Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform.

With current plans for manned missions to Mars and beyond, the need to better understand, prevent, and counteract the harmful effects of long-duration spaceflight on the body is becoming increasingly important. In this study, an automated heart-on-a-chip platform was flown to the International Space Station on a 1-mo mission during which contractile cardiac function was monitored in real-time. Upon return to Earth, engineered human heart tissues (EHTs) were further analyzed with ultrastructural imaging and RNA sequencing to investigate the impact of prolonged microgravity on cardiomyocyte function and health. Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage. Transcriptomic analyses showed an up-regulation of genes and pathways associated with metabolic disorders, heart failure, oxidative stress, and inflammation, while genes related to contractility and calcium signaling showed significant down-regulation. Finally, in silico modeling revealed a potential link between oxidative stress and mitochondrial dysfunction that corresponded with RNA sequencing results. This represents an in vitro model to faithfully reproduce the adverse effects of spaceflight on three-dimensional (3D)-engineered heart tissue.

Factors mediating spaceflight-induced skeletal muscle atrophy.

Skeletal muscle atrophy is a well-known consequence of spaceflight. Because of the potential significant impact of muscle atrophy and muscle dysfunction on astronauts and their mission, a thorough understanding of the mechanisms of this atrophy and the development of effective countermeasures is critical. Spaceflight-induced muscle atrophy is similar to atrophy seen in many terrestrial conditions, and therefore our understanding of this form of atrophy may also contribute to the treatment of atrophy in humans on Earth. The unique environmental features humans encounter in space include the weightlessness of microgravity, space radiation, and the distinctive aspects of living in a spacecraft. The disuse and unloading of muscles in microgravity are likely the most significant factors that mediate spaceflight-induced muscle atrophy and have been extensively studied and reviewed. However, there are numerous other direct and indirect effects on skeletal muscle that may be contributing factors to the muscle atrophy and dysfunction seen as a result of spaceflight. This review offers a novel perspective on the issue of muscle atrophy in space by providing a comprehensive overview of the unique aspects of the spaceflight environment and the various ways in which they can lead to muscle atrophy. We systematically review the potential contributions of these different mechanisms of spaceflight-induced atrophy and include findings from both actual spaceflight and ground-based models of spaceflight in humans, animals, and in vitro studies.

How businesses are working together to deliver NASA/JPL-designed ventilators to the world in the fight against COVID-19.

In response to the COVID-19 pandemic, NASA Jet Propulsion Laboratory (JPL) engineers had embarked on an ambitious project to design a reliable, easy-to-use, and low-cost ventilator that was made of readily available parts to address the unexpected global shortage of these lifesaving devices. After successfully designing and building the VITAL (Ventilator Intervention Technology Accessible Locally) ventilator in record time, FDA Emergency Use Authorization (EUA) was obtained and then the license to manufacture and sell these ventilators was made available to select companies through a competitive process. STARK Industries, LLC (STARK), located in Columbus, OH, USA, was one of only eight U.S. companies to be selected to receive this worldwide license. Motivated by its mission to improve human health and well-being through innovated medical technologies, STARK accepted the challenge of further developing the VITAL technology and manufacturing the ventilators in large quantities and making them available to those in need around the world. To this end, Spiritus Medical, Inc (Spiritus) was spun off from STARK to focus on the ventilator business. Through collaborative efforts with various corporate, academic, governmental, and non-profit partners, Spiritus was able to successfully begin manufacturing and selling its ventilators. Due to its low-cost nature and its straightforward design, this ventilator is ideal for use in developing countries where ventilators are in short supply and affordability is a major consideration. This is a story of how NASA's ingenuity, based on space-based know-how and experience, was used to rapidly design this innovative ventilator. And by forging partnerships with highly qualified and motivated partners such as STARK and Spiritus, NASA has succeeded in translating this work into technology that could potentially save thousands of lives in the fight against the COVID-19 pandemic.

Factors Associated with Mutations: Their Matching Rates to Cardiovascular and Neurological Diseases.

Monogenic hypertension is rare and caused by genetic mutations, but whether factors associated with mutations are disease-specific remains uncertain. Given two factors associated with high mutation rates, we tested how many previously known genes match with (i) proximity to telomeres or (ii) high adenine and thymine content in cardiovascular diseases (CVDs) related to vascular stiffening. We extracted genomic information using a genome data viewer. In human chromosomes, 64 of 79 genetic loci involving >25 rare mutations and single nucleotide polymorphisms satisfied (i) or (ii), resulting in an 81% matching rate. However, this high matching rate was no longer observed as we checked the two factors in genes associated with essential hypertension (EH), thoracic aortic aneurysm (TAA), and congenital heart disease (CHD), resulting in matching rates of 53%, 70%, and 75%, respectively. A matching of telomere proximity or high adenine and thymine content projects the list of loci involving rare mutations of monogenic hypertension better than those of other CVDs, likely due to adoption of rigorous criteria for true-positive signals. Our data suggest that the factor-disease matching rate is an accurate tool that can explain deleterious mutations of monogenic hypertension at a >80% match-unlike the relatively lower matching rates found in human genes of EH, TAA, CHD, and familial Parkinson's disease.

Penguin megrivirus, a novel picornavirus from an Adélie penguin (Pygoscelis adeliae).

The complete genome sequence of a novel megrivirus of the family Picornaviridae was determined from nucleic acid extracted from a pool of six faecal specimens of Adélie penguins. The samples were collected near Bellingshausen Station, King George Island of the South Shetland Islands, Antarctica. Penguin megrivirus is the first megrivirus with a predicted L protein. It has an L-3-5-4 genome layout, a type IV IRES, and a long 3' untranslated region of 668 nt.

Increased resource use in lung transplant admissions in the lung allocation score era.

RATIONALE: In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize 1-year survival. It resulted in transplantation of older and sicker patients without changing 1-year survival. Its effect on resource use is unknown. OBJECTIVES: To determine changes in resource use over time in lung transplant admissions. METHODS: Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges among lung transplant and other solid-organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource use, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, which was not seen in other solid-organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort ($569,942 [$53,229] vs. $407,489 [$28,360]) along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant use of extracorporeal membrane oxygenation (odds ratio, 2.35; 95% confidence interval, 1.56-3.55) and higher incidence of tracheostomy (odds ratio, 1.52; 95% confidence interval, 1.22-1.89). CONCLUSIONS: LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant.

Association of Nurse-to-Patient Ratio with mortality and preventable complications following aortic valve replacement.

OBJECTIVE: To examine hospital resources associated with patient outcomes for aortic valve replacement (AVR), including inpatient adverse events and mortality. STUDY DESIGN: We used the Nationwide Inpatient Sample to identify AVR procedures from 1998 to 2010 and the American Hospital Association Annual Survey to augment hospital characteristics. Primary outcomes included mortality and the development of adverse events, identified using standardized patient safety indicators (PSI). Patient and hospital characteristics associated with PSI development were evaluated using univariate and multivariate analyses. RESULTS: An estimated 410,157 AVRs at 5009 hospitals were performed in the US between 1998 and 2010. The number of procedures grew annually by 4.72% (p=0.0003) in high volume hospitals, 4.48% in medium volume hospitals (p<0.0001), and 2.03% in low volume hospitals (p=0.154). Mortality was highest in low volume hospitals, 4.70%, decreased from 4.14% to 3.73% in medium and high volume hospitals, respectively (p=0.0002). Rates of PSIs did not vary significantly across volume terciles (p=0.254). Multivariate logistic regression analysis showed low volume hospitals had increased risk of mortality as compared with high volume hospitals (odds ratio [OR]: 1.42; 95% confidence interval [CI]: 1.01 to 2.00), while hospital volume was not associated with adverse events. PSI development was associated with small hospitals as compared with large (OR: 1.63, 95% CI: 1.16 to 2.28) and inversely associated with higher nurse-to-patient ratio (OR: 0.94, 95% CI: 0.90 to 0.99). CONCLUSIONS: The volume-outcomes relationship was associated with mortality outcomes but not postoperative complications. We identified structural differences in hospital size, nurses-to-patient ratio, and nursing skill level indicative of high quality outcomes.

Reduced GLP-1R availability in the caudate nucleus with Alzheimer's disease.

The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of GLP-1R agonists, mimicking a 30 amino acid ligand, GLP-1, extends to the treatment of neurodegenerative conditions, with a particular focus on Alzheimer's disease (AD). However, the mechanism that underlies regulation of GLP-1R availability in the brain with AD remains poorly understood. Here, using whole transcriptome RNA-Seq of the human postmortem caudate nucleus with AD and chronic hydrocephalus (CH) in the elderly, we found that GLP-1R and select mRNAs expressed in glucose dysmetabolism and dyslipidemia were significantly altered. Furthermore, we detected human RNA indicating a deficiency in doublecortin (DCX) levels and the presence of ferroptosis in the caudate nucleus impacted by AD. Using the genome data viewer, we assessed mutability of GLP-1R and 39 other genes by two factors associated with high mutation rates in chromosomes of four species. Surprisingly, we identified that nucleotide sizes of GLP-1R transcript exceptionally differed in all four species of humans, chimpanzees, rats, and mice by up to 6-fold. Taken together, the protein network database analysis suggests that reduced GLP-1R in the aged human brain is associated with glucose dysmetabolism, ferroptosis, and reduced DCX+ neurons, that may contribute to AD.

Simulated microgravity attenuates myogenesis and contractile function of 3D engineered skeletal muscle tissues.

While the effects of microgravity on inducing skeletal muscle atrophy have been extensively studied, the impacts of microgravity on myogenesis and its mechanisms remain unclear. In this study, we developed a microphysiological system of engineered muscle tissue (EMT) fabricated using a collagen / Matrigel composite hydrogel and murine skeletal myoblasts. This 3D EMT model allows non-invasive quantitative assessment of contractile function. After applying a 7-day differentiation protocol to induce myotube formation, the EMTs clearly exhibited sarcomerogenesis, myofilament formation, and synchronous twitch and tetanic contractions with electrical stimuli. Using this 3D EMT system, we investigated the effects of simulated microgravity at 10-3 G on myogenesis and contractile function utilizing a random positioning machine. EMTs cultured for 5 days in simulated microgravity exhibited significantly reduced contractile forces, myofiber size, and differential expression of muscle contractile, myogenesis regulatory, and mitochondrial biogenesis-related proteins. These results indicate simulated microgravity attenuates myogenesis, resulting in impaired muscle function.

Mutability of druggable kinases and pro-inflammatory cytokines by their proximity to telomeres and A+T content.

Mutations of protein kinases and cytokines are common and can cause cancer and other diseases. However, our understanding of the mutability in these genes remains rudimentary. Therefore, given previously known factors which are associated with high mutation rates, we analyzed how many genes encoding druggable kinases match (i) proximity to telomeres or (ii) high A+T content. We extracted this genomic information using the National Institute of Health Genome Data Viewer. First, among 129 druggable human kinase genes studied, 106 genes satisfied either factors (i) or (ii), resulting in an 82% match. Moreover, a similar 85% match rate was found in 73 genes encoding pro-inflammatory cytokines of multisystem inflammatory syndrome in children. Based on these promising matching rates, we further compared these two factors utilizing 20 de novo mutations of mice exposed to space-like ionizing radiation, in order to determine if these seemingly random mutations were similarly predictable with this strategy. However, only 10 of these 20 murine genetic loci met (i) or (ii), leading to only a 50% match. When compared with the mechanisms of top-selling FDA approved drugs, this data suggests that matching rate analysis on druggable targets is feasible to systematically prioritize the relative mutability-and therefore therapeutic potential-of the novel candidates.

Biomanufacturing of 3D Tissue Constructs in Microgravity and their Applications in Human Pathophysiological Studies.

The growing interest in bioengineering in-vivo-like 3D functional tissues has led to novel approaches to the biomanufacturing process as well as expanded applications for these unique tissue constructs. Microgravity, as seen in spaceflight, is a unique environment that may be beneficial to the tissue-engineering process but cannot be completely replicated on Earth. Additionally, the expense and practical challenges of conducting human and animal research in space make bioengineered microphysiological systems an attractive research model. In this review, published research that exploits real and simulated microgravity to improve the biomanufacturing of a wide range of tissue types as well as those studies that use microphysiological systems, such as organ/tissue chips and multicellular organoids, for modeling human diseases in space are summarized. This review discusses real and simulated microgravity platforms and applications in tissue-engineered microphysiological systems across three topics: 1) application of microgravity to improve the biomanufacturing of tissue constructs, 2) use of tissue constructs fabricated in microgravity as models for human diseases on Earth, and 3) investigating the effects of microgravity on human tissues using biofabricated in vitro models. These current achievements represent important progress in understanding the physiological effects of microgravity and exploiting their advantages for tissue biomanufacturing.

X-linked hydrocephalus genes: Their proximity to telomeres and high A + T content compared to Parkinson's disease.

Proximity to telomeres (i) and high adenine and thymine (A + T) content (ii) are two factors associated with high mutation rates in human chromosomes. We have previously shown that >100 human genes when mutated to cause congenital hydrocephalus (CH) meet either factor (i) or (ii) at 91% matching, while two factors are poorly satisfied in human genes associated with familial Parkinson's disease (fPD) at 59%. Using the sets of mouse, rat, and human chromosomes, we found that 7 genes associated with CH were located on the X chromosome of mice, rats, and humans. However, genes associated with fPD were in different autosomes depending on species. While the contribution of proximity to telomeres in the autosome was comparable in CH and fPD, high A + T content played a pivotal contribution in X-linked CH (43% in all three species) than in fPD (6% in rodents or 13% in humans). Low A + T content found in fPD cases suggests that PARK family genes harbor roughly 3 times higher chances of methylations in CpG sites or epigenetic changes than X-linked genes.

TRPV4 mRNA is elevated in the caudate nucleus with NPH but not in Alzheimer's disease.

Symptoms of normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD) are somewhat similar, and it is common to misdiagnose these two conditions. Although there are fluid markers detectable in humans with NPH and AD, determining which biomarker is optimal in representing genetic characteristics consistent throughout species is poorly understood. Here, we hypothesize that NPH can be differentiated from AD with mRNA biomarkers of unvaried proximity to telomeres. We examined human caudate nucleus tissue samples for the expression of transient receptor potential cation channel subfamily V member 4 (TRPV4) and amyloid precursor protein (APP). Using the genome data viewer, we analyzed the mutability of TRPV4 and other genes in mice, rats, and humans through matching nucleotides of six genes of interest and one house keeping gene with two factors associated with high mutation rate: 1) proximity to telomeres or 2) high adenine and thymine (A + T) content. We found that TRPV4 and microtubule associated protein tau (MAPT) mRNA were elevated in NPH. In AD, mRNA expression of TRPV4 was unaltered unlike APP and other genes. In mice, rats, and humans, the nucleotide size of TRPV4 did not vary, while in other genes, the sizes were inconsistent. Proximity to telomeres in TRPV4 was <50 Mb across species. Our analyses reveal that TRPV4 gene size and mutability are conserved across three species, suggesting that TRPV4 can be a potential link in the pathophysiology of chronic hydrocephalus in aged humans (>65 years) and laboratory rodents at comparable ages.

Drug-Targeted Genomes: Mutability of Ion Channels and GPCRs.

Mutations of ion channels and G-protein-coupled receptors (GPCRs) are not uncommon and can lead to cardiovascular diseases. Given previously reported multiple factors associated with high mutation rates, we sorted the relative mutability of multiple human genes by (i) proximity to telomeres and/or (ii) high adenine and thymine (A+T) content. We extracted genomic information using the genome data viewer and examined the mutability of 118 ion channel and 143 GPCR genes based on their association with factors (i) and (ii). We then assessed these two factors with 31 genes encoding ion channels or GPCRs that are targeted by the United States Food and Drug Administration (FDA)-approved drugs. Out of the 118 ion channel genes studied, 80 met either factor (i) or (ii), resulting in a 68% match. In contrast, a 78% match was found for the 143 GPCR genes. We also found that the GPCR genes (n = 20) targeted by FDA-approved drugs have a relatively lower mutability than those genes encoding ion channels (n = 11), where targeted genes encoding GPCRs were shorter in length. The result of this study suggests that the use of matching rate analysis on factor-druggable genome is feasible to systematically compare the relative mutability of GPCRs and ion channels. The analysis on chromosomes by two factors identified a unique characteristic of GPCRs, which have a significant relationship between their nucleotide sizes and proximity to telomeres, unlike most genetic loci susceptible to human diseases.

PDMS-PEG Block Copolymer and Pretreatment for Arresting Drug Absorption in Microphysiological Devices.

Poly(dimethylsiloxane) (PDMS) is a commonly used polymer in organ-on-a-chip devices and microphysiological systems. However, due to its hydrophobicity and permeability, it absorbs drug compounds, preventing accurate drug screening applications. Here, we developed an effective and facile method to prevent the absorption of drugs by utilizing a PDMS-PEG block copolymer additive and drug pretreatment. First, we incorporated a PDMS-PEG block copolymer into PDMS to address its inherent hydrophobicity. Next, we addressed the permeability of PDMS by eliminating the concentration gradient via pretreatment of the PDMS with the drug prior to experimentally testing drug absorption. The combined use of a PDMS-PEG block copolymer with drug pretreatment resulted in a mean reduction of drug absorption by 91.6% in the optimal condition. Finally, we demonstrated that the proposed method can be applied to prevent drug absorption in a PDMS-based cardiac microphysiological system, enabling more accurate drug studies.

Cardiac effects and clinical applications of MG53.

Heart disease remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for treatment and prevention. Mitsugumin 53 (MG53), also known as TRIM72, is a TRIM family protein that was found to be involved in cell membrane repair and primarily found in striated muscle. Its role in skeletal muscle regeneration and myogenesis has been well documented. However, accumulating evidence suggests that MG53 has a potentially protective role in heart tissue, including in ischemia/reperfusion injury of the heart, cardiomyocyte membrane injury repair, and atrial fibrosis. This review summarizes the regulatory role of MG53 in cardiac tissues, current debates regarding MG53 in diabetes and diabetic cardiomyopathy, as well as highlights potential clinical applications of MG53 in treating cardiac pathologies.

Multi-Cellular Functions of MG53 in Muscle Calcium Signaling and Regeneration.

Since its identification in 2009, multiple studies have indicated the importance of MG53 in muscle physiology. The protein is produced in striated muscles but has physiologic implications reaching beyond the confines of striated muscles. Roles in muscle regeneration, calcium homeostasis, excitation-contraction coupling, myogenesis, and the mitochondria highlight the protein's wide-reaching impact. Numerous therapeutic applications could potentially emerge from these physiologic roles. This review summarizes the current literature regarding the role of MG53 in the skeletal muscle. Therapeutic applications are discussed.

Effects of Spaceflight on Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Structure and Function.

With extended stays aboard the International Space Station (ISS) becoming commonplace, there is a need to better understand the effects of microgravity on cardiac function. We utilized human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study the effects of microgravity on cell-level cardiac function and gene expression. The hiPSC-CMs were cultured aboard the ISS for 5.5 weeks and their gene expression, structure, and functions were compared with ground control hiPSC-CMs. Exposure to microgravity on the ISS caused alterations in hiPSC-CM calcium handling. RNA-sequencing analysis demonstrated that 2,635 genes were differentially expressed among flight, post-flight, and ground control samples, including genes involved in mitochondrial metabolism. This study represents the first use of hiPSC technology to model the effects of spaceflight on human cardiomyocyte structure and function.

Anticoagulation management following left ventricular assist device implantation is similar across all provider strategies.

OBJECTIVES: Thromboembolic and bleeding events are potential complications following left ventricular assist device implantation. A tight control of the international normalized ratio (INR) is believed to be crucial in the reduction of postimplant complications. There is significant variability among institutions as to whether a device implanting centre should be managing the INR. In this study, we evaluated the effect of INR management strategies in maintaining a therapeutic INR. METHODS: A retrospective review was utilized to identify patients implanted with either the HeartMate II or the HeartWare HVAD between January 2011 and February 2016. Patients were stratified into 4 groups based on the post-discharge INR management strategy: outside hospital system anticoagulation clinic, outside hospital primary care provider, implanting centre anticoagulation clinic or implanting centre ventricular assist device office. The INR data were collected and analysed for both the early (discharge, 7, 14, 21 and 30 days) and late (3, 6, 9 and 12 months) postoperative periods. RESULTS: There were 163 patients identified during the study period who met the study inclusion criteria: 49 (30%) patients were managed by an outside hospital system anticoagulation clinic, 59 (36.2%) patients by an outside hospital physician/primary care provider, 22 (13.5%) patients by the implanting centre anticoagulation clinic and 33 (20.2%) patients by the implanting centre ventricular assist device office. There were no statistically significant differences found between management strategies across all time points. CONCLUSIONS: There was no statistically significant difference found between the management strategies examined. Regardless of the chosen INR management strategy, patients have similar INR values and postoperative outcomes.

Zinc in Wound Healing Modulation.

Wound care is a major healthcare expenditure. Treatment of burns, surgical and trauma wounds, diabetic lower limb ulcers and skin wounds is a major medical challenge with current therapies largely focused on supportive care measures. Successful wound repair requires a series of tightly coordinated steps including coagulation, inflammation, angiogenesis, new tissue formation and extracellular matrix remodelling. Zinc is an essential trace element (micronutrient) which plays important roles in human physiology. Zinc is a cofactor for many metalloenzymes required for cell membrane repair, cell proliferation, growth and immune system function. The pathological effects of zinc deficiency include the occurrence of skin lesions, growth retardation, impaired immune function and compromised would healing. Here, we discuss investigations on the cellular and molecular mechanisms of zinc in modulating the wound healing process. Knowledge gained from this body of research will help to translate these findings into future clinical management of wound healing.