Effects of Running on Sand vs. Stable Ground on Kinetics and Muscle Activities in Individuals With Over-Pronated Feet

Background: In terms of physiological and biomechanical characteristics, over-pronation of the feet has been associated with distinct muscle recruitment patterns and ground reaction forces during running.Objective: The aim of this study was to evaluate the effects of running on sand vs. stable ground on ground-reaction-forces (GRFs) and electromyographic (EMG) activity of lower limb muscles in individuals with over-pronated feet (OPF) compared with healthy controls.Methods: Thirty-three OPF individuals and 33 controls ran at preferred speed and in randomized-order over level-ground and sand. A force-plate was embedded in an 18-m runway to collect GRFs. Muscle activities were recorded using an EMG-system. Data were adjusted for surface-related differences in running speed.Results: Running on sand resulted in lower speed compared with stable ground running (p < 0.001; d = 0.83). Results demonstrated that running on sand produced higher tibialis anterior activity (p = 0.024; d = 0.28). Also, findings indicated larger loading rates (p = 0.004; d = 0.72) and greater vastus medialis (p < 0.001; d = 0.89) and rectus femoris (p = 0.001; d = 0.61) activities in OPF individuals. Controls but not OPF showed significantly lower gluteus-medius activity (p = 0.022; d = 0.63) when running on sand.Conclusion: Running on sand resulted in lower running speed and higher tibialis anterior activity during the loading phase. This may indicate alterations in neuromuscular demands in the distal part of the lower limbs when running on sand. In OPF individuals, higher loading rates together with greater quadriceps activity may constitute a proximal compensatory mechanism for distal surface instability.

Repurposing of the enhancer-promoter communication underlies the compensation of Mesp2 by Mesp1

Organisms are inherently equipped with buffering systems against genetic perturbations. Genetic compensation, the compensatory response by upregulating another gene or genes, is one such buffering mechanism. Recently, a well-conserved compensatory mechanism was proposed: transcriptional adaptation of homologs under the nonsense-mediated mRNA decay pathways. However, this model cannot explain the onset of all compensatory events. We report a novel genetic compensation mechanism operating over the Mesp gene locus. Mesp1 and Mesp2 are paralogs located adjacently in the genome. Mesp2 loss is partially rescued by Mesp1 upregulation in the presomitic mesoderm (PSM). Using a cultured PSM induction system, we reproduced the compensatory response in vitro and found that the Mesp2-enhancer is required to promote Mesp1. We revealed that the Mesp2-enhancer directly interacts with the Mesp1 promoter, thereby upregulating Mesp1 expression upon the loss of Mesp2. Of note, this interaction is established by genomic arrangement upon PSM development independently of Mesp2 disruption. We propose that the repurposing of this established enhancer-promoter communication is the mechanism underlying this compensatory response for the upregulation of the adjacent gene.

A New Framework to Interpret Individual Inter-Hemispheric Compensatory Communication after Stroke

Stroke constitutes the main cause of adult disability worldwide. Even after application of standard rehabilitation protocols, the majority of patients still show relevant motor impairment. Outcomes of standard rehabilitation protocols have led to mixed results, suggesting that relevant factors for brain re-organization after stroke have not been considered in explanatory models. Therefore, finding a comprehensive model to optimally define patient-dependent rehabilitation protocols represents a crucial topic in clinical neuroscience. In this context, we first report on the rehabilitation models conceived thus far in the attempt of predicting stroke rehabilitation outcomes. Then, we propose a new framework to interpret results in stroke literature in the light of the latest evidence regarding: (1) the role of the callosum in inter-hemispheric communication, (2) the role of prefrontal cortices in exerting a control function, and (3) diaschisis mechanisms. These new pieces of evidence on the role of callosum can help to understand which compensatory mechanism may take place following a stroke. Moreover, depending on the individual impairment, the prefrontal control network will play different roles according to the need of high-level motor control. We believe that our new model, which includes crucial overlooked factors, will enable clinicians to better define individualized motor rehabilitation protocols.

Decreased mitochondrial D-loop region methylation mediates an increase in mitochondrial DNA copy number in CADASIL

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a typical neurodegenerative disease associated with mitochondrial dysfunction. Methylation of the D-loop region and mitochondrial DNA copy number (mtDNAcn) play a critical role in the maintenance of mitochondrial function. However, the association between D-loop region methylation, mtDNAcn and CADASIL remains unclear. Methods Overall, 162 individuals were recruited, including 66 CADASIL patients and 96 age- and sex-matched controls. After extracting genomic DNA from the peripheral white blood cells, levels of D-loop methylation and mtDNAcn were assessed using MethylTarget sequencing and real-time PCR, respectively. Results We observed increased mtDNAcn and decreased D-loop methylation levels in CADASIL patients compared to the control group, regardless of gender stratification. Besides, we found a negative correlation between D-loop methylation levels and mtDNAcn. Mediation effect analysis shows that the proportion of the association between mtDNAcn and CADASIL that is mediated by D-loop methylation is 11.6% (95% CI 5.6, 22.6). After gender stratification, the proportions of such associations that are mediated by D-loop methylation in males and females were 7.2% (95% CI 2.4, 19.8) and 22.0% (95% CI 7.4, 50.1), respectively. Conclusion Decreased methylation of the D-loop region mediates increased mtDNAcn in CADASIL, which may be caused by a compensatory mechanism of mitochondrial dysfunction in patients with CADASIL.

Surgical and Functional Outcomes of Expansive Open-Door Laminoplasty for Patients With Mild Kyphotic Cervical Alignment

Objective: To evaluate the cervical dynamics, neurological function, pain, and quality of life in patients with mild cervical kyphotic alignment who underwent expansive unilateral open-door laminoplasty (ELAP).Methods: In this retrospective single-center study, we reviewed the surgical outcomes of 80 patients with cervical spondylotic myelopathy who were followed for at least 2 years. The patients were categorized into the preoperative kyphotic group (C2–7 angle < 0°) and nonkyphotic group (angle ≥ 0°). We compared clinical information, radiographic parameters, Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) scores, and cervical Japanese Orthopaedic Association (JOA) scores between the groups.Results: The kyphotic and nonkyphotic groups comprised 17 and 63 patients, respectively. The preoperative C2–7 angles were -3.7° in the kyphotic group and 15.4° in the nonkyphotic group (p < 0.01). In the kyphotic group, kyphotic alignment improved to lordosis at the final follow-up (2.6°, p = 0.01). The preoperative (16.4° vs. 24.1°, p < 0.01) and finalfollow-up (17.8° vs. 24.5°, p < 0.01) C7 slopes were significantly smaller in the kyphotic group. ELAP reduced pain in the arms or hands (p = 0.02) and improved the JOA scores (p < 0.01) in the kyphotic group. Patient-reported outcomes assessed using the JOACMEQ showed comparable effective rates in both groups.Conclusion: Patients with mild cervical kyphosis showed smaller C7 slopes as a compensatory mechanism. Kyphotic angles significantly improved to lordosis after ELAP, resulting in favorable clinical outcomes. ELAP is a useful surgical option for patients even if they present mild kyphotic cervical angles.

Sirtuins and Sepsis: Cross Talk between Redox and Epigenetic Pathways

Sepsis and septic shock are the leading causes of death among hospitalized patients in the US. The immune response in sepsis transitions from a pro-inflammatory and pro-oxidant hyper-inflammation to an anti-inflammatory and cytoprotective hypo-inflammatory phase. While 1/3rd sepsis-related deaths occur during hyper-, a vast majority of sepsis-mortality occurs during the hypo-inflammation. Hyper-inflammation is cytotoxic for the immune cells and cannot be sustained. As a compensatory mechanism, the immune cells transition from cytotoxic hyper-inflammation to a cytoprotective hypo-inflammation with anti-inflammatory/immunosuppressive phase. However, the hypo-inflammation is associated with an inability to clear invading pathogens, leaving the host susceptible to secondary infections. Thus, the maladaptive immune response leads to a marked departure from homeostasis during sepsis-phases. The transition from hyper- to hypo-inflammation occurs via epigenetic programming. Sirtuins, a highly conserved family of histone deacetylators and guardians of homeostasis, are integral to the epigenetic programming in sepsis. Through their anti-inflammatory and anti-oxidant properties, the sirtuins modulate the immune response in sepsis. We review the role of sirtuins in orchestrating the interplay between the oxidative stress and epigenetic programming during sepsis.

Decreased miR-497-5p Suppresses IL-6 Induced Atrophy in Muscle Cells

Interleukin-6 (IL-6) is a pro-inflammatory cytokine associated with skeletal muscle wasting in cancer cachexia. The control of gene expression by microRNAs (miRNAs) in muscle wasting involves the regulation of thousands of target transcripts. However, the miRNA-target networks associated with IL6-induced muscle atrophy remain to be characterized. Here, we show that IL-6 promotes the atrophy of C2C12 myotubes and changes the expression of 20 miRNAs (5 up-regulated and 15 down-regulated). Gene Ontology analysis of predicted miRNAs targets revealed post-transcriptional regulation of genes involved in cell differentiation, apoptosis, migration, and catabolic processes. Next, we performed a meta-analysis of miRNA-published data that identified miR-497-5p, a down-regulated miRNAs induced by IL-6, also down-regulated in other muscle-wasting conditions. We used miR-497-5p mimics and inhibitors to explore the function of miR-497-5p in C2C12 myoblasts and myotubes. We found that miR-497-5p can regulate the expression of the cell cycle genes CcnD2 and CcnE1 without affecting the rate of myoblast cellular proliferation. Notably, miR-497-5p mimics induced myotube atrophy and reduced Insr expression. Treatment with miR-497-5p inhibitors did not change the diameter of the myotubes but increased the expression of its target genes Insr and Igf1r. These genes are known to regulate skeletal muscle regeneration and hypertrophy via insulin-like growth factor pathway and were up-regulated in cachectic muscle samples. Our miRNA-regulated network analysis revealed a potential role for miR-497-5p during IL6-induced muscle cell atrophy and suggests that miR-497-5p is likely involved in a compensatory mechanism of muscle atrophy in response to IL-6.

Acute impact of an endurance race on biventricular and biatrial myocardial strain in competitive male and female triathletes evaluated by feature-tracking CMR

Objectives Cardiac adaptation in endurance athletes is a well-known phenomenon, but the acute impact of strenuous exercise is rarely reported on. The aim of this study was to analyze the alterations in biventricular and biatrial function in triathletes after an endurance race using novel feature-tracking cardiac magnetic resonance (FT-CMR). Methods Fifty consecutive triathletes (45 ± 10 years; 80% men) and twenty-eight controls were prospectively recruited, and underwent 1.5-T CMR. Biventricular and biatrial volumes, left ventricular ejection fraction (LVEF), FT-CMR analysis, and late gadolinium imaging (LGE) were performed. Global systolic longitudinal (GLS), circumferential (GCS), and radial strain (GRS) were assessed. CMR was performed at baseline and following an endurance race. High-sensitive troponin T and NT-proBNP were determined. The time interval between race completion and CMR was 2.3 ± 1.1 h (range 1–5 h). Results Post-race troponin T (p < 0.0001) and NT-proBNP (p < 0.0001) were elevated. LVEF remained constant (62 ± 6 vs. 63 ± 7%, p = 0.607). Post-race LV GLS decreased by tendency (− 18 ± 2 vs. − 17 ± 2%, p = 0.054), whereas GCS (− 16 ± 4 vs. − 18 ± 4%, p < 0.05) and GRS increased (39 ± 11 vs. 44 ± 11%, p < 0.01). Post-race right ventricular GLS (− 19 ± 3 vs. − 19 ± 3%, p = 0.668) remained constant and GCS increased (− 7 ± 2 vs. − 8 ± 3%, p < 0.001). Post-race left atrial GLS (30 ± 8 vs. 24 ± 6%, p < 0.0001) decreased while right atrial GLS remained constant (25 ± 6 vs. 24 ± 6%, p = 0.519). Conclusions The different alterations of post-race biventricular and biatrial strain might constitute an intrinsic compensatory mechanism following an acute bout of endurance exercise. The combined use of strain parameters may allow a better characterization of ventricular and atrial function in endurance athletes. Key Points • Triathletes demonstrate a decrease of LV global longitudinal strain by tendency and constant RV global longitudinal strain following an endurance race. • Post-race LV and RV global circumferential and radial strains increase, possibly indicating a compensatory mechanism after an acute endurance exercise bout. • Subgroup analyses of male triathletes with focal myocardial fibrosis did not demonstrate alterations in biventricular and biatrial strain after an endurance race.

Regulation of protein complex partners as a compensatory mechanism in aneuploid tumors

Aneuploidy, a state of chromosome imbalance, is a hallmark of human tumors, but its role in cancer still remains to be fully elucidated. To understand the consequences of whole chromosome-level aneuploidies on the proteome, we integrated aneuploidy, transcriptomic and proteomic data from hundreds of TCGA/CPTAC tumor samples. We found a surprisingly large number of expression changes happened on other, non-aneuploid chromosomes. Moreover, we identified an association between those changes and co-complex members of proteins from aneuploid chromosomes. This co-abundance association is tightly regulated for aggregation-prone aneuploid proteins and those involved in a smaller number of complexes. On the other hand, we observe that complexes of the cellular core machinery are under functional selection to maintain their stoichiometric balance in aneuploid tumors. Ultimately, we provide evidence that those compensatory and functional maintenance mechanisms are established through post-transcriptional control and that the degree of success of a tumor to deal with aneuploidy-induced stoichiometric imbalance impacts the activation of cellular protein degradation programs and patient survival.

A Novel and Atypical Nf-Kb Proinflammatory Program Regulated by A Camkii-Proteasome Axis Is Involved in the Early Activation of Muller Glia by High Glucose

BackgroundDiabetic retinopathy (DR) is a microvascular complication of diabetes with a heavy impact on the life-quality of subjects and with a dramatic burden for health and economic systems on a global scale.Although the pathogenesis of DR is largely unknown, several preclinical data have pointed out to a main role of Muller glia, a cell type which spans across the retina layers providing nourishment and support for Retina Ganglion Cells (RGCs), in sensing glycemia and in acquiring a proinflammatory polarization in response to this insult.ResultsBy using a validated experimental model of DR in vitro, the rMC1 cells challenged with high glucose, we uncovered the induction of an early (within minutes) and atypical NF-kB signalling pathway regulated by a CamKII-proteasome axis. Phosphorylation of proteasome subunit Rpt6 (at serine 120) by CamKII stimulated the accelerated turnover of IkBα (i.e., the natural inhibitor of p65-50 transcription factor), regardless of the phosphorylation at serine 32 which labels canonical NF-kB signalling. This event allowed the p65-p50 heterodimer to migrate into the nucleus and to induce the selective transcription of IL-8, Il-1β and MCP-1. Pharmacological inhibition of CamKII or proteasome stopped this proinflammatory program, whereas introduction of a Rpt6 phospho-dead mutant (Rpt6-S120A) stimulated a paradoxical effect on NF-kB probably through the activation of a compensatory mechanism which may involve phosphorylation of 20S α4 subunit.ConclusionsThis study introduces a novel pathway of MG activation by high glucose and casts some light on the biological relevance of proteasome post-translational modifications in modulating pathways regulated through targeted proteolysis.