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114 records · Page 7

Dual blockade of IL-10 and PD-1 leads to control of SIV viral rebound following analytical treatment interruption

Human immunodeficiency virus (HIV) persistence during antiretroviral therapy (ART) is associated with heightened plasma interleukin-10 (IL-10) levels and PD-1 expression. We hypothesized that IL-10 and PD-1 blockade would lead to control of viral rebound following analytical treatment interruption (ATI). Twenty-eight ART-treated, simian immunodeficiency virus (SIV)mac 239 -infected rhesus macaques (RMs) were treated with anti-IL-10, anti-IL-10 plus anti-PD-1 (combo) or vehicle. ART was interrupted 12 weeks after introduction of immunotherapy. Durable control of viral rebound was observed in nine out of ten combo-treated RMs for >24 weeks post-ATI. Induction of inflammatory cytokines, proliferation of effector CD8 + T cells in lymph nodes and reduced expression of BCL-2 in CD4 + T cells pre-ATI predicted control of viral rebound. Twenty-four weeks post-ATI, lower viral load was associated with higher frequencies of memory T cells expressing TCF-1 and of SIV-specific CD4 + and CD8 + T cells in blood and lymph nodes of combo-treated RMs. These results map a path to achieve long-lasting control of HIV and/or SIV following discontinuation of ART.

60 APPLIED LIFE SCIENCES↗

LSTM-Based Data Integration to Improve Snow Water Equivalent Prediction and Diagnose Error Sources

Accurate prediction of snow water equivalent (SWE) can be valuable for water resource managers. Recently, deep learning methods such as long short-term memory (LSTM) have exhibited high accuracy in simulating hydrologic variables and can integrate lagged observations to improve prediction, but their benefits were not clear for SWE simulations. Here we tested an LSTM network with data integration (DI) for SWE in the western United States to integrate 30-day-lagged or 7-day-lagged observations of either SWE or satellite-observed snow cover fraction (SCF) to improve future predictions. SCF proved beneficial only for shallow-snow sites during snowmelt, while lagged SWE integration significantly improved prediction accuracy for both shallow- and deep-snow sites. The median Nash–Sutcliffe model efficiency coefficient (NSE) in temporal testing improved from 0.92 to 0.97 with 30-day-lagged SWE integration, and root-mean-square error (RMSE) and the difference between estimated and observed peak SWE values d max were reduced by 41% and 57%, respectively. DI effectively mitigated accumulated model and forcing errors that would otherwise be persistent. Moreover, by applying DI to different observations (30-day-lagged, 7-day-lagged), we revealed the spatial distribution of errors with different persistent lengths. For example, integrating 30-day-lagged SWE was ineffective for ephemeral snow sites in the southwestern United States, but significantly reduced monthly-scale biases for regions with stable seasonal snowpack such as high-elevation sites in California. These biases are likely attributable to large interannual variability in snowfall or site-specific snow redistribution patterns that can accumulate to impactful levels over time for nonephemeral sites. These results set up benchmark levels and provide guidance for future model improvement strategies.

54 ENVIRONMENTAL SCIENCES↗

Intranasal Nanoparticle Vaccination Elicits a Persistent, Polyfunctional CD4 T Cell Response in the Murine Lung Specific for a Highly Conserved Influenza Virus Antigen That Is Sufficient To Mediate Protection from Influenza Virus Challenge

We report lung-localized CD4 T cells play a critical role in the control of influenza virus infection and can provide broadly protective immunity. However, current influenza vaccination strategies primarily target influenza hemagglutinin (HA) and are administered peripherally to induce neutralizing antibodies. We have used an intranasal vaccination strategy targeting the highly conserved influenza nucleoprotein (NP) to elicit broadly protective lung-localized CD4 T cell responses. The vaccine platform consists of a self-assembling nanolipoprotein particle (NLP) linked to NP with an adjuvant. We have evaluated the functionality, in vivo localization, and persistence of the T cells elicited. Our study revealed that intranasal vaccination elicits a polyfunctional subset of lung-localized CD4 T cells that persist long term. A subset of these lung CD4 T cells localize to the airway, where they can act as early responders following encounter with cognate antigen. Polyfunctional CD4 T cells isolated from airway and lung tissue produce significantly more effector cytokines IFN-γ and TNF-α, as well as cytotoxic functionality. When adoptively transferred to naive recipients, CD4 T cells from NLP:NP-immunized lung were sufficient to mediate 100% survival from lethal challenge with H1N1 influenza virus.

59 BASIC BIOLOGICAL SCIENCES↗

Minimal cyclic behavior in sheared amorphous solids

Although jammed packings of soft spheres exist in potential energy landscapes with a vast number of minima, when subjected to cyclic shear they may revisit the same configurations repeatedly. Simple hysteretic spin models, in which particle rearrangements are represented by interacting spin flips called hysterons, capture many features of this periodic behavior. Yet it has been unclear to what extent individual rearrangements can be described by such binary objects and how such objects interact with one another. Using a particularly sensitive algorithm, we identify rearrangements in simulated jammed packings and select pairs of rearrangements that undo one another to create periodic cyclic behavior. We find that the rearrangement pairs surprisingly persist down to the smallest increments in strain, even in the smallest systems we can study. We explore the statistics of these rearrangement pairs and find that there is a relation between the amount of hysteresis and the energy drop and mean-square displacement of the particles; these results are inconsistent with the scaling found in models that treat rearrangements as localized buckling events. Finally, our analysis shows that there is no clean distinction between the particle motions that represent the identity of a single, individual rearrangement and the particle motions that lead to interactions between separated rearrangements or hysterons. These results offer insight into how complex systems such as amorphous solids can reach a limit cycle.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗

Review of Human Cognitive Performance in Spaceflight

Human space exploration is inherently hazardous, particularly for lon g duration (LD) missions (22 days or longer). Maintenance of cognitive functioning is essential, but flight environments pose numerous pote ntial risks to the brain and cognitive performance (eg, radiation, to xins, chronic stress, sleep deprivation, hypercarbia, fluid shifts, h ormone imbalances, and injury). There have been persistent anecdotal reports of cognitive deficits during missions, but an up?-to-date rev iew of the evidence for such changes has remained unavailable. Method s: We identified and reviewed English language publications found via electronic searches in PubMed, PsycInfo, Inspec, the NASA Technical Report Server, and the Defense Technical Information Center, plus rec ursive searches of publication bibliographies. Search terms included the word cognition, cognitive, or performance along with spaceflight, flight, mission, or closely related terms. Results: Inter?-study variability precluded meta?-analysis. Some 32 published studies involving cognitive assessment during spaceflight were identified, involving a total of 110 participants (mean: 3.4 participants per study). The lo ngest?-duration study spanned 438 days, with six additional studies i nvolving flight durations of 90 days, and 11 more studies involved fl ight durations exceeding 21 days. The available evidence failed to st rongly support or refute the existence of cognitive deficits in LD sp aceflight, in part due to inadequate power or control conditions. Evi dence of increased variability in cognitive performance during spacef light, both within and between individuals, was common. Discussion: T hese results represent a negative finding based on small numbers of s ubjects for any given cognitive function. The increased variability within and (particularly) between individuals highlights the potential danger of generalizing from case studies. A mismatch therefore remain s between anecdotal reports describing generalized cognitive slowing, attention and memory problems during missions and the experimental e vidence supporting such deficits. Since a major justification for man ned spaceflight rests with the cognitive flexibility of humans, addit ional studies and further analysis of existing operational data appea rs warranted.

Strangman, Gary↗

Probing Cretaceous-Paleogene crustal thickness in southern Tibet using quartz-zircon chronobarometry

Knowledge of the crustal thickness history of southern Tibet during the India-Asia collision is key to understanding what deformation mechanisms accommodated northward propagating crustal shortening. Thermoisotopic models suggest that a relatively thin margin of southern Asia persisted from ca. 200 to 45 Ma whereas trace element paleodepth proxies are interpreted to indicate a thinning phase from ca. 100 to 65 Ma when the crust reached ∼30 km-thickness. As neither of these methods directly measures crustal thickness, resolution of this conflict awaits development of a method that can. Here, in this study, we place bounds on the thickening history of southern Tibet using coupled quartz-zircon thermobarometry and U-Pb geochronology of granitoid plutons in the Gangdese batholith. We find that crustal thicknesses were as high (or higher) as 60–75 km at 65 Ma, or 10–15 Ma prior to the onset of hard continental collision. Magmatic inflation in the lower crust likely contributed to crustal thickening and thermal weakening of the lower crust, suggesting that pure shear in the lower crust was likely the primary accommodation mechanism for N-S shortening during collision. These data are in partial agreement with results of thermoisotopic models of crustal thickness but contradict thickness histories derived from empirical trace element proxies.

Chronobarometry↗