bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association between Poverty and Gene Expression within Peripheral Blood Mononuclear Cells in a Diverse Baltimore City Cohort
Authors: Arnold Nicole S , Noren Hooten Nicole , Zhang Yongqing , Lehrmann Elin , Wood William , Camejo Nunez Wendy , Thorpe Roland J , Evans Michele K , Dluzen Douglas
Published: May 2020

Socioeconomic status (SES), living in poverty, and other social determinants of health contribute to health disparities in the United States. African American (AA) men living below poverty in Baltimore City have a higher incidence of mortality when compared to either white males or AA females living below poverty. Previous studies in our laboratory and elsewhere suggest that environmental conditions are associated with differential gene expression (DGE) patterns in peripheral blood mononuclear cells (PBMCs). DGE have also been associated with hypertension and cardiovascular disease (CVD) and correlate with race and sex. However, no studies have investigated how poverty status associates with DGE between male and female AAs and whites living in Baltimore City. We examined DGE in 52 AA and white participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) cohort, who were living above or below 125% of the 2004 federal poverty line at time of sample collection. We performed a microarray to assess DGE patterns in PBMCs from these participants. AA males and females living in poverty had the most genes differentially-expressed compared with above poverty controls. Gene ontology (GO) analysis identified unique and overlapping pathways related to the endosome, single-stranded RNA binding, long-chain fatty-acyl-CoA biosynthesis, toll-like receptor signaling, and others within AA males and females living in poverty and compared with their above poverty controls. We performed RT-qPCR to validate top differentially-expressed genes in AA males. We found that KLF6, DUSP2, RBM34, and CD19 are expressed at significantly lower levels in AA males in poverty and KCTD12 is higher compared to above poverty controls. This study serves as an additional link to better understand the gene expression response in peripheral blood mononuclear cells in those living in poverty.
Loss of Taste and Smell as Distinguishing Symptoms of COVID-19
Authors: Dawson Patrick , Rabold Elizabeth M. , Laws Rebecca L. , Conners Erin E. , Gharpure Radhika , Yin Sherry , Buono Sean , Dasu Trivikram , Bhattacharyya Sanjib , Westergaard Ryan P. , Pray Ian W. , Ye Dongni , Nabity Scott A. , Tate Jacqueline E. , Kirking Hannah L.
Published: May 2020

Olfactory and taste dysfunctions have emerged as symptoms of COVID-19. Among individuals with COVID-19 enrolled in a household study, loss of taste and/or smell was the fourth most commonly reported symptom (26/42; 62%), and among household contacts, it had the highest positive predictive value (83%; 95% CI: 55-95%) for COVID-19. These findings support consideration of loss of taste and/or smell in possible case identification and testing prioritization for COVID-19.
The Influence of Contextual Factors on the Initial Phases of the COVID-19 Outbreak across U.S. Counties
Authors: Messner Wolfgang , Payson Sarah E
Published: May 2020

Objectives: To examine the influence of county- and state-level characteristics on the initial phases of the COVID-19 outbreak across U.S. counties up to April 14, 2020.
Methods: We used a statistical exponential growth model for the outbreak. Contextual factors at county- and state-level were simultaneously tested with a multilevel linear model. All data was publicly available.
Results: Collectivism was positively associated with the outbreak rate. The racial and ethnic composition of counties contributed to outbreak differences, affecting Black/African and Asian Americans most. Counties with a higher median age had a stronger outbreak, as did counties with more people below the age of 18. Higher income, education, and personal health were generally associated with a lower outbreak. Obesity was negatively related to the outbreak. Smoking was negatively related, but only directionally informative. Air pollution was another significant contributor to the outbreak, but population density did not give statistical significance.
Conclusions: Because of high intrastate and intercounty variation in contextual factors, policy makers need to target pandemic responses to the smallest subdivision possible, so that countermeasures can be implemented effectively.
Measuring Metacognition of Direct and Indirect Parameters of Voluntary Movement
Authors: Arbuzova Polina , Peters Caroline , Röd Lukas , Koß Christina , Maurer Heiko , Maurer Lisa K. , Müller Hermann , Verrel Julius , Filevich Elisa
Published: May 2020

We can make exquisitely precise movements without the apparent need for conscious monitoring. But can we monitor the low-level movement parameters when prompted? And what are the mechanisms that allow us to monitor our movements? To answer these questions, we designed a semi-virtual ball throwing task. On each trial, participants first threw a virtual ball by moving their arm (with or without visual feedback, or replayed from a previous trial) and then made a two-alternative forced choice on the resulting ball trajectory. They then rated their confidence in their decision. We measured metacognitive efficiency usingmeta-d’/d’ and compared it between different informational domains of the first-order task (motor, visuomotor or visual information alone), as well as between two different versions of the task based on different parameters of the movement: proximal (position of the arm) or distal (resulting trajectory of the ball thrown).

We found that participants were able to monitor their performance based on distal motor information as well as when proximal information was available. Their metacognitive efficiency was also equally high in conditions with different sources of information available. The analysis of correlations across participants revealed an unexpected result: while metacognitive efficiency correlated between informational domains (which would indicate domain-generality of metacognition), it did not correlate across the different parameters of movement. We discuss possible sources of this discrepancy and argue that specific first-order task demands may play a crucial role in our metacognitive ability and should be considered when making inferences about domain-generality based on correlations.
Enzymatic dissociation induces transcriptional and proteotype bias in brain cell populations
Authors: Mattei Daniele , Ivanov Andranik , van Oostrum Marc , Pantelyushin Stanislav , Richetto Juliet , Mueller Flavia , Beffinger Michal Matheus , Schellhammer Linda , vom Berg Johannes , Wollscheid Bernd , Beule Dieter , Paolicelli Rosa Chiara , Meyer Urs
Published: May 2020

Different cell isolation techniques exist for transcriptomic and proteotype profiling of brain cells. Here, we provide a systematic investigation of the influence of different cell isolation protocols on transcriptional and proteotype profiles in mouse brain tissue by taking into account single-cell transcriptomics of brain cells, proteotypes of microglia and astrocytes, and flow cytometric analysis of microglia. We show that standard enzymatic digestion of brain tissue at 37°C induces profound and consistent alterations in the transcriptome and proteotype of neuronal and glial cells, as compared to an optimized mechanical dissociation protocol at 4°C. These findings emphasize the risk of introducing technical biases and biological artefacts when implementing enzymatic digestion-based isolation methods for brain cell analyses.
A Novel System for The Comprehensive Collection of Nonvolatile Molecules from Human Exhaled Breath
Authors: Chen Dapeng , Bryden Wayne A , McLoughlin Michael
Published: May 2020

Characterization of nonvolatile molecules in exhaled breath particles can be used for respiratory disease monitoring and diagnosis. Conventional methods for the collection of nonvolatile molecules in breath heavily rely on the physical properties of exhaled breath particles. Strategies taking advantage of their chemical properties have not yet been explored. In the present study, we developed a column system in which the surface chemistry between organic nonvolatile molecules and octadecyl carbon chain was exploited for the comprehensive collection of metabolites, lipids, and proteins. We demonstrated that the collection system had the capture efficiency of 99% and the capacity to capture representative nonvolatile molecules. The collection system was further evaluated using human subjects and proteins collected from human exhaled breath were characterized and identified using gel electrophoresis and bottom-up proteomics. The identified 303proteins from mass spectrometry were further searched against reported bronchoalveolar lavage fluid proteomes and it was shown that 60 proteins have the tissue origin of lower respiratory airways. In summary, we demonstrate that our collection system can collect nonvolatile molecules from human exhaled breath in an efficient and comprehensive manner and has the potential to be used for the study of respiratory diseases.
Reducing Exposures to Airborne Particles Through Improved Filtration: A High-Level Modeling Analysis
Authors: Dillon Michael B , Sextro Richard G
Published: May 2020

Indoor airborne particulates are well-known health hazards and filtration is one common method of reducing exposures. Based on our previously developed Regional Shelter Analysis methodology and parameters that characterize the existing US building stock, we perform a high-level assessment of the potential benefits of upgrading existing filters in furnace and in heating, ventilation, and air conditioning systems using off-the-shelf filters. We use three metrics to assess the improvement: Building Transmission Factor (a measure of protection against outdoor airborne particles), Indoor Normalized Time and Space Integrated Air Concentration (a measure of indoor exposure to indoor-origin airborne particles), and Building Exit Fraction (fraction of indoor airborne particles that are released to the outdoor atmosphere). We also discuss the potential reduction in regional exposures due to particles exiting the building and exposing downwind building occupants.

Our modeling indicates that while buildings provide their occupants passive protection against airborne particulate hazards, including but not limited to PM2.5, PM10, and wildfire smoke; improving particle filtration efficiency may further improve this protection. The degree of improvement varies with particle size and building type. Of the building types studied, apartments are predicted to benefit most, with greater than a factor of 2 improvement (≥50% reduction in exposures) for 1 micron particle exposures when using MERV 7 to 12 rated filters. Non-residential buildings were notably less responsive to improved filtration but had the highest Building Exit Fractions with 30% to 40% of indoor airborne particles released to the outdoor atmosphere (apartment buildings only released 6% to 9%). Improvements predicted for single family homes were intermediate between apartments and non-residential buildings. Improvements in the Regional Exposure metric are larger, ranging from a factor of 2.5x to 10x for residences (when using MERV 7 to 12 rated filters) and up to 25x for large apartments with MERV 14 or 15 rated filters. The results of our modeling analysis are broadly consistent with the limited experimental data and modeling results available in the literature.
Early and massive testing saves lives: COVID-19 related infections and deaths in the United States during March of 2020
Authors: Hittner James B. , Fasina Folorunso O. , Hoogesteijn Almira L. , Piccinini Renata , Kempaiah Prakasha , Smith Stephen D. , Rivas Ariel L.
Published: May 2020

To optimize epidemiologic interventions, predictors of mortality should be identified. The US COVID-19 epidemic data, reported up to 31 March 2020, were analyzed using kernel regularized least squares regression. Six potential predictors of mortality were investigated: (i) the number of diagnostic tests performed in testing week I; (ii) the proportion of all tests conducted during week I of testing; (iii) the cumulative number of (test-positive) cases through 3-31-2020, (iv) the number of tests performed/million citizens; (v) the cumulative number of citizens tested; and (vi) the apparent prevalence rate, defined as the number of cases/million citizens. Two metrics estimated mortality: the number of deaths and the number of deaths/million citizens. While both expressions of mortality were predicted by the case count and the apparent prevalence rate, the number of deaths/million citizens was ≈3.5 times better predicted by the apparent prevalence rate than the number of cases. In eighteen states, early testing/million citizens/population density was inversely associated with the cumulative mortality reported by 31 March, 2020. Findings support the hypothesis that early and massive testing saves lives. Other factors —e.g., population density— may also influence outcomes. To optimize national and local policies, the creation and dissemination of high resolution geo-referenced, epidemic data is recommended.
COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status
Authors: Thomas Tiffany , Stefanoni Davide , Reisz Julie A , Nemkov Travis , Bertolone Lorenzo , Francis Richard O , Hudson Krystalyn E , Zimring James C , Hansen Kirk C , Hod Eldad A , Spitalnik Steven L , D'Alessandro Angelo
Published: May 2020

Previous studies suggest a role for systemic reprogramming of host metabolism during viral pathogenesis to fuel rapidly expanding viral proliferation, for example by providing free amino acids and fatty acids as building blocks. In addition, general alterations in metabolism can provide key understanding of pathogenesis. However, little is known about the specific metabolic effects of SARS-COV-2 infection. The present study evaluated the serum metabolism of COVID-19 patients (n=33), identified by a positive nucleic acid test of a nasopharyngeal swab, as compared to COVID-19-negative control patients (n=16). Targeted and untargeted metabolomics analyses specifically identified alterations in the metabolism of tryptophan into the kynurenine pathway, which is well-known to be involved in regulating inflammation and immunity. Indeed, the observed changes in tryptophan metabolism correlated with serum interleukin-6 (IL-6) levels. Metabolomics analysis also confirmed widespread dysregulation of nitrogen metabolism in infected patients, with decreased circulating levels of most amino acids, except for tryptophan metabolites in the kynurenine pathway, and increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and kidney dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis in COVID-19 patients. Metabolite levels in these pathways correlated with clinical laboratory markers of inflammation and disease severity (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study of the metabolic consequences of COVID-19 infection in a clinical cohort identified amino acid metabolism (especially kynurenine and cysteine/taurine) and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.
Automated Quantification of Mitochondrial Fragmentation in an In-Vitro Parkinson’s Disease Model
Authors: Rees Daniel J. , Roberts Luke , Carisi M. Carla , Morgan Alwena H. , Brown M. Rowan , Davies Jeffrey S.
Published: May 2020

Neuronal mitochondrial fragmentation is a phenotype exhibited in models of neurodegeneration such as Parkinson’s Disease. Delineating the dysfunction in mitochondrial dynamics found in diseased states can aid our understanding of underlying mechanisms for disease progression and possibly identify novel therapeutic approaches. Advances in microscopy and the availability of intuitive open-access software has accelerated the rate of image acquisition and analysis, respectively. These developments allow routine biology researchers to rapidly turn hypotheses into results. In this protocol, we describe the utilisation of cell culture techniques, high-content imaging (HCI), and subsequent open-source image analysis pipeline for the quantification of mitochondrial fragmentation in the context of an in-vitro Parkinson’s Disease model.
Cell size statistics in cell lineages and population snapshots with different growth regimes and division strategies
Authors: Totis Niccolò , Nieto César , Küper Armin , Vargas-García César , Singh Abhyudai , Waldherr Steffen
Published: May 2020

Growing populations of bacteria control their growth and division reaching narrow distributions of cell-sizes. In this paper we explored how different combinations of growth regimes and division mechanisms lead to different cell-size statistics in these populations. Deterministic and stochastic modeling were used to describe the size distribution of a population of cells that is observed from two different perspectives: as single cell lineages, i.e. random paths in the lineage tree, or as snapshots, at given times, of a population in which all descendants of a single ancestor cell are observed. Our time-dependent approaches allowed us to obtain both the transient dynamics and the steady state values for the main statistical moments of the cell-size distribution. Also, we established mathematical relationships among the statistics in the two considered perspectives, thus improving our knowledge of how cells control their growth and proliferation.
Spinal motoneuron firing properties mature from rostral to caudal during post-natal development of the mouse
Authors: Smith Calvin C. , Brownstone Robert M.
Published: May 2020

Altricial mammals are born with immature nervous systems comprised of circuits that do not yet have the neuronal properties and connectivity required to produce future behaviours. During the critical period of post-natal development, neuronal properties are tuned to participate in functional circuits. In rodents, cervical motoneurons are born prior to lumbar motoneurons, and spinal cord development follows a sequential rostro-caudal sequence. Here we asked whether birth order is reflected in the post-natal development of electrophysiological properties. We show that motoneurons of both segments have similar properties at birth and follow the same developmental profile, with maximal firing increasing and excitability decreasing into the 3rdpost-natal week. However, these maturative processes occur in cervical prior to lumbar motoneurons, correlating to the timing of arrival of descending systems. These results suggest that motoneuron properties do not mature by cell autonomous mechanisms alone, but rather depend on developing descending and spinal circuits.
Single-cell RNA-sequencing of peripheral neuroblastic tumors reveals an aggressive transitional cell state at the junction of an adrenergic-mesenchymal transdifferentiation trajectory
Authors: Yuan Xiaojun , Seneviratne Janith A. , Du Shibei , Xu Ying , Chen Yijun , Jin Qianya , Jin Xuanxuan , Balachandran Anushree , Huang Shihao , Xu Yanli , Zhai Yue , Lu Liumei , Tang Mengjie , Dong Yushuang , Cheung Belamy B. , Marshall Glenn M. , Shi Weiyang , Zhang Chao , Carter Daniel R.
Published: May 2020

Peripheral neuroblastic tumors (PNTs) are the most common extracranial solid tumors in early childhood. They represent a spectrum of neural crest derived tumors including neuroblastoma, ganglioneuroblastoma and ganglioneuroma. PNTs exhibit heterogeneity due to interconverting malignant cell states described as adrenergic/nor-adrenergic or mesenchymal/neural crest cell in origin. The factors determining individual patient levels of tumor heterogeneity, their impact on the malignant phenotype, and the presence of other cell states are unknown. Here, single-cell RNA-sequencing analysis of 4267 cells from 7 PNTs demonstrated extensive transcriptomic heterogeneity. Trajectory modelling showed that malignant neuroblasts move between adrenergic and mesenchymal cell states via a novel state that we termed a “transitional” phenotype. Transitional cells are characterized by gene expression programs linked to a sympathoadrenal development, and aggressive tumor phenotypes such as rapid proliferation and tumor dissemination. Among primary bulk tumor patient cohorts, high expression of the transitional gene signature was highly predictive of poor prognosis when compared to adrenergic and mesenchymal expression patterns. High transitional gene expression in neuroblastoma cell lines identified a similar transitional H3K27-acetylation super-enhancer landscape, supporting the concept that PNTs have phenotypic plasticity and transdifferentiation capacity. Additionally, examination of PNT microenvironments, found that neuroblastomas contained low immune cell infiltration, high levels of non-inflammatory macrophages, and low cytotoxic T lymphocyte levels compared with more benign PNT subtypes. Modeling of cell-cell signaling in the tumor microenvironment predicted specific paracrine effects toward the various subtypes of malignant cells, suggesting further cell-extrinsic influences on malignant cell phenotype. Collectively, our study reveals the presence of a previously unrecognized transitional cell state with high malignant potential and an immune cell architecture which serve both as potential biomarkers and therapeutic targets.
Profiling of small non-coding RNAs across cellular and biofluid compartments: implications for multiple sclerosis immunopathology
Authors: Zheleznyakova Galina Yurevna , Piket Eliane , Needhamsen Maria , Hagemann-Jensen Michael , Ekman Diana , Khademi Mohsen , Nimer Faiez Al , Scicluna Patrick , Faridani Omid R , Olsson Tomas , Piehl Fredrik , Jagodic Maja
Published: May 2020

Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is associated with dysregulation of microRNAs (miRNA). We here analyzed all classes of small non-coding RNAs (sncRNAs) in matching peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells and cell-free CSF from relapsing-remitting (RRMS, n=12 in relapse, n=11 in remission), secondary progressive (SPMS, n=6) MS patients and non-inflammatory and inflammatory neurological disease controls (NINDC, n=11; INDC, n=5). We show widespread changes in small nuclear, nucleolar, transfer RNAs and miRNAs. In CSF cells, 133/133 and 115/117 differentially expressed sncRNAs are increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65/67 differentially expressed PBMC sncRNAs are decreased in RRMS compared to NINDC. The striking contrast between periphery and CNS suggests that sncRNA-mediated mechanisms, including alternative splicing, RNA degradation and mRNA translation, regulate the transcriptome of pathogenic cells primarily in the target organ.
SYNAPTIC RELEASE POTENTIATION AT AGING AUDITORY RIBBON SYNAPSES
Authors: Peineau Thibault , Belleudy Séverin , Pietropaolo Susanna , Bouleau Yohan , Dulon Didier
Published: May 2020

Age-related hidden hearing loss is often described as a cochlear synaptopathy that results from a progressive degeneration of the inner hair cell (IHC) ribbon synapses. The functional changes occurring at these synapses during aging are not fully understood. Here, we characterized this aging process in IHCs of C57BL/6J mice, a strain which is known to carry a cadherin23 mutation and experiences early hearing loss with age. These mice, while displaying a large increase in auditory brainstem thresholds due to 50 % loss of IHC synaptic ribbons at middle age (postnatal day 365), paradoxically showed enhanced acoustic startle reflex suggesting a hyperacusis-like response. The auditory defect was associated with a large shrinkage of the IHCs’ cell body and a drastic enlargement of their remaining presynaptic ribbons which were facing enlarged postsynaptic AMPAR clusters. Presynaptic Ca2+microdomains and the capacity of IHCs to sustain high rates of exocytosis were largely increased, while on the contrary the expression of the fast repolarizing BK channels, known to negatively control transmitter release, was decreased. This age-related synaptic plasticity in IHCs suggested a functional potentiation of synaptic transmission at the surviving synapses, a process that could partially compensate the decrease in synapse number and underlie hyperacusis.
Dopamine influences attentional rate modulation in Macaque posterior parietal cortex
Authors: van Kempen Jochem , Brandt Christian , Distler Claudia , Bellgrove Mark A. , Thiele Alexander
Published: May 2020

Cognitive neuroscience has made great strides in understanding the neural substrates of attention, but our understanding of its neuropharmacology remains incomplete. Although dopamine has historically been studied in relation to frontal functioning, emerging evidence suggests important dopaminergic influences in parietal cortex. We recorded single- and multi-unit activity whilst iontophoretically administering dopaminergic agonists and antagonists while rhesus macaques performed a spatial attention task. Out of 88 units, 50 revealed activity modulation by drug administration. Dopamine inhibited firing rates according to an inverted-U shaped dose-response curve and increased gain variability. Dopamine modulated attention-related rate changes and Fano Factors in broad and narrow-spiking units, respectively. D1 receptor antagonists diminished firing rates according to a monotonic function and interacted with attention modulating gain variability in broad-spiking units. Finally, both drugs decreased the pupil light reflex. These data show that dopamine shapes neuronal responses and modulates attentional processing in parietal cortex.
Resource availability and disturbance shape maximum tree height across the Amazon
Authors: Gorgens Eric , Nunes Matheus Henrique , Jackson Tobias , Coomes David , Keller Michael , Reis Cristiano Rodrigues , Valbuena Rubén , Rosette Jacqueline , de Almeida Danilo Roberti Alves , Gimenez Bruno , Cantinho Roberta , Motta Alline Zagnolli , Assis Mauro , de Souza Pereira Francisca Rocha , Spanner Gustavo , Higuchi Niro , Ometto Jean Pierre
Published: May 2020

The factors shaping the distribution of giant tropical trees are poorly understood, despite its importance as a link between evolutionary biology and ecosystem biogeochemistry. The recent discovery of clusters of trees over 80 metres tall in the Guiana Shield region of the Amazon rainforest challenges the current understanding of the factors controlling the growth and survival of giant trees. The new discovery led us to revisit the question: what determines the distribution of the tallest trees of the Amazon?

Here, we used high-resolution airborne LiDAR (Light Detection and Ranging) surveys to measure canopy height across 282,750 ha of primary old-growth and secondary forests throughout the entire Brazilian Amazon to investigate the relationship between the occurrence of giant trees and the environmental factors that influence their growth and survival. Our results suggest that the factors controlling where trees grow extremely tall are distinct from those controlling their longevity. Trees grow taller in areas with high soil clay content (> 42%), lower radiation (< 130 clear days per year) and wind speeds, avoiding alluvial areas (elevations higher than 40 m a.s.l), and with an optimal precipitation range of 1,500 to 2,500 mm yr-1. We then used an envelope model to determine the environmental conditions that support the very tallest trees (i.e. over 70 m height). We found that, as opposed to the myriad of interacting factors that control the maximum height at a large scale, wind speed had by far the largest influence on the distribution of these sentinel trees, and explained 67% of the probability of finding trees over 70 m in the Brazilian Amazon forest.

The high-resolution pan-Amazon LiDAR data showed that environmental variables that drive growth in height are fundamentally different from environmental variables that support their survival. While precipitation and temperature seem to have lower importance for their survival than expected from previous studies, changes in wind and radiation regimes could reshape our forested biomes. This should be carefully considered by policy-makers when identifying important hotspots for the conservation of biodiversity in the Amazon.
A characterization of the electrophysiological, morphological and input domains of vasoactive intestinal peptide (VIP) interneurons in the medial entorhinal cortex (MEC)
Authors: Badrinarayanan Saishree , Manseau Frédéric , Lim Byung Kook , Williams Sylvain , Brandon Mark P.
Published: May 2020

Circuit interactions within the medial entorhinal cortex (MEC) translate movement into a coherent code for spatial location. Entorhinal principal cells are subject to strong lateral inhibition, suggesting that a disinhibitory mechanism may drive their activation. Cortical Vasoactive Intestinal Peptide (VIP) expressing inhibitory neurons predominantly contact interneurons, providing a local disinhibitory mechanism. Here, we investigate the electrophysiological and morphological properties of VIP cells usingin vitrowhole-cell patch clamp recordings and use rabies-mediated circuit tracing to discover long-range inputs that may modulate this population in mice. We report physiological and morphological properties of VIP cells that differ across lamina and along the dorsal-ventral MEC axis. Furthermore, we reveal long-range inputs to VIP neurons from regions known to encode proprioceptive and auditory information, including the mesencephalic trigeminal nucleus and superior para-olivary nuclei, respectively. These results characterize the properties of VIP cells and reveal sensory modalities that could drive disinhibition in the MEC.
Mechano-regulation of bone adaptation is controlled by the localin vivoenvironment and logarithmically dependent on loading frequency
Authors: Scheuren Ariane C. , Vallaster Paul , Kuhn Gisela A. , Paul Graeme R. , Malhotra Angad , Kameo Yoshitaka , Müller Ralph
Published: May 2020

It is well established that cyclic, but not static, mechanical loading has anabolic effects on bone. However, the function describing the relationship between the loading frequency and the amount of bone adaptation remains unclear. Using a combined experimental and computational approach, this study aimed to investigate whether bone mechano-regulation is controlled by mechanical signals in the localin vivoenvironment and dependent on loading frequency. Specifically, by combiningin vivomicro-computed tomography (micro-CT) imaging with micro-finite element (micro-FE) analysis, we monitored the changes in microstructural as well as the mechanicalin vivoenvironment (strain energy density (SED) and SED gradient) of mouse caudal vertebrae over 4 weeks of either cyclic loading at varying frequencies of 2Hz, 5Hz, or 10Hz, respectively or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of bone formation and a decreased probability of bone resorption. In all loading groups, the SED gradient was superior in the determination of local bone formation and resorption events as compared to SED. Cyclic loading induced positive net remodeling rates when compared to sham and static loading, mainly due to an increase in mineralizing surface and a decrease in eroded surface. Consequently, bone volume fraction increased over time in 2Hz, 5Hz and 10Hz (+15%, +21% and +24%, p<0.0001), while static loading led to a decrease in bone volume fraction (−9%, p≤0.001). Furthermore, regression analysis revealed a logarithmic relationship between loading frequency and the net change in bone volume fraction over the four week observation period (R2=0.74). In conclusion, these results suggest that bone adaptation is regulated by mechanical signals in the localin vivoenvironment and furthermore, that mechano-regulation is logarithmically dependent on loading frequency with frequencies below a certain threshold having catabolic effects, and those above anabolic effects. This study thereby provides valuable insights towards a better understanding of the mechanical signals influencing bone formation and resorption in the localin vivoenvironment.
The demographic buffering strategy has a threshold of effectiveness to increases in environmental stochasticity
Authors: Rodríguez-Caro R.C. , Capdevila P. , Graciá E. , Barbosa J. M. , Giménez A. , Salguero-Gómez R.
Published: May 2020

Animal populations have developed multiple strategies to deal with environmental change. Among them, the demographic buffering strategy consists on constraining the temporal variation of the vital rate(s) (e.g., survival, growth, reproduction) that most affect(s) the overall performance of the population. Given the increase in environmental stochasticity of the current global change scenario, identifying the thresholds beyond which populations are not able to remain viable -despite their potential buffering strategies- is of utmost importance.

Tortoises are known to buffer the temporal variation in survival (i.e.this vital rate has the highest contribution to the population growth rateλ) at the expense of a high variability on reproductive rates (lowest contribution toλ). To identify the potential threshold in buffering ability, here we use field data collected across a decade on 15 locations ofTestudo graecaalong South-Eastern Spain. We analyse the effects of environmental variables (precipitation, temperature, and NDVI) on the probability of laying eggs and the number of eggs per clutch. Finally, we couple the demographic and environmental data to parametrise integral projection models (IPMs) to simulate the effects of different scenarios of drought recurrence on population growth rate.

We find that droughts negatively affect the probability of laying eggs, but the overall effects on the population growth rates ofT. graecaunder the current drought frequencies (one per decade) are negligible. However, increasing the annual frequency of droughts decreases the buffering ability ofT. graecapopulations, with a threshold at three droughts per decade.

Although some species may buffer current environmental regimes by carefully orchestrating how their vital rates vary through time, a demographic buffering strategy may alone not warrant population viability in extreme regimes. Our findings support the hypothesis that the buffering strategy indeed has a threshold of effectiveness. Our methodological approach also provides a useful pipeline for ecologists and managers to determine how effective the management of environmental drivers can be for demographically buffering populations, and which scenarios may not provide long-term species persistence.
Expression of tyrosine hydroxylase gene from rat leads to oxidative stress in potato plants
Authors: Kostyn Kamil , Boba Aleksandra , Kostyn Anna , Starzycki Michał , Szopa Jan , Kulma Anna
Published: May 2020

Catecholamines are biogenic aromatic amines common among both animals and plants. In animals they are synthesized via tyrosine hydroxylation, while in plants, both hydroxylation or decarboxylation of tyrosine are possible, depending on the species, though no tyrosine hydroxylase – a counterpart of animal enzyme has been identified yet. It is known that in potato plants it is the decarboxylation of tyrosine that leads to catecholamine production. In this paper we present the effects of induction of an alternative route of catecholamine production by introducing tyrosine hydroxylase gene from rat. We demonstrate that an animal system can be used by the plant, however, it does not function to synthesize catecholamines. Instead it leads to elevated reactive oxygen species content and constant stress condition to the plant which responds with elevated antioxidant level and further with improved resistance to infection.

One sentence summary

Introduction of rat tyrosine hydroxylase gene to potato disturbs catecholamine synthesis, causes oxidative stress and activates antioxidant response.
Simvastatin Therapy Attenuates Memory Deficits that Associate with Brain Monocyte Infiltration in Chronic Hypercholesterolemia
Authors: Don-Doncow Nicholas , Vanherle Lotte , Matthes Frank , Petersen Sine Kragh , Matuskova Hana , Rattik Sara , Härtlova Anetta , Meissner Anja
Published: May 2020

Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. Cardiovascular therapeutics (e.g., statins and anti-hypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/-mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/-but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/-mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.
Optimal coordination and reorganization of photosynthetic properties in C4grasses
Authors: Zhou Haoran , Akçay Erol , Helliker Brent
Published: May 2020

C3and C4are major functional types in terrestrial biosphere models, with photosynthesis traits as important input parameters. The evolution of C4required reorganizations of Calvin-Benson-cycle and coordination of C4-cycle enzymes, resulting in divergences of physiological traits between C3and C4. In addition, photosynthesis further optimized after the evolution of C4causing diversification within C4lineages due to different evolutionary histories. We combined optimality modeling, physiological measurements and phylogenetic analysis to examine how various aspects of C4photosynthetic machinery were reorganized and coordinated within C4lineages and as compared to closely-related C3in grasses. Optimality models and measurements indicated a higher maximal electron transport to maximal Rubisco carboxylation ratio (Jmax/Vcmax) in C4than C3, consistent with the optimal prediction to maximize photosynthesis. The coordination between Calvin-Benson and C4cycles (Vpmax/Vcmax), however, is in line with the optimal modeling results under 200 ppm, as opposed to current CO2. Such inconsistencies can be explained by a slowly declining assimilation rate beyond optimalVpmax/Vcmax. Although rapid coordination occurred early in C4evolution, C4is still under optimizing processes and photosynthetic measures have continued to increase across time. Lastly, better understandings ofJmax/Vcmax,Vpmax/Vcmaxand fluorescence-based-electron-transport proffer enhanced approaches to parameterize terrestrial biosphere models.
Loss of Photosynthetic RhythmThermal Plasticity Under Domestication and Repurposing Drivers of Circadian Clock (DOC) Loci for Adaptive Breeding in Barley
Authors: Prusty Manas R. , Bdolach Eyal , Yamamoto Eiji , Neyhart Jeffrey L. , Tiwari Lalit D. , Pillen Klaus , Doron-Feigenbaum Adi , Smith Kevin P. , Fridman Eyal
Published: May 2020

Circadian clock rhythms are critical to control physiological and development traits, allowing, plants to adapt to changing environments. Here we show that the circadian rhythms of cultivated barley (Hordeum vulgare) have slowed and amplitude increased under domestication by comparing with its wild ancestor (H. spontaneum). Moreover, we show a significant loss of thermal plasticity during barley evolution for the period and more extensively for amplitude. Our genetic analysis indicates that wild allele at epistatic loci, which mutually condition clock variation and its thermal plasticity in interspecific crosses, are absent in a contemporary barley breeding panel. These epistatic interactions include conditioned effects of Drivers of Circadian (DOC) clock loci on chromosome 3 and 5, which mediate amplitude decrease and period lengthening, respectively, under domestication. Notably, two significant loci,DOC3.1andDOC5.1, which are not associated with clock diversity in cultivated breeding material, do show pleiotropic effects on flowering time and grain yield at multiple experimental sites across the U.S. in a temperature-dependent manner. We suggest that transition from winter growth of wild barley (H. spontaneum) to spring growth of modern cultivars included the loss and repurposing of circadian clock regulators to yield adaptation by mechanisms yet to be clarified.

Significance statement

Circadian clock rhythms are crucial factors affecting crop adaptation to changing environments. If faced with increased temperature plants could respond with temperature compensation adaptation and maintain clock rhythms, or they can change period and/or amplitude to adapt. We used a combination of approaches: high-throughput clock analysis under optimal and elevated heat conditions, genome-wide association study (GWAS) with cultivated and wild diversity panels to identify changes under domestication and quantitative trait loci (QTL) that control the clock and its responses, and QTL-environment association for testing environmentally-conditioned effects of these QTLongrain yield and flowering timingacross US. Our findings provide insights into changes of circadian rhythms under domestication and genetic tools for plant breeders to develop better-adapted cultivars to changing environments.
A SNAI2-PEAK1 stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting a cytokine expression profile that converges on PI3K/Akt signaling
Authors: Hamalian Sarkis , Güth Robert , Runa Farhana , Molnar Justin , Vickers Eric , Agajanian Megan , Humphries Jonathan , Humphries Martin J. , Tchou Julia , Zervantonakis Ioannis K. , Kelber Jonathan A.
Published: May 2020

Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor progression and targeted therapy resistance remain poorly understood, presenting significant clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton- and focal adhesion-associated pseudokinase that promotes cell state plasticity and cancer metastasis by mediating growth factor-integrin signaling crosstalk. Here, we determined that stromal PEAK1 expression predicts poor outcomes in HER2-positive breast cancers high in SNAI2 expression and enriched for MSC content. Notably, we identified that mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and MSCs require PEAK1 to potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-positive breast cancer cells. Analysis of PEAK1-dependent secreted factors from MSCs revealed a CCL4-, INHBA- and GDF5-focused network that converged on PI3K/Akt signaling. In this regard, we observed that MSC expression of PEAK1 is required for sustained Akt phosphorylation in neighboring HER2-positive breast cancer cells following lapatinib treatment. Finally, we uncovered a significant correlation between INHBA and PEAK1 expression levels in breast cancer, and that INHBA is an excellent predictor of disease relapse and decreased survival in HER2-positive tumors enriched for PEAK1 expression and MSC content. Importantly, we provide the first evidence that PEAK1 promotes tumorigenic phenotypes through a previously unrecognized SNAI2-PEAK1-INHBA-PI3K/Akt stromal to tumor cell signaling axis. These results establish a new, targetable intercellular mechanism that may be leveraged to improve targeted therapy responses and patient outcomes in breast cancer and other stroma-rich malignancies.
Quantification of proteins, protein complexes and mRNA in single cells by proximity-sequencing
Authors: Vistain Luke , Van Phan Hoang , Jordi Christian , Chen Mengjie , Reddy Sai T. , Tay Savaş
Published: May 2020

Multiplexed analysis of single-cells enables accurate modeling of cellular behaviors, classification of new cell types, and characterization of their functional states. Here we present proximity-sequencing (Prox-seq), a method for simultaneous measurement of an individual cell’s proteins, protein complexes and mRNA. Prox-seq utilizes deep sequencing and barcoded proximity assays to measure proteins and their complexes from all pairwise combinations of targeted proteins, in thousands of single-cells. The number of measured protein complexes scales quadratically with the number of targeted proteins, providing unparalleled multiplexing capacity. We developed a high-throughput experimental and computational pipeline and demonstrated the potential of Prox-Seq for multi-omic analysis with a panel of 13 barcoded proximity probes, enabling the measurement of 91 protein complexes, along with thousands of mRNA molecules in single T-cells and B-cells. Prox-seq provides access to an untapped yet powerful measurement modality for single-cell phenotyping and can discover new protein interactions in signaling and drug studies.
Spatiotemporal Evaluation of The Human Footprint in Colombia: Four Decades of Anthropic Impact in Highly Biodiverse Ecosystems
Authors: Correa Ayram Camilo Andrés , Etter Andres , Díaz-Timoté Jhonatan Julián , Buriticá Susana Rodríguez , Ramírez Wilson , Corzo Germán
Published: May 2020

The maintenance of biodiversity and the capacity of natural systems to provide goods and services for people is affected on different levels by the intensity of human activities on ecosystems. In this study, we apply a Legacy-adjusted Human Footprint Index (LHFI) to evaluate the spatiotemporal variation of anthropic impact in Colombia in 1970, 1990, 2000 and 2015. We identified hotspots of change in LHFI and we evaluated the intensity of anthropic pressures in natural regions and ecosystems. We found that LHFI in Colombia increased between 1970 and 2015. The Andean and Caribbean regions presented the highest levels of anthropic impact, remaining stable over time. Hotspots of change were mainly located in the following regions: Andean (Antioquia, Cauca and Valle del Cauca states), Amazon (Amazonas, parts of Meta, Guaviare and Putumayo states) and Orinoco (Casanare and parts of Meta and Vichada states). In addition, ecosystems that under the IUCN ecosystem risk categories are Critically Endangered (CR) and Vulnerable (VU) were the most affected by a high level of human impact. Spatiotemporal evaluation of the human footprint in Colombia provides new insights about trends in human pressures on ecosystems and constitutes an analytical tool with high potential for harmonizing land use planning and biodiversity conservation.