Neuroprotective Effects of a Small Mitochondrially-Targeted Tetrapeptide Elamipretide in Neurodegeneration

Neural mitochondrial dysfunction, neural oxidative stress, chronic neuroinflammation, toxic protein accumulation, and neural apoptosis are common causes of neurodegeneration. Elamipretide, a small mitochondrially-targeted tetrapeptide, exhibits therapeutic effects and safety in several mitochondria-related diseases. In neurodegeneration, extensive studies have shown that elamipretide enhanced mitochondrial respiration, activated neural mitochondrial biogenesis via mitochondrial biogenesis regulators (PCG-1α and TFAM) and the translocate factors (TOM-20), enhanced mitochondrial fusion (MNF-1, MNF-2, and OPA1), inhibited mitochondrial fission (Fis-1 and Drp-1), as well as increased mitophagy (autophagy of mitochondria). In addition, elamipretide has been shown to attenuate neural oxidative stress (hydrogen peroxide, lipid peroxidation, and ROS), neuroinflammation (TNF, IL-6, COX-2, iNOS, NLRP3, cleaved caspase-1, IL-1β, and IL-18), and toxic protein accumulation (Aβ). Consequently, elamipretide could prevent neural apoptosis (cytochrome c, Bax, caspase 9, and caspase 3) and enhance neural pro-survival (Bcl2, BDNF, and TrkB) in neurodegeneration. These findings suggest that elamipretide may prevent the progressive development of neurodegenerative diseases via enhancing mitochondrial respiration, mitochondrial biogenesis, mitochondrial fusion, and neural pro-survival pathway, as well as inhibiting mitochondrial fission, oxidative stress, neuroinflammation, toxic protein accumulation, and neural apoptosis. Elamipretide or mitochondrially-targeted peptide might be a targeted agent to attenuate neurodegenerative progression.

Association of ADHD and Obesity in Hispanic Children on the US-Mexico Border: A Retrospective Analysis

Pediatric obesity and Attention Deficit Hyperactivity Disorder (ADHD) are rising health concerns in the United States, especially among Hispanic children and adolescents. Research on Hispanic children and adolescents indicates disproportionately higher prevalence rates of obesity in this community but scant data on ADHD prevalence rates. In contrast, a plethora of research studies across the general population examines the relationship between childhood obesity and ADHD. In addition, there is a lack of research that examines the role of ethnicity and sub-ethnic group correlations in ADHD, particularly in the Hispanic population. Existing studies in the general population indicate ADHD may be a risk factor for being overweight compared to normal controls. The objective of the present study is to examine the prevalence of obesity in children with ADHD compared to children in the general population in a predominately Hispanic sample on the US-Mexico border. A total of 7,270 pediatric medical records were evaluated. The retrospective analysis included Body Mass Index (BMI) and related health variables, and ethnicity and showed that children with ADHD are more likely to be underweight. In conclusion, no significant relationship existed between obesity and ADHD among Hispanic children on the US-Mexico Border, and instead we found the opposite correlation.

Integrated Analysis to Obtain Potential Prognostic Signature in Glioblastoma

Glioblastoma multiforme (GBM) is the most malignant and multiple tumors of the central nervous system. The survival rate for GBM patients is less than 15 months. We aimed to uncover the potential mechanism of GBM in tumor microenvironment and provide several candidate biomarkers for GBM prognosis. In this study, ESTIMATE analysis was used to divide the GBM patients into high and low immune or stromal score groups. Microenvironment associated genes were filtered through differential analysis. Weighted gene co-expression network analysis (WGCNA) was performed to correlate the genes and clinical traits. The candidate genes’ functions were annotated by enrichment analyses. The potential prognostic biomarkers were assessed by survival analysis. We obtained 81 immune associated differentially expressed genes (DEGs) for subsequent WGCNA analysis. Ten out of these DEGs were significantly associated with targeted molecular therapy of GBM patients. Three genes (S100A4, FCGR2B, and BIRC3) out of these genes were associated with overall survival and the independent test set testified the result. Here, we obtained three crucial genes that had good prognostic efficacy of GBM and may help to improve the prognostic prediction of GBM.

Contributions of Body-Orientation to Mental Ball Dropping Task During Out-of-Body Experiences

Out-of-body experiences (OBEs) provide fascinating insights into our understanding of bodily self-consciousness and the workings of the brain. Studies that examined individuals with brain lesions reported that OBEs are generally characterized by participants experiencing themselves outside their physical body (i.e., disembodied feeling) (Blanke and Arzy, 2005). Based on such a characterization, it has been shown that it is possible to create virtual OBEs in immersive virtual environments (Ehrsson, 2007; Ionta et al., 2011b; Bourdin et al., 2017). However, the extent to which body-orientation influences virtual OBEs is not well-understood. Thus, in the present study, 30 participants (within group design) experienced a full-body ownership illusion (synchronous visuo-tactile stimulation only) induced with a gender-matched full-body virtual avatar seen from the first-person perspective (1PP). At the beginning of the experiment, participants performed a mental ball dropping (MBD) task, seen from the location of their virtual avatar, to provide a baseline measurement. After this, a full-body ownership illusion (embodiment phase) was induced in all participants. This was followed by the virtual OBE illusion phase of the experiment (disembodiment phase) in which the first-person viewpoint was switched to a third-person perspective (3PP), and participants' disembodied viewpoint was gradually raised to 14 m above the virtual avatar, from which altitude they repeated the MBD task. During the experiment, this procedure was conducted twice, and the participants were allocated first to the supine or the standing body position at random. Results of the MBD task showed that the participants experienced increased MBD durations during the supine condition compared to the standing condition. Furthermore, although the findings from the subjective reports confirmed the previous findings of virtual OBEs, no significant difference between the two postures was found for body ownership. Taken together, the findings of the current study make further contributions to our understanding of both the vestibular system and time perception during OBEs.

Evidence for Three Subgroups of Female FMR1 Premutation Carriers Defined by Distinct Neuropsychiatric Features: A Pilot Study

Over 200 Cytosine-guanine-guanine (CGG) trinucleotide repeats in the 5′ untranslated region of the Fragile X mental retardation 1 (FMR1) gene results in a “full mutation,” clinically Fragile X Syndrome (FXS), whereas 55 – 200 repeats result in a “premutation.” FMR1 premutation carriers (PMC) are at an increased risk for a range of psychiatric, neurocognitive, and physical conditions. Few studies have examined the variable expression of neuropsychiatric features in female PMCs, and whether heterogeneous presentation among female PMCs may reflect differential presentation of features in unique subgroups. In the current pilot study, we examined 41 female PMCs (ages 17–78 years) and 15 age-, sex-, and IQ-matched typically developing controls (TDC) across a battery of self-report, eye tracking, expressive language, neurocognitive, and resting state EEG measures to determine the feasibility of identifying discrete clusters. Secondly, we sought to identify the key features that distinguished these clusters of female PMCs. We found a three cluster solution using k-means clustering. Cluster 1 represented a psychiatric feature group (27% of our sample); cluster 2 represented a group with executive dysfunction and elevated high frequency neural oscillatory activity (32%); and cluster 3 represented a relatively unaffected group (41%). Our findings indicate the feasibility of using a data-driven approach to identify naturally occurring clusters in female PMCs using a multi-method assessment battery. CGG repeat count and its association with neuropsychiatric features differ across clusters. Together, our findings provide important insight into potential diverging pathophysiological mechanisms and risk factors for each female PMC cluster, which may ultimately help provide novel and individualized targets for treatment options.

Autonomic Dysfunction in Autism Spectrum Disorder

Background: There have been previous reports of enhanced sympathoexcitation in autism spectrum disorder (ASD). However, there has been no formal investigation of autonomic dysfunction in ASD. Also, the joint hypermobile form of Ehlers-Danlos syndrome (hE-DS) that maybe overrepresented in ASD and orthostatic related autonomic dysfunction. This study examined the comorbidity of ASD, autonomic dysfunction and hE-DS in two UK autonomic national referral centers. Proven, documented and globally accepted clinical autonomic investigations were used to assess neuro-cardiovascular autonomic function in a cohort of ASD subjects and in age-matched healthy controls.Methods: Clinical data from 28 referrals with a confirmed diagnosis of ASD over a 10-year period were compared with 19 age-matched healthy controls. Autonomic function was determined using methods established in the centers previously described in detail.Results: 20/28 ASD had a diagnosed autonomic condition; 9 had the postural tachycardia syndrome (PoTS), 4 PoTS and vasovagal syncope (VVS), 3 experienced presyncope, 1 essential hyperhidrosis, 1 orthostatic hypotension, 1 VVS alone and 1 a combination of PoTS, VVS and essential hyperhidrosis. 16/20 ASD with autonomic dysfunction had hE-DS. In ASD, basal heart rate and responses to orthostatic tests of autonomic function were elevated, supporting previous findings of increased sympathoexcitation. However, sympathetic vasoconstriction was impaired in ASD.Conclusion: Intermittent neuro-cardiovascular autonomic dysfunction affecting heart rate and blood pressure was over-represented in ASD. There is a strong association with hE-DS. Autonomic dysfunction may further impair quality of life in ASD, particularly in those unable to adequately express their experience of autonomic symptoms.

Analysis of Career-Advancement for Medical School Graduates During the COVID-19 Pandemic at a Chinese Teaching Hospital

The COVID-19 pandemic has led to widespread social and economic disruptions in the balance of labor market. Our study aims to analyze the career-advancement of medical school graduates during the COVID-19 pandemic and the associated influencing factors. We collected and compared the career-advancement data of medical school graduates at a Chinese teaching hospital from 2016 to 2020. A self-designed 20-element medical graduates employment questionnaire and a Chinese adaptation of the General self-efficacy scale were distributed by the Questionnaire Star platform. Univariate analysis (Pearson's Chi-square-test and Fisher's exact-test) and subsequent binary logistic regression were used. Findings demonstrated that the career-advancement rate of medical graduate students in 2020 is 71.3%, which is significantly lower than that for the preceding 4 years from 2016 to 2019 (p < 0.001). Of the 251 employed medical school graduates, 159 (63.3%) have signed an employment agreement or contract, 83 (33.1%) are pursuing continued education domestically, and 9 (3.6%) have offers from foreign institutions. Univariate analysis revealed statistical differences of medical graduates' employment among various specialties, oral defense completion, job search start date, CV submission times, participation in a probationary period, and self-efficacy. Significant predictors for successful employment were early job search and self-efficacy by logistic regression model (χ2 = 12.719, p < 0.001). Most medical graduates assumed that the COVID-19 pandemic had a major (40.6%) or moderate (48%) impact on career-advancement. The COVID-19 pandemic has profoundly impacted the career-advancement of medical school graduates in 2020. We should make adaptive changes to improve the career-advancement of medical graduates.

Silencing of Activity During Hypoxia Improves Functional Outcomes in Motor Neuron Networks in vitro

The effects of hypoxia, or reduced oxygen supply, to brain tissue can be disastrous, leading to extensive loss of function. Deoxygenated tissue becomes unable to maintain healthy metabolism, which leads to increased production of reactive oxygen species (ROS) and loss of calcium homoeostasis, with damaging downstream effects. Neurons are a highly energy demanding cell type, and as such they are highly sensitive to reductions in oxygenation and some types of neurons such as motor neurons are even more susceptible to hypoxic damage. In addition to the immediate deleterious effects hypoxia can have on neurons, there can be delayed effects which lead to increased risk of developing neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), even if no immediate consequences are apparent. Furthermore, impairment of the function of various hypoxia-responsive factors has been shown to increase the risk of developing several neurodegenerative disorders. Longitudinal assessment of electrophysiological network activity is underutilised in assessing the effects of hypoxia on neurons and how their activity and communication change over time following a hypoxic challenge. This study utilised multielectrode arrays and motor neuron networks to study the response to hypoxia and the subsequent development of the neuronal activity over time, as well as the effect of silencing network activity during the hypoxic challenge. We found that motor neuron networks exposed to hypoxic challenge exhibited a delayed fluctuation in multiple network activity parameters compared to normoxic networks. Silencing of activity during the hypoxic challenge leads to maintained bursting activity, suggesting that functional outcomes are better maintained in these networks and that there are activity-dependent mechanisms involved in the network damage following hypoxia.

Impact of Canal-Otolith Integration on Postural Control

Roll tilt vestibular perceptual thresholds, an assay of vestibular noise, have recently been shown to be associated with suboptimal balance performance in healthy older adults. However, despite the strength of this correlation, the use of a categorical (i.e., pass/fail) balance assessment limits insight into the impacts of vestibular noise on postural sway. As a result, an explanation for this correlation has yet to be determined. We hypothesized that the correlation between roll tilt vestibular thresholds and postural control reflects a shared influence of sensory noise. To address this hypothesis, we measured roll tilt perceptual thresholds at multiple frequencies (0.2 Hz, 0.5 Hz, 1 Hz) and compared each threshold to quantitative measures of quiet stance postural control in 33 healthy young adults (mean = 24.9 years, SD = 3.67). Our data showed a significant linear association between 0.5 Hz roll tilt thresholds and the root mean square distance (RMSD) of the center of pressure in the mediolateral (ML; β = 5.31, p = 0.002, 95% CI = 2.1–8.5) but not anteroposterior (AP; β = 5.13, p = 0.016, 95% CI = 1.03–9.23) direction (Bonferroni corrected α of 0.006). In contrast, vestibular thresholds measured at 0.2 Hz and 1 Hz did not show a significant correlation with ML or AP RMSD. In a multivariable regression model, controlling for both 0.2 Hz and 1 Hz thresholds, the significant effect of 0.5 Hz roll tilt thresholds persisted (β = 5.44, p = 0.029, CI = 0.60–10.28), suggesting that the effect cannot be explained by elements shared by vestibular thresholds measured at the three frequencies. These data suggest that vestibular noise is significantly associated with the temporospatial control of quiet stance in the mediolateral plane when visual and proprioceptive cues are degraded (i.e., eyes closed, standing on foam). Furthermore, the selective association of quiet-stance sway with 0.5 Hz roll tilt thresholds, but not thresholds measured at lower (0.2 Hz) or higher (1.0 Hz) frequencies, may reflect the influence of noise that results from the temporal integration of noisy canal and otolith cues.