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Abstract Organismal adaptations to spaceflight have been characterized at the molecular level in model organisms, including Drosophila and C. elegans. Here, we extend molecular work to energy metabolism and sex hormone signaling in mice and humans. We found spaceflight induced changes in insulin and estrogen signaling in rodents and humans. Murine changes were most prominent in the liver, where we observed inhibition of insulin and estrogen receptor signaling with concomitant hepatic insulin resistance and steatosis. Based on the metabolic demand, metabolic pathways mediated by insulin and estrogen vary among muscles, specifically between the soleus and extensor digitorum longus. In humans, spaceflight induced changes in insulin and estrogen related genes and pathways. Pathway analysis demonstrated spaceflight induced changes in insulin resistance, estrogen signaling, stress response, and viral infection. These data strongly suggest the need for further research on the metabolic and reproductive endocrinologic effects of space travel, if we are to become a successful interplanetary species.

Abstract Background Olfactory neuroblastoma is a rare malignancy of the anterior skull base typically treated with surgery and adjuvant radiation. Although outcomes are fair for low-grade disease, patients with high-grade, recurrent, or metastatic disease oftentimes respond poorly to standard treatment methods. We hypothesized that an in-depth evaluation of the olfactory neuroblastoma tumor immune microenvironment would identify mechanisms of immune evasion in high-grade olfactory neuroblastoma as well as rational targetable mechanisms for future translational immunotherapeutic approaches. Methods Multispectral immunofluorescence and RNAScope evaluation of the tumor immune microenvironment was performed on forty-seven clinically annotated olfactory neuroblastoma samples. A retrospective chart review was performed and clinical correlations assessed. Results A significant T cell infiltration was noted in olfactory neuroblastoma samples with a stromal predilection, presence of myeloid-derived suppressor cells, and sparse natural killer cells. A striking decrease was observed in MHC-I expression in high-grade olfactory neuroblastoma compared to low-grade disease, representing a mechanism of immune evasion in high-grade disease. Mechanistically, the immune effector stromal predilection appears driven by low tumor cell MHC class II (HLA-DR), CXCL9, and CXCL10 expression as those tumors with increased tumor cell expression of each of these mediators correlated with significant increases in T cell infiltration. Conclusion These data suggest that immunotherapeutic strategies that augment tumor cell expression of MHC class II, CXCL9, and CXCL10 may improve parenchymal trafficking of immune effector cells in olfactory neuroblastoma and augment immunotherapeutic responses.

Abstract Persistently high, worldwide mortality from cancer highlights the unresolved challenges of disease surveillance and detection that impact survival. Development of a non-invasive, blood-based biomarker would transform survival from cancer. We demonstrate the functionality of ultra-high content analyses of a newly identified population of tumor cells that are hybrids between neoplastic and immune cells in patient matched tumor and peripheral blood specimens. Using oligonucleotide conjugated antibodies (Ab-oligo) permitting cyclic immunofluorescence (cyCIF), we present analyses of phenotypes among tumor and peripheral blood hybrid cells. Interestingly, the majority of circulating hybrid cell (CHC) subpopulations were not identified in tumor-associated hybrids. These results highlight the efficacy of ultra-high content phenotypic analyses using Ab-oligo based cyCIF applied to both tumor and peripheral blood specimens. The combination of a multiplex phenotypic profiling platform that is gentle enough to analyze blood to detect and evaluate disseminated tumor cells represents a novel approach to exploring novel tumor biology and potential utility for developing the population as a blood-based biomarker in cancer.

Purpose: The purpose of this investigation was to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) for pulmonary metastases from pediatric sarcomas. Methods and Materials: This study was a single institutional retrospective chart review including patients younger than 21 years of age at diagnosis who had received SBRT for pulmonary metastasis from metastatic sarcoma. Our current electronic record system was queried for all eligible patients. Primary endpoint was tumor response as defined by Respone Evaluation Criteria in Solid Tumors 1.1 criteria. Secondarily, we analyzed factors that affected tumor response as well as toxicity of treatment. Median dose was 50 Gy ranging from 30 to 60 Gy in 5 fractions to the planning tumor volume. Results: There were 7 patients, ranging in age from 6 to 21 years with a total of 14 pulmonary lesions treated with SBRT. Median and mean follow-up times for the 7 patients were 10.6 months and 15.9 months, respectively. The complete response rate was 50%, partial response 21%, stable disease 21%, and progressive disease 7%. Four of the 7 patients were treated with concurrent systemic therapy, 3 of which were targeted oral therapies. Additionally, we observed that patients who were on targeted therapy such as regorafenib or pazopanib seemed to have better local control compared with patients without targeted therapy. Conclusions: With an overall response rate of 92%, SBRT provided a noninvasive effective palliative treatment option with few side effects in this small retrospective study of 7 patients. A larger prospective clinical trial is warranted to evaluate the role of SBRT in the treatment of unresectable metastatic pediatric sarcomas.

Collagen VI-related dystrophies (COL6-RDs) are a group of severe, congenital-onset muscular dystrophies for which there is no effective causative treatment. Dominant-negative mutations are common in COL6A1, COL6A2, and COL6A3 genes, encoding the collagen α1, α2, and α3 (VI) chains. They act by incorporating into the hierarchical assembly of the three α (VI) chains and consequently produce a dysfunctional collagen VI extracellular matrix, while haploinsufficiency for any of the COL6 genes is not associated with disease. Hence, allele-specific transcript inactivation is a valid therapeutic strategy, although selectively targeting a pathogenic single nucleotide variant is challenging. Here, we develop a small interfering RNA (siRNA) that robustly, and in an allele-specific manner, silences a common glycine substitution (G293R) caused by a single nucleotide change in COL6A1 gene. By intentionally introducing an additional mismatch into the siRNA design, we achieved enhanced specificity toward the mutant allele. Treatment of patient-derived fibroblasts effectively reduced the levels of mutant transcripts while maintaining unaltered wild-type transcript levels, rescuing the secretion and assembly of collagen VI matrix by reducing the dominant-negative effect of mutant chains. Our findings establish a promising treatment approach for patients with the recurrent dominantly negative acting G293R glycine substitution.

HemoCue analyzers are standard point-of-care devices for measuring blood hemoglobin concentration ([Hb]). The utility of these photometers has been demonstrated for all vertebrate lineages including birds, yet because most vertebrates except mammals possess nucleated red-blood cells, their [Hb] readings are inflated upward in these taxa and require a correction factor relative to the reference calibration. We field tested the newest of these analyzers, Hb801, against its predecessor, the Hb201+. Because of differences in the photometry methods, these two analyzers were not found to be equivalent for taxa with nucleated red-blood cells, such as birds. Whereas a correction factor of 1.0–1.4 g/dL is required for the Hb201+, it may be that no correction factor is required for the Hb801. Further study of the Hb801 relative to a gold-standard reference in non-mammalian lineages is warranted.

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

Abstract Background Immunomodulation by mesenchymal stromal cells (MSCs) can occur through trophic factor mechanisms, however, intravenously infused MSCs are rapidly cleared from the body yet a potent immunotherapeutic response is still observed. Recent work suggests that monocytes contribute to the clearance of MSCs via efferocytosis, the body’s natural mechanism for clearing dead and dying cells in a non-inflammatory manner. This begs the questions of how variations in MSC quality affect monocyte phenotype and if viable MSCs are even needed to elicit an immunosuppressive response. Methods Herein, we sought to dissect MSC’s trophic mechanism from their efferocytic mechanisms and determine if the viability of MSCs prior to efferocytosis influences the resultant phenotype of monocytes. We cultured viable or heat-inactivated human umbilical cord MSCs with human peripheral blood mononuclear cells for 24 h and observed changes in monocyte surface marker expression and secretion profile. To isolate the effect of efferocytosis from MSC trophic factors, we used cell separation techniques to remove non-efferocytosed MSCs before challenging monocytes to suppress T-cells or respond to inflammatory stimuli. For all experiments, viable and heat-inactivated efferocytic-licensing of monocytes were compared to non-efferocytic-licensing control. Results We found that monocytes efferocytose viable and heat-inactivated MSCs equally, but only viable MSC-licensed monocytes suppress activated T-cells and suppression occurred even after depletion of residual MSCs. This provides direct evidence that monocytes that efferocytose viable MSCs are immunosuppressive. Further characterization of monocytes after efferocytosis showed that uptake of viable-but not heat inactivated-MSC resulted in monocytes secreting IL-10 and producing kynurenine. When monocytes were challenged with LPS, IL-2, and IFN-γ to simulate sepsis, monocytes that had efferocytosed viable MSC had higher levels of IDO while monocytes that efferocytosed heat inactivated-MSCs produced the lowest levels of TNF-α. Conclusion Collectively, these studies show that the quality of MSCs efferocytosed by monocytes polarize monocytes toward distinctive immunosuppressive phenotypes and highlights the need to tailor MSC therapies for specific indications.

Accretion is a universal astrophysical process that plays a key role in cosmic history, from the epoch of reionization to galaxy and stellar formation and evolution. Accreting stellar-mass black holes in X-ray binaries are one of the best laboratories to study the accretion process and probe strong gravity—and most importantly, to measure the angular momentum, or spin, of black holes, and its role as a powering mechanism for relativistic astrophysical phenomena. Comprehensive characterization of the disk-corona system of accreting black holes, and their co-evolution, is fundamental to measurements of black hole spin. Here, we use simulated data to demonstrate how key unanswered questions in the study of accreting stellar-mass black holes will be addressed by the High Energy X-ray Probe (HEX-P). HEX-P is a probe-class mission concept that will combine high spatial resolution X-ray imaging and broad spectral coverage (0.2–80 keV) with a sensitivity superior to current facilities (including XMM-Newton and NuSTAR) to enable revolutionary new insights into a variety of important astrophysical problems. We illustrate the capability of HEX-P to: 1) measure the evolving structures of black hole binary accretion flows down to low (≲ 0.1%) Eddington-scaled luminosities via detailed X-ray reflection spectroscopy; 2) provide unprecedented spectral observations of the coronal plasma, probing its elusive geometry and energetics; 3) perform detailed broadband studies of stellar mass black holes in nearby galaxies, thus expanding the repertoire of sources we can use to study accretion physics and determine the fundamental nature of black holes; and 4) act as a complementary observatory to a range of future ground and space-based astronomical observatories, thus providing key spectral measurements of the multi-component emission from the inner accretion flows of black hole X-ray binaries.

TRIM24 regulates transcriptional elongation from the HIV-1 promoter through its interaction with TFII-I, and by recruitment of P-TEFb.

Abstract Expression of the HIV-1 genome by RNA Polymerase II is regulated at multiple steps, as are most cellular genes, including recruitment of general transcription factors and control of transcriptional elongation from the core promoter. We recently discovered that tripartite motif protein TRIM24 is recruited to the HIV-1 Long Terminal Repeat (LTR) by interaction with TFII-I and causes transcriptional elongation by stimulating association of PTEF-b/ CDK9. Because TRIM24 is required for stimulation of transcription from the HIV-1 LTR, we were surprised to find that IACS-9571, a specific inhibitor of the TRIM24 C-terminal bromodomain, induces HIV-1 provirus expression in otherwise untreated cells. IACS-9571 reactivates HIV-1 in T cell lines bearing multiple different provirus models of HIV-1 latency. Additionally, treatment with this TRIM24 bromodomain inhibitor encourages productive HIV-1 expression in newly infected cells and inhibits formation of immediate latent transcriptionally repressed provirus. IACS-9571 synergizes with PMA, ionomycin, TNF-α and PEP005 to activate HIV-1 expression. Furthermore, co-treatment of CD4 + T cells from individuals with HIV-1 on antiretroviral therapy (ART) with PEP005 and IACS-9571 caused robust provirus expression. Notably, IACS-9571 did not cause global activation of T cells; rather, it inhibited induction of IL2 and CD69 expression in human PBMCs and Jurkat T cells treated with PEP005 or PMA. These observations indicate the TRIM24 bromodomain inhibitor IACS-9571 represents a novel HIV-1 latency reversing agent (LRA), and unlike other compounds with this activity, causes partial suppression of T cell activation while inducing expression of latent provirus.

Measurement(s) carbon dioxide • methane • carbon monoxide Technology Type(s) spectroscopy Sample Characteristic - Environment city Sample Characteristic - Location North America

Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCIIloLyve1+TimD4+ (Major histocompatibility complex class IIlow lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental–cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCIIloLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy. Video Abstract:

Introduction: Cognitive impairment is a debilitating symptom in people with multiple sclerosis (MS). Most of the neuropsychological tasks have little resemblance to everyday life. There is a need for ecologically valid tools for assessing cognition in real-life functional contexts in MS. One potential solution would involve the use of virtual reality (VR) to exert finer control over the task presentation environment; however, VR studies in the MS population are scarce.Objectives: To explore the utility and feasibility of a VR program for cognitive assessment in MS.Methods: A VR classroom embedded with a continuous performance task (CPT) was assessed in 10 non-MS adults and 10 people with MS with low cognitive functioning. Participants performed the CPT with distractors (i.e., WD) and without distractors (i.e., ND). The Symbol Digit Modalities Test (SDMT), California Verbal Learning Test—II (CVLT-II), and a feedback survey on the VR program was administered.Results: People with MS exhibited greater reaction time variability (RTV) compared to non-MS participants, and greater RTV in both WD and ND conditions was associated with lower SDMT.Conclusions: VR tools warrant further research to determine their value as an ecologically valid platform for assessing cognition and everyday functioning in people with MS.

Abstract Remote sensing imagery can provide critical information on the magnitude and extent of damage caused by forest pests and pathogens. However, monitoring short‐term changes in deciduous forest condition caused by defoliating insects is challenging and requires approaches that directly account for seasonal vegetation dynamics. We implemented a previously published harmonic modeling approach for forest condition monitoring in Google Earth Engine and systematically assessed the relative ability of condition change products generated using various model parameterizations for predicting pest abundances and defoliation during the 2016–2018 gypsy moth (Lymantria dispar) outbreak in southern New England. Our comparisons revealed that most models made reasonable predictions of changes in canopy condition and egg and larval abundances of L. dispar, indicating a strong correlation between our harmonic‐based estimates of condition change and defoliator activity. The greatest differences in predictive ability were in the spectral domain, with assessments based on Tasseled Cap Greenness, Simple Ratio, and the Enhanced Vegetation Index ranking among the top models, and the commonly used Normalized Difference Vegetation Index consistently exhibiting poorer performance. We also observed notable differences in the magnitude of scores for different baseline periods. Additionally, we found that Landsat‐based condition scores better explained larval abundance than egg mass counts, which have historically been used as a proxy for later‐season larval abundance, indicating that our remote sensing approach may be more accurate and cost‐effective for generating consistent retrospective assessments of L. dispar population abundance in addition to estimates of canopy damage. These findings provide important linkages between spectral changes detected using a harmonic modeling approach and biophysical aspects of defoliator activity, with potential to extend monitoring and prediction to regional or even continental scales.

Abstract The development of bioorthogonal fluorogenic probes constitutes a vital force to advance life sciences. Tetrazine‐encoded green fluorescent proteins (GFPs) show high bioorthogonal reaction rate and genetic encodability but suffer from low fluorogenicity. Here, we unveil the real‐time fluorescence mechanisms by investigating two site‐specific tetrazine‐modified superfolder GFPs via ultrafast spectroscopy and theoretical calculations. Förster resonance energy transfer is quantitatively modeled and revealed to govern the fluorescence quenching; for GFP150‐Tet with a fluorescence turn‐on ratio of ∼9, it contains trimodal subpopulations with good (P1), random (P2), and poor (P3) alignments between the transition dipole moments of protein chromophore (donor) and tetrazine tag (Tet‐v2.0, acceptor). By rationally designing a more free/tight environment, we created new mutants Y200A/S202Y to introduce more P2/P1 populations and improve the turn‐on ratios to ∼14/31, making the fluorogenicity of GFP150‐Tet‐S202Y the highest among all up‐to‐date tetrazine‐encoded GFPs. In live eukaryotic cells, the GFP150‐Tet‐v3.0‐S202Y mutant demonstrates notably increased fluorogenicity, substantiating our generalizable design strategy. Key points Ultrafast spectroscopy reveals FRET in action and inhomogeneous populations with different transition dipole moment alignments. Rational protein design of two new superfolder GFP mutants with record‐high fluorogenicity. Bioimaging application of the designed bioorthogonal protein mutant in live eukaryotic cells.

HIV-1 provirus expression is controlled by signaling pathways that are responsive to T cell receptor engagement, including those involving Ras and downstream protein kinases. The induction of transcription from the HIV-1 LTR in response to Ras signaling requires binding of the Ras-responsive element binding factor (RBF-2) to conserved cis elements flanking the enhancer region, designated RBE3 and RBE1. RBF-2 is composed minimally of the USF1, USF2, and TFII-I transcription factors. We recently determined that TFII-I regulates transcriptional elongation from the LTR through recruitment of the co-activator TRIM24. However, the function of USF1 and USF2 for this effect are uncharacterized. Here, we find that genetic deletion of USF2 but not USF1 in T cells inhibits HIV-1 expression. The loss of USF2 caused a reduction in expression of the USF1 protein, an effect that was not associated with decreased USF1 mRNA abundance. USF1 and USF2 were previously shown to exist predominately as heterodimers and to cooperatively regulate target genes. To examine cooperativity between these factors, we performed RNA-seq analysis of T cell lines bearing knockouts of the genes encoding these factors. In untreated cells, we found limited evidence of coordinated global gene regulation between USF1 and USF2. In contrast, we observed a high degree of genome-wide cooperative regulation of RNA expression between these factors in cells stimulated with the combination of PMA and ionomycin. In particular, we found that the deletion of USF1 or USF2 restricted T cell activation response. These observations indicate that USF2, but not USF1, is crucial for HIV-1 expression, while the combined function of these factors is required for a robust T cell inflammatory response.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

The transient black hole X-ray binary MAXI J1803−298 was discovered on 2021 May 1, as it went into outburst from a quiescent state. As the source rose in flux it showed periodic absorption dips and fit the timing and spectral characteristics of a hard-state accreting black hole. We report on the results of a Target-of-Opportunity observation with NuSTAR obtained near the peak outburst flux beginning on 2021 May 13, after the source had transitioned into an intermediate state. MAXI J1803−298 is variable across the observation, which we investigate by extracting spectral and timing products separately for different levels of flux throughout the observation. Our timing analysis reveals two distinct potential quasiperiodic oscillations (QPOs) which are not harmonically related at 5.4 ± 0.2 Hz and 9.4 ± 0.3 Hz, present only during periods of lower flux. With clear relativistic reflection signatures detected in the source spectrum, we applied several different reflection models to the spectra of MAXI J1803−298. Here we report our results, utilizing high-density reflection models to constrain the disk geometry, and assess changes in the spectrum dependent on the source flux. With a standard broken power-law emissivity, we find a near-maximal spin for the black hole, and we are able to constrain the inclination of the accretion disk at 75° ± 2°, which is expected for a source that has shown periodic absorption dips. We also significantly detect a narrow absorption feature at 6.91 ± 0.06 keV with an equivalent width between 4 and 9 eV, which we interpret as the signature of a disk wind.

Methane (CH _4 ) emissions from the oil and natural gas (O&G) supply chain have been demonstrated to be one of the largest anthropogenic greenhouse gas emission sources ripe for mitigation to limit near-term climate warming. In recent years, exploration and production (E&P) operators have made public commitments to reducing their greenhouse gas emission intensity, yet little empirical information has been made available in the public domain to allow an accurate comparison of their emissions performance. In this study, we utilize a series of aircraft surveys of large CH _4 point source emissions (∼10 ^1 –10 ^4 kg CH _4 hr ^−1 ) related to O&G production in the Permian Basin to enable comparison of company-level production-sector emission intensities. We calculate gas and total energy production normalized emission intensities for several of the largest E&P operators in the Permian Basin accounting for ∼85% of production within the flight region. We find differences of more than an order of magnitude in emission intensity across operators, with nearly half demonstrating a ⩾50% improvement in performance from 2019 to 2021. With the availability of such publicly attributed emissions data anticipated to increase in the future, we provide methodological insights and cautions to developing operator metrics from future empirical datasets.

Objective: To synthesize qualitative literature exploring the lived experience of healthcare workers (HCWs) who cared for patients during the following infectious disease outbreaks (IDOs): the 2003 SARS epidemic, 2009 H1N1 pandemic, 2012 MERS outbreak, and 2014 EVD epidemic. We aim to reveal the collective experience of HCWs during these four IDOs and to create a reference for comparison of current and future IDOs. Methods: Three electronic databases were searched, yielding 823 results after duplicates were removed. Forty qualitative and mixed-methods studies met the criteria for full file review. Fourteen studies met the inclusion and exclusion criteria. The data from the Results or Findings sections were manually coded and themes were conceptualized using thematic analysis. Results: Of the 14 studies, 28.6% focused on SARS, 21.4% on H1N1, 21.4% on MERS, and 28.6% on EVD. Studies occurred in six different countries and included physicians, nurses, paramedics, and emergency medical technicians as participants. Five themes were conceptualized: Uncertainty, Adapting to Change, Commitment, Sacrifice, and Resilience. Conclusion: This review identified the collective experience of HCWs caring for patients during four 21st century IDOs. This qualitative systematic review offers a reference to compare similarities and differences of other IDOs, including the COVID-19 pandemic.

Abstract Anthropogenic carbon dioxide (CO2) emissions dominate uncertainties in the global carbon budget. Global inventories, such as the National Greenhouse Gas Inventories, have latencies of 12–24 months and may not keep pace with rapidly changing infrastructure, particularly in the developing world. Our work reveals that airborne and satellite imaging spectrometers provide 3–30 m spatial resolution and accurate quantification of CO2 emissions at the facility scale. Examples from 17 coal and gas fired power plants across the United States demonstrate robust correlation and 21% agreement on average between our remotely sensed estimates and simultaneous in situ measured emissions. We highlight four examples of coal‐fired power plants in India, Poland, and South Korea, where we quantify significant carbon dioxide emissions from power plants where limited public emissions data exist. Leveraging previous work on methane (CH4) plume detection, we present a strategy to exploit joint CO2 and CH4 plume imaging to quantify carbon emissions across widely distributed industrial infrastructure, including facilities that co‐emit CO2 and CH4. We show an example of a coal operation, where we attribute 25% of greenhouse gas emissions to coal extraction (CH4) and the remaining 75% to energy generation (CO2). Satellite spectrometers could track high emitting coal‐fired power plants that collectively contribute to 60% or more of global coal CO2 emissions. Multiple revisits and coordinated targeting of these high emitting facilities by multiple spaceborne instruments will be key to reducing uncertainties in global anthropogenic CO2 emissions and supporting emissions mitigation strategies.

This article interprets the Marian icon “In Thee All Creation Rejoices” as the theological, liturgical, and visual context for the prisoners' play scene in Dostoevsky's Notes from the House of the Dead. Both the “All Creation” icon and the John of Damascus Hymn that it illustrates, feature prominently in St. Basil's liturgy, which, like the prisoners' play, accompanies the Nativity holiday. The author emphasizes the visual orientation of the novel beginning with the narrator’s description of his collected writings as “Scenes from the House of the Dead”. The visual elements of the “All Creation” icon reappear within the chapter called “Predstavlenie”, in which the narrator Gorianchikov describes the “strange picture” of the prison theater, play and audience. The author contends that the play is a literary performance of the icon and its central theme of sobornost’. The prison play house “scene” mimics the visually polyphonic icon by crowding the prison theater with spectators who sit in front, above, behind and around the stage, on which a female lead appears. These spectators both perform and watch the play, becoming co-creators of the spectacle. Whereas the Nativity feast ends in the prisoners’ debauchery and isolation, the day following Nativity by contrast, the day of the play, culminates in the joy of the shared feast of the Theotokos. Her presence, in the form of the “All Creation” icon that lurks beneath the surface of the chapter at the novel’s core, advocates for amnesty over punishment of criminals, as did Dostoevsky.

An increase in cell size with age is a characteristic feature of replicative aging in budding yeast. Deletion of the gene encoding Whi5 results in shortened duration of G1 and reduced cell size, and has been previously suggested to increase replicative lifespan. Upon careful analysis of multiple independently derived haploid and homozygous diploid whi5Δ mutants, we find no effect on lifespan, but we do confirm the reduction in cell size. We suggest that instead of antagonizing lifespan, the elongated G1 phase of the cell cycle during aging may actually play an important role in allowing aged cells time to repair accumulating DNA damage. Keywords: Cell cycle regulation, Replicative aging, Saccharomyces cerevisiae

Viruses are the most important cause of infectious encephalitis in mammals worldwide; several thousand people, primarily the very young and the elderly, are impacted annually, and few therapies are reliably successful once neuroinvasion has occurred. To understand how viruses contribute to neuropathology, and to develop tools to prevent or ameliorate such infections, it is crucial to define if and how viruses disseminate among the different cell populations within the highly complex central nervous system.

Background: The study aimed to evaluate the effects of transcranial direct current stimulation (tDCS) on cognition, mood disturbance, pain, and fatigue in people with multiple sclerosis (PwMS).Methods: A literature search was performed on articles published between January 1990 and May 2020 in Pubmed, Medline, and Web of Science using the following keywords and their abbreviation in combinations: multiple sclerosis and transcranial direct current stimulation. Mean effect size (ES) and 95% confidence interval were calculated for each domain of interest.Results: Seventeen articles with a total of 383 PwMS were included in this analysis. For cognition, a strong effect size was found for the trial administering the Symbol Digit Modalities Test (ES: 1.15), whereas trials applying the Attention Network Test showed a negative effect size of −0.49. Moderate to strong effect sizes were observed for mood disturbance (mean ES: 0.92), pain (mean ES: 0.59), and fatigue (mean ES: 0.60). Further subgroup analyses for MS-related fatigue showed that both high and low intensities of stimulation lead to nearly the same degree of favorable effects. More pronounced effects were observed in studies administering the Fatigue Severity Scale compared with studies using other fatigue measures such as the Modified Fatigue Impact Scale.Conclusion: These results provide preliminary evidence that tDCS has a favorable effect on cognitive processing speed, mood disturbance, pain, and fatigue in MS. However, the effects on cognition and fatigue vary based on the specific assessment used.

Molecular dynamics (MD) simulations were used to investigate the binding of four ligands to the Val122Ile mutant of the protein transthyretin. Dissociation, misfolding, and subsequent aggregation of mutated transthyretin proteins are associated with the disease Familial Amyloidal Cardiomyopathy. The ligands investigated were the drug candidate AG10 and its decarboxy and N-methyl derivatives along with the drug tafamidis. These ligands bound to the receptor in two halogen binding pockets (HBP) designated AB and A’B’. Inter-ligand distances, solvent accessible surface areas, root mean squared deviation measurements, and extracted structures showed very little change in the AG10 ligands' conformations or locations within the HBP during the MD simulation. In addition, the AG10 ligands experienced stable, two-point interactions with the protein by forming hydrogen bonds with Ser-117 residues in both the AB and A’B’ binding pockets and Lysine-15 residues found near the surface of the receptor. Distance measurements showed these H-bonds formed simultaneously during the MD simulation. Removal of the AG10 carboxylate functional group to form decarboxy-AG10 disrupted this two-point interaction causing the ligand in the AB pocket to undergo a conformational change during the MD simulation. Likewise, addition of a methyl group to the AG10 hydrazone functional group also disrupted the two-point interaction by decreasing hydrogen bonding interactions with the receptor. Finally, MD simulations showed that the tafamidis ligands experienced fewer hydrogen bonding interactions than AG10 with the protein receptor. The tafamidis ligand in pocket A’B’ was also found to move deeper into the HBP during the MD simulation. Keywords: Molecular dynamics simulation, Transthyretin, Tafamidis, AG10, Val122Ile mutant

Offshore oil and natural gas platforms are responsible for about 30% of global oil and natural gas production. Despite the large share of global production there are few studies that have directly measured atmospheric methane emanating from these platforms. This study maps CH _4 emissions from shallow water offshore oil and gas platforms with an imaging spectrometer by employing a method to capture the sun glint reflection from the water directly surrounding the target areas. We show how remote sensing with imaging spectrometers and glint targeting can be used to efficiently observe offshore infrastructure, quantify methane emissions, and attribute those emissions to specific infrastructure types. In 2021, the Global Airborne Observatory platform, which is an aircraft equipped with a visible shortwave infrared imaging spectrometer, surveyed over 150 offshore platforms and surrounding infrastructure in US federal and state waters in the Gulf of Mexico representing ∼8% of active shallow water infrastructure there. We find that CH _4 emissions from the measured platforms exhibit highly skewed super emitter behavior. We find that these emissions mostly come from tanks and vent booms or stacks. We also find that the persistence and the loss rate from shallow water offshore infrastructure tends to be much higher than for typical onshore production.

Abstract Introduction Self-administered in-home digital therapeutics could expand access to cognitive rehabilitation for individuals with multiple sclerosis (MS), over half of whom experience cognitive impairment (CI). However, feasibility in an MS population must be clarified. This study was conducted to assess the feasibility of deploying a videogame-like digital treatment for CI in MS, including initial efficacy and barriers to adherence. Methods In this pilot study, 21 participants with MS completed an in-clinic baseline neurological evaluation. Cognitive tests included paper-and-pencil Brief International Cognitive Assessment for Multiple Sclerosis [BICAMS—which included the Symbol Digit Modalities Test (SDMT)] and other unsupervised tablet-based tests (including Match: an unsupervised test of executive functions and processing speed, developed at UCSF; and the Cogstate MS Battery). Participants then completed an in-home, tablet-based, videogame-like investigational digital treatment (Project: EVO™) for 25 min daily, 5 days weekly, for 4 weeks. This was followed by a repeat in-clinic evaluation. Results Of the 21 participants (mean [standard deviation, SD] age 53.8 [11.6] years, median Expanded Disability Status Scale (EDSS) 2.5 [SD 2.0, IQR [2–3.5]]) enrolled to use the digital therapeutic at home (mean [SD] SDMT z score: − 0.21 [1.16]), 18 completed the study, during which they completed an average of 19.7 days (median [SD]: 20.5 [8.4]). Overall, 78% of these 18 participants completed 75% of prescribed days (i.e., at least 15), and 50% completed all 20 days or more. Over the 4-week period, scores of processing speed improved significantly (based on one-sided t test), including SDMT (p = 0.003) and Match (p = 0.006). The Cogstate DET test (psychomotor function) also increased (p = 0.006). Mean increase in SDMT was 3.6 points. Male sex, not being employed, and higher baseline anxiety all were significantly associated with greater improvement in SDMT over the 4-week period. Interestingly, lower baseline cognitive scores were associated with greater number of sessions completed (e.g., SDMT: p = 0.003, R 2 = 0.44). Adjusting for employment, a proxy for time available, did not significantly improve the model fit. Discussion Deploying an in-home digital tool to improve processing speed in MS is feasible, and shows preliminary efficacy. A larger, randomized controlled clinical trial is ongoing.

We quantify hourly on-road fossil fuel carbon dioxide (FFCO2) emissions at the road segment level for the Los Angeles (LA) megacity based on observed traffic data, and characterize emission patterns across space and time. This on-road FFCO2 emissions dataset for LA (from Hestia version 1.0), based on actual traffic volume, provides emissions per vehicle kilometer travelled (VKT)—an important metric for greenhouse gas (GHG) reductions. We further identify emissions hotpots that can help state and local policy makers plan the most effective GHG reduction strategies. On-road vehicle traffic accounts for half of the FFCO2 emissions in LA, of which 41% is from arterials (intermediate road type). Arterials also have the largest C emissions intensity—FFCO2 per VKT—possibly from high traffic congestion and fleet composition. Non-interstate emissions hotspots (> 419 tC lane-km-1) are equally dominated by arterials and collectors (the lowest road type) in terms of FFCO2 emissions though collectors have a higher VKT. These hotspots occur in densely populated areas and developed landuse classes, largely in LA (67%) and Orange (18%) counties, and provide specific targets for emissions reduction efforts. The estimated uncertainties for interstate, arterial and collector emissions per road length are ± 2.1, ± 0.5 and ± 18.0%, respectively. Our overall estimates compare reasonably well with other products, DARTE and FIVE but with substantial differences in spatial distribution. The method for developing this dataset is easily replicable in other urban landscapes, and represents a powerful tool for carbon cycle science and regional policy makers.

Ecological interactions increasingly occur in the context of anthropogenic landscape alteration, such as landscape fragmentation, which engenders numerous changes to abiotic and biotic processes. Theory and empirical evidence suggest that species that are ecologically specialized or positioned at higher trophic levels are most sensitive to the effects of landscape fragmentation, yet the mechanisms underlying this sensitivity remain hypothetical. Here we present an initial test of the hypothesis that landscape fragmentation affects tri-trophic interactions more severely for dietary specialist than for generalist insect herbivores. We specifically tested a bottom-up hypothesis, that fragmentation reduces hostplant food quality to herbivores, with the most pronounced effects for dietary specialists. We also tested a top-down hypothesis, that fragmentation reduces parasitism of caterpillars, with the most pronounced effects on dietary specialists. We studied interactions among trees, caterpillars, and parasitoids in forest fragments (3–1013 ha) in Connecticut, U.S.A. in 2017 and 2018. To address the bottom-up hypothesis, we measured the growth performance of multiple dietary specialist and generalist caterpillar species fed leaves from red maple and witch hazel trees sampled from large or small forest patches. We assessed the top-down hypothesis by quantifying mortality from insect parasitoids of many of the same caterpillar species on these tree species sampled from a range of forest patch sizes. Fragmentation did not reduce herbivore growth performance for either dietary specialist or generalist caterpillars even though it accelerated desiccation rates of leaves of both tree species over the growing season. However, dietary specialization increased herbivore sensitivity to yearly variation in food quality, as the growth efficiency of specialist caterpillars varied between 2017 and 2018, while that of generalist caterpillars did not. As predicted, parasitism rates of dietary specialist caterpillars declined as forest fragment size declined, whereas parasitism of generalists was independent of fragment size. Therefore, interactions involving dietary specialist herbivores were most sensitive to top-down environmental variation. Assuming that dietary specialist caterpillars are primarily attacked by host-specific parasitoids, this top-down effect is consistent with the trophic theory of island biogeography, which predicts the sharpest declines of ecologically specialized predators and parasites in small habitat patches.

Even with effective viral control, HIV-infected individuals are at a higher risk for morbidities associated with older age than the general population, and these serious non-AIDS events (SNAEs) track with plasma inflammatory and coagulation markers. The cell subsets driving inflammation in aviremic HIV infection are not yet elucidated. Also, whether ART-suppressed HIV infection causes premature induction of the inflammatory events found in uninfected elderly or if a novel inflammatory network ensues when HIV and older age co-exist is unclear. In this study we measured combinational expression of five inhibitory receptors (IRs) on seven immune cell subsets and 16 plasma markers from peripheral blood mononuclear cells (PBMC) and plasma samples, respectively, from a HIV and Aging cohort comprised of ART-suppressed HIV-infected and uninfected controls stratified by age (≤35 or ≥50 years old). For data analysis, multiple multivariate computational algorithms [cluster identification, characterization, and regression (CITRUS), partial least squares regression (PLSR), and partial least squares-discriminant analysis (PLS-DA)] were used to determine if immune parameter disparities can distinguish the subject groups and to investigate if there is a cross-impact of aviremic HIV and age on immune signatures. IR expression on gamma delta (γδ) T cells exclusively separated HIV+ subjects from controls in CITRUS analyses and secretion of inflammatory cytokines and cytotoxic mediators from γδ T cells tracked with TIGIT expression among HIV+ subjects. Also, plasma markers predicted the percentages of TIGIT+ γδ T cells in subjects with and without HIV in PSLR models, and a PLS-DA model of γδ T cell IR signatures and plasma markers significantly stratified all four of the subject groups (uninfected younger, uninfected older, HIV+ younger, and HIV+ older). These data implicate γδ T cells as an inflammatory driver in ART-suppressed HIV infection and provide evidence of distinct “inflamm-aging” processes with and without ART-suppressed HIV infection.

Methane (CH _4 ), an important greenhouse gas and pollutant, has been targeted for mitigation. Our recent California airborne survey identified >500 CH _4 point source super-emitters, which accounted for 34%–46% of the statewide CH _4 emissions inventory for 2016 (Duren et al 2019 Nature 575 180–184). Individual plumes were observed in close proximity to expected methane emitting infrastructure, including gas storage facilities, hydrocarbon storage tanks, landfills, dairy lagoons, and pipeline leaks. In order to systematically attribute these plumes to their sources, we developed Vista-CA a geospatial database, that contains more than 900 000 validated CH _4 infrastructure elements in the state of California. In parallel, we developed a complimentary algorithm that attributes any individual CH _4 plume observation to the most likely Vista-CA source with 99% accuracy. The present study illustrates the capabilities of the Vista-CA CH _4 database along with the Airborne Visible/Infrared Imaging Spectrometer—Next Generation airborne CH _4 retrievals to locate and attribute CH _4 point sources to specific economic sectors to improve the state CH _4 budget and identify mitigation targets.

Accurate and timely detection, quantification, and attribution of methane emissions from Underground Gas Storage (UGS) facilities is essential for improving confidence in greenhouse gas inventories, enabling emission mitigation by facility operators, and supporting efforts to assess facility integrity and safety. We conducted multiple airborne surveys of the 12 active UGS facilities in California between January 2016 and November 2017 using advanced remote sensing and in situ observations of near-surface atmospheric methane (CH _4 ). These measurements where combined with wind data to derive spatially and temporally resolved methane emission estimates for California UGS facilities and key components with spatial resolutions as small as 1–3 m and revisit intervals ranging from minutes to months. The study spanned normal operations, malfunctions, and maintenance activity from multiple facilities including the active phase of the Aliso Canyon blowout incident in 2016 and subsequent return to injection operations in summer 2017. We estimate that the net annual methane emissions from the UGS sector in California averaged between 11.0 ± 3.8 GgCH _4 yr ^−1 (remote sensing) and 12.3 ± 3.8 GgCH _4 yr ^−1 ( in situ ). Net annual methane emissions for the 7 facilities that reported emissions in 2016 were estimated between 9.0 ± 3.2 GgCH _4 yr ^−1 (remote sensing) and 9.5 ± 3.2 GgCH _4 yr ^−1 ( in situ ), in both cases around 5 times higher than reported. The majority of methane emissions from UGS facilities in this study are likely dominated by anomalous activity: higher than expected compressor loss and leaking bypass isolation valves. Significant variability was observed at different time-scales: daily compressor duty-cycles and infrequent but large emissions from compressor station blow-downs. This observed variability made comparison of remote sensing and in situ observations challenging given measurements were derived largely at different times, however, improved agreement occurred when comparing simultaneous measurements. Temporal variability in emissions remains one of the most challenging aspects of UGS emissions quantification, underscoring the need for more systematic and persistent methane monitoring.

Solid waste management represents one of the largest anthropogenic methane emission sources. However, precise quantification of landfill and composting emissions remains difficult due to variety of site-specific factors that contribute to landfill gas generation and effective capture. Remote sensing is an avenue to quantify process-level emissions from waste management facilities. The California Methane Survey flew the Next Generation Airborne Visible/Infrared Imaging Spectrometer (AVIRIS-NG) over 270 landfills and 166 organic waste facilities repeatedly during 2016–2018 to quantify their contribution to the statewide methane budget. We use representative methane retrievals from this campaign to present three specific findings where remote sensing enabled better landfill and composting methane monitoring: (1) Quantification of strong point source emissions from the active face landfills that are difficult to capture by in situ monitoring or landfill models, (2) emissions that result from changes in landfill infrastructure (design, construction, and operations), and (3) unexpected large emissions from two organic waste management methods (composting and digesting) that were originally intended to help mitigate solid waste emissions. Our results show that remotely-sensed emission estimates reveal processes that are difficult to capture in biogas generation models. Furthermore, we find that airborne remote sensing provides an effective avenue to study the temporally changing dynamics of landfills. This capability will be further improved with future spaceborne imaging spectrometers set to launch in the 2020s.

PURPOSE:Human females have a unique duration of post-reproductive longevity, during which sex-specific mechanisms ma influence later-life mechanisms of neuronal resilience and vulnerability. The maintenance of energy metabolism, through the oxidative phosphorylation (OXPHOS) apparatus, is essential for brain health. Given the known association between reproductive period (years from menarche to menopause) and cognitive aging, we examined the hypothesis that cumulative estrogen exposure across the lifetime may be associated with differential methylation of genes in the OXPHOS pathway. METHODS:Using DNA methylation patterns in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 426 women prospectively followed until death in the Religious Orders Study and Rush Memory and Aging Project, we examined the relationship between reproductive period (subtracting age at menarche from age at menopause) and DNA methylation of a published set of autosomal OXPHOS genes previously implicated in stroke susceptibility. We then performed an unsupervised analysis of methylation levels across the Hallmark pathways from the Molecular Signatures Database. RESULTS:We observed a strong association between reproductive period and DNA methylation status across OXPHOS CpGs. We replicated this association between reproductive period and DNA methylation in a much larger set of OXPHOS genes in our unsupervised analysis. Here, reproductive period also showed associations with methylation in genes related to E2F, MYC and MTORC1 signaling, fatty acid metabolism and DNA repair. CONCLUSION:This study provides evidence from both a supervised and unsupervised analyses, that lifetime cumulative endogenous steroid exposures may play a role in maintenance of post-menopausal cellular balance, including in brain tissue.

Chagas disease is a complex vector borne parasitic disease involving blood feeding Triatominae (Hemiptera: Reduviidae) insects, also known as kissing bugs, and the vertebrates they feed on. This disease has tremendous impacts on millions of people and is a global health problem. The etiological agent of Chagas disease, Trypanosoma cruzi (Kinetoplastea: Trypanosomatida: Trypanosomatidae), is deposited on the mammalian host in the insect's feces during a blood meal, and enters the host's blood stream through mucous membranes or a break in the skin. Identifying the blood meal sources of triatomine vectors is critical in understanding Chagas disease transmission dynamics, can lead to identification of other vertebrates important in the transmission cycle, and aids management decisions. The latter is particularly important as there is little in the way of effective therapeutics for Chagas disease. Several techniques, mostly DNA-based, are available for blood meal identification. However, further methods are needed, particularly when sample conditions lead to low-quality DNA or to assess the risk of human cross-contamination. We demonstrate a proteomics-based approach, using liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify host-specific hemoglobin peptides for blood meal identification in mouse blood control samples and apply LC-MS/MS for the first time to Triatoma dimidiata insect vectors, tracing blood sources to species. In contrast to most proteins, hemoglobin, stabilized by iron, is incredibly stable even being preserved through geologic time. We compared blood stored with and without an anticoagulant and examined field-collected insect specimens stored in suboptimal conditions such as at room temperature for long periods of time. To our knowledge, this is the first study using LC-MS/MS on field-collected arthropod disease vectors to identify blood meal composition, and where blood meal identification was confirmed with more traditional DNA-based methods. We also demonstrate the potential of synthetic peptide standards to estimate relative amounts of hemoglobin acquired when insects feed on multiple blood sources. These LC-MS/MS methods can contribute to developing Ecohealth control strategies for Chagas disease transmission and can be applied to other arthropod disease vectors.