Simulation of electron transport in quantum well devices

Double barrier resonant tunneling diodes (DBRTD) have received much attention as possible terahertz devices. Despite impressive experimental results, the specifics of the device physics (i.e., how the electrons propagate through the structure) are only qualitatively understood. Therefore, better transport models are warranted if this technology is to mature. In this paper, the Lattice Wigner function is used to explain the important transport issues associated with DBRTD device behavior

Sex differences in the cerebral BOLD signal response to painful heat stimuli

There are limited data addressing the question of sex differences in pain-related cerebral processing. This study examined whether pain-related blood oxygenation level-dependent (BOLD) signal change measured with functional magnetic resonance imaging (fMRI) demonstrated sex differences, under conditions of equivalent pain perception. Twenty-eight healthy volunteers (17 women, 11 men) were subject to a fMRI scan while noxious heat stimuli were applied to the dorsum of the left foot. Significant BOLD signal modulation was observed in several nociceptive processing regions of interest (ROIs) in all subjects. There were no sex differences in the spatial extent of BOLD signal change for any ROI, but the signal amplitude was lower for women in most ROIs and significantly so for the primary somatosensory cortex (S1), the midanterior cingulate cortex, and the dorsolateral prefrontal cortex (DLPFC). The BOLD signal response could be positive or negative, and frequently, both polarities were observed within a single ROI. In most ROIs, women show proportionately more voxels with negative signal change than men, and this difference was statistically significant for the S1 and the DLPFC. The time course of the negative signal change was very similar to that of the positive signal change, suggesting that the latter was not “driving” the former. The location of negative and positive clusters formed distinct patterns in several of the ROIs, and these patterns suggest something other than a local “steal” phenomenon as an explanation for the negative signal changes. Sex differences in baseline cerebral blood flow may contribute to the BOLD signal differences observed in this study

Quantitative and morphological characteristics of the human corneal endothelium in relation to age, gender, and ethnicity in cataract populations of South Asia

Purpose: To describe the differences of corneal endothelial cell densities, cell size variability and cell hexagonality in cataract populations of south Asia between sexes and ethnic groups. Methods: 1,235 eyes of 1,235 male and female patients 40-75 years of age with senile cataract were examined with non contact specular microscopy with semi-automated analysis technique. The cell data of the study population was analyzed in relation to age, sex, and ethnic groups. Mean arithmetic differences and the coefficient of variation of repeated observations were calculated to estimate precision of the technique utilized. The main outcome measures were corneal endothelial cell density, cell size variability and cell hexagonality. Results: The mean corneal endothelial cell density was 2,720 cells/mm2, mean cell size variability was 37.8% and percent cell hexagonality 40%. We found statistical significant difference between the three ethnic populations in all the corneal endothelial cell measurements (p < 0.0001). Females had a 2.9% greater cell density than males (p = 0.0001). There was no significant difference in mean cell density according to age. Variability of cell size, however, increased with age (p < 0.001). These findings were consistent across the three ethnic groups. Conclusions: In a total sample of 1,235 eyes distributed evenly in three cataract patient populations of south Asia, we found statistically significant differences of corneal endothelial cell densities of cell size variability and cell hexagonality between sexes and ethnic groups

Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex

Introduction: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). Methods: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. Results: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free\u3epain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection\u27s FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction Conclusion: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions

Neuromodulation Techniques for Drug-Resistant Epilepsy: Effects on Seizures and Quality of Life

Introduction: Although there are over twenty antiseizure drugs currently available, around one third of patients with epilepsy do not benefit from these medications. Patients with drug-resistant epilepsy (DRE) experience higher rates of hospitalization, notable decline in cognitive and physical abilities, diminished quality of life, and sudden unexpected death. Neuromodulation techniques such as Vagus Nerve Stimulation (VNS), Responsive Neurostimulation (RNS), and Deep Brain Stimulation (DBS) are quickly emerging as alternative and adjunct therapies for epilepsy, offering patients and physicians a new avenue of treatment. Despite their promise, a notable gap exists in comprehensive, comparative data assessing the efficacy and suitability of these techniques across diverse patient demographics and epilepsy types. Here, we evaluated the efficacy of VNS, RNS, and DBS in reducing seizure frequency and the impact on quality of life of patients with drug resistant epilepsy. Methods: We developed a comprehensive search strategy to identify relevant studies in PubMed, Medline, and PubMed Central, utilizing Medical Subject Headings (MeSH) terms and keywords. The search yielded 123 potential studies for further review. We screened for relevance, participant age group, and English language. After comprehensive screening, 16 studies were deemed suitable for this study. A total of 438 patients diagnosed with DRE were included. They were assigned to DBS, VNS, and RNS. This research adhered to the PRISMA recommendations. Results: At 24 months, DBS showed a decrease in total seizure frequency of 49.16% (±SD 41.65), and a decrease of focal to bilateral tonic–clonic seizures (FBTCS) of 67.93% (±SD 33.33). In patients with focal seizures and mesial temporal sclerosis, DBS resulted in a median reduction of 75.5% in seizure frequency, with 77% reduction in focal-to-bilateral tonic–clonic seizures (p = 0.008). RNS had 58.1% reduction in seizure frequency, while VNS had 46.3%. Responder rates were higher for RNS (66.7%) compared to VNS (45.5%) at 1 year. Additionally, patients receiving VNS in combination with SV2A modulators or slow sodium channel inhibitors had higher response rate and seizure freedom. Conclusion: The emergence of neuromodalities as a treatment option for patients with drug-resistant epilepsy has provided hope for better prognosis and improved quality of life. Our findings revealed neuromodulation treatment reduced seizure frequency, while showing fewer executive dysfunction symptoms and improvements in sleep and cognition. Although neuromodalities have significantly reduced seizure frequency and increased responder rates, the magnitude of the effect varied considerably between treatment modalities with DBS showing larger effect sizes. Furthermore, several challenges hinder the widespread adoption of neuromodulation, such as variable patient responses and device-related complications, and the need for ongoing adjustments remain significant. Future research should thus focus on reducing the cost of implanting and maintenance of such modalities, making neuromodulation and accessible treatment modalities for the near future

Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Modulatory Network

Central sensitization is a driving mechanism in many chronic pain patients, and manifests as hyperalgesia and allodynia beyond any apparent injury. Recent studies have demonstrated analgesic effects of motor cortex (M1) stimulation in several chronic pain disorders, yet its neural mechanisms remain uncertain. We evaluated whether anodal M1 transcranial direct current stimulation (tDCS) would mitigate central sensitization as measured by indices of secondary hyperalgesia. We used a capsaicin-heat pain model to elicit secondary mechanical hyperalgesia in 27 healthy subjects. In an assessor and subject-blind randomized, sham-controlled, crossover trial, anodal M1 tDCS decreased the intensity of pinprick hyperalgesia more than cathodal or sham tDCS. To elucidate the mechanism driving analgesia, subjects underwent fMRI of painful mechanical stimuli prior to and following induction of the pain model, after receiving M1 tDCS. We hypothesized that anodal M1 tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical stimuli. Anodal tDCS normalized the effects of central sensitization on neurophysiological responses to mechanical pain in the medial prefrontal cortex, pregenual anterior cingulate cortex, and periaqueductal gray, important regions in the DPM network. Taken together, these results provide support for the hypothesis that anodal M1-tDCS reduces central sensitization-induced hyperalgesia through the DPM network in humans

Interlink between Genomics by GTEX Portal and Gut Microbiome in Autism Spectrum Disorder

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and highly restrictive sensory patterns which results from aberrant early-life central nervous system functioning. While ASD has been traditionally associated with molecular genetic alterations, emerging evidence underscores the role of environmental elements. In fact, pathologic genetic variations of key regulator genes coupled with environmental factors, such as: advanced maternal age, poor maternal health during pregnancy, gestational diabetes mellitus, and altered gut microbiome and/or secondary environmental challenges to the offspring in early childhood have all been attributed to increased risk of developing ASD. In efforts to understand the complex relationship of genetics and gut microbiome with ASD pathogenicity, the present study, we used GTEx Portal to understand the interlink between genes associated with ASD pathogenecity and the gut microbiome. Methods: GTex Portal, EMBAse databases were investigated in the present study. Using SfariGene,14 genes with the highest association of ASD manifestations were classified as high confidence genes and thoroughly examined for body expression, chromosomal location, mechanism of action, and symptom manifestation. Results: Based on the GTE Portal, genes such as SHANK3, NRXN1, SYNGAP1, DYRK1A, and CUL3 are most highly expressed elsewhere throughout the body. High confidence genes had the highest expression were observed in three brain regions. SHANK3 was expressed highly in the cerebellum. MECP2, PTEN, SCN2A, NRXN1, and DYRK1A were expressed highly in the cerebellar hemisphere. CHD8, POGZ, and ANK2 had equal expressions in the cerebellum and cerebral hemisphere while CNTNAP2, TBR1, and GRIN2B were most highly expressed in the frontal cortex. SYNGAP1 and CUL3 had a wide variety of low expressions in most regions of the brain. High-impact genes, primarily regulators of gene expression, brain development, and connectivity, are commonly associated with intellectual disabilities, particularly in ASD. The most common manifestation was intellectual/cognitive disability, seen in 10 of 14 genes. Gut microbiome showed increased levels of p-cresol (4-methylphenol) due to widespread gastrointestinal bacterial activity, antibiotic overuse, and longer intestinal transit time, resulting in improper hippocampal neuronal development and neuronal mitochondria toxicity. Conclusions: Based on our findings, the neurological mechanisms including- gene expression, brain development, and neural connectivity are the key pathways associated in the three key brain regions - cerebellum, cerebral hemisphere, and frontal cortex in ASD, However the wide variability in chromosomal deletions and manifestations underscores its complexity. GTex analysis suggests a foundation for developing potential novel tool to understand the interlink between gene expression in different brain regions and its implication in the gut microbial pathways in ASD

Is the 2015 eye care service delivery profile in Southeast Asia closer to universal eye health need!

Purpose: The year 2015 status of eye care service profile in Southeast Asia countries was compared with year 2010 data to determine the state of preparedness to achieve the World Health Organization global action plan 2019. Methods: Information was collected from the International Agency for Prevention of Blindness country chairs and from the recent PubMed referenced articles. The data included the following: blindness and low vision prevalence, national eye health policy, eye health expenses, presence of international non-governmental organizations, density of eye health personnel, and the cataract surgical rate and coverage. The last two key parameters were compared with year 2010 data. Results: Ten of 11 country chairs shared the information, and 28 PubMed referenced publications were assessed. The prevalence of blindness was lowest in Bhutan and highest in Timor-Leste. Cataract surgical rate was high in India and Sri Lanka. Cataract surgical coverage was high in Thailand and Sri Lanka. Despite increase in number of ophthalmologists in all countries (except Timor-Leste), the ratio of the population was adequate (1:100,000) only in 4 of 10 countries (Bhutan, India, Maldives and Thailand), but this did not benefit much due to unequal urban-rural divide. Conclusion: The midterm assessment suggests that all countries must design the current programs to effectively address both current and emerging causes of blindness. Capacity building and proportionate distribution of human resources for adequate rural reach along with poverty alleviation could be the keys to achieve the universal eye health by 2019. Keywords: Eye care delivery; Southeast Asia; Universal eye health

VPS29 Is Not an Active Metallo-Phosphatase but Is a Rigid Scaffold Required for Retromer Interaction with Accessory Proteins

VPS29 is a key component of the cargo-binding core complex of retromer, a protein assembly with diverse roles in transport of receptors within the endosomal system. VPS29 has a fold related to metal-binding phosphatases and mediates interactions between retromer and other regulatory proteins. In this study we examine the functional interactions of mammalian VPS29, using X-ray crystallography and NMR spectroscopy. We find that although VPS29 can coordinate metal ions Mn2+ and Zn2+ in both the putative active site and at other locations, the affinity for metals is low, and lack of activity in phosphatase assays using a putative peptide substrate support the conclusion that VPS29 is not a functional metalloenzyme. There is evidence that structural elements of VPS29 critical for binding the retromer subunit VPS35 may undergo both metal-dependent and independent conformational changes regulating complex formation, however studies using ITC and NMR residual dipolar coupling (RDC) measurements show that this is not the case. Finally, NMR chemical shift mapping indicates that VPS29 is able to associate with SNX1 via a conserved hydrophobic surface, but with a low affinity that suggests additional interactions will be required to stabilise the complex in vivo. Our conclusion is that VPS29 is a metal ion-independent, rigid scaffolding domain, which is essential but not sufficient for incorporation of retromer into functional endosomal transport assemblies