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The SpaceX Inspiration4 mission provided a unique opportunity to study the impact of spaceflight on the human body. Biospecimen samples were collected from the crew at different stages of the mission, including before (L-92, L-44, L-3 days), during (FD1, FD2, FD3), and after (R + 1, R + 45, R + 82, R + 194 days) spaceflight, creating a longitudinal sample set. The collection process included samples such as venous blood, capillary dried blood spot cards, saliva, urine, stool, body swabs, capsule swabs, SpaceX Dragon capsule HEPA filter, and skin biopsies, which were processed to obtain aliquots of serum, plasma, extracellular vesicles, and peripheral blood mononuclear cells. All samples were then processed in clinical and research laboratories for optimal isolation and testing of DNA, RNA, proteins, metabolites, and other biomolecules. This paper describes the complete set of collected biospecimens, their processing steps, and long-term biobanking methods, which enable future molecular assays and testing. As such, this study details a robust framework for obtaining and preserving high-quality human, microbial, and environmental samples for aerospace medicine in the Space Omics and Medical Atlas (SOMA) initiative, which can also aid future experiments in human spaceflight and space biology.

Supplementary Figure from Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity

Supplementary Table from Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T–produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.

Tumor-associated macrophages (TAMs) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably to PD1 blockade, and significantly extended mouse survival. Anti-tumor effects were mediated by F4.CAR-T-produced IFN-γ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigens and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof-of-principle evidence to support CAR-T targeting of TAMs as a means to enhance antitumor immunity.

Tumor-associated macrophages (TAM) are one of the most abundant cell types in many solid tumors and typically exert protumor effects. This has led to an interest in macrophage-depleting agents for cancer therapy, but approaches developed to date have had limited success in clinical trials. Here, we report the development of a strategy for TAM depletion in mouse solid tumor models using chimeric antigen receptor (CAR) T cells targeting the macrophage marker F4/80 (F4.CAR-T). F4.CAR-T cells effectively killed macrophages in vitro and in vivo without toxicity. When injected into mice bearing orthotopic lung tumors, F4.CAR-T cells infiltrated tumor lesions and delayed tumor growth comparably with PD-1 blockade, and significantly extended mouse survival. Antitumor effects were mediated by F4.CAR-T–produced IFNγ, which promoted upregulation of MHC molecules on cancer cells and tumor-infiltrating myeloid cells. Notably, F4.CAR-T promoted expansion of endogenous CD8 T cells specific for tumor-associated antigen and led to immune editing of highly antigenic tumor cell clones. Antitumor impact was also observed in mouse models of ovarian and pancreatic cancer. These studies provide proof of principle to support CAR T-cell targeting of TAMs as a means to enhance antitumor immunity.

The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.

Background Peripheral arterial disease is mainly caused by atherosclerosis and is characterized by decreased circulation, lower blood pressure, and insufficient tissue perfusion in the lower extremities. The hemodynamics of standing and altered gravity environments have been well studied relative to arm blood pressures but are less well understood for ankle pressures. Methods Because regional blood pressure depends, in part, on the gravitational pressure gradient, we hypothesized that artificial gravity exposure on a short-arm centrifuge with the center of rotation above the head would increase blood pressure in the lower extremities. Cardiovascular parameters for 12 healthy subjects were measured during exposure to supine short-arm centrifugation at 20, 25, and 30 revolutions per minute (rpm), corresponding to centripetal accelerations of 0.94, 1.47, and 2.11 Gz at the foot level, respectively. Results Systolic ankle blood pressure significantly increased at all levels of centrifugation. Ankle-brachial indices (the ratio of systolic ankle to arm blood pressures) increased significantly from 1.17 ± 0.03 to 1.58 ± 0.03 at 0.94 Gz ( P < 0.005), 1.74 ± 0.02 at 1.47 Gz ( P < 0.005), and 1.89 ± 0.06 at 2.11 Gz ( P < 0.005). Systolic arm blood pressure significantly increased at 2.11 Gz, but heart rate did not change significantly. All parameters returned to normal after cessation of centrifugation. Conclusions We demonstrated that short-radius centrifugation leads to an increase in ankle-brachial indices. This could have potential implications for the treatment of peripheral arterial disease.

Developments in photoplethysmography (PPG) hardware make this device a promising tool for non-invasive deep-tissue hemodynamic measurements. The aim of this study was to validate the use of PPG as a tool for non-invasive bone hemodynamic measurements. A new PPG device capable of measuring bone hemodynamic responses was designed, tested and validated. Validation experiments included cold exposure, arterial occlusion, skin occlusion and nitroglycerin exposure. Cold exposure resulted in a decrease in skin perfusion (p = 0.011) and bone perfusion (p = 0.005); arterial occlusion also resulted in decreased skin perfusion (p < 0.001) and bone perfusion (p = 0.008), with arterial occlusion resulting in a greater decrease in perfusion than cold exposure. The independence of the skin and bone PPG signals was demonstrated by the ability to independently increase (p = 0.003) and decrease (p = 0.005) the skin signal without significantly affecting the bone signal. Our experiments build upon and expand previous PPG developments and validation studies. Our custom-made PPG hardware represents a state-of-the-art tool for non-invasive monitoring of deep tissues, and our data support the use of PPG as a valid tool for measuring bone hemodynamic responses in vivo.

Adequate blood supply and circulation to the bones is required to maintain a healthy skeleton. Inadequate blood perfusion is associated with numerous bone pathologies and a decrease in bone mineral density, yet bone hemodynamics remains poorly understood. This study aims to 1) quantify bone hemodynamic responses to changes in external pressure, and 2) identify the predominant mechanisms regulating bone hemodynamic responses to pressure changes. Photoplethysmography was used to measure bone and skin perfusion in response to changes in external pressure. Single-limb pressure chamber experiments were performed over a pressure range of -50 to +50mmHg. Bone perfusion is decreased at all negative pressures, and larger decrements in perfusion are observed at the more extreme pressure differences. At positive pressures we observed an initial increase in perfusion followed by activation of intramuscular pressure receptors at +30mmHg, which overrides the initial response and results in decreased perfusion at the highest positive pressure levels. The myogenic effect is observed and is shown to be the predominant control mechanism in bone over a wide range of pressure exposures. Greater understanding of these hemodynamic mechanisms may be important in developing new drugs and therapies to treat various bone disorders.

INTRODUCTION In 1980 Katkov and Chestukhin measured blood pressures and oxygenation invasively at various body tilt angles at different locations on the body, including the foot. To our knowledge, such measurements have not been performed noninvasively. Therefore, the purpose of this study was to measure toe blood pressure (TBP) and lower limb muscle oxygenation noninvasively at various body tilt angles, and to assess the use of a Finometer for noninvasive TBP measurements. Our noninvasive results are compared with those performed by Katkov and Chestukhin. We hypothesized that: 1) the Finometer provides a noninvasive measurement of TBP at different tilt angles; and 2) muscle oxygenation is highest with 0 and -6 degrees, and decreases with increased head-up tilt (HUT). METHODS There were 10 subjects who were exposed to different body tilt angles (-6, 0, 10, 30, 70, and 90 degrees). At each angle we measured TBP noninvasively with a Finometer and muscle tissue oxygenation by near infrared spectroscopy. RESULTS We found a strong correlation between TBP using the Finometer and TBP predicted by adding the hydrostatic component due to body tilt to the standard arm blood pressure measurement. At 10, 30, 70, and 90 degrees both TBP and tissue oxygenation were significantly different from the 0 degree (supine) level. Oxygenation decreased and TBP increased with higher HUT angles. No differences were observed in TBP or oxygenation between -6 and 0 degree. CONCLUSIONS The Finometer accurately measures TBP noninvasively with body tilt. Also, muscle oxygenation is highest at small HUT angles and decreases with increased HUT.

Head turns performed while rotating about another axis result in a cross-coupled stimulus (CCS) to the vestibular system. The CCS causes a tumbling sensation, and the magnitude of the tumbling sensation is dependent on the type of head turn (HT) that is performed. Asymmetric CCS responses to different rotational directions are widely acknowledged, yet poorly understood. The objective of this study was to: 1) correctly describe the asymmetries in responses to different configurations of CCS stimulation and 2) test two previously proposed hypotheses for explaining the asymmetries, dominant direction, and dominant end position. The dominant direction hypothesis states that the tumbling sensations evoked by the CCS will be more intense for certain directions of the tumbling sensation than for others. The dominant end position hypothesis states that head turns ending in the nose-up position result in more intense sensations than those ending on the side positions. Subjects performed four types of 60-degree yaw head turns while lying horizontally on a centrifuge. Subjects were either supine or prone, while rotating clockwise or counterclockwise. Three experimental conditions were tested: clockwise supine (n = 33); counterclockwise supine (n = 10); and clockwise prone (n = 10). Subjective tumbling intensity scores were recorded for each head turn. Head turns to the left are dominant for clockwise supine centrifugation (P < 0.0001) and head turns to the right are dominant for counterclockwise supine centrifugation (P = 0.0020), matching what is expected from previous studies. However, for prone centrifugation, head turns to the left are more intense than head turns to the right (P = 0.0078), refuting the dominant direction hypothesis. The dominant end position effect is small in magnitude and cannot by itself explain the asymmetries. For every test condition, there is a dominant direction, but the dominant direction is not just a function of the HT and centrifuge rotation directions, instead it is also dependent on the subject's orientation on the centrifuge. An alternative perceived danger hypothesis that matches the data from all three experiments is proposed.