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At least 1,621 records · Page 90

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NASA NTRSDate not supplied

A MULTI TARGETED DIETARY SUPPLEMENT AS A POTENTIAL COUNTERMEASURE FOR DEEP SPACE EXPLORATION

Future deep space exploration to the Moon and Mars and beyond are currently major goals of NASA. Space flight presents unique challenges to the human physiology from the combined effects of microgravity, social isolation, altered circadian rhythm and radiation. Oxidative stress has been implicated as a crucial factor in space environment induced injury. Elucidating these detrimental effects on the central nervous system and brain is a primary objective, as they may result in adverse changes in astronaut behavior, mood and performance of critical tasks. We were recently funded by HRP Human Factors Behavioral Performance (HFBP) Element to test the hypothesis that Galactic Cosmic Ray Simulation (GCRsim) Ionizing Radiation (IR), microgravity and social isolation combine synergistically to trigger an oxidative stress response that alters immune homeostasis, brain structure and function, and neurobehavioral and cognitive performance. This project will identify potential biomarkers for, and mechanisms underlying, structural and functional changes in the immune and nervous systems leading to behavioral/cognitive performance deficits, and its potential application to develop effective countermeasures to mitigate negative health effects of long duration space habitation. Countermeasures to offset neurological damaged and cognitive deficits are paramount for protecting astronauts during deep space transits, but many countermeasures have been found to be unsuitable in ground-based model studies. We have developed a multi targeted dietary supplement (MTDS) designed to simultaneously ameliorate oxidative stress, inflammatory processes, energetic shortfalls, and membrane and mitochondrial deterioration. Administration of this MTDS has improved cognition and longevity in age accelerated and normal aging mice. Specifically, the MTDS was found to prevent a decline in mitochondrial complex III activity and cell loss, as well as prevent an increase in protein carbonyls and mitochondrial 3-nitrotyrosine in the brain of these mice. Further, administration of the MTDS was also found to reduce bone marrow chromosomal aberrations, DNA damage, lymphocyte apoptosis after whole body exposure of 2 Gy γ radiation. Mice exposed to a high dose cranially (10 Gy) had decreased cognitive responses (seen as increased latency time to uncover buried food and decreased novel object recognition), increased plasma 8-OHdG levels, increased markers of cell stress in the brain, decreased hippocampal brain-derived neurotrophic factor (BDNF) protein and decreased plasma levels of cytokines, all of which were ameliorated with treatment of the MTDS. As we have shown the supplement is protective in models of cognitive damage similar space environment stressors, particularly increased oxidative stress, we propose it may be a suitable countermeasure for upcoming deep space exploration.

Stephanie Puukila↗

NASA NTRSDate not supplied

Method Development for In-situ Detection of Latent Herpesvirus DNA from Saliva using Nanopore Sequencing

Research toward latent herpesvirus reactivation has been intensively addressed through Space Shuttle and International Space Station (ISS) investigations. This work has provided the understanding that persistent reactivation of herpesviruses from asymptomatic crew can be detected through viral shedding in saliva, urine, and blood. Occasionally, viral reactivation from the latency stage can pose a threat to crew health (clinical manifestation) before, during, and after flight missions. Furthermore, previous work detailing correlations with immunity indicate that monitoring viral reactivation could be implemented to assess potential immune dysfunction. While in-flight monitoring is desirable, there is no well-established procedure or method for real-time evaluations, and research to date has relied on postflight, ground-based analysis. The development of portable molecular technologies like the miniPCR™ (miniPCR Bio) thermal cycler and the MinION™ sequencer (Oxford Nanopore Technologies) have confirmed that real-time monitoring is possible in extreme and low resource environments. These devices, combined with simple sample preparation methods, have been used to demonstrate bacterial identification onboard the ISS, as well as rapid viral detection in remote locations on Earth. The work here builds upon previous molecular advancements onboard the ISS toward the development and validation of a spaceflight-compatible method for viral detection from crew samples. Several herpesviruses can be detected in saliva, which provides a non-invasive means to collect samples for monitoring. While the basis for this method lies in previous spaceflight investigations, key points for method optimization include DNA extraction from saliva, viral primer selection, and bioinformatic processes for data analysis. To increase viral yield, numerous DNA extraction methods have been evaluated and will be discussed in detail. For initial development and testing, varicella-zoster virus (VZV) is being targeted though open reading frame 51 and 63 (ORF51, ORF63), as the replication origin-binding protein is highly expressed during latency. Optimization of the thermal cycling parameters has resulted in the ability to test the entire process. The full method has been tested with both viral VZV DNA standards and saliva spiked with varying concentrations of VZV. Viral sequence data were mapped to the reference sequence using minimap2. Prior to mapping, DNA sequencing reads were filtered for length and quality, barcodes were removed, and alignment identity calculated. Following further assessments, statistics were compared across multiple sequencing experiments and are being used to determine the success of the protocols. Forward work will include the incorporation of herpes simplex virus 1 (HSV-1) and Epstein-Barr virus (EBV) primers as well as the validation of results to the terrestrial qPCR standard assay. Upon full validation of the developed method, saliva will be collected from 20 healthy subjects and spiked with viral DNA. These samples will be split and assayed with the MinION and standard qPCR assay.

Hang N Nguyen↗

NASA NTRSDate not supplied

Spaceflight Food System Impacts to Nutritional Adequacy, Health, Performance, and Resources in Space Exploration

Despite high physical standards and training protocols, physiological and behavioral decrements have been documented in astronauts on both short (1-2 weeks) and long (6+ month) missions in spaceflight, including dysregulation of the immune system, cardiovascular and musculoskeletal deconditioning, ophthalmic changes, weight loss, and increased stress and fatigue. Optimizing food and nutrition intakes are key underpinnings for the proper function and performance of all physiological systems and the resulting physical and behavioral health and performance outcomes of astronauts. Much has been learned about the role of nutrition in human health on Earth over the past hundred years, from the identity and role of specific vitamins to the importance of the quantities of some nutrients to immune function. The requirements for providing adequate nutrition to astronauts seem obvious. However, providing a safe, reliable, and nutritious food system for space exploration missions remains a challenge. In fact, food is one of the greatest resource and logistical challenges, which is part of why it remains a “red” risk for Mars missions.

Grace L Douglas↗

NASA NTRSDate not supplied

HemoCue ISS Tech Demo - Results and Lessons Learned

During long duration space missions, astronauts experience immune system dysregulation [1], and white blood cell (WBC) count can give vital information about the body’s immune response. The ability to measure WBC count is currently an unmet need on the International Space Station (ISS) and for future exploration missions. To address this need, the Human Research Program’s (HRP) Exploration Medical Capability (ExMC) Element, along with the Research Operations and Integration (ROI) Element and the NASA Johnson Space Center Immunology Lab, flew HemoCue®, a commercial-off-the-shelf analyzer with the ability to measure whole blood WBC count with 5-part differential to ISS in December 2020.

Exploration Medical Capability↗

NASA NTRS2022

Dermatitis during Spaceflight Associated with HSV-1 Reactivation

Human alpha herpesviruses herpes simplex virus (HSV-1) and varicella zoster virus (VZV) establish latency in various cranial nerve ganglia and often reactivate in response to stress-associated immune system dysregulation. Reactivation of Epstein Barr virus (EBV), VZV, HSV-1, and cytomegalovirus (CMV) is typically asymptomatic during spaceflight, though live/infectious virus has been recovered and the shedding rate increases with mission duration. The risk of clinical disease, therefore, may increase for astronauts assigned to extended missions (>180 days). Here, we report, for the first time, a case of HSV-1 skin rash (dermatitis) occurring during long-duration spaceflight. The astronaut reported persistent dermatitis during flight, which was treated onboard with oral antihistamines and topical/oral steroids. No HSV-1 DNA was detected in 6-month pre-mission saliva samples, but on flight day 82, a saliva and rash swab both yielded 4.8 copies/ng DNA and 5.3 × 104 copies/ng DNA, respectively. Post-mission saliva samples continued to have a high infectious HSV-1 load (1.67 × 107 copies/ng DNA). HSV-1 from both rash and saliva samples had 99.9% genotype homology. Additional physiological monitoring, including stress biomarkers (cortisol, dehydroepiandrosterone (DHEA), and salivary amylase), immune markers (adaptive regulatory and inflammatory plasma cytokines), and biochemical profile markers, including vitamin/mineral status and bone metabolism, are also presented for this case. These data highlight an atypical presentation of HSV-1 during spaceflight and underscore the importance of viral screening during clinical evaluations of in-flight dermatitis to determine viral etiology and guide treatment.

Satish K. Mehta↗

NASA NTRSDate not supplied

Gene expression changes in peripheral blood mononuclear cells of ISS crewmembers suggest impacts of spaceflight on cell death

In space, living organisms are exposed to numerous stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. This study is part of the Functional Immune Project, intended to determine alterations in crewmembers` immunobiology before, during, and after spaceflight. For this project, blood samples were collected from International Space Station (ISS) crewmembers at the following time points: i) at two pre-flight time points of 180 days (L180) and 45 days (L45) before launch. ii) During flight, blood was drawn at approximately the midpoint (mid-flight, MF) of the mission, and shortly before egress from the ISS (late-flight, LF). iii) Post-flight blood samples were collected within 24 hrs (R0), 30 days (R30) and 90 days (R90) after landing. For each crewmember, blood was also drawn from a matching test subject on the ground at the corresponding time point. For both the ISS crewmembers and the ground control subjects, total RNA was isolated from peripheral blood mononuclear cells (PBMC) and mRNA was analysed using next generation RNA-sequencing (NGS). Differentially expressed genes were determined by performing contrast analysis. Using the data from all of the time points from the ground control subjects as a control, a number of dysregulated genes were identified in astronauts at MF, LF and R0, including downregulations of several cell cycle related genes including CDKN1A and VEGFA at MF and LF. Pathway analysis of these differentially expressed genes indicated that, in space, pathways associated with autophagy and senescence were affected. Our analysis also indicated that the genes related to metabolisms were downregulated in the microgravity environment. Taken together, our data suggests that PBMC in the ISS crewmembers may be starved, resulting in autophagy and delayed senescence in space. Such findings are in agreement with delayed cell death in PBMC under simulated microgravity conditions on the ground and offer an explanation for telomere lengthening that has been reported among the ISS astronauts in flight.

Maria Moreno-Villanueva↗

NASA NTRSDate not supplied

Gene Expression Changes in Peripheral Blood Mononuclear Cells of ISS Crewmembers Suggest Impacts of Spaceflight on Cell Death

In space, living organisms are exposed to numerous stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. This study is part of the Functional Immune Project, intended to determine alterations in crewmembers` immunobiology before, during, and after spaceflight. For this project, blood samples were collected from International Space Station (ISS) crewmembers at the following time points: i) at two pre-flight time points of 180 days (L180) and 45 days (L45) before launch. ii) During flight, blood was drawn at approximately the midpoint (mid-flight, MF) of the mission, and shortly before egress from the ISS (late-flight, LF). iii) Post-flight blood samples were collected within 24 hrs (R0), 30 days (R30) and 90 days (R90) after landing. For each crewmember, blood was also drawn from a matching test subject on the ground at the corresponding time point. For both the ISS crewmembers and the ground control subjects, total RNA was isolated from peripheral blood mononuclear cells (PBMC) and mRNA was analysed using next generation RNA-sequencing (NGS). Differentially expressed genes were determined by performing contrast analysis. Using the data from all of the time points from the ground control subjects as a control, a number of dysregulated genes were identified in astronauts at MF, LF and R0, including downregulations of several cell cycle related genes including CDKN1A and VEGFA at MF and LF. Pathway analysis of these differentially expressed genes indicated that, in space, pathways associated with autophagy and senescence were affected. Our analysis also indicated that the genes related to metabolisms were downregulated in the microgravity environment. Taken together, we hypothesize that PBMC in the ISS crewmembers may be starved, resulting in autophagy and delayed senescence in space. Such findings are in agreement with delayed cell death in PBMC under simulated microgravity conditions on the ground and offer an explanation for telomere lengthening that has been reported among the ISS astronauts in flight

Maria Moreno-Villanueva↗

NASA NTRSDate not supplied

Plasma and Brain Cytokine Responses to Single and Combinatorial Spaceflight Stressors in Male and Female Mice

Spaceflight involves exposure to multiple environmental stressors, including Ionizing Radiation (IR), microgravity, and social isolation. We hypothesize that spaceflight stressors combine synergistically to trigger an oxidative stress response that, in turn, alters immune homeostasis, brain structure/function, and neurobehavioral/cognitive performance. Here, we report plasma and brain cytokine findings from two studies of crew age-matched (24-week-old) male and female mice exposed to simulated 5-Ion GCRsim at the NASA Space Radiation Laboratory (NSRL). In Study 1, mice were exposed to 0, 5, 15, or 50cGy 5-ion GCRsim. Immune and brain measures were acquired either at ‘Acute’ (within 3 days post-irradiation; IR), ‘Intermediate’ (IR+14 days) or ‘Delayed’ (IR+125 days) timepoints. In Study 2, mice were exposed singly and in combination to 15cGy 5-ion GCRsim, simulated microgravity via continuous head-down tilt/hindlimb unloading (HU), and social isolation. Plasma and brain cytokine cytokine profiling revealed sex-specific as well as sex-common responses. Notably, plasma granulocyte colony stimulating factor (GCSF) levels showed significant regulation compared to a single stressor alone, suggesting a potential biomarker responder. Increased GCSF was correlated with corresponding increased blood neutrophil populations. Futhermore, our study provides evidence for robust effects of HU relative to IR alone. This project addresses NASA’s efforts to characterize risks in both women and men in anticipation of future space missions beyond low earth orbit (BLEO). Ensuring crew health and performance during extended transits to the moon and beyond necessitates that sensorimotor and cognitive abilities remain strong to avoid potentially catastrophic health and safety outcomes.

mouse radiation hindlimb unloading spaceflight↗

NASA NTRSDate not supplied

Dry Saliva Development-Artemis

Prior to the deployment of prolonged deep space missions which may carry increased crew health risks, it is essential to determine the effect that missions beyond the Van Allen Belt will have on physiology. Historically the National Aeronautics and Space Administration (NASA), Human Research Program (HRP) has developed, conducted, and delivered research findings and countermeasures that will maintain the health and safety of crews aboard the International Space Station (ISS) in anticipation of future exploration class missions. To support these objectives, research operations on ISS typically include the collection and storage of human physiological samples and their return to Earth for analysis. Transition to Gateway and Artemis lunar exploration will limit the available up mass and biosample return capability resulting in new challenges to monitor crew health during the mission. The Artemis lunar missions provide a perfect opportunity to assess new technology that could support crew biosample return that is compatible with the severe operational constraints of Artemis mission design. Dried biosample chemistry analysis is a potential technology that can enable the collection of samples and tracking of crew health during these exploration class missions. The development and implementation of dried biosample chemistry technology for tracking immune health, viral reactivation and hormone fluctuations provide a simple alternative strategy for sample collection and sample return (light weight non-conditioned stowage option) for the continuation of human research during Artemis missions. Saliva is established as an informative biosample that has both its own unique available analytes as well as others that are also present in blood. Saliva is already routinely collected from ISS astronauts for the detection of stress hormones and latent virus DNA. The ‘Dry Saliva’ book sample collection/storage protocol, already successfully deployed to ISS, represents a perfect method for collecting biosamples from Gateway and Artemis astronauts because it requires a simple, non-invasive sample collection protocol, minimum volume, and uses non-conditioned storage. We are currently conducting an expanded stability study of the dry saliva analyte platform to include additional stress hormones, cytokines, antimicrobial proteins, and latent virus DNA as well as other markers of immunity and inflammation. Validation testing on parabolic flight will establish collection methods for saliva and blood to dry sampling substrates to finalize the collection protocols for flight. For the new expanded analyte stability study, a short-term stability study with time points out to 14 days has been completed with analysis underway to determine whether additional analytes could be recovered, as well as assessing the best storage conditions for the samples collected. In parallel, a long-term stability study is being conducted out to 1 year to improve the stability of some unstable analytes. To this end, the NASA Johnson Space Center’s Immunology/Virology lab is currently finalizing the saliva dry chemistry platform, including assay compatibility and stability studies. This technology is approved to be implemented, as part of the ‘Biomarkers’ study, during Artemis II through Artemis IV lunar missions.

Mayra Nelman-Gonzalez↗

DOE OSTI2011

Nucleic acids encoding modified human immunodeficiency virus type 1 (HIV-1) group M consensus envelope glycoproteins

The present invention relates, in general, to an immunogen and, in particular, to an immunogen for inducing antibodies that neutralizes a wide spectrum of HIV primary isolates and/or to an immunogen that induces a T cell immune response. The invention also relates to a method of inducing anti-HIV antibodies, and/or to a method of inducing a T cell immune response, using such an immunogen. The invention further relates to nucleic acid sequences encoding the present immunogens.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2011

Structure of the F-spondin Domain of Mindin an Integrin Ligand and Pattern Recognition Molecule

Mindin (spondin-2) is an extracellular matrix protein of unknown structure that is required for efficient T-cell priming by dendritic cells. Additionally, mindin functions as a pattern recognition molecule for initiating innate immune responses. These dual functions are mediated by interactions with integrins and microbial pathogens, respectively. Mindin comprises an N-terminal F-spondin (FS) domain and C-terminal thrombospondin type 1 repeat (TSR). We determined the structure of the FS domain at 1.8-A resolution. The structure revealed an eight-stranded antiparallel beta-sandwich motif resembling that of membrane-targeting C2 domains, including a bound calcium ion. We demonstrated that the FS domain mediates integrin binding and identified the binding site by mutagenesis. The mindin FS domain therefore represents a new integrin ligand. We further showed that mindin recognizes lipopolysaccharide (LPS) through its TSR domain, and obtained evidence that C-mannosylation of the TSR influences LPS binding. Through these dual interactions, the FS and TSR domains of mindin promote activation of both adaptive and innate immune responses.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2012

The peptide-receptive transition state of MHC-1 molecules: Insight from structure and molecular dynamics

MHC class I (MHC-I) proteins of the adaptive immune system require antigenic peptides for maintenance of mature conformation and immune function via specific recognition by MHC-I-restricted CD8(+) T lymphocytes. New MHC-I molecules in the endoplasmic reticulum are held by chaperones in a peptide-receptive (PR) transition state pending release by tightly binding peptides. In this study, we show, by crystallographic, docking, and molecular dynamics methods, dramatic movement of a hinged unit containing a conserved 3(10) helix that flips from an exposed 'open' position in the PR transition state to a 'closed' position with buried hydrophobic side chains in the peptide-loaded mature molecule. Crystallography of hinged unit residues 46-53 of murine H-2L(d) MHC-I H chain, complexed with mAb 64-3-7, demonstrates solvent exposure of these residues in the PR conformation. Docking and molecular dynamics predict how this segment moves to help form the A and B pockets crucial for the tight peptide binding needed for stability of the mature peptide-loaded conformation, chaperone dissociation, and Ag presentation.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Application of Low Dose Radiation Adaptive Response to Control Aging-Related Disease

Oxidative damage has been implicated in the pathogenesis of most aging-related diseases including neurodegenerative diseases. Antioxidant supplementation has been found to be ineffective in reducing such diseases, but increased endogenous production of antioxidants from the adaptive response due to physical and cognitive exercises (which increase oxidative metabolism and oxidative stress) has been effective in reducing some of the diseases. Low dose radiation (LDR), which increases oxidative stress and results in adaptive response of increased antioxidants, may provide an alternative method of controlling the aging-related diseases. We have studied the effect of LDR on the induction of adaptive response in rat brains and the effectiveness of the LDR in reducing the oxidative damage caused by subsequent high dose radiation. We have also investigated the effect of LDR on apomorphine-induced rotations in the 6-hydroxydopamine (6-OHDA) unilaterally-lesioned rat model of Parkinson's disease (PD). LDR was observed to initiate an adaptive response in the brain, and reduce the oxidative damage from subsequent high dose radiation exposure, confirming the effectiveness of LDR adaptive response in reducing the oxidative damage from the free radicals due to high dose radiation. LDR resulted in a slight improvement in Tyrosine hydroxylase expression on the lesioned side of substantia nigra (indicative of its protective effect on the dopaminergic neurons), and reduced the behavioral symptoms in the 6-OHDA rat model of PD. Translation of this concept to humans, if found to be applicable, may be a possible approach for controlling the progression of PD and other neurodegenerative diseases. Since any translation of the concept to humans would be hindered by the currently prevalent carcinogenic concerns regarding LDR based on the linear no-threshold (LNT) model, we have also studied the justifications for the use of the LNT model. One of the shortcomings of the LNT model is that it ignores the effects of any adaptive response of the body to the LDR. The importance of considering adaptive response becomes obvious when one considers the sharp contrast between (i) the failure of well-designed anti-angiogenesis therapies which resulted in aggressive tumors because of ignoring adaptive response and (ii) the occasional cure of untreated metastatic lesions likely due to the incidental adaptive response from the LDR exposure to parts of the body during radiation therapy of a primary tumor, known as the abscopal effect. Another shortcoming of the LNT model is that it pays exclusive attention to increase in mutations, which is not a decisive factor in the occurrence of clinical cancers, as the cause of excess cancers. On the other hand, LNT model ignores the immune system response, which plays a very important role in preventing occult cancers from becoming clinical cancers, as demonstrated by the large increase in cancers in organ transplant patients whose immune system is suppressed. There is also recent epidemiological evidence against the LNT model. A re-analysis of the latest update to the atomic bomb survivor data has shown that the data no longer support the LNT model but are consistent with the radiation hormesis hypothesis. A re-analysis of cancer incidence data of Taiwanese apartment dwellers that were exposed to LDR from contaminated building materials has also shown a reduction in cancers from the LDR. The present LDR carcinogenic concerns would preclude any human study of cancer prevention using LDR, since the study would require subjecting a large asymptomatic population to LDR. However, pilot studies of radiation hormesis in cancer patients may be more acceptable since these would require irradiation of limited numbers of patients in order to assess the effectiveness of the LDR treatments. Some of the LDR applications that may be considered for cancer patients are: LDR treatment of early stage cancers without the adverse side effects of current treatments such as radiation therapy or chemotherapy, adjuvant LDR treatment of cancer patients undergoing radiation therapy for better tumor control and reduced metastasis, and the use of LDR treatment following radiation therapy to reduce the risk of second cancers from the radiation therapy. Studies of LDR for the control of early-stage neurodegenerative diseases may also be more acceptable since currently there are no effective treatments available for controlling these diseases, and since such studies would require LDR exposure to limited parts of the brain, and the carcinogenic risk from such treatments would be very small due to the low radiation tissue-weighting factor for the brain. Success in these studies can lead to the study of LDR for preventing and controlling other aging-related diseases.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗

DOE OSTI2018

Mosaic HIV envelope immunogenic polypeptides

Disclosed herein are mosaic HIV envelope (Env) polypeptides that can elicit an immune response to HIV (such as cytotoxic T cell (CTL), helper T cell, and/or humoral responses). Also disclosed are sets of the disclosed mosaic Env polypeptides, which include two or more (for example, three) of the polypeptides. Also disclosed herein are methods for treating or inhibiting HIV in a subject including administering one or more of the disclosed immunogenic polypeptides or compositions to a subject infected with HIV or at risk of HIV infection. In some embodiments, the methods include inducing an immune response to HIV in a subject comprising administering to the subject at least one (such as two, three, or more) of the immunogenic polypeptides or at least one (such as two, three, or more) nucleic acids encoding at least one of the immunogenic polypeptides disclosed herein.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Precise microbiota engineering at the cellular level

Stably immunized cells and methods of making stably immunized cells are provided. Methods of altering the microbiota of an ecological environment are provided. Methods of modifying target chromosomes are provided. Methods of delivering genetic material to target cells are provided.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

SPT-3G D1: Foreground-Robust Lensing Templates for Primordial Gravitational Wave Searches

Gravitational lensing of the cosmic microwave background (CMB) generates B-mode polarization that acts as a source of contamination to searches for B modes generated by primordial gravitational waves (PGWs). The strongest constraint on PGW B modes is already significantly limited by lensing B modes, as shown in the most recent BICEP result. In this work, we present CMB lensing B-mode templates constructed using SPT-3G and Planck data, which characterize the lensing B modes and can be used to improve PGW B-mode searches. We use SPT-3G data from the 2019 and 2020 observing seasons for the E modes and the CMB-reconstructed lensing potential, and a cosmic infrared background (CIB) map from Planck as an external lensing tracer. To test for extragalactic foreground biases in the lensing template, we consider CMB lensing reconstruction variants with different levels of foreground immunity: the standard and profile-hardened global minimum variance (GMV) quadratic estimators, and a polarization-only quadratic estimator. We validate the template construction using Gaussian simulations and Agora simulations with realistic non-Gaussian foregrounds. From simulations, we find that foreground-induced biases are strongly suppressed for the template constructed with the profile-hardened GMV + CIB tracer, with residual bias below 10% of the statistical uncertainty on the template power spectrum. Data difference tests on this template similarly show no evidence for significant foreground contamination. This foreground-immune lensing template achieves delensed residual BB power of $A_{\rm lens}^{\rm res} \simeq 0.48$ averaged over $20 \leq \ell \leq 200$, the highest delensing efficiency lensing template to date. These results demonstrate and validate a method to construct foreground-robust lensing templates which will be used in upcoming delensed PGW B-mode analyses of BICEP data.

Nakato, Y. [Stanford U.]↗

DOE OSTI2019

Human V H 1-69 Gene-Encoded Human Monoclonal Antibodies against Staphylococcus aureus IsdB Use at Least Three Distinct Modes of Binding To Inhibit Bacterial Growth and Pathogenesis

Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region IGHV1-69 gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of IGHV1-69-encoded mAbs blocks S. aureus heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden in vivo by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of IGHV1-69-encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that IGHV1-69-encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against S. aureus infection.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Challenges and the Evolving Landscape of Assessing Blood-Based PD-L1 Expression as a Biomarker for Anti-PD-(L)1 Immunotherapy

While promising, PD-L1 expression on tumor tissues as assessed by immunohistochemistry has been shown to be an imperfect biomarker that only applies to a limited number of cancers, whereas many patients with PD-L1-negative tumors still respond to anti-PD-(L)1 immunotherapy. Recent studies using patient blood samples to assess immunotherapeutic responsiveness suggests a promising approach to the identification of novel and/or improved biomarkers for anti-PD-(L)1 immunotherapy. In this review, we discuss the advances in our evolving understanding of the regulation and function of PD-L1 expression, which is the foundation for developing blood-based PD-L1 as a biomarker for anti-PD-(L)1 immunotherapy. We further discuss current knowledge and clinical study results for biomarker identification using PD-L1 expression on tumor and immune cells, exosomes, and soluble forms of PD-L1 in the peripheral blood. Finally, we discuss key challenges for the successful development of the potential use of blood-based PD-L1 as a biomarker for anti-PD-(L)1 immunotherapy.

59 BASIC BIOLOGICAL SCIENCES↗