 patients. In the population with abnormal hemoglobin, parasite densities on admission and parasite clearance rates were significantly lower in the HbSC group compatrine and artesunate amodiaquine in the treatment of uncomplicated Plasmodium falciparum malaria in patients with abnormal hemoglobin, the increased delay of parasite clearance may represent a threat to health in these patients in relation with sickle cell crisis, which could support selection of parasites resistant to artemisinin.

To propose a modification of the Kodama classification to classify type III lesions of alveolar echinococcosis (AE) that do not have microcysts.

200 magnetic resonance imaging (MRI) images of AE liver lesions from four endemic regions of the world were classified according to Kodama, distinguishing within type III those with microcysts from those without. Each center included 50 MRIs of patients with unoperated AA liver lesions. The first 50 cases were classified by a first reader in the presence of four second-line readers from each region. Then each second-line reader classified his or her 50 cases.

In all centers, type III lesions were predominant 58% of the total lesions and 23% of them were without microcysts. The average age of the patients was 47 years. In China, the patients were on average younger and the lesions larger. German patients had more lesions within the liver. Type I and II lesions, synonymous with earlier diagnosis, were more common in Europe.

The Kodama classification needed to be modified because of the existence of a significant proportion of unclassifiable lesions. This is especially true since the presence of microcysts is an informative element of parasite activity. Therefore, this study proposes a Kodama-XUUB classification with type IIIa lesions having microcysts and type IIIb lesions not having microcysts.

The Kodama classification needed to be modified because of the existence of a significant proportion of unclassifiable lesions. This is especially true since the presence of microcysts is an informative element of parasite activity. Therefore, this study proposes a Kodama-XUUB classification with type IIIa lesions having microcysts and type IIIb lesions not having microcysts.

Obstructive sleep apnea (OSA) is a heterogeneous, complex disease. We aimed to identify OSA phenotypes through cluster analysis and to perform a long-term follow-up to validate the phenotypes.

We applied a Partitioning Around Medioids technique in a cohort of 1217 participants recently diagnosed with OSA. We performed a 5-year follow-up analyzing the incidence of comorbidities, chronic medication, hospital admissions, mortality, and the influence of continuous positive airway pressure (CPAP) treatment on mortality risk.

We identified three phenotypes two predominantly male clusters, one composed of middle-aged participants with overweight, moderate OSA, and cardiovascular risk factors, and the other consisting of older, obese participants with severe OSA, cardiovascular risk factors, ischemic heart disease (18.4%) and atrial fibrillation (9.7%). The third cluster was composed by 77% of female participants, with moderate OSA, cardiovascular risk factors, the highest prevalence of depression (15.7%), and high prescription of antidepressants (55.1%), anxiolytics (40.0%), hypnotics and sedatives (11.1%), nonsteroidal anti-inflammatory drugs (67.9%), and weak opioids (15.1%). The baseline characteristics of each cluster maintained the same trend over time regarding the incidence of new comorbidities, medication intake, hospitalization rates, and reasons for admission. The absence of CPAP treatment was associated with a significantly higher risk of all-cause mortality (HR 5.84, CI 2.9-11.8), especially in the older men (HR 7.7, CI 4.06-14.63) and predominantly female clusters (HR 2.79, CI 1.34-5.79).

We identified three phenotypes with relevant clinical and prognostic implications in order to improve personalized strategies in OSA management.

We identified three phenotypes with relevant clinical and prognostic implications in order to improve personalized strategies in OSA management.