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The world’s largest lakes, including the Laurentian Great Lakes, have experienced significant surface warming and loss of ice cover over the last several decades. Although changing surface conditions have received substantial research interest, changes below the surface remain largely unexplored, despite their importance for turbulent mixing, nutrient cycling, and primary production. In this study, we investigate changes in subsurface thermal structure and timing in Lake Michigan-Huron related to ongoing climate warming. This work utilizes atmospheric reanalysis data to drive the Great Lakes Finite Volume Community Ocean Model (GL-FVCOM), providing three-dimensional hydrodynamic and ice simulations between 1979 and 2021. Results are used to analyze trends in ice and temperature dynamics, revealing significant changes in annually averaged ice cover (− 2.1– − 5.2%/decade), ice thickness (− 0.68 – − 2.0 cm/decade), surface temperature (+ 0.47– + 0.51 $$^\circ{\rm C}$$ ∘ C /decade), and bottom temperature (+ 0.26– + 0.29 $$^\circ{\rm C}$$ ∘ C /decade) over the last 40 years, especially in ecologically important bays (e.g., Green Bay, Saginaw Bay). Significant warming was observed at all depth layers (0–270 m), with warming trends in the epilimnion and hypolimnion that agreed well with recent analysis of observational data in Lake Michigan. Shifting stratification dynamics led to dramatic changes in modelled overturning behavior, and earlier spring turnover dates (− 2.2– − 7.5 days/decade) and later fall turnover dates (+ 2.5– + 6.3 days/decade) led to a net lengthening of the stratified period. This study presents one of the most comprehensive analyses of changes in Great Lakes subsurface temperatures to date, providing important context for future climate modelling and coastal management efforts in the region.

Application of lake models coupled within earth-system prediction models, especially for predictions from days to weeks, requires accurate initialization of lake temperatures. Commonly used methods to initialize lake temperatures include interpolation of global sea-surface temperature (SST) analyses to inland lakes, daily satellite-based observations, or model-based reanalyses. However, each of these methods have limitations in capturing the temporal characteristics of lake temperatures (e.g., effects of anomalously warm or cold weather) for all lakes within a geographic region and/or during extended cloudy periods. An alternative lake-initialization method was developed which uses two-way-coupled cycling of a small-lake model within an hourly data assimilation system of a weather prediction model. The lake model simulated lake temperatures were compared with other estimates from satellite and in situ observations and interpolated-SST data for a multi-month period in 2021. The lake cycling initialization, now applied to two operational US NOAA weather models, was found to decrease errors in lake surface temperature from as much as 5–10 K vs. interpolated-SST data to about 1–2 K compared to available in situ and satellite observations.

Background Developing a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells' proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection. Methods Using 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets. Results An exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature's negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell-mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature's negative predictive value was 90.6% and its positive predictive value was 77.8%. Conclusions Our findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.

Application of lake models coupled within earth-system prediction models, especially for short-term predictions from days to weeks, requires accurate initialization of lake temperatures. Here, we describe a lake initialization method by cycling within an hourly updated weather prediction model to constrain lake temperature evolution. We compare these simulated lake temperature values with other estimates from satellite and in situ and interpolated-SST data sets for a multi-month period in 2021. The lake cycling initialization, now applied to two operational US NOAA weather models, was found to decrease errors in lake temperature from as much as 5–10 K (using interpolated-SST data) to about 1–2 K (comparing with available in situ and satellite observations.

This study models the amount of contrast that could be conserved in computed tomographic examinations in the context of the current global shortage of iodinated contrast media.

Despite success in hematologic malignancies, chimeric antigen receptor (CAR) T cells have been less effective in solid tumors, in part because of the heterogeneous expression of the CAR-specific target antigen (1° Ag) found within the tumor mass. In combination with a CAR, bispecific T cell engagers (BiTEs) can target additional tumor antigens (2° Ag) while engaging CD3 signaling molecules on T cells, providing a unique way to address tumor heterogeneity, mitigate antigen escape and further potentiate durable effector function. However, in generating off-the-shelf universal CAR-T and NK cells, a combination strategy is not feasible as neither modified cell product is compatible to specifically engage with a BiTE. In developing allogeneic CAR-T cells, the T cell receptor (TCR) surface expression must be eliminated to prevent graft versus host disease, but the absence of surface TCR expression leads to loss of surface CD3 expression and BiTE compatibility. Similarly, NK cells naturally lack TCR expression and have no surface CD3 molecules for BiTE engagement. Here we discuss the development of a novel chimeric CD3ε fusion receptor (CD3-CFR) with a modified transmembrane and endodomain enabling surface expression in TCR-less T or NK cells, allowing for a novel combinatorial solution between universal CAR-T or NK cells with BiTEs in an allogeneic setting. CD3-CFR signal transduction was initially investigated in TRAC knockout NFAT reporter (T-KO) Jurkat cells engineered with CD3-CFR and co-cultured with EpCAM+ target cells. When soluble EpCAM-BiTE was added to the co-culture, the observed 6.9-fold increase in NFAT activity indicated successful engagement associated with the interaction of CD3-CFR, target cells and the BiTE. CD3-CFR T-KO Jurkat cells were further modified to secrete the EpCAM-BiTE and showed increased NFAT activity, demonstrating the feasibility of self-secreting BiTE-mediated targeting through CD3-CFR signaling. We next engineered CD3-CFR expressing iPSC-derived CAR-T (iT) cells to show preserved T cell differentiation kinetics and maintained CAR activity against 1° Ag positive targets (>90% cytolysis). Importantly, while CAR-iT cells showed only background lysis of 1° Ag negative tumor cells, CD3-CFR+ CAR-iT cells were able to lyse ~99% of 1° Ag negative tumor cells with the addition of soluble EpCAM-BiTE targeting the 2° Ag. When CD3-CFR+ CAR-iT cells were further engineered to secrete the EpCAM-BiTE, CD3-CFR+ BiTE+ CAR-iT cells demonstrated superior killing of heterogenous tumors compared to CD3-CFR+ BiTE- CAR-iT cells (70% vs. 5% cytolysis). Taken together these data demonstrate for the first time that CD3 expression and BiTE engagement can be combined in a universal iPSC-derived CAR-iT cell product to overcome antigen heterogeneity and enhance efficacy in solid tumor settings. Citation Format: Eigen Peralta, Dan Lu, Mark Landon, Hui-Yi Chu, Amit Mehta, Philip Chu, Alec Witty, Tom Lee, Bahram Valamehr. Chimeric CD3 fusion receptors expressed on iPSC-derived universal TCR-less CAR-T and -NK cells synergize with bispecific engagers to enhance antitumor activity and limit antigen escape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5513.

New Onset Diabetes After Transplantation (NODAT) is a serious metabolic complication. While β-cell dysfunction is considered the main contributing factor in the development of NODAT, the precise pathogenesis is not well understood. Cytokines are thought to be involved in the inflammation of islet β-cells in diabetes; however, few studies have investigated this hypothesis in NODAT. A total of 309 kidney transplant recipients (KTRs) were included in this study. An association between kidney transplants, and the development of diabetes after transplant (NODAT) was investigated. Comparison was made between KTRs who develop diabetes (NODAT cases) or did not develop diabetes (control), using key cytokines, IL-6 G (− 174)C, macrophage mediator; IL-4 C (− 490)T, T helper (Th)-2 cytokine profile initiator; Th-1 cytokine profile initiator interferon-γ T (+ 874) A gene and TGF β1 C (+ 869) T gene polymorphisms were investigated. The genes were amplified using well-established polymerase chain reaction (PCR) techniques in our laboratory. Compared to the AA and AT genotypes of interferon gamma (IFNG), there was a strong association between the TT genotype of IFNG and NODAT kidney transplant recipients (KTRs) versus non-NODAT KTRs (p = 0.005). The AA genotype of IFNG was found to be predominant in the control group (p = 0.004). Also, significant variations of IL6 G (− 174) C, IL-4 C (− 590) T, interferon-γ T (+ 874) A gene and transforming growth factor β1 C (+ 869) T may contribute to NODAT. Our data is consistent with theTh-1/T-reg pathway of immunity. Further larger pan Arab studies are required to confirm our findings.

Groundwater historically has been a critical but understudied, underfunded, and underappreciated natural resource, although recent challenges associated with both groundwater quantity and quality have raised its profile. This is particularly true in the Laurentian Great Lakes (LGL) region, where the rich abundance of surface water results in the perception of an unlimited water supply but limited attention on groundwater resources. As a consequence, groundwater management recommendations in the LGL have been severely constrained by our lack of information. To address this information gap, a virtual summit was held in June 2021 that included invited participants from local, state, and federal government entities, universities, non-governmental organizations, and private firms in the region. Both technical (e.g., hydrologists, geologists, ecologists) and policy experts were included, and participants were assigned to an agricultural, urban, or coastal wetland breakout group in advance, based on their expertise. The overall goals of this groundwater summit were fourfold: (1) inventory the key (grand) challenges facing groundwater in Michigan; (2) identify the knowledge gaps and scientific needs, as well as policy recommendations, associated with these challenges; (3) construct a set of conceptual models that elucidate these challenges; and (4) develop a list of (tractable) next steps that can be taken to address these challenges. Absent this type of information, the sustainability of this critical resource is imperiled.

Solid organ transplantation is a lifesaving therapy for patients with end-organ disease. Current immunosuppression protocols are not designed to target antigen-specific alloimmunity and are uncapable of preventing chronic allograft injury. As myeloid-derived suppressor cells (MDSCs) are potent immunoregulatory cells, we tested whether donor-derived MDSCs can protect heart transplant allografts in an antigen-specific manner. C57BL/6 (H2Kb, I-Ab) recipients pre-treated with BALB/c MDSCs were transplanted with either donor-type (BALB/c, H2Kd, I-Ad) or third-party (C3H, H2Kk, I-Ak) cardiac grafts. Spleens and allografts from C57BL/6 recipients were harvested for immune phenotyping, transcriptomic profiling and functional assays. Single injection of donor-derived MDSCs significantly prolonged the fully MHC mismatched allogeneic cardiac graft survival in a donor-specific fashion. Transcriptomic analysis of allografts harvested from donor-derived MDSCs treated recipients showed down-regulated proinflammatory cytokines. Immune phenotyping showed that the donor MDSCs administration suppressed effector T cells in recipients. Interestingly, significant increase in recipient endogenous CD11b+Gr1+ MDSC population was observed in the group treated with donor-derived MDSCs compared to the control groups. Depletion of this endogenous MDSCs with anti-Gr1 antibody reversed donor MDSCs-mediated allograft protection. Furthermore, we observed that the allogeneic mixed lymphocytes reaction was suppressed in the presence of CD11b+Gr1+ MDSCs in a donor-specific manner. Donor-derived MDSCs prolong cardiac allograft survival in a donor-specific manner via induction of recipient’s endogenous MDSCs.

Summary During neonatal development, sensory cortices generate spontaneous activity patterns shaped by both sensory experience and intrinsic influences. How these patterns contribute to the assembly of neuronal circuits is not clearly understood. Using longitudinal in vivo calcium imaging in un-anesthetized mouse pups, we show that spatially segregated functional assemblies composed of interneurons and pyramidal cells are prominent in the somatosensory cortex by postnatal day (P) 7. Both reduction of GABA release and synaptic inputs onto pyramidal cells erode the emergence of functional topography, leading to increased network synchrony. This aberrant pattern effectively blocks interneuron apoptosis, causing increased survival of parvalbumin and somatostatin interneurons. Furthermore, the effect of GABA on apoptosis is mediated by inputs from medial ganglionic eminence (MGE)-derived but not caudal ganglionic eminence (CGE)-derived interneurons. These findings indicate that immature MGE interneurons are fundamental for shaping GABA-driven activity patterns that balance the number of interneurons integrating into maturing cortical networks.

The basolateral amygdala (BLA) plays a vital role in associating sensory stimuli with salient valence information. Excitatory principal neurons (PNs) undergo plastic changes to encode this association; however, local BLA inhibitory interneurons (INs) gate PN plasticity via feedforward inhibition (FFI). Despite literature implicating parvalbumin expressing (PV+) INs in FFI in cortex and hippocampus, prior anatomical experiments in BLA implicate somatostatin expressing (Sst+) INs. The lateral entorhinal cortex (LEC) projects to BLA where it drives FFI. In the present study, we explored the role of interneurons in this circuit. Using mice, we combined patch clamp electrophysiology, chemogenetics, unsupervised cluster analysis, and predictive modeling and found that a previously unreported subpopulation of fast-spiking Sst+ INs mediate LEC→BLA FFI.

BackgroundTransforming growth factor beta (TGFβ) is an immuno-suppressive cytokine present in the tumor microenvironment (TME) that creates considerable challenges for the treatment of solid tumors. Small molecule inhibitors targeting TGFβ exist, but the pleiotropic nature of TGFβ signaling suggests that a more targeted approach is preferential, especially in the context of cellular therapy. We hypothesized that primary T cells and iPSC-derived chimeric antigen receptor-T cells (CAR-iT cells) would benefit not only from blockade of TGFβ signaling, but also from re-direction of the signaling event toward specific cytokine pathways that activate cell function. Here we discuss novel synthetic TGFβ redirector constructs that overcome TME limitations and enhance CAR-iT cell function for improved efficacy in treating solid tumors.MethodsTo identify activation pathways for redirection of TGFβ signaling, we screened a panel of cytokines for their effect on the anti-tumor activity of CAR-iT cells. We then developed synthetic redirector receptors where a TGFBR2 ectodomain was fused to the top selected cytokine receptor endodomains. Redirection of TGFβ signaling was confirmed by phospho-flow of key signaling proteins. Anti-tumor activity of CAR-iT cells expressing these synthetic redirector constructs was tested in serial restimulation assays in the absence of cytokine support and in the presence of recombinant TGFβ (rTGFβ).ResultsA dose-dependent decrease in CAR-iT cell cytolytic capacity in the presence of rTGFβ was observed, with the activity of CAR-iT cells rescued in the presence of unique cytokines. We designed and tested synthetic TGFβ redirector constructs and demonstrated a rTGFβ-dependent increase in pSTAT5 positive cells (2.8-fold over control). The serial stimulation assay was then used to test CAR-iT cells engineered with synthetic TGFβ redirector receptors. After three rounds of restimulation, an increase in tumor cell numbers for non-engineered and dominant negative TGFBR2 CAR-iT cell controls was observed (41-fold and 32-fold increase over base input, respectively). In contrast, the synthetic TGFβ redirector receptor improved the ability of CAR-iT cells to control tumor cell growth with remarkable efficiency, limiting tumor growth to only 1.5-fold over three rounds of restimulation.ConclusionsThese studies demonstrate that a novel synthetic construct comprised of fusion of cytokine endodomains to a TGFBR2 ectodomain can be deployed to hijack the immuno-suppressive signal of TGFβ often found in the TME and activate CAR-iT cells for enhanced anti-tumor activity in solid tumors. Additional studies are underway to assess the temporal expression and activity of these synthetic redirector receptors in various preclinical models which will be further discussed.

Although chimeric antigen receptor (CAR)-T cells have been transformational for several liquid tumors, their effectiveness in treating a variety of solid tumors has been limited in part because the heterogeneity of tumor-associated antigens found in many bulky tumors represents a major obstacle to the development and the delivery of effective CAR-T cell therapies in cancer. Here we demonstrate that iPSC-derived CAR-T (CAR-iT) cells are an ideal off-the-shelf approach that can be engineered to perform antibody-dependent cell-mediated cytotoxicity (ADCC) to facilitate multi-antigen targeting with the introduction of various monoclonal antibodies (mAbs). Under this strategy, while the CAR is equipped to predominantly target antigen 1, targeting additional tumor associated antigens through the use of various mAbs can be leveraged through ADCC. To this end, CAR-iT cells were genetically edited at the iPSC stage to uniformly express a novel high-affinity variant (158V), non-cleavable CD16A (hnCD16) Fc receptor to recognize and bind to the Fc fragment of mAbs and facilitate ADCC. When combined with therapeutic mAbs targeting HER2, EGFR, or PDL1, the cytolytic efficacy of hnCD16+ CAR-iT cells was significantly enhanced compared to parental CAR-iT cells in several tumor models, including ovarian, HER2+ breast, and triple-negative breast cancers, underscoring the flexibility of a combined CAR and ADCC – mediated targeting approach. Importantly, although both CD16A and CAR signaling share common CD3ζ pathways, simultaneous activation did not appreciably attenuate the activation and effector function of CAR-iT cells. Moreover, hnCD16+ CAR-iT cells demonstrated enhanced control in an established triple negative breast cancer solid tumor xenograft model. The control of antigenically heterogenous tumors by hnCD16+ CAR-iT cells was also significantly improved when compared to parental CAR-iT cells. To confirm selectivity and avoidance of immunoglobulin interference with functional output, various in vitro cellular cytotoxicity assays were conducted with IgG1 to confirm that hnCD16 requires crosslinking to elicit ADCC while maintaining full potentiation of CAR function. Additional in vitro and in vivo studies are ongoing and will be presented. Collectively, the data demonstrates that CAR-iT cells can be further modified with hnCD16 Fc receptor to elicit ADCC and the combination of CAR and hnCD16 is a unique approach to tackling tumor heterogeneity often found in bulky tumors. Citation Format: Martin Hosking, Soheila Shirinbak, Joy Grant, Wen-I Yeh, Yijia Pan, Mochtar Pribadi, Amit Mehta, Amanda Yzaguirre, Philip Chu, Shohreh Sikaroodi, Angela Gentile, Bruce Walcheck, Jianming Wu, Anhco Nguyen, Bahram Valamehr. A unique strategy to arm iPSC-derived CAR-T cells to perform antibody-directed cellular cytotoxicity to facilitate multi-antigen targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1497.

The development of chimeric antigen receptor (CAR) T cell therapeutics is widely recognized as a significant advancement for the treatment of cancer. However, several obstacles currently impede the broad use of CAR T cells, including the inherent process variability, cost of manufacturing, the absolute requirement for precise and uniform genetic editing in the allogeneic setting, and the challenge to keep pace with clonal heterogeneity and tumor growth. Utilizing our previously described induced pluripotent stem cell (iPSC)-derived T (iT) cell platform, we illustrate here the unique ability to address these challenges by creating a consistent CAR iT cell product that can be repeatedly manufactured in large quantities from a renewable iPSC master cell bank that has been engineered to mitigate the occurrence of graft versus host disease (GvHD), antigen escape and tumor relapse. Utilizing our proprietary cellular reprogramming and engineering platform and stage-specific T cell differentiation protocol, we demonstrate that iPSC can be engineered at the single cell level to generate a fully characterized clonal iPSC line, which can then be accessed routinely to yield CAR iT cells in a highly scalable manufacturing process (>100,000 fold expansion). Through bi-allelic targeting of a CAR into the T cell receptor alpha constant (TRAC) region, we generated CAR iT cells with uniform CAR expression (99.0 ± 0.5% CAR+) and complete elimination of T cell receptor (TCR) expression to avoid GvHD in the allogeneic setting. We elected to utilize the 1XX-CAR configuration, which has demonstrated superior anti-tumor performance relative to other CAR designs and when introduced into iT cells displayed enhanced antigen specificity (% specific cytotoxicity at E:T=10:1, antigen positive group: 86.4 ± 7.8; antigen null group: 8.9 ± 3.5). To enhance persistence without reliance on exogenous cytokine support, we engineered signaling-fusion complexes, including IL-7 receptor fusion (RF), into iPSC and studied its impact on iT phenotype, persistence, and efficacy. In vitro, IL-7RF clones demonstrated improved anti-tumor activity in a serial antigen dependent tumor challenge assay (Day 10, relative tumor counts, IL-7RF group: 1.95 ± 0.01; control group: 57.56 ± 4.55, P Collectively, the described studies demonstrate that iPSCs are an ideal cellular source to generate large-quantities of uniformly multi-edited off-the-shelf CAR T cell products that include a best-in-class CAR design, enhanced product modalities, and complete elimination of TCR expression to avoid the potential of GvHD while maintaining high anti-tumor efficacy in allogeneic setting. Disclosures Hsia: Fate Therapeutics Inc.: Current Employment. Clarke:Fate Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lee:Fate Therapeutics, Inc.: Current Employment. Robbins:Fate Therapeutics, Inc.: Current Employment. Denholtz:Fate Therapeutics, Inc: Current Employment. Hanok:Fate Therapeutics, Inc.: Current Employment. Carron:Fate Therapeutics, Inc.: Current Employment. Navarrete:Fate Therapeutics, Inc.: Current Employment. ORourke:Fate Therapeutics, Inc.: Current Employment. Sung:Fate Therapeutics, Inc.: Current Employment. Gentile:Fate Therapeutics, Inc.: Current Employment. Nguyen:Fate Therapeutics, Inc.: Current Employment. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company.

The Mississippi River and its delta and plume provide insights into research-informed approaches to managing river-dominated coastal zones.

Graphical Abstract and Summary The basolateral amygdala (BLA) plays a vital role in associating sensory stimuli with salient valence information. Excitatory principal neurons (PNs) undergo plastic changes to encode this association; however, local BLA inhibitory interneurons (INs) gate PN plasticity via feedforward inhibition (FFI). Despite literature implicating parvalbumin expressing (PV+) INs in FFI in cortex and hippocampus, prior anatomical experiments in BLA implicate somatostatin expressing (Sst+) INs. The lateral entorhinal cortex (LEC), a brain region carrying olfactory information, projects to BLA where it drives FFI. In the present study, we asked whether LEC input mediates plasticity in BLA and explored the role of interneurons in this circuit. We combined patch clamp electrophysiology, chemogenetics, unsupervised cluster analysis, and predictive modeling and found that a previously unreported subpopulation of fast-spiking Sst+ INs mediate LEC→BLA FFI and gate plasticity. Our study raises the question whether this circuit is involved in plasticity in olfactory learning.

Perineuronal nets (PNNs) are a form of aggregate Extracellular Matrix (ECM) in the brain. Recent evidence suggests that the postnatal deposition of PNNs may play an active role in regulating neuroplasticity and, potentially, neurological disorders. Observations of high levels of PNN expression around somas, proximal dendrites, and axon initial segments of a subtype of neurons have also led to proposals that PNNs may modulate the intrinsic properties of the neurons they ensheathe. While high levels of PNNs are postnatally expressed throughout the neocortex, it is still unclear how they impact the neuronal physiology of the many classes and subtypes of neurons that exist. In this study, we demonstrate that Chondroitinase ABC digestion of PNNs from acute cortical slices from juvenile mice (P28–35) resulted in neuron-specific impacts on intrinsic physiology. Fast spiking (FS) interneurons showed decreased input resistance, resting membrane potential (RMP), reduced action potential (AP) peaks and altered spontaneous synaptic inputs. Low-Threshold Spiking interneurons showed altered rebound depolarizations and decreased frequency of spontaneous synaptic inputs. Putative excitatory neurons; regular spiking, bursting, and doublet phenotypes did not demonstrate any alterations. Our data indicate that chABC-sensitive PNNs may specifically regulate the intrinsic and synaptic physiology of inhibitory interneurons. © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

This paper presents the use of a novel through-transmission ultrasonic (TTU) Acoustography non-destructive evaluation (NDE) method to detect foreign object inclusion (FOI) defects in graphite epoxy composite laminates. The study employed three different composite test standards with varied size FOI defects embedded at varying depth within the composite laminates. For validation, Acoustography results were directly compared with conventional immersion TTU testing and infrared thermography (IRT) methods. From results obtained, it was demonstrated that the Signal-to-Noise Ratio (SNR) measurements for Acoustography were more than 6:1 and were in good correlation with immersion TTU and IRT results. The defect sizing ability of TTU Acoustography for FOI defects in graphite epoxy composite laminates were also in strong correlation with immersion TTU and IRT techniques. Finally, for the three laboratory systems employed in this study, typical panel TTU Acoustography inspection time was just about three minutes to scan a 300 mm × 300 mm (11.8″ × 11.8″) area, which was more than three times faster compared to IRT and sixty times faster to conventional immersion TTU C-Scan techniques. This is a very significant finding for the reason that Acoustography is being developed as a faster, more efficient, and affordable alternative to traditional ultrasonic inspection systems for composite manufacturing quality control and quality assurance (QC/QA) and field maintenance of composite structure applications.

A new coupled ocean-wave model has been developed and tested as a new component of the Coupled Ocean/Atmosphere Mesoscale Prediction System (COAMPS(circle)). The modeling system is comprised of the Simulating WAves Nearshore (SWAN) wave model and the Navy Coastal Ocean Model (NCOM). The models are two-way coupled using the Earth System Modeling Framework (ESMF). The ocean model has been modified to incorporate the effect of the Stokes drift current, wave radiation stresses due to horizontal gradients of the momentum flux of surface waves, enhancement of bottom drag in shallow water, and enhanced vertical mixing due to Langmuir turbulence. The wave model ingests surface currents (wave-current interaction) and water levels. The system is designed to support the Navy's ocean forecast requirements for regional and coastal domains. Validation studies for the Florida Straits and Virginia coastal area are presented. The system will run at the Naval Oceanographic Office and at the Fleet Numerical Meteorology and Oceanography Center.

Intraventricular hemorrhage (IVH) results in neural cell death and white matter injury in premature infants. No therapeutic strategy is currently available against this disorder. Bone morphogenetic protein (BMP) signaling suppresses oligodendrocyte development through basic-helix-loop-helix (bHLH) transcription factors and promotes astrocytosis. Therefore, we hypothesized that IVH in premature newborns initiates degeneration and maturation arrest of oligodendrocyte lineage and that BMP inhibition alleviates hypomyelination, gliosis, and motor impairment in the survivors of IVH. To test the hypotheses, a rabbit model of IVH was used in which premature rabbit pups (E29) are treated with intraperitoneal glycerol at 2 h of age to induce IVH; and the pups with IVH exhibit hypomyelination and gliosis at 2 weeks of postnatal age. Maturation of oligodendrocyte lineage was evaluated by specific markers, and the expression of bHLH transcription factors was assessed. BMP levels were measured in both premature rabbit pups and autopsy materials from premature infants. Recombinant human noggin was used to suppress BMP action; and neurobehavioral performance, myelination and gliosis were assessed in noggin-treated pups compared with untreated controls. We found that IVH resulted in apoptosis and reduced proliferation of oligodendrocyte progenitors, as well as arrested maturation of preoligodendrocytes in rabbits. BMP4 levels were significantly elevated in both rabbit pups and human premature infants with IVH compared with controls. Importantly, BMP inhibition by recombinant human noggin restored the levels of phospho-Smad1/5/8, Olig2 transcription factor, oligodendrocyte maturation, myelination, astrocyte morphology, and motor function in premature pups with IVH. Hence, BMP inhibition might enhance neurological recovery in premature infants with IVH.

Individuals who are dually enrolled in Medicare and Medicaid have a high burden of disease and disability that often requires care in the form of long-term services and supports (LTSS). Medicaid is the primary payer for LTSS for dual eligible enrollees, and in 2010, LTSS for dual eligible beneficiaries accounted for 24 percent of all Medicaid spending (Musumeci 2013). LTSS may be delivered in institutions such as nursing facilities, but in some cases, care in home and community-based settings may be more cost-effective and better aligned with beneficiary preferences. A number of provisions in the Affordable Care Act aim to expand home and community-based services (HCBS) as an alternative to nursing facility care, including increasing the federal match rate to state Medicaid programs for personal care assistant services (Community First Choice option), expanding Medicaid eligibility for state plan and waiver programs, and enhanced federal matching rates for states to rebalance LTSS expenditures toward HCBS (Harrington et al. 2012). Policies that support the LTSS workforce, such as raising payment rates for personal care assistants, may boost the capacity of Medicaid programs to substitute HCBS for nursing facility use (Seavey and Marquand 2011; Kaye 2014). Within Medicaid, low reimbursement rates can act as a barrier to HCBS access, with an inadequate number of providers willing to provide services (Harrington et al. 2002). Jobs in personal care services, whether in home or institutional settings, are typically characterized as poor in quality, with low wages, limited flexibility and minimal opportunity for advancement, and high rates of disability (Seavey and Marquand 2011). Low wage rates for personal care assistants in particular are cited as a major source of worker dissatisfaction, high turnover, and consequently, a shortage of high-quality providers (Seavey and Marquand 2011). Raising payment rates for personal care assistants in Medicaid may increase HCBS utilization by improving stability in the personal care workforce. Higher wages are associated with longer job spells and reduced turnover among those providing home health and personal care services (Baughman and Smith 2012; Butler et al. 2014). There may be elasticity in the supply of personal care assistants in response to payment rates, because a large proportion of care is provided by informal caregivers (Feinberg et al. 2011). A handful of states, including California, have historically allowed family members (e.g., spouses, children, siblings, and other relatives) to be reimbursed as personal care assistants through Medicaid HCBS. The use of paid family members is growing nationally as other states expand consumer-directed personal care programs that allow beneficiaries to choose their preferred care providers (Newcomer, Kang, and Doty 2012). Higher payment rates for personal care assistants may thus encourage use of HCBS by favorably offsetting lost wages associated with informal caregiving (Heitmuller and Inglis 2007). Increased investments in HCBS are associated with lower rates of informal caregiving (Stabile, Laporte, and Coyte 2006; Rice, Kasper, and Pezzin 2009). Thus, higher wages for personal care assistants may increase HCBS access by boosting the supply of formal providers, both relatives and nonrelatives. It is not known whether higher reimbursement rates for personal assistants would impact the likelihood that beneficiaries would receive HCBS in lieu of institutional care. States that have increased investments in Medicaid HCBS programs have experienced declines in rates of nursing facility use among adults over 65, and spending on institutional care (Kaye, LaPlante, and Harrington 2009; Miller 2011). Alternatively, policies that increase access to HCBS, such as higher payment rates, may primarily expand use of LTSS among those in the community who would have otherwise foregone services. Growth in state HCBS expenditures has been accompanied by rising LTSS use among beneficiaries residing in the community (Kemper et al. 2008; Kane et al. 2013). To our knowledge, no study has empirically examined the relationships between payment rates for personal care assistants and use of Medicaid HCBS. Although Medicaid is jointly administered by the federal and state governments, states retain control of provider payment rates, including those for personal care assistants delivering home and community-based services. In some states, including California, the state sets a base range, and then the counties determine payment rates within the limits established by the state. In California, counties (through the auspices of a Public Authority which functions as the “employer of record”) negotiate with the local union representatives to establish the prevailing rate (California Department of Social Services2007). There is some flexibility to account for caregiver experience and tenure. Thus, although the Medicaid eligibility criteria for HCBS are the same across California's 58 counties, there is substantial within-state variation in payment rates for personal care assistants (Newcomer et al. 2011). Some of the variation might be attributed to county differences in cost-of-living; but the demand for LTSS relative to the available supply of caregivers in a county can also influence the negotiated payment rates for personal care services. In this study, we capitalize on the variation within a single state to examine the associations between payment rates for personal care assistants and the likelihood of receipt of HCBS among those dually eligible for Medicaid and Medicare. We hypothesize that after adjusting for differences in individual and county characteristics, the county payment rate for personal care services will be associated with: Increased likelihood of discharge to the community with home and community-based services. We propose that counties with higher payment rates will have a greater availability of personal care assistants, thus increasing access to HCBS and likelihood of use. Decreased likelihood of discharge to nursing facilities. Assuming that higher payment rates improve access to HCBS, and there remains unmet demand for LTSS provided in noninstitutional settings, we propose that some beneficiaries may elect to receive HCBS as an alternative to discharge to a nursing facility.

The ocean-wave component of the Coupled Ocean/Atmosphere Mesoscale Prediction System (COAMPS) has been validated for four test cases: (1) Hurricane Ivan, (2) Okinawa Trough, (3) Florida Straits, and (4) Adriatic Sea. Wave properties including the Stokes Drift Current, wave radiation stress and enhancement of bottom drag are passed from the wave to ocean model NCOM. The ocean model passes surface currents and water levels to the wave model SWAN. Ocean-wave coupling shows improvement and better model predictability in winds, waves, sea surface temperature, currents, sonic layer depth and associated acoustic properties. Comparisons to in situ measurements showed improved wave predictions when surface currents were included. Current-wave model interaction showed substantial improvements in high-wind conditions. The long-term test cases successfully demonstrated the capability of operational COAMPS and ESMF coupler functionality, both in model accuracy and system robustness for operational implementation

In rodents, the barrel cortex is a specialized area within the somatosensory cortex that processes signals from the mystacial whiskers. We investigated the normal development of myelination in the barrel cortex of mice, as well as the effects of sensory deprivation on this pattern. Deprivation was achieved by trimming the whiskers on one side of the face every other day from birth. In control mice, myelin was not present until postnatal day 14 and did not show prominence until postnatal day 30; adult levels of myelination were reached by the end of the second postnatal month. Unbiased stereology was used to estimate axon density in the interbarrel septal region and barrel walls as well as the barrel centers. Myelin was significantly more concentrated in the interbarrel septa/barrel walls than in the barrel centers in both control and sensory-deprived conditions. Sensory deprivation did not impact the onset of myelination but resulted in a significant decrease in myelinated axons in the barrel region and decreased the amount of myelin ensheathing each axon. Visualization of the oligodendrocyte nuclear marker Olig2 revealed a similar pattern of myelin as seen using histochemistry, but with no significant changes in Olig2+ nuclei following sensory deprivation. Consistent with the anatomical results showing less myelination, local field potentials revealed slower rise times following trimming. Our results suggest that myelination develops relatively late and can be influenced by sensory experience.

Lunar In Situ Resource Utilization (ISRU) consists of a number of tasks starting with mining of lunar regolith, followed by the transfer of regolith to an oxygen extraction reactor and finally processing the regolith and storing of extracted oxygen. The transfer of regolith from the regolith hopper at the ground level to an oxygen extraction reactor many feet above the surface could be accomplished in different ways, including using a mechanical auger, bucket ladder system or a pneumatic system. The latter system is commonly used on earth when moving granular materials since it offers high reliability and simplicity of operation. In this paper, we describe a pneumatic regolith feed system, delivering feedstock to a Carbothermal reactor and lessons learned from deploying the system during the 2010 ISRU field campaign on the Mauna Kea, Hawaii.