Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM)

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and control subjects underwent fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction. Methods: Activated midbrain nuclei were inferred by a re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI subjects showed greater activation during cognition than ME/CFS in the left pedunculotegmental nucleus. Post exercise, ME/CFS subjects showed greater activation than GWI ones for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI, indicating reciprocal patterns of activation. The controls had no changes. Conclusions: Exercise caused the opposite effects with increased activation in ME/CFS but decreased activation in GWI, indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

Wearing a KN95/FFP2 Facemask Has Subtle Effects on Functional Salience Network Interaction

BackgroundWide use of wearing a facemask is one of the many consequences of the COVID-19 pandemic. We used resting-state fMRI to search for subtle changes in brain functional connectivity, expected notably related to the high-level salience (SN) and default mode networks (DMN).Materials and MethodsProspective crossover design resting fMRI study with/without wearing a tight FFP2/KN95 facemask, including 24 consecutive male participants (mean age ± SD = 29.9 ± 6.9 years) at 3T. As physiological parameters, respiration frequency and heart rate were monitored. Data analysis was performed using the CONN toolbox.ResultsWearing an FFP2/KN95 facemask did not impact respiration or heart rate but resulted in a significant reduction in functional connectivity between the SN as the seed region and the left middle frontal and precentral gyrus. No difference was found when the DMN, sensorimotor, visual, dorsal attention or language networks were used as seed regions.ConclusionsThe wearing of tight FFP2/KN95 facemasks in men decreases the functional connectivity of the SN, which is known to be involved in communication, social behavior and self-awareness. This phenomenon was confined to the left frontal and precentral gyrus. Our results imply that the wearing of a facemask could impact our ability to detect and react appropriately to salient stimuli by altering the functional connectivity of the SN.

Novel Risk Associations between microRNA Polymorphisms and Gastric Cancer in a Chilean Population

Gastric cancer (GC) is the fifth leading cause of cancer deaths in the world, with variations across geographical regions and ethnicities. Emerging evidence indicates that miRNA expression is dysregulated in GC and its polymorphisms may contribute to these variations, which has yet to be explored in Latin American populations. In a case-control study of 310 GC patients and 311 healthy donors from Chile, we assessed the association of 279 polymorphisms in 242 miRNA genes. Two novel polymorphisms were found to be associated with GC: rs4822739:C>G (miR-548j) and rs701213:T>C (miR-4427). Additionally, rs1553867776:T>TCCCCA (miR-4274) and rs12416605:C>T (miR-938) were associated with intestinal-type GC, and rs4822739:C>G (miR-548j) and rs1439619:T>G (miR-3175) with TNM I-II stage. The polymorphisms rs6149511:T> TGAAGGGCTCCA (miR-6891), rs404337:G>A (miR-8084), and rs1439619:T>G (miR-3175) were identified among H.pylori-infected GC patients and rs7500280:T>C (miR-4719) and rs1439619:T>G (miR-3175) were found among H. pylori cagPAI+ infected GC cases. Prediction analysis suggests that seven polymorphisms could alter the secondary structure of the miRNA, and the other one is located in the seed region of miR-938. Targets of miRNAs are enriched in GC pathways, suggesting a possible biological effect. In this study, we identified seven novel associations and replicated one previously described in Caucasian population. These findings contribute to the understanding of miRNA genetic polymorphisms in the GC pathogenesis.

Bioinformatic Evaluation of the miRNAs Targeting ACE2 Gene in COVID-19

Introduction: Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which began in late 2019 in Wuhan, China, has become a global epidemic. Angiotensin 2 converting enzyme (ACE2) acts as a receptor for host function to cause acute coronavirus 2 acute respiratory syndrome (SARS-CoV-2). ACE2 is abundantly expressed in different cells of different human organs. In human physiology, ACE2 is a major player in the renin-angiotensin-aldosterone (RAAS) system by degrading angiotensin II. Many factors have been associated with altered ACE2 expression and the severity and progression of COVID-19, including microRNAs that may be effective in it. Identifying pathological changes due to SARS-CoV-2 infection is important because it has major implications for understanding the pathophysiology of COVID-19 and developing evidence-based treatment strategies. Currently, many intervention strategies are being explored in ongoing clinical trials. Objective: The aim of this study is to use bioinformatics databases to find potential antiviral therapies against SARS-CoV-2 through host microRNAs (miRNAs) that can reduce viral gene expression to inhibit virus entry and replication. Methods: Using different algorithms in TargetScan, DIANA, ENCORI and miRWalk databases, the potential microRNAs were identified that target ACE2. Then, a score table was prepared from the candidate microRNAs, based on the affinity of the seed region of microRNAs and the 3`-UTR region of the ACE2 gene. Finally, microRNAs with higher scores were chosen as candidates for practical analysis. Results: The results of Bioinformatical analysis showed that Has-miR-200c-3p, Has-miR-29a, Has-miR-29c, and Has-miR-942 are most likely to inhibit ACE2. These microRNAs are the most potent factors that might be affected on ACE2 during virulence. Conclusion: It seems that ACE2 is under the control of the miR-200c-3p and plays a crucial role in the pathophysiology process. Therefore, this microRNA can be considered as a suitable new candidate for experimental evaluation.

Functional Network Connectivity Imprint In Febrile Seizures

Complex febrile seizures (CFS), a subset of paediatric febrile seizures (FS), have been studied for their prognosis, epileptogenic potential and neurocognitive outcome. We evaluated their functional connectivity differences with simple febrile seizures (SFS) in children with recent-onset FS. Resting-state fMRI (rsfMRI) datasets of 24 children with recently diagnosed FS (SFS n=11; CFS n=13) were analysed. Functional connectivity (FC) was estimated using time series correlation of seed region to whole brain voxels and network topology was assessed using graph theory measures. Regional connectivity differences were correlated with clinical characteristics (FDR corrected p < 0.05). CFS patients demonstrated increased FC of the bilateral middle temporal pole (MTP), and bilateral thalami when compared to SFS. Network topology study revealed increased clustering coefficient and decreased participation coefficient in basal ganglia and thalamus suggesting an inefficient-unbalanced network topology in patients with CFS. The number of seizure recurrences negatively correlated with the integration of Left Thalamus ( r= -0.58 ) and FC measures of Left MTP to 'Right Supplementary Motor and left Precentral' connectivity (r=-0.53). The FC of Right MTP to Left Amygdala, Putamen, Parahippocampal, and Orbital Frontal Cortex ( r=0.61 ) and FC of Left Thalamus to left Putamen, Pallidum, Caudate, Thalamus Hippocampus and Insula (r 0.55) showed a positive correlation to the duration of the longest seizure. The findings of the current study report altered connectivity in children with CFS proportional to the seizure recurrence and duration. Regardless of the causal/consequential nature, such observations demonstrate the imprint of these disease-defining variables of febrile seizures on the developing brain.

Biological features between miRNAs and their targets are unveiled from deep learning models

MicroRNAs (miRNAs) are ~ 22 nucleotide ubiquitous gene regulators. They modulate a broad range of essential cellular processes linked to human health and diseases. Consequently, identifying miRNA targets and understanding how they function are critical for treating miRNA associated diseases. In our earlier work, a hybrid deep learning-based approach (miTAR) was developed for predicting miRNA targets. It performs substantially better than the existing methods. The approach integrates two major types of deep learning algorithms: convolutional neural networks (CNNs) and recurrent neural networks (RNNs). However, the features in miRNA:target interactions learned by miTAR have not been investigated. In the current study, we demonstrated that miTAR captures known features, including the involvement of seed region and the free energy, as well as multiple novel features, in the miRNA:target interactions. Interestingly, the CNN and RNN layers of the model perform differently at capturing the free energy feature: the units in RNN layer is more unique at capturing the feature but collectively the CNN layer is more efficient at capturing the feature. Although deep learning models are commonly thought “black-boxes”, our discoveries support that the biological features in miRNA:target can be unveiled from deep learning models, which will be beneficial to the understanding of the mechanisms in miRNA:target interactions.

Critical role of backbone coordination in the mRNA recognition by RNA induced silencing complex

Despite its functional importance, the molecular mechanism underlying target mRNA recognition by Argonaute (Ago) remains largely elusive. Based on extensive all-atom molecular dynamics simulations, we constructed quasi-Markov State Model (qMSM) to reveal the dynamics during recognition at position 6-7 in the seed region of human Argonaute 2 (hAgo2). Interestingly, we found that the slowest mode of motion therein is not the gRNA-target base-pairing, but the coordination of the target phosphate groups with a set of positively charged residues of hAgo2. Moreover, the ability of Helix-7 to approach the PIWI and MID domains was found to reduce the effective volume accessible to the target mRNA and therefore facilitate both the backbone coordination and base-pair formation. Further mutant simulations revealed that alanine mutation of the D358 residue on Helix-7 enhanced a trap state to slow down the loading of target mRNA. Similar trap state was also observed when wobble pairs were introduced in g6 and g7, indicating the role of Helix-7 in suppressing non-canonical base-paring. Our study pointed to a general mechanism for mRNA recognition by eukaryotic Agos and demonstrated the promise of qMSM in investigating complex conformational changes of biomolecular systems.

Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM)

Background: Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), Gulf War Ill-ness (GWI) and control subjects had fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction Methods: Activated midbrain nuclei were inferred by re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI had greater activation during cognition than ME/CFS in left pedunculotegmental nucleus. Postexercise ME/CFS had greater activation than GWI for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI indicating reciprocal patterns of activation. Controls had no changes. Conclusions: Exercise caused opposite effects with increased activation in ME/CFS but decreased activation in GWI indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.