Inclusion and adaptation beyond disability: Using virtual reality to foster empathy.

BACKGROUND: Virtual reality (VR) has the potential to be a powerful tool in promoting empathy towards inclusion, particularly for individuals with impairments such as mobility difficulties, vision deficits, or autism but also about pregnancy, which can create temporary difficulties. By immersing users in simulated environments that replicate the experiences of those with different abilities, VR can create a sense of understanding and empathy for those who face challenges in their daily lives. For example, VR experiences can simulate the experience of navigating space as someone with a mobility impairment, providing a new perspective and appreciation for the difficulties that others face. Similarly, VR experiences can simulate the experience of vision impairment, pregnancy, or autism, providing a window into the challenges faced by those with these conditions and fostering empathy and understanding. MATERIAL AND METHODS: During the development of this study, field experts were consulted to ensure the robustness of the methods employed. Then, questionnaires were specifically developed to explore disabilities and challenges related to inclusion and were administered to a large population. Additionally, guided interviews were conducted with individuals who possess specific impairments to gather first-hand insights. RESULTS: The results obtained from the questionnaires and interviews provide a comprehensive overview of the inclusion challenges that necessitate attention and resolution. By drawing on the expertise of both experts and individuals with lived experiences, a holistic landscape of inclusion challenges has been established. CONCLUSIONS: The VR emerges as a powerful tool for promoting inclusion and fostering understanding among individuals. Its capacity to create immersive experiences that facilitate empathy has the potential to reshape society into a more compassionate and empathetic one. By leveraging the unique capabilities of VR, we can bridge the gap between different perspectives, fostering greater understanding, acceptance, and inclusivity. Med Pr. 2023;74(3):171-85.

Pericyte dysfunction and impaired vasomotion are hallmarks of islets during the pathogenesis of type 1 diabetes.

Pancreatic islets are endocrine organs that depend on their microvasculature to function. Along with endothelial cells, pericytes comprise the islet microvascular network. These mural cells are crucial for microvascular stability and function, but it is not known if/how they are affected during the development of type 1 diabetes (T1D). Here, we investigate islet pericyte density, phenotype, and function using living pancreas slices from donors without diabetes, donors with a single T1D-associated autoantibody (GADA+), and recent onset T1D cases. Our data show that islet pericyte and capillary responses to vasoactive stimuli are impaired early on in T1D. Microvascular dysfunction is associated with a switch in the phenotype of islet pericytes toward myofibroblasts. Using publicly available RNA sequencing (RNA-seq) data, we further found that transcriptional alterations related to endothelin-1 signaling and vascular and extracellular matrix (ECM) remodeling are hallmarks of single autoantibody (Aab)+ donor pancreata. Our data show that microvascular dysfunction is present at early stages of islet autoimmunity.

A Defect in Mitochondrial Complex III but Not in Complexes I or IV Causes Early ß-Cell Dysfunction and Hyperglycemia in Mice.

Mitochondrial metabolism and oxidative respiration are crucial for pancreatic ß-cell function and stimulus secretion coupling. Oxidative phosphorylation (OxPhos) produces ATP and other metabolites that potentiate insulin secretion. However, the contribution of individual OxPhos complexes to ß-cell function is unknown. We generated ß-cell-specific, inducible OxPhos complex knock-out (KO) mouse models to investigate the effects of disrupting complex I, complex III, or complex IV on ß-cell function. Although all KO models had similar mitochondrial respiratory defects, complex III caused early hyperglycemia, glucose intolerance, and loss of glucose-stimulated insulin secretion in vivo. However, ex vivo insulin secretion did not change. Complex I and IV KO models showed diabetic phenotypes much later. Mitochondrial Ca2+ responses to glucose stimulation 3 weeks after gene deletion ranged from not affected to severely disrupted, depending on the complex targeted, supporting the unique roles of each complex in ß-cell signaling. Mitochondrial antioxidant enzyme immunostaining increased in islets from complex III KO, but not from complex I or IV KO mice, indicating that severe diabetic phenotype in the complex III-deficient mice is causing alterations in cellular redox status. The present study highlights that defects in individual OxPhos complexes lead to different pathogenic outcomes. ARTICLE HIGHLIGHTS: Mitochondrial metabolism is critical for ß-cell insulin secretion, and mitochondrial dysfunction is involved in type 2 diabetes pathogenesis. We determined whether individual oxidative phosphorylation complexes contribute uniquely to ß-cell function. Compared with loss of complex I and IV, loss of complex III resulted in severe in vivo hyperglycemia and altered ß-cell redox status. Loss of complex III altered cytosolic and mitochondrial Ca2+ signaling and increased expression of glycolytic enzymes. Individual complexes contribute differently to ß-cell function. This underscores the role of mitochondrial oxidative phosphorylation complex defects in diabetes pathogenesis.

Oligodendrocyte death initiates synchronous remyelination to restore cortical myelin patterns in mice.

Myelin degeneration occurs in neurodegenerative diseases and aging. In these conditions, resident oligodendrocyte progenitor cells (OPCs) differentiate into oligodendrocytes that carry out myelin repair. To investigate the cellular dynamics underlying these events, we developed a noninflammatory demyelination model that combines intravital two-photon imaging with a single-cell ablation technique called two-photon apoptotic targeted ablation (2Phatal). Oligodendrocyte 2Phatal in both sexes results in a myelin degeneration cascade that triggers rapid forms of synchronous remyelination on defined axons. This remyelination is driven by oligodendrocytes differentiated from a subset of morphologically distinct, highly branched OPCs. Moreover, remyelination efficiency depends on the initial myelin patterns, as well as the age of the organism. In summary, using 2Phatal, we show a form of rapid synchronous remyelination, mediated by a distinct subset of OPCs, capable of restoring the original myelin patterning in adulthood but not aging.

Pericyte Control of Blood Flow in Intraocular Islet Grafts Impacts Glucose Homeostasis in Mice.

The pancreatic islet depends on blood supply to efficiently sense plasma glucose levels and deliver insulin and glucagon into the circulation. Long believed to be passive conduits of nutrients and hormones, islet capillaries were recently found to be densely covered with contractile pericytes with the capacity to locally control blood flow. Here, we determined the contribution of pericyte regulation of islet blood flow to plasma insulin and glucagon levels and glycemia. Selective optogenetic activation of pericytes in intraocular islet grafts contracted capillaries and diminished blood flow. In awake mice, acute light-induced stimulation of islet pericytes decreased insulin and increased glucagon plasma levels, producing hyperglycemic effects. Interestingly, pericytes are the targets of sympathetic nerves in the islet, suggesting that sympathetic control of hormone secretion may occur in part by modulating pericyte activity and blood flow. Indeed, in vivo activation of pericytes with the sympathetic agonist phenylephrine decreased blood flow in mouse islet grafts, lowered plasma insulin levels, and increased glycemia. We further show that islet pericytes and blood vessels in living human pancreas slices responded to sympathetic input. Our findings indicate that pericytes mediate vascular responses in the islet that are required for adequate hormone secretion and glucose homeostasis. Vascular and neuronal alterations that are commonly seen in the islets of people with diabetes may impair regulation of islet blood flow and thus precipitate islet dysfunction.

In Vitro Matured Human Pluripotent Stem Cell-Derived Cardiomyocytes Form Grafts With Enhanced Structure and Function in Injured Hearts.

BACKGROUND: Human pluripotent stem cell (hPSC)-derived cardiomyocytes (hPSC-CMs) have tremendous promise for application in cardiac regeneration, but their translational potential is limited by an immature phenotype. We hypothesized that large-scale manufacturing of mature hPSC-CMs could be achieved through culture on polydimethylsiloxane (PDMS)-lined roller bottles and that the transplantation of these cells would mediate better structural and functional outcomes than with conventional immature hPSC-CM populations. METHODS: We comprehensively phenotyped hPSC-CMs after in vitro maturation for 20 and 40 days on either PDMS or standard tissue culture plastic substrates. All hPSC-CMs were generated from a transgenic hPSC line that stably expressed a voltage-sensitive fluorescent reporter to facilitate in vitro and in vivo electrophysiological studies, and cardiomyocyte populations were also analyzed in vitro by immunocytochemistry, ultrastructure and fluorescent calcium imaging, and bulk and single-cell transcriptomics. We next compared outcomes after the transplantation of these populations into a guinea pig model of myocardial infarction using end points including histology, optical mapping of graft- and host-derived action potentials, echocardiography, and telemetric electrocardiographic monitoring. RESULTS: We demonstrated the economic generation of >1×108 mature hPSC-CMs per PDMS-lined roller bottle. Compared with their counterparts generated on tissue culture plastic substrates, PDMS-matured hPSC-CMs exhibited increased cardiac gene expression and more mature structural and functional properties in vitro. More important, intracardiac grafts formed with PDMS-matured myocytes showed greatly enhanced structure and alignment, better host-graft electromechanical integration, less proarrhythmic behavior, and greater beneficial effects on contractile function. CONCLUSIONS: We describe practical methods for the scaled generation of mature hPSC-CMs and provide the first evidence that the transplantation of more mature cardiomyocytes yields better outcomes in vivo.

Re-evaluation of gestational age as a predictor for subsequent preterm birth.

BACKGROUND: To evaluate gestational age as a predictor of subsequent preterm birth. MATERIALS AND METHODS: This was a retrospective birth cohort study to evaluate gestational age as a predictor of subsequent preterm birth. Participants were mothers who gave birth to their first two children in Western Australia, 1980-2015 (N = 255,151 mothers). For each week of final gestational age of the first birth, we calculated relative risks (RR) and absolute risks (AR) of subsequent preterm birth defined as final gestational age before 28, 32, 34 and <37 weeks. Risks were unadjusted to preserve risk factor profiles at each week of gestation. RESULTS: The relative risks of second birth before 28, 32, and 34 weeks' gestation were all approximately twenty times higher for mothers whose first birth had a gestational age of 22 to 30 weeks compared to those whose first birth was at 40 weeks' gestation. The absolute risks of second birth before 28, 32, and 34 weeks' gestation for these mothers had upper confidence limits that were all less than 16.74%. The absolute risk of second birth before 37 weeks was highest at 32.11% (95% CI: 30.27, 34.02) for mothers whose first birth was 22 to 30 weeks' gestation. For all gestational ages of the first child, the lowest quartile and median gestational age of the second birth were at least 36 weeks and at least 38 weeks, respectively. Sensitivity and positive predictive values were all below 35%. CONCLUSION: Relative risks of early subsequent birth increased markedly with decreasing gestational age of the first birth. However, absolute risks of clinically significant preterm birth (<28 weeks, <32 weeks, <34 weeks), sensitivity and positive predictive values remained low. Early gestational age is a strong risk factor but a poor predictor of subsequent preterm birth.

Pancreatic ß-Cells Communicate With Vagal Sensory Neurons.

BACKGROUND AND AIMS: Destroying visceral sensory nerves impacts pancreatic islet function, glucose metabolism, and diabetes onset, but how islet endocrine cells interact with sensory neurons has not been studied. METHODS: We characterized the anatomical pattern of pancreatic sensory innervation by combining viral tracing, immunohistochemistry, and reporter mouse models. To assess the functional interactions of ß-cells with vagal sensory neurons, we recorded Ca2+ responses in individual nodose neurons in vivo while selectively stimulating ß-cells with chemogenetic and pharmacologic approaches. RESULTS: We found that pancreatic islets are innervated by vagal sensory axons expressing Phox2b, substance P, calcitonin-gene related peptide, and the serotonin receptor 5-HT3R. Centrally, vagal neurons projecting to the pancreas terminate in the commissural nucleus of the solitary tract. Nodose neurons responded in vivo to chemogenetic stimulation of ß-cells and to pancreas infusion with serotonin, but were not sensitive to insulin. Responses to chemogenetic and pharmacologic stimulation of ß-cells were blocked by a 5-HT3R antagonist and were enhanced by increasing serotonin levels in ß-cells. We further confirmed directly in living pancreas slices that sensory terminals in the islet were sensitive to serotonin. CONCLUSIONS: Our study establishes that pancreatic ß-cells communicate with vagal sensory neurons, likely using serotonin signaling as a transduction mechanism. Serotonin is coreleased with insulin and may therefore convey information about the secretory state of ß-cells via vagal afferent nerves.

Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis.

AIMS/HYPOTHESIS: Islet vascular fibrosis may play an important role in the progression of type 2 diabetes, but there are no mouse models allowing detailed mechanistic studies to understand how a dysfunctional islet microvasculature contributes to diabetes pathogenesis. Here we report that the transgenic AktTg mouse, unlike other mouse strains, shows an increased deposition of extracellular matrix (ECM) proteins in perivascular regions, allowing us to study the cellular mechanisms that lead to islet vascular fibrosis. METHODS: Using immunohistochemistry, we labelled the islet microvasculature and ECM in pancreas sections of AktTg mice and human donors and performed lineage tracing to follow the fate of islet pericytes. We compared islet microvascular responses in living pancreas slices from wild-type and AktTg mice. RESULTS: We found that vascular pericytes proliferate extensively, convert into profibrotic myofibroblasts and substantially contribute to vascular fibrosis in the AktTg mouse model. The increased deposition of collagen I, fibronectin and periostin within the islet is associated with diminished islet perfusion as well as impaired capillary responses to noradrenaline (norepinephrine) and to high glucose in living pancreas slices. CONCLUSIONS/INTERPRETATION: Our study thus illustrates how the AktTg mouse serves to elucidate a cellular mechanism in the development of islet vascular fibrosis, namely a change in pericyte phenotype that leads to vascular dysfunction. Because beta cells in the AktTg mouse are more numerous and larger, and secrete more insulin, in future studies we will test the role beta cell secretory products play in determining the phenotype of pericytes and other cells residing in the islet microenvironment under physiological and pathophysiological conditions. Graphical abstract.

Sporadic activation of an oxidative stress-dependent NRF2-p53 signaling network in breast epithelial spheroids and premalignancies.

Breast and mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal three-dimensional (3D) spheroids are cultured in basement membrane, and one such state is associated with stress tolerance and poor response to anticancer therapeutics. Here, we found that this state was jointly coordinated by the NRF2 and p53 pathways, which were costabilized by spontaneous oxidative stress within 3D cultures. Inhibition of NRF2 or p53 individually disrupted some of the transcripts defining the regulatory state but did not yield a notable phenotype in nontransformed breast epithelial cells. In contrast, combined perturbation prevented 3D growth in an oxidative stress-dependent manner. By integrating systems models of NRF2 and p53 signaling in a single oxidative stress network, we recapitulated these observations and made predictions about oxidative stress profiles during 3D growth. NRF2 and p53 signaling were similarly coordinated in normal breast epithelial tissue and hormone-negative ductal carcinoma in situ lesions but were uncoupled in triple-negative breast cancer (TNBC), a subtype in which p53 is usually mutated. Using the integrated model, we correlated the extent of this uncoupling in TNBC cell lines with the importance of NRF2 in the 3D growth of these cell lines and their predicted handling of oxidative stress. Our results point to an oxidative stress tolerance network that is important for single cells during glandular development and the early stages of breast cancer.

Secretory Functions of Macrophages in the Human Pancreatic Islet Are Regulated by Endogenous Purinergic Signaling.

Endocrine cells of the pancreatic islet interact with their microenvironment to maintain tissue homeostasis. Communication with local macrophages is particularly important in this context, but the homeostatic functions of human islet macrophages are not known. In this study, we show that the human islet contains macrophages in perivascular regions that are the main local source of the anti-inflammatory cytokine interleukin-10 (IL-10) and the metalloproteinase MMP9. Macrophage production and secretion of these homeostatic factors are controlled by endogenous purinergic signals. In obese and diabetic states, macrophage expression of purinergic receptors MMP9 and IL-10 is reduced. We propose that in those states, exacerbated ß-cell activity due to increased insulin demand and increased cell death produce high levels of ATP that downregulate purinergic receptor expression. Loss of ATP sensing in macrophages may reduce their secretory capacity.

Análise clínico-epidemiológica dos atendimentos em um centro de referência em imunobiológicos especiais na amazônia / Análisis clínico-epidemiológico de la atención en un centro de referencia em inmunobiológicos especiales em la amazonia / Clinical-epidemiological analysis of the care services at a special immunobiological reference center in the amazon

RESUMO Objetivo: descrever o perfil clínico-epidemiológico do atendimento no Centro de Referência em Imunobiológicos Especiais de Hospital na Amazônia. Método: descritivo de abordagem quantitativa e analisado por meio da estatística descritiva e inferencial. O Sistema de Informação do Centro de Referência para Imunobiológicos Especiais (antigo) e Sistema de Informação do Programa Nacional de Imunização (atual) foram as bases utilizadas, entre 2006 e 2016. Resultados: foram administradas 77.077 doses de imunobiológicos; 25,2% corresponderam à vacina influenza inativada; insuficiência renal crônica foi a principal indicação (19%). O sistema atual registrou 18.267 doses de imunobiológicos administrados entre os anos de 2014 a 2016; sendo 37,8% correspondente à vacina influenza inativada; não foram informadas 42,5% das indicações, sendo HIV/AIDS 18,2%. Infectologia foi a especialidade que mais encaminhou para vacinação (18,3%). Conclusão: a acurácia dos dados foi comprometida pela falta de completude nos sistemas de informação. Observou-se subutilização do serviço pela população local.

RESUMEN: Objetivo: describir el perfil clínico-epidemiológico de la atención brindada por el Centro de Referencia para Inmunobiológicos Especiales de un Hospital de la Amazonía. Método: descriptivo con enfoque cuantitativo y analizado mediante estadística descriptiva e inferencial. El Sistema de Información del Centro de Referencia para Inmunobiológicos Especiales (antiguo) y el Sistema de Información del Programa Nacional de Inmunización (actual) se utilizaron como base de datos entre 2006 y 2016. Resultados: se administraron 77,077 dosis de inmunobiológicos; el 25,2% correspondió a la vacuna inactivada contra la influenza; La insuficiencia renal crónica fue la indicación principal (19%). El sistema actual registró 18.267 dosis de inmunobiológicos administradas entre los años 2014 y 2016; siendo que el 37,8% correspondió a la vacuna inactivada contra la influenza; El 42,5% de las indicaciones no fueron informadas, y el porcentaje informado de VIH / SIDA fue de 18,2%. La especialidad que más derivaciones realizó para vacunación fue la de infectología (18,3%). Conclusión: la precisión de los datos se vio comprometida por la falta de integridad en los sistemas de información. Se observó la subutilización del servicio por la población local.

ABSTRACT Objective: to describe the clinical-epidemiological profile of the care service at the Reference Center for Special Immunobiologicals of Hospital in the Amazon. Method: a descriptive study, of a quantitative approach and analyzed by means of the descriptive and inferential statistics. The Information System of the Reference Center for Special Immunobiologicals (former) and the Information System of the National Immunization Program (current) were the databases used, between 2006 and 2016. Results: 77,077 doses of immunobiological vaccines were administered; 25.2% corresponded to the inactivated influenza vaccine; chronic renal failure was the main indication (19%). The current system recorded 18,267 doses of immunobiological vaccines administered between the years 2014 to 2016; 37.8% of which were inactivated influenza vaccines; 42.5% of the indications were not reported, with HIV/AIDS being 18.2%. Infectologia foi a especialidade que mais encaminhou para vacinação (18,3%). Conclusion: the data accuracy has been compromised by the incompleteness in the information systems. We observed underutilization of the service by the local population.

Asociaciones polínicas de sedimentos superficiales del norte de la región chaqueña argentina / Pollen assemblages of surface sediments from the North of the Argentine Chaco region

Resumen La vegetación chaqueña esta condicionada por diversas presiones ambientales que afectan la fisionomía del paisaje. Con el objetivo de reconocer cambios espaciales de la vegetación y distinguir indicadores de disturbios naturales (inundaciones, sequías) y/o antrópicos (incendios, malezas de cultivos y pastoreo), se analizó la composición y distribución de las asociaciones polínicas de sedimentos superficiales sobre un gradiente ambiental al norte de la región chaqueña argentina (23°-27° S & 59°63° W). Se tomaron 35 muestras en un gradiente de 600 km en dirección SE-NO. El análisis se realizó con métodos multivariados y el índice de valor de importancia (IVI). La zonación mostró un reemplazo gradual de biotipos y taxones. En la zona oriental dominó el polen de palmeras (Copernica alba), hierbas (Poaceae) y árboles altos (Schinopsis balansae). Hacia la zona central predominó el polen de árboles bajos (Schinus, Prosopis ruscifolia, Pisonia zapallo), arbustos (Celtis, Castela) y hierbas (Amaranthaceae/Chenopodiaceae, Poaceae). La zona occidental presentó altos contenidos de polen de árboles altos (Schinopsis balansae, Schinopsis lorentzii, Astronium). Se detectaron conjuntos polínicos que permitieron discernir contingencias ambientales, como las inundaciones (Copernicia alba, Juncaginaceae, Cyperaceae) y actividades antrópicas, tales como incendios (Trithrinax, Shinus, Aspidosperma quebracho-blanco), malezas de cultivos (Amaranthaceae/ Chenopodiaceae, Gomphrena, Urticaceae, Ambrosia) y pastoreo (Prosopis ruscifolia, Prosopis kuntzei, Capparicordis, Cerciduim praecox). Los tipos polínicos más importantes fueron: Schinopsis balansae (9 %), Celtis (8.4 %), Poaceae (7.5 %), Schinus (6.9 %), Copernicia alba (3.7 %), entre otros. Se diferenciaron tres asociaciones polínicas que representaron las comunidades de: 1) palmares y sabanas, 2) bosques bajos y matorrales y 3) bosques altos, que se distribuyeron en umbrales de precipitación de 1 100 - 1 000, 1 000 -850 y 850 - 700 mm respectivamente. Los resultados amplían el conocimiento sobre las asociaciones polínicas de la región chaqueña argentina, ofreciendo una buena perspectiva para interpretar la dinámica del paisaje durante el Holoceno en la región.(AU)

Abstract Chaco vegetation is conditioned by several environmental pressures affecting the physiognomy of the landscape. With the aim to recognize the spatial changes of vegetation and distinguish indicators of natural (floods, droughts) and/or anthropogenic disturbances (fires, weeds of crops and grazing), we analyzed the composition and distribution of pollen assemblages of surface sediments along an environmental in the north of Argentine Chaco region (23°-27° S, 59°-63° W). Thirty-five samples were taken into an environmental gradient comprising 600 km length in SE-NW direction. The analyses was performed by multivariate methods and the importance value index (IVI). Zonation showed a gradual replacement of biotypes and taxa. In the Eastern zone, the pollen of palms (Copernica alba), herbs (Poaceae) and high trees (Schinopsis balansae) were dominant. Towards the middle zone, the pollen of low trees (Schinus, Prosopis ruscifolia, Pisonia zapallo), shrubs (Celtis, Castela) and herbs (Amaranthaceae/Chenopodiaceae, Poaceae) were dominant. The western zone recorded the highest content of pollen of high trees (Schinopsis balansae, Schinopsis lorentzii, Astronium). Pollen types were detected that allowed to discern environmental contingencies, such as floods (Copernicia alba, Juncaginaceae, Cyperaceae) and anthropic activities, such as fires (Trithrinax, Shinus, Aspidosperma quebracho-blanco), weeds of crops (Amaranthaceae/Chenopodiaceae, Gomphrena, Urticaceae, Ambrosia) and grazing (Prosopis ruscifolia, Prosopis kuntzei, Capparicordis, Cerciduim praecox). The most important pollen types were: Schinopsis balansae (9 %), Celtis (8.4 %), Poaceae (7.5 %), Schinus (6.9 %), Copernicia alba (3.7 %), among others. Three pollen assemblages were differentiated which represent the follow communities: 1) palms and savannas, 2) low forests and scrublands and 3) high forests, that are distributed in precipitation thresholds corresponding to, 1 100 - 1 000, 1 000 - 850 and 850 - 700 mm respectively. Results expand the knowledge about the pollen assemblages of the Argentine Chaco region, offering a good perspective to interpret the dynamic of the landscape during the Holocene in the region.(AU)

The Pericyte of the Pancreatic Islet Regulates Capillary Diameter and Local Blood Flow.

Efficient insulin secretion requires a well-functioning pancreatic islet microvasculature. The dense network of islet capillaries includes the islet pericyte, a cell that has barely been studied. Here we show that islet pericytes help control local blood flow by adjusting islet capillary diameter. Islet pericytes cover 40% of the microvasculature, are contractile, and are innervated by sympathetic axons. Sympathetic adrenergic input increases pericyte activity and reduces capillary diameter and local blood flow. By contrast, activating beta cells by increasing glucose concentration inhibits pericytes, dilates islet capillaries, and increases local blood flow. These effects on pericytes are mediated by endogenous adenosine, which is likely derived from ATP co-released with insulin. Pericyte coverage of islet capillaries drops drastically in type 2 diabetes, suggesting that, under diabetic conditions, islets lose this mechanism to control their own blood supply. This may lead to inadequate insulin release into the circulation, further deteriorating glycemic control.

Tumor-Suppressor Inactivation of GDF11 Occurs by Precursor Sequestration in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous carcinoma in which various tumor-suppressor genes are lost by mutation, deletion, or silencing. Here we report a tumor-suppressive mode of action for growth-differentiation factor 11 (GDF11) and an unusual mechanism of its inactivation in TNBC. GDF11 promotes an epithelial, anti-invasive phenotype in 3D triple-negative cultures and intraductal xenografts by sustaining expression of E-cadherin and inhibitor of differentiation 2 (ID2). Surprisingly, clinical TNBCs retain the GDF11 locus and expression of the protein itself. GDF11 bioactivity is instead lost because of deficiencies in its convertase, proprotein convertase subtilisin/kexin type 5 (PCSK5), causing inactive GDF11 precursor to accumulate intracellularly. PCSK5 reconstitution mobilizes the latent TNBC reservoir of GDF11 in vitro and suppresses triple-negative mammary cancer metastasis to the lung of syngeneic hosts. Intracellular GDF11 retention adds to the concept of tumor-suppressor inactivation and reveals a cell-biological vulnerability for TNBCs lacking therapeutically actionable mutations.

Computational Models of Reactive Oxygen Species as Metabolic Byproducts and Signal-Transduction Modulators.

Reactive oxygen species (ROS) are widely involved in intracellular signaling and human pathologies, but their precise roles have been difficult to enumerate and integrate holistically. The context- and dose-dependent intracellular effects of ROS can lead to contradictory experimental results and confounded interpretations. For example, lower levels of ROS promote cell signaling and proliferation, whereas abundant ROS cause overwhelming damage to biomolecules and cellular apoptosis or senescence. These complexities raise the question of whether the many facets of ROS biology can be joined under a common mechanistic framework using computational modeling. Here, we take inventory of some current models for ROS production or ROS regulation of signaling pathways. Several models captured non-intuitive observations or made predictions that were later verified by experiment. There remains a need for systems-level analyses that jointly incorporate ROS production, handling, and modulation of multiple signal-transduction cascades.

Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics.

The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can reveal a station's history, such as marine-associated bacteria in a hurricane-flooded station. Some evidence of pathogens was found (Bacillus anthracis), but a lack of reported cases in NYC suggests that the pathogens represent a normal, urban microbiome. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of cities.

Breadth of tuning in taste afferent neurons varies with stimulus strength.

Gustatory stimuli are detected by taste buds and transmitted to the hindbrain via sensory afferent neurons. Whether each taste quality (sweet, bitter and so on) is encoded by separate neurons ('labelled lines') remains controversial. We used mice expressing GCaMP3 in geniculate ganglion sensory neurons to investigate taste-evoked activity. Using confocal calcium imaging, we recorded responses to oral stimulation with prototypic taste stimuli. Up to 69% of neurons respond to multiple tastants. Moreover, neurons tuned to a single taste quality at low concentration become more broadly tuned when stimuli are presented at higher concentration. Responses to sucrose and monosodium glutamate are most related. Although mice prefer dilute NaCl solutions and avoid concentrated NaCl, we found no evidence for two separate populations of sensory neurons that encode this distinction. Altogether, our data suggest that taste is encoded by activity in patterns of peripheral sensory neurons and challenge the notion of strict labelled line coding.