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INTRODUCTION: Remembering and imagining personal events that are rich in episodic (i.e., event-specific) detail is compromised in older adults who have mild cognitive impairment, a known risk factor for Alzheimer’s disease dementia. Less clear is whether lower episodic detail generation is associated with higher risk for Alzheimer’s disease dementia before mild clinical decline is detectable. METHODS: We compared past and future autobiographical thinking in clinically normal older adult carriers of the Alzheimer’s disease-associated apolipoprotein E e4 allele (APOE4) (n = 39) to demographically and neuropsychologically similar non-APOE4 carriers (n = 43). RESULTS: APOE4 carriers showed a robust reduction for episodic details, but not for non-episodic details when remembering past events and imagining future events. DISCUSSION: Despite normal neuropsychological functioning, past and future autobiographical thinking are commonly compromised in older APOE4 carriers. Reduced episodic detail generation, therefore, may be an early cognitive associate of higher risk for Alzheimer’s disease dementia.

The non-obese diabetic (NOD) mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally-protected from developing diabetes, and currently studies characterising this cohort are very limited. Here, using both immunofluorescence and multi-parameter flow cytometry we focus on the pancreatic islet morphology and immune infiltrate observed in naturally-protected NOD mice. We show that naturally-protected NOD mice are characterised by an increased frequency of insulin-containing, smaller sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed towards a regulatory phenotype in both T and B-cell compartments. Pancreatic islets have an increased frequency of IL-10 producing B cells and associated cell surface markers. Resident memory CD69+CD8+ T cells show a significant shift towards reduced CD103 expression, while CD4+ T cells have increased FoxP3+CTLA4+ expression. These data indicate that naturally-protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets.

Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8+T-cells, escaping central and peripheral tolerance, contribute to beta-cell destruction. Using G9Cα-/-CD8+T-cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα-/-CD8+T-cell cytotoxicity and DC-induced proliferation, they failed to sufficiently regulate T-cells stimulated by anti-CD3/CD28. In contrast, non-MHC matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T-cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.

In the past few years, huge advances have been made in techniques to analyse cells at an individual level using RNA sequencing, and many of these have precipitated exciting discoveries in the immunology of type 1 diabetes (T1D). This review will cover the first papers to use scRNAseq to characterise human lymphocyte phenotypes in T1D in the peripheral blood, pancreatic lymph nodes and islets. These have revealed specific genes such as IL-32 that are differentially expressed in islet –specific T cells in T1D. scRNAseq has also revealed wider gene expression patterns that are involved in T1D and can predict its development even predating autoantibody production. Single cell sequencing of TCRs has revealed V genes and CDR3 motifs that are commonly used to target islet autoantigens, although truly public TCRs remain elusive. Little is known about BCR repertoires in T1D, but scRNAseq approaches have revealed that insulin binding BCRs commonly use specific J genes, share motifs between donors and frequently demonstrate poly-reactivity. This review will also summarise new developments in scRNAseq technology, the insights they have given into other diseases and how they could be leveraged to advance research in the type 1 diabetes field to identify novel biomarkers and targets for immunotherapy.

The Integrated Exposure Uptake Biokinetic Model for Lead in Children (IEUBK model) was developed by the U.S. Environmental Protection Agency to support assessments of health risks to children from exposures to lead (Pb).This study evaluated performance of IEUBK model (v2.0) as it would be typically applied at Superfund sites to predict blood Pb levels (BLLs) in populations of children.The model was evaluated by comparing model predictions of BLLs to 1144 observed BLLs in a population of children at the Bunker Hill Superfund Site for which there were paired estimates of environmental Pb concentrations.Predicted population geometric mean (GM) BLLs (GM: 3.4 µg/dL, 95% CI: 3.3, 3.5) were within 0.3 µg/dL of observed (GM: 3.6 µg/dL, 95% CI: 3.5, 3.8). The model predicted the observed age trend in GM BLLs and explained ~90% of the variance in the observed age-stratified GM BLLs. The mean predicted probability of exceeding 5 µg/dL (PAlthough the more general applicability of these findings to other populations remains to be determined in future studies, our results support applications of the IEUBK model (v2.0) for informing risk-based decisions regarding remediation of soils and mitigation of exposures at Superfund sites where the majority of the exposure unit GM BLLs are expected to be ≤5 µg/dL and where it is desired to limit the predicted probability of exceeding 5 µg/dL to5%.

Decreasing renal glomerular filtration rate (GFR) in association with increasing blood cadmium levels was reported in epidemiological studies of general populations. Dependence of cadmium clearance on GFR has implications for interpreting causation in these studies. Associations between cadmium clearance and creatinine clearance, a metric of GFR, were evaluated in a sample of the U.S. population. Blood to urine cadmium clearance and serum creatinine clearance were estimated in approximately 6000 individuals included in the National Health and Nutrition Examination Survey (NHANES 2009-2016). Linear regression models explained approximately 45% of variance in cadmium clearance in adults, with 74% of the explained variance attributed to creatinine clearance and 25% explained by age. In adolescents (12-20 years), linear regression models explained 55% of variance in cadmium clearance with99% of the explained variance attributed to creatinine clearance. The models predicted that halving creatinine clearance would result in a 40% decrease in cadmium clearance and a 20% rise in blood cadmium. Dependence of cadmium clearance on GFR has implications for assigning causation to studies in which increasing blood cadmium levels have been associated with increasing risk of low GFR. Statistical associations between blood cadmium and low GFR, such as elevated odds ratios in upper percentile strata of populations, may be partially a consequence of lower cadmium clearance in association with low GFR that is reverse causation.

Blood lead (Pb) clearance (CbPb) and serum creatinine clearance (CsCr), a metric of glomerular filtration rate (GFR), were estimated in approximately 7,600 subjects from the NHANES (2009-2016). Median CbPb in adults was 0.04 L/day (5th-95th percentile range: 0.01-0.12). Linear regression models explained approximately 68% of variance in CbPb in adults, with98% of explained variance attributed to CsCr. These results provide an improved quantitative understanding of the possible effects of reverse causality in the interpretation of studies of associations between blood Pb and decrements in GFR.

Autobiographical memory consists of distinct memory types varying from highly abstract to episodic. Self trait knowledge, which is considered one of the more abstract types of autobiographical memory, is thought to rely on regions of the autobiographical memory neural network implicated in schema representation, including the medial prefrontal cortex, and critically, not the medial temporal lobes. The current case study introduces an individual who, as a consequence of bilateral posterior cerebral artery strokes, experienced extensive medial temporal lobe damage with sparing of the medial prefrontal cortex. Interestingly, in addition to severe retrograde and anterograde episodic and autobiographical fact amnesia, this individual’s self trait knowledge was impaired for his current and pre-morbid personality traits. Yet, further assessment revealed that this individual had preserved conceptual knowledge for personality traits, could reliably and accurately rate another person’s traits, and could access his own self-concept in a variety of ways. In addition to autobiographical memory loss, he demonstrated impairment on non-personal semantic memory tests, most notably on tests requiring retrieval of unique knowledge. This rare case of amnesia suggests a previously unreported role for the medial temporal lobes in personal trait knowledge, which we propose reflects the critical role of this neural region in the storage and retrieval of personal semantics that are experience-near, meaning autobiographical facts grounded in spatiotemporal contexts.

This work addresses task planning under uncertainty for precision agriculture applications whereby task costs are uncertain and the gain of completing a task is proportional to resource consumption (such as water consumption in precision irrigation). The goal is to complete all tasks while prioritizing those that are more urgent, and subject to diverse budget thresholds and stochastic costs for tasks. To describe agriculture-related environments that incorporate stochastic costs to complete tasks, a new Stochastic-Vertex-Cost Aisle Graph (SAG) is introduced. Then, a task allocation algorithm, termed Next-Best-Action Planning (NBA-P), is proposed. NBA-P utilizes the underlying structure enabled by SAG, and tackles the task planning problem by simultaneously determining the optimal tasks to perform and an optimal time to exit (i.e. return to a base station), at run-time. The proposed approach is tested with both simulated data and real-world experimental datasets collected in a commercial vineyard, in both single- and multi-robot scenarios. In all cases, NBA-P outperforms other evaluated methods in terms of return per visited vertex, wasted resources resulting from aborted tasks (i.e. when a budget threshold is exceeded), and total visited vertices., To appear in Robotics and Automation Letters

The non-obese diabetic (NOD) mouse develops spontaneous type 1 diabetes, with some features of disease that are very similar to the human disease. However, a proportion of NOD mice are naturally-protected from developing diabetes, and currently studies characterising this cohort are very limited. Here, using both immunofluorescence and multi-parameter flow cytometry we focus on the pancreatic islet morphology and immune infiltrate observed in naturally-protected NOD mice. We show that naturally-protected NOD mice are characterised by an increased frequency of insulin-containing, smaller sized, pancreatic islets. Although mice remain diabetes free, florid immune infiltrate remains. However, this immune infiltrate is skewed towards a regulatory phenotype in both T and B-cell compartments. Pancreatic islets have an increased frequency of IL-10 producing B cells and associated cell surface markers. Resident memory CD69+CD8+T cells show a significant shift towards reduced CD103 expression, while CD4+T cells have increased FoxP3+CTLA4+expression. These data indicate that naturally-protected NOD mice have a unique islet signature and provide new insight into regulatory mechanisms within pancreatic islets.

The REgolith X-ray Imaging Spectrometer (REXIS) instrument on board NASA's OSIRIS-REx mission to the asteroid Bennu is a Class-D student collaboration experiment designed to detect fluoresced X-rays from the asteroid's surface to measure elemental abundances. In July and November 2019 REXIS collected ~615 hours of integrated exposure time of Bennu's sun-illuminated surface from terminator orbits. As reported in Hoak et al. (2021), the REXIS data do not contain a clear signal of X-ray fluorescence from the asteroid, in part due to the low incident solar X-ray flux during periods of observation. To support the evaluation of the upper limits on the detectable X-ray signal that may provide insights for the properties of Bennu's regolith, we present an overview of the REXIS instrument, its operation, and details of its in-flight calibration on astrophysical X-ray sources. This calibration includes the serendipitous detection of the transient X-ray binary MAXI J0637-430 during Bennu observations, demonstrating the operational success of REXIS at the asteroid. We convey some lessons learned for future X-ray spectroscopy imaging investigations of asteroid surfaces., Comment: 36 pages, 18 figures, accepted for publication in Space Science Reviews

Several high-throughput, high-resolution X-ray mission concepts now under study, including Lynx, a flagship, and AXIS, a probe, require large-format imaging detectors with performance at least as good as the best current generation devices but with much higher readout rates. We are investigating the potential of new CCD detector technology developed at MIT Lincoln Laboratory for meeting the needs of these missions. This technology features low-voltage charge transfer and fast, low-noise amplifiers. Deployed in a multiple output sensor architecture with low-power (application-specific integrated circuit) signal processing, this technology offers an attractive path to the high frame rates and low power consumption required. This approach is one of three candidates selected for development for Lynx, and it has also been included in the AXIS baseline. Here we report recent progress in developing this technology, with a focus on two characteristics critical to good low-energy response: read noise and charge packet size. We have measured read noise below 4 electrons, RMS (the Lynx requirement) at pixel rates up to 2.5 MHz in both front- and back-illuminated test devices, with transfer clock levels of ±1.5 V. We have also exploited the 8 µm pixel size of test detectors to measure the spatial extent of X-ray induced charge packets as a function of detector bias. We infer a root-mean-square radius 4 µm for charge packets originating at the entrance window of a 50 μm thick back-illuminated detector under high-bias (-20 V) conditions. We note that the high pixel ’aspect ratio’ (thickness : pixel size ≈ 6 : 1) of our test devices is similar to that expected for Lynx and AXIS detectors, and discuss implications of our charge cloud size measurements for noise requirements for these missions

Next-generation X-ray imaging missions require fast, low-noise detectors that can survive the harsh environment of space without significant loss of performance. As part of a detector development effort toward a mission such as Lynx, we report on the effects of proton exposure on the spectral performance, dark current and charge transfer effciency of an MIT Lincoln Lab CCID93. The CCD has 8 micron pixels and can be clocked with 2.5MHz pixel speeds with CMOS compatible voltage swings. The 40 MeV proton dose is chosen to represent typical on orbit exposure. Variations with charge injection, temperature, and clocking speed are explored.

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Structural color is a pervasive natural phenomenon, caused by photonic nanostructures that refract light. Diverse organisms employ structural color to mediate ecological interactions and create specific optical effects such as iridescence. Despite its importance for living systems, the developmental, genetic, and evolutionary processes that generate structural color largely remain mysterious. Here, we focus on simple photonic structures, thin film reflectors, in the lower lamina of Junonia butterfly scales. We present multiple lines of evidence that the thickness of the lamina quantitatively controls lamina color, which is an important determinant of overall wing color, even when pigments are also present. First, in a lineage of buckeye butterflies artificially selected for blue wing color for 12 generations, a thicker lamina resulted in a color shift from brown to blue. A similar lamina thickness increase explains the appearance of blue scales in butterflies with mutations in the optix wing patterning gene. Finally, lamina thickness variation underlies the color diversity that distinguishes seasonal variants, sexes, and species throughout the genus Junonia. Thus, quantitatively tuning a single dimension of the existing scale architecture allows butterflies to evolve a broad spectrum of hues over both microevolutionary and macroevolutionary time frames. Because the lower lamina is an intrinsic component of typical butterfly scales, our findings imply that lamina structural color influences wing color in most butterflies. Significance Statement Structural colors, which result from photonic nanostructures that refract light and can create iridescence, are an important tool for many organisms. We use thin films, which are morphologically simple nanostructures that generate structural color in the lower lamina of butterfly scales, to dissect how photonic structures evolve. By combining interspecies comparisons with two different experimental approaches—artificial selection on wing color, and genetically engineered mutation of the optix wing patterning gene—we demonstrate that lamina thickness controls the wavelength (hue) of the structural color. These lamina structural colors are ubiquitous in the genus Junonia, and determine wing color along with pigments. Our results suggest that lamina structural colors probably exist in most butterflies, and that tuning lamina thickness facilitates wing color evolution.

Sleep loss contributes to the development of cardiovascular, metabolic, and neurological disorders by promoting a systemic proinflammatory phenotype. The neuroendocrine-immune mechanisms contributing to such pathologies are poorly understood. The sympathetic nervous system (SNS) regulates immunity and is often activated following sleep disturbances. The aims of this study were to determine 1) the effect of SNS inhibition on inflammatory responses to sleep fragmentation (SF) and 2) whether homeostasis can be restored after 1 wk of recovery sleep. We measured stress responses (norepinephrine and corticosterone), gene expression levels of pro- and anti-inflammatory cytokines in peripheral (heart, liver, and spleen) tissues, and protein levels of cytokines and chemokines in serum of female mice that were subjected to acute SF for 24 h, chronic SF for 8 wk, or 7 days of recovery after chronic SF. In each experiment, SF and control mice were chemically sympathectomized with 6-hydroxydopamine (6-OHDA) or injected with vehicle. Both acute and chronic SF elevated mRNA and protein levels of cytokines in peripheral tissues. Changes in inflammatory responses mirrored stress-axes activation, with increased corticosterone and norepinephrine in SF mice. 6-OHDA treatment significantly alleviated SF-induced inflammation, thus providing evidence of SNS regulation of peripheral inflammation from SF. Effects of chronic SF were more severe than acute SF, and 1 wk of recovery from SF sufficiently alleviated peripheral inflammatory responses but not NE responses.

There are now a number of different mouse models for type 1 diabetes. The best known is the nonobese diabetic (NOD) mouse which has a genetic susceptibility to autoimmune diabetes with some features that are similar to human type 1 diabetes. The mice also have a propensity to other autoimmune diatheses, including autoimmune thyroid disease and sialadenitis. In addition, it is well known that environmental factors affect the incidence of disease in these mice. While there are other rodent models, including numerous transgenic and knockout models, as well as those that express human proteins, none of these develop spontaneous diabetes over a period of time, when the natural history can be studied. We focus here on the unmanipulated NOD mouse and discuss features of the husbandry and investigation of the mice that allow for use of these long-studied mice in the pathogenesis of an autoimmune type of diabetes.

Type 1 diabetes is an autoimmune disease resulting in the loss of insulin production and, consequently, hyperglycemia. The nonobese diabetic (NOD) mouse develops spontaneous diabetes with considerable similarity to the disease in humans. Immunological studies using the NOD mouse model allow for the investigation of the natural history of the disease and leukocyte and lymphocyte pathogenic and regulatory functions, as well as testing potential therapies for intervention. The analyses of the cellular events leading up to diabetes may utilize different in vitro cellular assays, immunohistochemistry, and in vivo adoptive transfer, to study mechanisms of the disease and the effects of therapeutic intervention. In this chapter, we describe some common techniques for phenotyping and mechanistic analyses of function, particularly of CD8+ T cells.

Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8(+) T cells, escaping central and peripheral tolerance, contribute to β-cell destruction. Using G9Cα(−/−)CD8(+) T cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the NOD mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα(−/−)CD8(+) T-cell cytotoxicity and dendritic cell–induced proliferation, they failed to sufficiently regulate T cells stimulated by anti-CD3/CD28. In contrast, non-MHC–matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.

Effects of dietary P level on the oral bioavailability of Pb present in soil were examined in a mouse model. Adult female C57BL/6 mice had free access to AIN-93G purified rodent diet amended with Pb as a soluble salt, Pb acetate, or in a soil matrix (NIST SRM 2710a). In these studies, the basal diet contained P at a nutritionally sufficient level (0.3% w/w) and the modified diets contained P at a lower (0.15%) or a higher (1.2%) level. For either dietary Pb source (Pb acetate or NIST SRM 2710a), low dietary P level markedly increased accumulation of Pb in bone, blood, and kidney. Tissue Pb levels in mice fed a high P in diet were not different from mice fed the basal P diet. Dietary P and Pb interacted to affect body weight change and feed efficiency in mice. The relative contribution of different Pb species in diet and feces was also affected by dietary P level. Differences in Pb species between diet and feces indicated that transformation of Pb species can occur during gastrointestinal tract transit. These interactions between Pb and P that alter Pb speciation may be important determinants of the bioavailability of Pb ingested in soil.

In diverse organisms, nanostructures that coherently scatter light create structural color, but how such structures are built remains mysterious. We investigate the evolution and genetic regulation of butterfly scale laminae, which are simple photonic nanostructures. In a lineage of buckeye butterflies artificially selected for blue wing color, we found that thickened laminae caused a color shift from brown to blue. Deletion of the optix patterning gene also altered color via lamina thickening, revealing shared regulation of pigments and lamina thickness. Finally, we show how lamina thickness variation contributes to the color diversity that distinguishes sexes and species throughout the genus Junonia. Thus, quantitatively tuning one dimension of scale architecture facilitates both the microevolution and macroevolution of a broad spectrum of hues. Because the lamina is an intrinsic component of typical butterfly scales, our findings suggest that tuning lamina thickness is an available mechanism to create structural color across the Lepidoptera., eLife digest From iridescent blues to vibrant purples, many butterflies display dazzling ‘structural colors’ created not by pigments but by microscopic structures that interfere with light. For instance, the scales that coat their wings can contain thin films of chitin, the substance that normally makes the external skeleton of insects. In slim layers, however, chitin can also scatter light to produce color, the way that oil can create iridescence at the surface of water. The thickness of the film, which is encoded by the genes of the butterfly, determines what color will be produced. Yet, little is known about how common thin films are in butterflies, exactly how genetic information codes for them, and how their thickness and the colors they produce can evolve. To investigate, Thayer et al. used a technique called Helium Ion Microscopy and examined the wings of ten related species of butterflies, showing that thin film structures were present across this sample. However, the different species have evolved many different structural colors over the past millions of years by changing the thickness of the films. Next, Thayer et al. showed that this evolution could be reproduced at a faster pace in the laboratory using common buckeye butterflies. These insects mostly have brown wings, but they can have specks of blue created by thin film structures. Individuals with more blue on their wings were mated and over the course of a year, the thickness of the film structures increased by 74%, leading to shiny blue butterflies. Deleting a gene called optix from the insects also led to blue wings. Optix was already known to control the patterns of pigments in butterflies, but it now appears that it controls structural colors as well. From solar panels to new fabrics, microscopic structures that can scatter light are useful in a variety of industries. Understanding how these elements exist and evolve in organisms may help to better design them for human purposes.