A single sequence of intermittent hypoxia does not alter stretch reflex excitability in able-bodied individuals.

Spasticity attributable to exaggerated stretch reflex pathways, particularly affecting the ankle plantar flexors, often impairs overground walking in persons with incomplete spinal cord injury. Compelling evidence from rodent models underscores how exposure to acute intermittent hypoxia (AIH) can provide a unique medium to induce spinal plasticity in key inhibitory pathways mediating stretch reflex excitability and potentially affect spasticity. In this study, we quantify the effects of a single exposure to AIH on the stretch reflex in able-bodied individuals.

A Research Protocol to Study the Priming Effects of Breathing Low Oxygen on Enhancing Training-Related Gains in Walking Function for Persons With Spinal Cord Injury: The BOST Trial.

Unlabelled: Brief episodes of low oxygen breathing (therapeutic acute intermittent hypoxia; tAIH) may serve as an effective plasticity-promoting primer to enhance the effects of transcutaneous spinal stimulation-enhanced walking therapy (WALK) in persons with chronic (>1 year) spinal cord injury (SCI). Pre-clinical studies in rodents with SCI show that tAIH and WALK therapies harness complementary mechanisms of plasticity to maximize walking recovery. Here, we present a multi-site clinical trial protocol designed to examine the influence of tAIH + WALK on walking recovery in persons with chronic SCI.

Transcutaneous spinal cord stimulation and its impact on cardiovascular autonomic regulation after spinal cord injury.

Individuals with spinal cord injury (SCI) have significant dysfunction in cardiovascular autonomic regulation. Although recent findings postulate that spinal cord stimulation improves autonomic regulation, limited scope of past methods have tested only above level sympathetic activation, leaving significant uncertainty. To identify whether transcutaneous spinal cord stimulation improves cardiovascular autonomic regulation, two pairs of well-matched individuals with and without high thoracic, complete SCI were recruited.

A pilot trial of Thymalfasin (Ta1) to prevent covid-19 infection and morbidities in renal dialysis patients: Preliminary report.

Purpose: Patients with end-stage renal disease (ESRD) on hemodialysis (HD) are considered particularly susceptible to infection with SARS-CoV2 on the basis of the immunodeficiency associated with advanced age, comorbidity burden, medication use, and need for frequent visits to dialysis clinics. In prior studies, thymalfasin (thymosin alpha 1, Ta1) has been shown to enhance antibody response to influenza vaccine and reduce influenza infection in geriatric populations, including hemodialysis patients, when used as an adjunct to influenza vaccine. Early in the COVID-19 pandemic we speculated that administration of Ta1 to HD patients would result in reduced rate and severity of COVID-19 infection.

A Wearable Mixed Reality Platform to Augment Overground Walking: A Feasibility Study.

Humans routinely modify their walking speed to adapt to functional goals and physical demands. However, damage to the central nervous system (CNS) often results in abnormal modulation of walking speed and increased risk of falls. There is considerable interest in treatment modalities that can provide safe and salient training opportunities, feedback about walking performance, and that may augment less reliable sensory feedback within the CNS after injury or disease.

Caffeine Enhances Intermittent Hypoxia-Induced Gains in Walking Function for People with Chronic Spinal Cord Injury.

Incomplete spinal cord injury (iSCI) often results in lifelong walking impairments that limit functional independence. Thus, treatments that trigger enduring improvement in walking after iSCI are in high demand. Breathing brief episodes of low oxygen (i.

Immune Modulation with Thymosin Alpha 1 Treatment.

Thymosin alpha 1 (Ta1) is a peptide originally isolated from thymic tissue as the compound responsible for restoring immune function to thymectomized mice. Ta1 has a pleiotropic mechanism of action, affecting multiple immune cell subsets that are involved in immune suppression. Ta1 acts through Toll-like receptors in both myeloid and plasmacytoid dendritic cells, leading to activation and stimulation of signaling pathways and initiation of production of immune-related cytokines.

Evaluation of thymosin α 1 in nonclinical models of the immune-suppressing indications melanoma and sepsis.

Objectives: Recent understanding of the complex pathophysiology of melanoma and severe sepsis suggests that immune-modulating compounds such as thymosin alpha 1 (INN: thymalfasin; abbreviated Ta1) could be useful in the treatment of these two unrelated immune-suppressing indications.

Research Design And Methods: Three nonclinical murine models were utilized, including: i) a lung metastasis B16 model; ii) a B16-based tumor growth model; and iii) a cecal-ligation and puncture (CLP) sepsis model.

Results: In the lung metastasis model, Ta1 treatment alone led to a 32% decrease in metastases (p < 0.

The regulation of limb stiffness in the context of locomotor tasks.

Locomotion on ramped surfaces requires modulation of both pattern generating circuits and limb stiffness. In order to meet the mechanical demands of locomotion under these conditions, muscular activation patterns must correspond to the appropriate functions, whether the muscles are serving as force generators or brakes. Limb stiffness is a critical mechanical property that determines how the body interacts with the environment, and is regulated by both intrinsic and neural mechanisms.

A PDMS-based integrated stretchable microelectrode array (isMEA) for neural and muscular surface interfacing.

Numerous applications in neuroscience research and neural prosthetics, such as electrocorticogram (ECoG) recording and retinal prosthesis, involve electrical interactions with soft excitable tissues using a surface recording and/or stimulation approach. These applications require an interface that is capable of setting up high-throughput communications between the electrical circuit and the excitable tissue and that can dynamically conform to the shape of the soft tissue. Being a compliant material with mechanical impedance close to that of soft tissues, polydimethylsiloxane (PDMS) offers excellent potential as a substrate material for such neural interfaces.

NMR structural studies of thymosin α1 and β-thymosins.

Thymosin proteins, originally isolated from fractionation of thymus tissue, represent a class of compounds that we now know are present in numerous other tissues, are unrelated to each other in a genetic sense, and appear to have different functions within the cell. Thymosin α1 (generic drug name thymalfasin; trade name Zadaxin) is derived from a precursor molecule, prothymosin, by proteolytic cleavage, and stimulates the immune system. Although the peptide is natively unstructured in aqueous solution, the helical structure has been observed in the presence of trifluoroethanol or unilamellar vesicles, and these studies are consistent with the presence of a dynamic helical structure whose sides are not completely hydrophilic or hydrophobic.

Thymosin α1 continues to show promise as an enhancer for vaccine response.

Thymosin α1 (Tα1) is an immune-modulating peptide that can be expected to improve response to vaccinations, as stimulated dendritic cells and T cells can act in concert to increase antibody production along with an improved cytotoxic response from the T cells themselves. Tα1 demonstrated efficacy in preclinical studies; subsequently, it was shown to enhance response to vaccinations in difficult-to-treat populations, including individuals immune suppressed due to age or hemodialysis, and leading to a decrease in later infections. During the 2009 pandemic outbreak of H1N1 influenza, mouse and ferret studies confirmed that the use of higher doses of Tα1 allowed for fewer injections than those used in the previous clinical studies.

NMR structure of human thymosin alpha-1.

800 MHz NMR structure of the 28-residue peptide thymosin alpha-1 in 40% TFE/60% water (v/v) has been determined. Restrained molecular dynamic simulations with an explicit solvent box containing 40% TFE/60% TIP3P water (v/v) were used, in order to get the 3D model of the NMR structure. We found that the peptide adopts a structured conformation having two stable regions: an alpha-helix region from residues 14 to 26 and two double β-turns in the N-terminal twelve residues which form a distorted helical structure.

Personalized medicine for mucositis: Bayesian networks identify unique gene clusters which predict the response to gamma-D-glutamyl-L-tryptophan (SCV-07) for the attenuation of chemoradiation-induced oral mucositis.

Gamma-D-glutamyl-L-tryptophan (SCV-07) demonstrated an overall efficacy signal in ameliorating oral mucositis (OM) in a clinical trial of head and neck cancer patients. However, not all SCV-07-treated subjects responded positively. Here we determined if specific gene clusters could discriminate between subjects who responded to SCV-07 and those who did not.

Thymosin alpha 1: past clinical experience and future promise.

Thymosin alpha 1, originally isolated as the compound responsible for reconstitution of immune function in thymectomized animal models, has enjoyed a wide-ranging clinical development program over the past decades, extending across multiple companies, indications, countries, and continents. This paper provides an overview of this complex picture. The extensive clinical studies began with small studies conducted with an impure mixture of peptides under the aegis of physician-sponsored INDs submitted to the US FDA, in subjects with primary immune deficiency such as DiGeorge syndrome.

Attenuation of radiation- and chemoradiation-induced mucositis using gamma-D-glutamyl-L-tryptophan (SCV-07).

Objective: To evaluate the efficacy of a novel immunomodulating peptide (SCV-07) in attenuating the course of radiation-induced mucositis in an established animal model of oral mucositis (OM).

Material And Methods: In three separate experiments, golden Syrian hamsters received either an acute radiation challenge to the buccal mucosa of eight fractionated doses of 7.5 Gy of radiation over a 2-week-period, or a combination of acute radiation and cisplatin.

Pelage insulation, litter size, and ambient temperature impact maternal energy intake and offspring development during lactation.

Energy balance during lactation critically influences survival and growth of a mother's offspring, and hence, her reproductive success. Most experiments have investigated the influence of a single factor (e.g.

An immunomodulating dipeptide, SCV-07, is a potential therapeutic for recurrent genital herpes simplex virus type 2 (HSV-2).

Herpes simplex virus type 2 (HSV-2) infections produce a recurrent disease state associated with susceptibility to other pathogens, including human immunodeficiency virus (HIV), and cannot be cured by current therapeutic treatments. The HSV-2 epidemic must therefore be addressed by therapeutic strategies that reduce recurrent lesions and ideally lack the possibility for development of drug resistance. To this end, the therapeutic potential of SCV-07 (gamma-D-glutamyl-L-tryptophan), a synthetic dipeptide with potent immunomodulatory and antimicrobial activity, was studied in the guinea pig model of recurrent genital HSV-2.

Maternal pinealectomy increases depressive-like responses in Siberian hamster offspring.

This study investigated the effect of maternal pinealectomy and postnatal pinealectomy on affective responses. Siberian hamsters were born to either pinealectomized or sham-operated dams and then underwent pinealectomy or a sham operation. Maternal pinealectomy increased depressive-like responses of offspring in the forced swim test.

Issues in pharmaceutical development of thymosin alpha1 from preclinical studies through marketing.

SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin alpha1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin alpha1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries.

Signaling pathways leading to the activation of IKK and MAPK by thymosin alpha1.

Thymosin alpha 1 (Talpha1) has therapeutic potential in the treatment of infectious diseases and cancer. However, the exact molecular pathways for Talpha1 action are not fully understood. We found that Talpha1 induces the production of interleukin-6 (IL-6), IL-10, and IL-12 in murine bone marrow-derived macrophages (BMDMs) through IKK and MAPK pathways.

Perinatal influences of melatonin on testicular development and photoperiodic memory in Siberian hamsters.

We assessed the influence of perinatal melatonin on reproductive development and adult responsiveness to melatonin. Testicular growth in an intermediate day length (14 : 10 h light/dark cycle) was substantially reduced in Siberian hamsters gestated by pinealectomised compared to pineal-intact females; gonadal development was normalised in offspring of pinealectomised dams that were pinealectomised at 3-4 days of age. Hamsters deprived of melatonin only during gestation, or both pre- and postnatally, underwent testicular involution during treatment with melatonin in adulthood.

Activation of IKK by thymosin alpha1 requires the TRAF6 signalling pathway.

Thymosin alpha1 (T(alpha)1) is noted for its immunomodulatory activities and therapeutic potential in treatment of infectious diseases and cancer. However, the molecular mechanism of its effectiveness is not completely understood. Here, we report that T(alpha)1 induces interleukin (IL)-6 expression through the I(kappa)B kinase (IKK) and nuclear factor-(kappa)B (NF-(kappa)B) pathway.

Short day lengths delay reproductive aging.

Caloric restriction and hormone treatment delay reproductive senescence in female mammals, but a natural model of decelerated reproductive aging does not presently exist. In addition to describing such a model, this study shows that an abiotic signal (photoperiod) can induce physiological changes that slow senescence. Relative to animals born in April, rodents born in September delay their first reproductive effort by up to 7 mo, at which age reduced fertility is expected.