Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients

Ambulation or walking is one of the main gaits of locomotion. In terrestrial animals, it may be defined as a series of rhythmic and bilaterally coordinated movement of the limbs which creates a forward movement of the body. This applies regardless of the number of limbs - from arthropods with six or more limbs to bipedal primates. These fundamental similarities among species may explain why comparable neural systems and cellular properties have been found, thus far, to control in similar ways locomotor rhythm generation in most animal models. The aim of this article is to provide a comprehensive review of the known structural and functional features associated with central nervous system (CNS) networks that are involved in the control of ambulation and other stereotyped motor patterns - specifically Central Pattern Generators (CPGs) that produce basic rhythmic patterned outputs for locomotion, micturition, ejaculation, and defecation. Although there is compelling evidence of their existence in humans, CPGs have been most studied in reduced models including in vitro isolated preparations, genetically-engineered mice and spinal cord-transected animals. Compared with other structures of the CNS, the spinal cord is generally considered as being well-preserved phylogenetically. As such, most animal models of SCI should be considered as valuable tools for the development of novel pharmacological strategies aimed at modulating spinal activity and restoring corresponding functions in chronic spinal cord-injured patients

Anxiolytics may promote locomotor function recovery in spinal cord injury patients

Recent findings in animal models of paraplegia suggest that specific nonbenzodiazepine anxiolytics may temporarily restore locomotor functions after spinal cord injury (SCI). Experiments using in vitro models have revealed, indeed, that selective serotonin receptor (5-HTR) ligands such as 5-HTR1A agonists, known as relatively safe anxiolytics, can acutely elicit episodes of rhythmic neuronal activity refered to as fictive locomotion in isolated spinal cord preparations. Along the same line, in vivo studies have recently shown that this subclass of anxiolytics can induce, shortly after systemic administration (eg, orally or subcutaneously), some locomotor-like hindlimb movements during 45–60 minutes in completely spinal cord-transected (Tx) rodents. Using ‘knock-out’ mice (eg, 5-HTR7-/-) and selective antagonists, it has been clearly established that both 5-HTR1A and 5-HTR7 were critically involved in mediating the pro-locomotor effects induced by 8-OH-DPAT (typically referred to as a 5-HTR1A agonist) in Tx animals. Taken together, these in vitro and in vivo data strongly support the idea that 5-HTR1A agonists may eventually become constitutive elements of a novel first-in-class combinatorial treatment aimed at periodically inducing short episodes of treadmill stepping in SCI patients

Is Propanediol a safer molecule than some other glycols in personal care and anti-aging biocosmeceutical products?

Propanediol (1,3-propanediol) is an ingredient increasingly used by the industry for electronic cigarettes, personal care creams and anti-aging serums among many other products. For some skin care purposes, it is used to enhance the transdermal absorption of other ingredients (e.g., the actives) enabling moisturizing effects and skin smoothness to be improved. Propanediol may be derived from corn although synthetic forms also exist. It is a chemical similar to other glycols such as propylene glycol (1,2-propanediol) but generally believed to be safer. This short communication reveals in fact that only limited scientific evidence of safety is available. Preliminary signs of toxicity have been found following administration of propanediol in humans although its dose-dependent toxicity and long-term side effects on health have not been significantly explored. Consequently, as of today, skin care and anti-aging products for elderly, a vulnerable population, should not automatically be considered as safe. Those comprising 1,3-propanediol should probably be used with caution until scientifically-proven safety data for the intended purposes are obtained by independent scientists

Are self-consciousness and mindfulness altered by aging?

It is well known that aging is the process of becoming older. It is also associated normally with a progressive loss of biological functions – both physical and mental –, underlied by naturally-occurring changes at the molecular level that may lead to the development of so-called aging-related health problems – e.g., Parkinson’s Disease, dementia, memory loss, cerebrovascular problems and Alzheimer’s Disease. Along this idea, a fundamental question remains – are self-consciousness and mindfulness also affected by these physiological or pathophysiological changes? This short article summarizes briefly some of the key sementic, conceptual, methodological and physiological issues that shall be addressed prior to tentatively providing answers to comparable questions

Multilevel Analysis of Locomotion in Immature Preparations Suggests Innovative Strategies to Reactivate Stepping after Spinal Cord Injury

Locomotion is one of the most complex motor behaviors. Locomotor patterns change during early life, reflecting development of numerous peripheral and hierarchically organized central structures. Among them, the spinal cord is of particular interest since it houses the central pattern generator (CPG) for locomotion. This main command center is capable of eliciting and coordinating complex series of rhythmic neural signals sent to motoneurons and to corresponding target-muscles for basic locomotor activity. For a long-time, the CPG has been considered a black box. In recent years, complementary insights from in vitro and in vivo animal models have contributed significantly to a better understanding of its constituents, properties and ways to recover locomotion after a spinal cord injury (SCI). This review discusses key findings made by comparing the results of in vitro isolated spinal cord preparations and spinal-transected in vivo models from neonatal animals. Pharmacological, electrical, and sensory stimulation approaches largely used to further understand CPG function may also soon become therapeutic tools for potent CPG reactivation and locomotor movement induction in persons with SCI or developmental neuromuscular disorder

Spinal Cord Injury Research in Mice: 2008 Review

Spinal cord injury (SCI) is an irreversible condition causing damage to myelinated fiber tracts that carry sensation and motor signals to and from the brain. SCI is also associated with gray matter damage and often life-threatening secondary complications. This mini-review aims to provide the nonspecialist reader with a comprehensive description of recent advances made in 2008 using murine models of SCI. A variety of approaches, including advanced genetics and molecular techniques, have allowed a number of key findings in the field of secondary degeneration, repair, regeneration (including insights from peripheral nerve lesion models), metabolic dysfunctions, and pharmacological neuromodulation

Genomewide Analysis of Inherited Variation Associated with Phosphorylation of PI3K/AKT/mTOR Signaling Proteins

While there exists a wealth of information about genetic influences on gene expression, less is known about how inherited variation influences the expression and post-translational modifications of proteins, especially those involved in intracellular signaling. The PI3K/AKT/mTOR signaling pathway contains several such proteins that have been implicated in a number of diseases, including a variety of cancers and some psychiatric disorders. To assess whether the activation of this pathway is influenced by genetic factors, we measured phosphorylated and total levels of three key proteins in the pathway (AKT1, p70S6K, 4E-BP1) by ELISA in 122 lymphoblastoid cell lines from 14 families. Interestingly, the phenotypes with the highest proportion of genetic influence were the ratios of phosphorylated to total protein for two of the pathway members: AKT1 and p70S6K. Genomewide linkage analysis suggested several loci of interest for these phenotypes, including a linkage peak for the AKT1 phenotype that contained the AKT1 gene on chromosome 14. Linkage peaks for the phosphorylated:total protein ratios of AKT1 and p70S6K also overlapped on chromosome 3. We selected and genotyped candidate genes from under the linkage peaks, and several statistically significant associations were found. One polymorphism in HSP90AA1 was associated with the ratio of phosphorylated to total AKT1, and polymorphisms in RAF1 and GRM7 were associated with the ratio of phosphorylated to total p70S6K. These findings, representing the first genomewide search for variants influencing human protein phosphorylation, provide useful information about the PI3K/AKT/mTOR pathway and serve as a valuable proof of concept for studies integrating human genomics and proteomics

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages