bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid disruption of the cortical microcirculation after mild traumatic brain injury
Authors: Witkowski Ellen D. , Erdener Şefik Evren , Kılıç Kıvılcım , Kura Sreekanth , Tang Jianbo , Postnov Dmitry D. , Lee Esther , Kong Sunnie , Boas David A. , Davison Ian G. 
Published: October 2019

AbstractTraumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can still lead to long-term neuropathology manifesting months or years later. Although the cellular stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to characterize deficits in the cortical microcirculation during both acute and chronic phases after mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking flow deficits in the capillary network, where 18% of vessels were completely occluded for extended periods after injury, and an additional >50% showed substantial stoppages. Decreased CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that acute post-injury periods may be key therapeutic windows for interventions that restore flow and mitigate metabolic stress.
Temporal contiguity training does not affect size-tolerant representations in object-selective cortex
Authors: Van Meel Chayenne , de Beeck Hans P. Op 
Published: October 2019

AbstractThe human visual system has a remarkable ability to reliably identify objects across variations in appearance, such as variations in viewpoint, lighting and size. Here we used fMRI in humans to test whether temporal contiguity training with natural and altered image dynamics can respectively build and break neural size tolerance for objects. Participants (N = 23) were presented with sequences of images of “growing” and “shrinking” objects. In half of the trials, the object also changed identity when the size change happened. According to the temporal contiguity hypothesis, and studies with a similar paradigm in monkeys, this training process should alter size tolerance. After the training phase, BOLD responses to each of the object images were measured in the scanner. Neural patterns in LOC and V1 contained information on size, similarity and identity. In LOC, the representation of object identity was partially invariant to changes in size. However, temporal contiguity training did not affect size tolerance in LOC. Size tolerance in human object-selective cortex is more robust to variations in input statistics than expected based on prior work in monkeys supporting the temporal contiguity hypothesis.
A quantitative narrative on movement, disease and patch exploitation in nesting agent groups
Authors: Getz Wayne M. , Salter Richard , Tallam Krti 
Published: October 2019

AbstractAnimal relocation data has recently become considerably more ubiquitous, finely structured (collection frequencies measured in minutes) and co-variate rich (physiology of individuals, environmental and landscape information, and accelerometer data). To better understand the impacts of ecological interactions, individual movement and disease on global change ecology, including wildlife management and conservation, it is important to have simulators that will provide demographic, movement, and epidemiology null models against which to compare patterns observed in empirical systems. Such models may then be used to develop quantitative narratives that enhance our intuition and understanding of the relationship between population structure and generative processes: in essence, along with empirical and experimental narratives, quantitative narratives are used to advance ecological epistemology. Here we describe a simulator that accounts for the influence of consumer-resource interactions, existence of social groups anchored around a central location, territoriality, group-switching behavior, and disease dynamics on population size. We use this simulator to develop new and reinforce existing quantitative narratives and point out areas for future study.Author summaryThe health and viability of species are of considerable concern to all nature lovers. Population models are central to our efforts to assess the numerical and ecological status of species and threats posed by climate change. Models, however, are crude caricatures of complex ecological systems. So how do we construct reliable assessment models able to capture processes essential to predicating the impacts of global change on population viability without getting tied up in their vast complexities? We broach this question and demonstrate how models focusing at the level of the individual (i.e., agent-based models) are tools for developing robust, narratives to augment narratives arising purely from empirical data sources and experimental outcomes. We do this in the context of nesting social groups, foraging for food, while exhibiting territoriality and group-switching behavior; and, we evaluate the impact of disease on the viability of such populations.
Brain Differences in the Prefrontal Cortex, Amygdala, and Hippocampus in Youth with Congenital Adrenal Hyperplasia
Authors: Herting Megan M. , Azad Anisa , Kim Robert , Geffner Mitchell E. , Kim Mimi S. 
Published: October 2019

ABSTRACTContextClassical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency results in hormone imbalances present both prenatally and postnatally that may impact the developing brain.ObjectiveTo characterize gray matter morphology in the prefrontal cortex and subregion volumes of the amygdala and hippocampus in youth with CAH, compared to age- and sex-matched controls.DesignA cross-sectional study of 27 CAH youth (16 female; 12.6 ± 3.4 year) and 35 typically developing, age- and sex-matched healthy controls (20 female; 13.0 ± 2.8 year) with 3-T magnetic resonance imaging scans. Brain volumes of interest included bilateral prefrontal cortex, and eight amygdala and six hippocampal subregions. Between-subject effects of group (CAH vs control) and sex, and their interaction (group-by-sex) on brain volumes were studied, while controlling for intracranial volume (ICV) and group differences in body mass index and bone age.ResultsCAH youth had smaller ICV and increased cerebrospinal fluid volume compared to controls. In fully-adjusted models, CAH youth had smaller bilateral, superior and caudal middle frontal volumes, and smaller left lateral orbito-frontal volumes compared to controls. Medial temporal lobe analyses revealed the left hippocampus was smaller in fully-adjusted models. CAH youth also had significantly smaller lateral nucleus of the amygdala and hippocampal subiculum and CA1 subregions.ConclusionsThis study replicates previous findings of smaller medial temporal lobe volumes in CAH patients, and suggests that lateral nucleus of the amygdala, as well as subiculum and subfield CA1 of the hippocampus are the most affected regions in CAH youth.PrécisWe collected brain scans of 27 youth with classical CAH and 35 healthy controls. Portions of the prefrontal cortex, amygdala, and hippocampus were smaller in CAH youth compared to controls.Disclosure SummaryMEG receives grant support from Novo Nordisk; consultant fees from Daiichi Sankyo, Ferring, Novo Nordisk, Nutrition & Growth Solutions, Pfizer, Sandoz, and Spruce Biosciences; serves on data safety monitoring boards for Ascendis, Millendo, and Tolmar; and receives royalties from McGraw-Hill and UpToDate.
A role of hypoxia inducible factor 1 alpha in Mouse Gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency
Authors: López-Rodríguez Darlah M. , Kirillov Varvara , Krug Laurie T. , Mesri Enrique A. , Andreansky Samita 
Published: October 2019

ABSTRACTThe hypoxia inducible factor 1 alpha (HIFIα) protein and the hypoxic microenvironment are critical for infection and pathogenesis by the oncogenic gammaherpesviruses (γHV) such as Kaposi’ Sarcoma-associated Herpes Virus (KSHV) and Epstein-Barr virus (EBV). However, understanding the role of HIFIα during the virus life cycle and its biological relevance in the context of host pathogenesis has been challenging due to the lack of animal models for human γHV. To study the role of HIFIα we employed the murine gammaherpesvirus 68 (MHV68), a rodent pathogen that readily infects laboratory mice. We show that MHV68 infection induces HIFIα protein and HIFIα-responsive gene expression in permissive cells. Deletion of HIFIα reduces virus production due to a global downregulation of viral gene expression. Most notable was the marked decrease in many viral genes bearing hypoxia regulatory element (HRE) such as viral G-Protein Coupled Receptor (vGPCR), which is known to activate HIF1α transcriptional activity during KSHV infection. Intranasal infection of HIF1αLoxP/LoxPmice with MHV68 expressing Cre-recombinase impaired virus expansion during early acute infection and affected lytic reactivation in the splenocytes explanted from mice. Moreover, low oxygen conditions accelerated lytic reactivation and enhanced virus production in MHV68 infected splenocytes. Thus, we conclude that HIFIα plays a critical role to promote virus replication. Our results highlight the importance of the mutual interactions of the oxygen-sensing machinery and gammaherpesviruses in viral replication and pathogenesis.AUTHOR SUMMARYThe host oxygen sensing machinery including the HIF1α pathway is important during the viral life cycle of oncogenic gammaherpesviruses such as KSHV and EBV. However, due to the host specificity, the effects of HIF1α in herpes biology is limited to studies within vitrosystems. Here, we study the role of HIF1α using the mouse gammaherpesvirus 68 (MHV68) that readily infects laboratory mice. We demonstrate that MHV68 infection upregulates HIF1α during replication and inactivation of HIF1α transcriptional activity significantly decreased viral genes expression which results in impaired virus productionin vitro. In vivo deletion of HIF1α impaired viral expansion during acute infection and affected reactivation from latency. These results show the importance of the interplay with the oxygen-sensing machinery in gammaherpesvirus infection and pathogenesis, placing the MHV68 mouse model as a unique platform to gain insight into this important aspect of oncogenic gamma-herpesviruses biology and to test HIF1α targeted therapeutics.
Pollinators in food webs: Mutualistic interactions increase diversity, stability, and function in multiplex networks
Authors: Hale Kayla R. S. , Valdovinos Fernanda S. , Martinez Neo D. 
Published: October 2019

ABSTRACTEcosystems are composed of complex networks of many species interacting in different ways. While ecologists have long studied food webs of feeding interactions, recent studies increasingly focus on mutualistic networks including plants that exchange food for reproductive services provided by animals such as pollinators. Here, we synthesize both types of consumer-resource interactions to better understand the controversial effects of mutualism on ecosystems at the species, guild, and whole-community levels. We find that consumer-resource mechanisms underlying plant-pollinator mutualisms can increase the persistence, productivity, abundance, and temporal stability of both mutualists and non-mutualists in food webs. These effects strongly increase with floral reward productivity and are qualitatively robust to variation in the prevalence of mutualism and pollinators feeding upon resources in addition to rewards. This work advances the ability of mechanistic network theory to synthesize different types of interactions and illustrates how mutualism can enhance the diversity, stability, and function of complex ecosystems.
Multiplex in situ hybridization within a single transcript: RNAscope reveals dystrophin mRNA dynamics
Authors: Hildyard J.C.W. , Rawson F. , Wells D.J. , Piercy R.J. 
Published: October 2019

AbstractDystrophin plays a vital role in maintaining muscle health, yet low mRNA expression, lengthy transcription time and the limitations of traditional in-situ hybridization (ISH) methodologies mean that the dynamics of dystrophin transcription remain poorly understood. RNAscope is highly sensitive ISH method that can be multiplexed, allowing detection of individual transcripts at sub-cellular resolution, with different target mRNAs assigned to distinct fluorophores. We present a novel approach, instead using RNAscope probes targeted to 5’ and 3’ regions of the same transcript: labelling muscle dystrophin mRNA in this manner allows transcriptional dynamics to be deciphered in health and disease, resolving both nascent myonuclear transcripts and exported mature mRNAs (the latter absent in dystrophic muscle, yet restored following therapeutic intervention). We show that even in healthy muscle, immature dystrophin mRNA predominates (60-80% of total), with the surprising implication that the half-life of a mature transcript is markedly shorter than the time invested in transcription: at the transcript level, supply may exceed demand. Our findings provide unique spatiotemporal insight into the behaviour of this long transcript (with implications for therapeutic approaches), and further suggests this modified multiplex ISH approach is well-suited to long genes, offering a highly tractable means to reveal complex transcriptional dynamics.
Distributed and Retinotopically Asymmetric Processing of Coherent Motion in Mouse Visual Cortex
Authors: Sit Kevin K. , Goard Michael J. 
Published: October 2019

ABSTRACTPerception of visual motion is important for a range of ethological behaviors in mammals. In primates, specific higher visual cortical regions are specialized for processing of coherent visual motion. However, the distribution of motion processing among visual cortical areas in mice is unclear, despite the powerful genetic tools available for measuring population neural activity. Here, we used widefield and 2-photon calcium imaging of transgenic mice expressing a calcium indicator in excitatory neurons to measure mesoscale and cellular responses to coherent motion across the visual cortex. Imaging of primary visual cortex (V1) and several higher visual areas (HVAs) during presentation of natural movies and random dot kinematograms (RDKs) revealed heterogeneous responses to coherent motion. Although coherent motion responses were observed throughout visual cortex, particular HVAs in the putative dorsal stream (PM, AL, AM) exhibited stronger responses than ventral stream areas (LM and LI). Moreover, beyond the differences between visual areas, there was considerable heterogeneity within each visual area. Individual visual areas exhibited an asymmetry across the vertical retinotopic axis (visual elevation), such that neurons representing the inferior visual field exhibited greater responses to coherent motion. These results indicate that processing of visual motion in mouse cortex is distributed unevenly across visual areas and exhibits a spatial bias within areas, potentially to support processing of optic flow during spatial navigation.
Division of labour promotes the spread of information in colony emigrations by the antTemnothorax rugatulus
Authors: Valentini Gabriele , Masuda Naoki , Shaffer Zachary , Hanson Jake R. , Sasaki Takao , Walker Sara Imari , Pavlic Theodore P. , Pratt Stephen C. 
Published: October 2019

AbstractThe fitness of group-living animals often depends on how well members share information needed for collective decision-making. Theoretical studies have shown that collective choices can emerge in a homogeneous group of individuals following identical rules, but real animals show much evidence for heterogeneity in the degree and nature of their contribution to group decisions. In social insects, for example, the transmission and processing of information is influenced by a well-organized division of labour. Studies that accurately quantify how this behavioural heterogeneity affects the spread of information among group members are still lacking. In this paper, we look at nest choices during colony emigrations of the antTemnothorax rugatulusand quantify the degree of behavioural heterogeneity of workers. Using methods from both machine learning and network analysis, we identify and characterize four behavioural castes of workers – primary, secondary, passive, and wandering – covering distinct roles in the spread of information during each emigration. This detailed characterization of the contribution of each worker can improve models of collective decision-making in this species and promises a deeper understanding of behavioural variation at the colony level.
Cortico-cortical feedback from V2 exerts a powerful influence over the visually evoked local field potential and associated spike timing in V1
Authors: Hartmann Till S. , Raja Sruti , Lomber Stephen G. , Born Richard T. 
Published: October 2019

AbstractThe local field potential (LFP) is generally thought to be dominated by synaptic activity within a few hundred microns of the recording electrode. The sudden onset of a visual stimulus causes a large downward deflection of the LFP recorded in primary visual cortex, known as a visually evoked potential (VEP), followed by rhythmic oscillations in the gamma range (30-80 Hz) that are often in phase with action potentials of nearby neurons. By inactivating higher visual areas that send feedback projections to V1, we produced a large decrease in amplitude of the VEP, and a strong attenuation of gamma rhythms in both the LFP and multi-unit activity, despite an overall increase in neuronal spike rates. Our results argue that much of the recurrent, rhythmic activity measured in V1 is strongly gated by feed-back from higher areas, consistent with models of coincidence detection that result in burst firing by layer 5 pyramidal neurons.
N-Acetyl Cysteine Abrogates Silver-Induced Reactive Oxygen Species in Human Cells Without Altering Silver-based Antimicrobial Activity
Authors: Shah Kush N. , Shah Parth N. , Mullen Andrew R. , Chen Qingquan , DeBerardinis Ralph J. , Cannon Carolyn L. 
Published: October 2019

AbstractSilver-based antimicrobials are widely used topically to treat infections associated with multi-drug resistant (MDR) pathogens. Expanding this topical use to aerosols to treat lung infections requires understanding and preventing silver toxicity in the respiratory tract. A key mechanism resulting in silver-induced toxicity is the production of reactive oxygen species (ROS). In this study, we have verified ROS generation in silver-treated bronchial epithelial (16HBE) cells prompting evaluation of three antioxidants, N-acetyl cysteine (NAC), ascorbic acid, and melatonin, to identify potential prophylactic agents. Among them, NAC was the only candidate that abrogated the ROS generation in response to silver exposure resulting in the rescue of these cells from silver-associated toxicity. Further, this protective effect directly translated to restoration of metabolic activity, as demonstrated by the normal levels of citric acid cycle metabolites in NAC-pretreated silver-exposed cells. As a result of the normalized citric acid cycle, cells pre-incubated with NAC demonstrated significantly higher levels of adenosine triphosphate (ATP) levels compared with NAC-free controls. Moreover, we found that this prodigious capacity of NAC to rescue silver-exposed cells was due not only to its antioxidant activity, but also to its ability to directly bind silver. Despite binding to silver, NAC did not alter the antimicrobial activity of silver.ImportanceAlthough silver is a potent, broad-spectrum antibiotic, silver-induced toxicity, primarily due to generation of ROS, remains a concern limiting its use beyond treatment of wounds. NAC has been widely used as an antioxidant to rescue eukaryotic cells from metal-associated toxicity. Thus, we have evaluated the capacity of NAC to abrogate silver toxicity in a human bronchial epithelial cell line (16HBE) as a step towards expanding the use of silver-based antimicrobials to treat lung infections. We found that NAC pre-incubation resurrects a healthy metabolic state in bronchial epithelial cells exposed to silver ions via a combination of its antioxidant and metal-binding properties. Finally, this ability of NAC to rescue silver-exposed eukaryotic cells does not alter the antimicrobial activity of silver. Thus, a silver-NAC combination holds tremendous potential as a future, non-toxic antimicrobial agent.
Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques
Authors: Winchell Caylin G. , Mishra Bibhuti B. , Phuah Jia Yao , Saqib Mohd , Nelson Samantha J. , Maiello Pauline , Causgrove Chelsea M. , Ameel Cassaundra L. , Stein Brianne , Borish H. Jacob , White Alexander G. , Klein Edwin C. , Zimmerman Matthew D. , Dartois Véronique , Lin Philana Ling , Sassetti Christopher M. , Flynn JoAnne L. 
Published: October 2019

AbstractIn 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.