Klavsenstephansen6621

Emerging evidence suggests that some cases of obesity and binge eating disorders may reflect an incentive-sensitization brain signature of cue hyper-reactivity, causing excessive 'wanting' to eat. Future findings on the neurobiological bases of 'liking' and 'wanting' can continue to improve understanding of both normal food reward and causes of clinical eating disorders.In vivo confocal microscopy (IVCM) allows the evaluation of the living human cornea at the cellular level. The non-invasive nature of this technique longitudinal, repeated examinations of the same tissue over time. Image analysis of two-dimensional time-lapse sequences of presumed immune cells with and without visible dendrites at the corneal sub-basal nerve plexus in the eyes of healthy individuals was performed. We demonstrated evidence that cells without visible dendrites are highly dynamic and move rapidly in the axial directions. A number of dynamic cells were observed and measured from three eyes of different individuals. The total average displacement and trajectory speeds of three cells without visible dendrites (N = 9) was calculated to be 1.12 ± 0.21 and 1.35 ± 0.17 μm per minute, respectively. One cell with visible dendrites per cornea was also analysed. Tracking dendritic cell dynamics in vivo has the potential to significantly advance the understanding of the human immune adaptive and innate systems. The ability to observe and quantify migration rates of immune cells in vivo is likely to reveal previously unknown insights into corneal and general pathophysiology and may serve as an effective indicator of cellular responses to intervention therapies.Ultraviolet A (UVA) light-based photoactivation of riboflavin (Rf) to induce corneal crosslinking (CXL) and mechanical stiffening is now a well-known treatment for corneal ectasia and Keratoconus that is being used in a topographically guided photorefractive intrastromal CXL (PiXL) procedure to treat low degrees of refractive errors. Alternative approaches for non-invasive treatment of refractive errors have also been proposed that use femtosecond lasers (FS) that provide much faster, more precise, and safer results than UVA CXL. One such treatment, nonlinear optical crosslinking (NLO CXL), has been able to replicate the effects of UVA CXL, while producing a smaller area of cellular damage and requiring a shorter procedure time. Unlike UVA CXL, the treatment volume of NLO CXL only occurs within the focal volume of the laser, which can be placed at any depth and scanned into any pattern for true topographically guided refractive correction. This review presents our experience with using FS lasers to photoactivate Rf and perform highly controlled corneal CXL that leads to mechanical stiffening and changes in corneal shape.The human serotonin1A receptor is a representative member of the superfamily of G protein-coupled receptors (GPCRs) and an important drug target for neurological disorders. Using a combination of biochemical, biophysical and molecular dynamics simulation approaches, we and others have shown that membrane cholesterol modulates the organization, dynamics and function of vertebrate serotonin1A receptors. Previous studies have shown that the cytoplasmic portion of transmembrane helix V (TM V) and the extramembraneous intracellular loop 3 are critical for G-protein coupling, phosphorylation and desensitization of the receptor. We have recently resolved a collage of putative cholesterol interaction motifs from the amino acid sequence overlapping this region. In this paper, we explore the sequence plasticity of this fragment that may have adapted to altered membrane lipidome, after vertebrates evolved from primordial invertebrates. Since invertebrates have lower levels of membrane cholesterol relative to vertebrates, we compared TM V sequence fragments from invertebrate serotonin1 receptors with vertebrate orthologs to infer the sequence plasticity in TM V. We report that the average number of cholesterol interaction motifs in TM V for diverse phyla represents an increasing trend that could mirror vertebrate evolution from primordial invertebrates. By statistical modeling, we propose that the collage of cholesterol interaction motifs in TM V of the human serotonin1A receptor may have evolved from rudimentary collages, reminiscent of primordial invertebrate orthologs. Taken together, we propose that a repertoire of cholesterol-philic nonsynonymous substitutions may have enhanced collage complexity in TM V during vertebrate evolution.The neuromuscular junction (NMJ) is a specialized synapse that is the point of connection between motor neurons and skeletal muscle. Although developmental studies have established the importance of cell-cell communication at the NMJ for the integrity and full functionality of this synapse, the contribution of this structure as a primary driver in motor neuron disease pathogenesis remains uncertain. Here, we consider the biology of the NMJ and review emerging lines of investigation that are highlighting the importance of cell-cell interaction at the NMJ in spinal muscular atrophy (SMA), X-linked spinal and bulbar muscular atrophy (SBMA), and amyotrophic lateral sclerosis (ALS). Ongoing research may reveal NMJ targets and pathways whose therapeutic modulation will help slow the progression of motor neuron disease, offering a novel treatment paradigm for ALS, SBMA, SMA, and related disorders.Mixed polydiacetylene (PDA) lipid vesicles mimic cell membranes and exhibit a colorimetric response induced by mechanical stress, which can be used to determine the affinity of proteins or molecules for lipid membranes. Due to a simple spectroscopic readout, PDA assays are amenable to high-throughput screens; however, these assays exhibit batch-to-batch variability. Sensitivity of the assay is also influenced by physicochemical properties associated with different lipids. Here, a method of normalizing PDA assays to reduce variability and enable direct comparison across lipid systems is described.Snakebite accidents are considered serious public health problems. They are often neglected, and individuals who have received insufficient treatment are subjected to various disabling alterations. Snake venoms are secretions composed of biologically active molecules capable of triggering local and systemic effects in envenomation victims. Bothropic snakes are responsible for most of the ophidian accidents in Brazil; their venoms are mainly related to local manifestations, due to a composition that is especially rich in proteases and phospholipases A2. The most common local damages are inflammation, with consequent cellular activation and release of inflammatory mediators, hemorrhage, edema, pain and (myo)necrosis, which may lead to amputation of the affected areas. Antivenom therapy is the main treatment for snakebites. However, the efficiency is mainly due to the neutralization of the toxins responsible for the systemic alterations. Thus, the local damages can evolve to markedly compromise the tissue. The complexity of these local effects associated with the toxicity of the snake venom components of the genus Bothrops, arouse interest in the study of the biochemical and pathophysiological mechanisms involved with the actions caused by toxins of the venom. Therefore, this review aims to analyze the edematogenic, hyperalgesic and myotoxic effects caused by Brazilian bothropic venoms in order to contribute to the study and elucidation of the mechanisms of action of its components and, consequently, enable discoveries of more effective combined therapies in the treatment of local damages resulting from envenoming.Oxidative damage on DNA arising from both endogenous and exogenous sources can result in base modifications that promote errors in replication as well as generating sites of base loss (abasic sites) that present unique challenges to maintaining genomic integrity. These lesions are excised by DNA glycosylases in the first step of the base excision repair pathway. Here we present the first crystal structure of a NEIL2 glycosylase, an enzyme active on cytosine oxidation products and abasic sites. The structure reveals an unusual "open" conformation not seen in NEIL1 or NEIL3 orthologs. NEIL2 is predicted to adopt a "closed" conformation when bound to its substrate. Combined crystallographic and solution-scattering studies show the enzyme to be conformationally dynamic in a manner distinct among the NEIL glycosylases and provide insight into the unique substrate preference of this enzyme. In addition, we characterized three cancer variants of human NEIL2, namely S140N, G230W, and G303R.

This study aimed to evaluate annual trends of early neonatal sepsis and antimicrobial use in very low birth weight infants for 12 years, as well as to identify microbiological agents, antimicrobial sensitivity profiles, and association with early neonatal death.

This was a retrospective cohort study including 1254 very low birth weight infants admitted from 2006 to 2017. Four groups were evaluated culture-confirmed sepsis; presumed neonatal sepsis; ruled out neonatal sepsis group; and infants not exposed to antibiotics.

The medians of gestational age and birth weight were 29 weeks (27-31) and 1090g (850-1310), respectively. The rates of culture-confirmed sepsis, presumed neonatal sepsis, ruled out neonatal sepsis, and not exposed to antibiotics were 1.3, 9.0, 15.4, and 74.3%, respectively. From the initial group of newborns whose antimicrobial treatment was administered for sepsis' suspicion, it was possible to discontinue antibiotic in 44%. The culture-confirmed sepsis rates remained stable (p=0.906). significant downward trend in the presumed neonatal sepsis rate and a significant upward trend in the ruled out neonatal sepsis group. The rate of not exposed to antibiotics infants was high, also presenting a significant downward trend. The identified bacteria were those commonly found and showed usual antimicrobial susceptibility patterns. Death predominantly occurred in groups that received antibiotic treatment.Bioprosthetic heart valves do not usually require formal anticoagulation as they are less thrombogenic than their mechanical counterparts. However, valve thrombosis has been reported after both transcatheter and surgical aortic bioprosthesis implantation. Short-term anticoagulation after surgical bioprosthesis implantation is often recommended while endothelialisation of the prosthesis takes place, particularly for mitral valve implants. There have been no reports of tissue heart valve thrombosis in transcatheter mitral valve replacement. We describe our experience and successful treatment of such a case.The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of familial Parkinson's disease (PD). This mutation results in dopaminergic neurodegeneration via dysregulated protein translation, although how alterations in protein synthesis contribute to neurodegeneration in human neurons is not known. Here we define the translational landscape in LRRK2-mutant dopaminergic neurons derived from human induced pluripotent stem cells (hiPSCs) via ribosome profiling. We found that mRNAs that have complex secondary structure in the 5' untranslated region (UTR) are translated more efficiently in G2019S LRRK2 neurons. This leads to the enhanced translation of multiple genes involved in Ca2+ regulation and to increased Ca2+ influx and elevated intracellular Ca2+ levels, a major contributor to PD pathogenesis. This study reveals a link between dysregulated translation control and Ca2+ homeostasis in G2019S LRRK2 human dopamine neurons, which potentially contributes to the progressive and selective dopaminergic neurotoxicity in PD.