bluuebunny/crossref_metadata_2025 huggingface dataset:
Heritability of the Mouse Brain Connectome
Authors: Wang Nian , Anderson Robert J , Ashbrook David G , Gopalakrishnan Vivek , Park Youngser , Priebe Carey E , Qi Yi , Vogelstein Joshua T , Williams Robert W , Johnson G Allan
Published: July 2019

Genome-wide association studies have demonstrated significant links between human brain structure and common DNA variants. Similar studies with rodents have been challenging because of smaller brain volumes. Using high field MRI (9.4T) and compressed sensing, we have achieved microscopic resolution and sufficiently high throughput for rodent population studies. We generated whole brain structural MRI and diffusion connectomes for four diverse isogenic lines of mice (C57BL/6J, DBA/2J, CAST/EiJ, and BTBR) at spatial resolution 20,000 times higher than human connectomes. We derived volumes, scalar diffusion metrics, and estimates of residual technical error for 166 regions in each hemisphere and connectivity between the regions. Volumes of discrete brain regions had the highest mean heritability (0.71 ± 0.23 SD, n = 332), followed by fractional anisotropy (0.54 ± 0.26), radial diffusivity (0.34 ± 0.022), and axial diffusivity (0.28 ± 0.19). Connection profiles were statistically different in 280 of 322 nodes across all four strains. Nearly 150 of the connection profiles were statistically different between the C57BL/6J, DBA/2J, and CAST/EiJ lines.
Warm nights disrupt global transcriptional rhythms in field-grown rice panicles
Authors: Desai Jigar S. , Lawas Lovely Mae F. , Valente Ashlee M. , Leman Adam R. , Grinevich Dmitry O. , Jagadish S.V. Krishna , Doherty Colleen J.
Published: July 2019

In rice, a small increase in nighttime temperatures reduces grain yield and quality. How warm nighttime temperatures (WNT) produce these detrimental effects is not well understood, especially in field conditions where the normal day to night temperature fluctuation exceeds the mild increase in nighttime temperature. We observed genome-wide disruption of gene expression timing during the reproductive phase on field-grown rice panicles acclimated to 2-3°C WNT. Rhythmically expressed transcripts were more sensitive to WNT than non-rhythmic transcripts. The system-wide transcriptional perturbations suggest that WNT disrupts the tight temporal coordination between internal molecular events and the environment resulting in reduced productivity. We identified transcriptional regulators whose predicted targets are enriched for sensitivity to WNT. The affected transcripts and candidate regulators identified through our network analysis explain molecular mechanisms driving sensitivity to WNT and candidates that can be targeted to enhance tolerance to WNT.
Biotransformation of D-xylose to D-xylonic acid coupled to medium chain length polyhydroxyalkanoate production in cellobiose-grownPseudomonas putidaEM42
Authors: Dvořák Pavel , Kováč Jozef , de Lorenzo Víctor
Published: July 2019

Co-production of two or more desirable compounds from low-cost substrates by a single microbial catalyst could greatly improve the economic competitiveness of many biotechnological processes. However, reports demonstrating the adoption of such co-production strategy are still scarce. In this study, the ability of genome-edited strainPsudomonas putidaEM42 to simultaneously valorise D-xylose and D-cellobiose -two important lignocellulosic carbohydrates -by converting them into the platform chemical D-xylonic acid and medium chain length polyhydroxyalkanoates, respectively, was investigated. Biotransformation experiments performed withP. putidaresting cells showed that promiscuous periplasmic glucose oxidation route can efficiently generate extracellular xylonate with high yield reaching 0.97 g per g of supplied xylose. Xylose oxidation was subsequently coupled to the growth ofP. putidawith cytoplasmic β-glucosidase BglC fromThermobifida fuscaon D-cellobiose. This disaccharide turned out to be a better co-substrate for xylose-to-xylonate biotransformation than monomeric glucose. This was because unlike glucose, cellobiose did not block oxidation of the pentose by periplasmic glucose dehydrogenase Gcd, but, similarly to glucose, it was a suitable substrate for polyhydroxyalkanoate formation inP. putida. Co-production of extracellular xylose-born xylonate and intracellular cellobiose-born medium chain length polyhydroxyalkanoates was established in proof-of-concept experiments withP. putidagrown on the disaccharide. This study highlights the potential ofP. putidaEM42 as a microbial platform for the production of xylonic acid, identifies cellobiose as a new substrate for mcl-PHA production, and proposes a fresh strategy for the simultaneous valorisation of xylose and cellobiose.
Whole-chromosome hitchhiking driven by a male-killing endosymbiont
Authors: Martin Simon H. , Singh Kumar Saurabh , Gordon Ian J. , Omufwoko Kennedy Saitoti , Collins Steve , Warren Ian A. , Munby Hannah , Brattström Oskar , Traut Walther , Martins Dino J. , Smith David A. S. , Jiggins Chris D. , Bass Chris , ffrench-Constant Richard H.
Published: July 2019

Neo-sex chromosomes are found in many taxa, but the forces driving their emergence and spread are poorly understood. The female-specific neo-W chromosome of the African monarch (or queen) butterflyDanaus chrysippuspresents an intriguing case study because it is restricted to a single ‘contact zone’ population, involves a putative colour patterning supergene, and co-occurs with infection by the the male-killing endosymbiontSpiroplasma. We investigated the origin and evolution of this system using whole genome sequencing. We first identify the ‘BC supergene’, a broad region of suppressed recombination across nearly half a chromosome, which links two colour patterning loci. Association analysis suggests that the genesyellowandarrowin this region control the forewing colour pattern differences betweenD. chrysippussubspecies. We then show that the same chromosome has recently formed a neo-W that has spread through the contact zone within ∼2200 years. We also assembled the genome of the male-killingSpiroplasma, and find that it shows perfect genealogical congruence with the neo-W, suggesting that the neo-W has hitchhiked to high frequency as the male killer has spread through the population. The complete absence of female crossing-over in the Lepidoptera causes whole-chromosome hitchhiking of a single neo-W haplotype, carrying a single allele of the BC supergene, and dragging multiple non-synonymous mutations to high frequency. This has created a population of infected females that all carry the same recessive colour patterning allele, making the phenotypes of each successive generation highly dependent on uninfected male immigrants. Our findings show how hitchhiking can occur between the unlinked genomes of host and endosymbiont, with dramatic consequences.
Gene expression of endangered coral (Orbicella spp.) in the Flower Garden Banks National Marine Sanctuary after Hurricane Harvey
Authors: Wright Rachel M. , Correa Adrienne M.S. , Quigley Lucinda A. , Davies Sarah W.
Published: July 2019

About 160 km south of the Texas–Louisiana border, the East and West Flower Garden Banks (FGB) have maintained >50% coral cover with infrequent and minor incidents of disease or bleaching since monitoring began in the 1970s. However, a storm that generated coastal flooding, which ultimately interacted with the reef system, triggered a mortality event in 2016 that killed 2.6% of the East FGB. To capture the immediate effects of storm-driven freshwater runoff on coral and symbiont physiology, we leveraged the heavy rainfall associated with Hurricane Harvey in late August 2017 by sampling FGB corals at two times: September 2017, when salinity was reduced; and one month later when salinity had returned to typical levels (~36 ppt in October 2017). Tissue samples (N = 47) collected midday were immediately preserved for gene expression profiling from two congeneric coral species (Orbicella faveolata and Orbicella franksi) from the East and West FGB to determine the physiological consequences of storm-derived runoff. In the coral, differences between host species and sampling time points accounted for the majority of differentially expressed genes. Gene ontology enrichment for genes differentially expressed immediately after Hurricane Harvey indicated increases in cellular oxidative stress responses. Although tissue loss was not observed on FGB reefs following Hurricane Harvey, our results suggest that poor water quality following this storm caused FGB corals to experience sub-lethal stress. We also found dramatic expression differences across sampling time points in the coral’s algal symbiont, Breviolum minutum. Some of these differentially expressed genes may be involved in the symbionts’ response to changing environments, whereas a group of differentially expressed post-transcriptional RNA modification genes also suggest a critical role of post-transcriptional processing in symbiont acclimatization. In this study, we cannot disentangle the effects of reduced salinity from the collection time point, so these expression patterns may also be related to seasonality. These findings highlight the urgent need for continued monitoring of these reef systems to establish a baseline for gene expression of healthy corals in the FGB system across seasons, as well as the need for integrated solutions to manage stormwater runoff in the Gulf of Mexico.
Intrinsic activity temporal structure reactivity to behavioural state change is correlated with depressive symptoms
Authors: Duncan Niall W. , Hsu Tzu-Yu , Cheng Paul Z. , Wang Hsin-Yi , Lee Hsin-Chien , Lane Timothy J.
Published: July 2019

The brain’s intrinsic activity plays a fundamental role in its function. In normal conditions this activity is responsive to behavioural context, changing as an individual switches between directed tasks and task-free conditions. A key feature of such changes is the movement of the brain between corresponding critical and sub-critical states, with these dynamics supporting efficient cognitive processing. Breakdowns in processing efficiency can occur, however, in brain disorders such as depression. It was therefore hypothesised that depressive symptoms would be related to reduced intrinsic activity responsiveness to changes in behavioural state. This was tested in a mixed group of major depressive disorder patients (n = 26) and healthy participants (n = 37) by measuring intrinsic EEG activity temporal structure, quantified with detrended fluctuation analysis (DFA), in eyes-closed and eyes-open task-free states and contrasting between the conditions. The degree to which DFA values changed between the states was found to be negatively correlated with depressive symptoms. DFA values did not differ between states at all in those with high symptom levels, meaning that the brain remained in a less flexible sub-critical condition. This sub-critical condition in the eyes-closed state was further found to correlate with levels of maladaptive rumination. This may reflect a general cognitive inflexibility resulting from a lack in neural activity reactivity that may predispose people to overly engage in self-directed attention. These results provide an initial link between intrinsic activity reactivity and psychological features found in psychiatric disorders.
Gut microbiota structure differs between honey bees in winter and summer
Authors: Kešnerová Lucie , Emery Olivier , Troilo Michaël , Liberti Joanito , Erkosar Berra , Engel Philipp
Published: July 2019

Adult honey bees harbor a specialized gut microbiota of relatively low complexity. While seasonal differences in community composition have been reported, previous studies have focused on compositional changes rather than differences in absolute bacterial loads. Moreover, little is known about the gut microbiota of winter bees, which live much longer than bees during the foraging season, and which are critical for colony survival. We quantified seven core members of the bee gut microbiota in a single colony over two years and characterized the community composition in 14 colonies during summer and winter. Our data shows that total bacterial loads substantially differ between foragers, nurses, and winter bees. Long-lived winter bees had the highest bacterial loads and the lowest community α-diversity, with a characteristic shift towards high levels of Bartonella and Commensalibacter, and a reduction of opportunistic colonizers. Using gnotobiotic bee experiments, we show that diet is a major contributor to the observed differences in bacterial loads. Overall, our study reveals that the gut microbiota of winter bees is remarkably different from foragers and nurses. Considering the importance of winter bees for colony survival, future work should focus on the role of the gut microbiota in winter bee health and disease.
Triple visual hemifield maps in optic chiasm hypoplasia
Authors: Ahmadi Khazar , Fracasso Alessio , Puzniak Robert J. , Gouws Andre D. , Yakupov Renat , Speck Oliver , Kaufmann Joern , Pestilli Franco , Dumoulin Serge O. , Morland Antony B. , Hoffmann Michael B.
Published: July 2019

In humans, each hemisphere comprises an overlay of two visuotopic maps of the contralateral visual field, one from each eye. Is the capacity of the visual cortex limited to these two maps or are plastic mechanisms available to host more maps? Using an integrative approach of submillimeter fMRI, diffusion-weighted imaging and population receptive field mapping, we found three hemiretinal inputs to converge onto the left hemisphere in a rare individual with chiasma hypoplasia. This generates extremely atypical responses in striate and extrastriate cortices, specifically an overlay of three hemifield representations. Unexpectedly, the effects of this large abnormality on visual function in daily life are not easily detected. We conclude that developmental plasticity including the re-wiring of local intra- and cortico-cortical connections is pivotal to support the coexistence and functioning of three hemifield maps within one hemisphere.
Identification of Polycomb Repressive Complex 1 and 2 Core Components in Hexaploid Bread Wheat
Authors: Strejčková Beáta , Čegan Radim , Pecinka Ales , Milec Zbyněk , Šafář Jan
Published: July 2019

Polycomb repressive complex 1 and 2 play important roles in epigenetic gene regulation by posttranslationally modifying specific histone residues. Polycomb repressive complex 2 is responsible for the trimethylation of lysine 27 on histone H3, while Polycomb repressive complex 1 catalyzes the monoubiquitination of histone H2A at lysine 119. Although these biochemical functions are evolutionarily conserved, studies in animals and plants, mainly Arabidopsis thaliana, showed that specific subunits have evolved into small gene families, with individual members acting at different developmental stages or responding to specific environmental stimuli. However, the evolution of polycomb group gene families in monocots, particularly those with complex allopolyploid origins, is unknown. Here, we present the in silico identification of the Polycomb repressive complex 1 and 2 subunits in allohexaploid bread wheat, the reconstruction of their evolutionary history and a transcriptional analysis over a series of 33 developmental stages. The identification and chromosomal location of the Polycomb repressive complex 1 and 2 core components in bread wheat may enable a deeper understanding of developmental processes, including vernalization in commonly grown winter wheat.
HIPK4 is essential for murine spermiogenesis
Authors: Crapster J. Aaron , Rack Paul G. , Hellmann Zane J. , Elias Joshua E. , Perrino John J. , Behr Barry , Li Yanfeng , Lin Jennifer , Zeng Hong , Chen James K.
Published: July 2019

Mammalian spermiogenesis is a remarkable cellular transformation, during which round spermatids elongate into chromatin-condensed spermatozoa. The signaling pathways that coordinate this process are not well understood, and we demonstrate here that homeodomain-interacting protein kinase 4 (HIPK4) is essential for spermiogenesis and male fertility in mice. HIPK4 is predominantly expressed in round and early elongating spermatids, and Hipk4 knockout males are sterile, exhibiting phenotypes consistent with oligoasthenoteratozoospermia. Hipk4 mutant sperm have reduced oocyte binding and are incompetent for in vitro fertilization, but they can still produce viable offspring via intracytoplasmic sperm injection. Ultrastructural analyses of HIPK4-null male germ cells reveal defects in the filamentous actin (F-actin)-scaffolded acroplaxome during spermatid elongation and abnormal head morphologies in mature spermatozoa. We further observe that HIPK4 overexpression induces branched F-actin structures in cultured fibroblasts, supporting a role for this kinase in cytoskeleton remodeling. Our findings establish HIPK4 as an essential regulator of sperm head shaping and potential target for male contraception.
Decreased Directed Functional Connectivity in the Psychedelic State
Authors: Barnett Lionel , Muthukumaraswamy Suresh D. , Carhart-Harris Robin L. , Seth Anil K.
Published: July 2019

Neuroimaging studies of the psychedelic state offer a unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localised, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data.
PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments
Authors: Léveillé Mélissa , Besse-Patin Aurèle , Jouvet Nathalie , Gunes Aysim , Jeromson Stewart , Khan Naveen P. , Sczelecki Sarah , Baldwin Cindy , Dumouchel Annie , Correia Jorge , Jannig Paulo , Boulais Jonathan , Ruas Jorge L. , Estall Jennifer L.
Published: July 2019

Liver is regularly exposed to changing metabolic and inflammatory environments. It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. PGC-1α is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation. However, it is not known how PGC-1α integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants expressed from different promoters. Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1α proteins in regulating hepatic metabolism and inflammatory signaling downstream of TNFα. PGC-1α1 and PGC-1α4 were expressed in hepatocytes and expression analysis uncovered shared and isoform-specific roles for these variants linked to metabolism and inflammation. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα signaling revealed that PGC-1α4 influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models illustrated that PGC-1α4 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNFα or LPS. This was in contrast to PGC-1α1, which reduced the expression of a wide inflammatory gene network, but did not prevent liver cell death in response to the cytokine. We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to metabolism and inflammation and identify PGC-1α4 as an important mitigator of apoptosis.
Striatal activity reflects cortical activity patterns
Authors: Peters Andrew J , Steinmetz Nicholas A , Harris Kenneth D , Carandini Matteo
Published: July 2019

The dorsal striatum is organized into domains that drive characteristic behaviors1–7, and receive inputs from different parts of the cortex8,9 which modulate similar behaviors10–12. Striatal responses to cortical inputs, however, can be affected by changes in connection strength13–15, local striatal circuitry16,17, and thalamic inputs18,19. Therefore, it is unclear whether the pattern of activity across striatal domains mirrors that across the cortex20–23 or differs from it24–28. Here we use simultaneous large-scale recordings in the cortex and the striatum to show that striatal activity can be accurately predicted by spatiotemporal activity patterns in the cortex. The relationship between activity in the cortex and the striatum was spatially consistent with corticostriatal anatomy, and temporally consistent with a feedforward drive. Each striatal domain exhibited specific sensorimotor responses that predictably followed activity in the associated cortical regions, and the corticostriatal relationship remained unvaried during passive states or performance of a task probing visually guided behavior. However, the task’s visual stimuli and corresponding behavioral responses evoked relatively more activity in the striatum than in associated cortical regions. This increased striatal activity involved an additive offset in firing rate, which was independent of task engagement but only present in animals that had learned the task. Thus, striatal activity largely reflects patterns of cortical activity, deviating from them in a simple additive fashion for learned stimuli or actions.
Analysis of the Human Connectome Data Supports the Notion of A “Common Model of Cognition” for Human and Human-Like Intelligence Across Domains
Authors: Stocco Andrea , Sibert Catherine , Steine-Hanson Zoe , Koh Natalie , Laird John E. , Lebiere Christian J. , Rosenbloom Paul
Published: July 2019

The Common Model of Cognition (CMC) is a recently proposed, consensus architecture intended to capture decades of progress in cognitive science on modeling human and human-like intelligence. Because of the broad agreement around it and preliminary mappings of its components to specific brain areas, we hypothesized that the CMC could be a candidate model of the large-scale functional architecture of the human brain. To test this hypothesis, we analyzed functional MRI data from 200 participants and seven different tasks that cover a broad range of cognitive domains. The CMC components were identified with functionally homologous brain regions through canonical fMRI analysis, and their communication pathways were translated into predicted patterns of effective connectivity between regions. The resulting dynamic linear model was implemented and fitted using Dynamic Causal Modeling, and compared against six alternative brain architectures that had been previously proposed in the field of neuroscience (three hierarchical architectures and three hub-and-spoke architectures) using a Bayesian approach. The results show that, in all cases, the CMC vastly outperforms all other architectures, both within each domain and across all tasks. These findings suggest that a common set of architectural principles that could be used for artificial intelligence also underpins human brain function across multiple cognitive domains.
Metabolic Modeling Elucidates the Transactions in the Rumen Microbiome and the Shifts upon Virome Interactions
Authors: Islam Mohammad Mazharul , Fernando Samodha C. , Saha Rajib
Published: July 2019

The complex microbial ecosystem within the bovine rumen plays a crucial role in host nutrition, health, and environmental impact. However, little is known about the interactions between the functional entities within the system, which dictates the community structure and functional dynamics and host physiology. With the advancements in high-throughput sequencing and mathematical modeling,in silicogenome-scale metabolic analysis promises to expand our understanding of the metabolic interplay in the community. In an attempt to understand the interactions between microbial species and the phages inside rumen, a genome-scale metabolic modeling approach was utilized by using key members in the rumen microbiome (a bacteroidete, a firmicute, and an archaeon) and the viral phages associated with them. Individual microbial host models were integrated into a community model using multi-level mathematical frameworks. An elaborate and heuristics-based computational procedure was employed to predict previously-unknown interactions involving the transfer of fatty acids, vitamins, coenzymes, amino acids, and sugars among the community members. While some of these interactions could be inferred by the available multi-omic datasets, our proposed method provides a systemic understanding of why these occur and how these affect the dynamics in a complex microbial ecosystem. To elucidate the functional role of the virome on the microbiome, local alignment search was used to identify the metabolic functions of the viruses associated with the hosts. The incorporation these functions demonstrated the role of viral auxiliary metabolic genes in relaxing the metabolic bottlenecks in the microbial hosts and complementing the inter-species interactions. Finally, a comparative statistical analysis of different biologically significant community fitness criteria identified the variation in flux space and robustness of metabolic capacities of the community members. Our elucidation of metabolite exchange among three members of rumen microbiome shows how their genomic differences and interactions with the viral strains shape up a highly sophisticated metabolic interplay and explains how such interactions across kingdoms can cause metabolic and compositional shifts in the community and affect the health, nutrition, and pathophysiology of the ruminant animal.
DNA and RNA-SIP revealNitrospira spp.as key drivers of nitrification in groundwater-fed biofilters
Authors: Gülay Arda , Fowler Jane , Tatari Karolina , Thamdrup Bo , Albrechtsen Hans-Jørgen , Al-Soud Waleed Abu , Sørensen Søren J. , Smets Barth F.
Published: July 2019

Nitrification, the oxidative process converting ammonia to nitrite and nitrate, is driven by microbes and plays a central role in the global nitrogen cycle. Our earlier metagenomics,amoA-amplicon, andamoA-qPCR based investigations of groundwater-fed biofilters indicated a consistently high abundance of comammoxNitrospira, and we hypothesized that these non-classical nitrifiers drive ammonia-N oxidation. Hence, we used DNA and RNA stable isotope probing (SIP) coupled with 16S rRNA amplicon sequencing to identify the active members in the biofilter community when subject to a continuous supply of NH4+or NO2−in the presence of13C-HCO3−(labelled) or12C-HCO3−(unlabelled). Allylthiourea (ATU) and sodium chlorate were added to inhibit autotrophic ammonia- and nitrite-oxidizing bacteria, respectively. Our results confirmed that lineage IINitrospiradominated ammonium oxidation in the biofilter community. A total of 78 (8 in RNA-SIP and 70 in DNA-SIP) and 96 (25 in RNA-SIP and 71 in DNA-SIP)Nitrospiraphylotypes (at 99% 16S rRNA sequence similarity) were identified as complete ammonia- and nitrite-oxidizing, respectively. We also detected significant HCO3−uptake byAcidobacteria subgroup10, Pedomicrobium, Rhizobactera, andAcidovoraxunder conditions that favoured ammonium oxidation. CanonicalNitrospiraalone drove nitrite oxidation in the biofilter community, and activity of archaeal ammonia oxidizing taxa was not detected in the SIP fractions. This study provides the firstin-situevidence of ammonia oxidation by comammoxNitrospirain an ecologically relevant complex microbiome.
Skin colonization by circulating neoplastic clones in cutaneous T-cell lymphoma
Authors: Iyer Aishwarya , Hennessey Dylan , O’Keefe Sandra , Patterson Jordan , Wang Weiwei , Ka-Shu Wong Gane , Gniadecki Robert
Published: July 2019

Mycosis fungoides (MF) is a mature T-cell lymphoma currently thought to develop primarily in the skin by a clonal expansion of a transformed, resident memory T-cell. However, this concept does not explain the key characteristics of MF such as the debut with multiple, widespread skin lesions or inability of skin directed therapies to provide cure. The testable inference of the mature T-cell theory is the clonality of MF with respect to all rearranged T-cell receptor (TCR) genes. Here we have used whole exome sequencing approach to detect and quantify TCRα, -β and -γ clonotypes in tumor cell clusters microdissected from MF lesions. This method allows us to calculate the tumor cell fraction of the sample and therefore an unequivocal identification of the TCR clonotypes as neoplastic. Analysis of TCR sequences from 29 patients with MF stage I-IV proved existence of multiple T-cell clones within the tumor cell fraction, with a considerable variation between patients and between lesions from the same patient (median 11 clones, range 2-80 clones/sample). We have also detected multiple neoplastic clones in the peripheral blood in all examined patients. Based on these findings we propose that circulating neoplastic T-cell clones continuously replenish the lesions of MF thus increasing their heterogeneity by a mechanism analogous to the consecutive tumor seeding. We hypothesize that circulating neoplastic clones might be a promising target for therapy and could be exploited as a potential biomarker in MF.
Paradoxically sparse chemosensory tuning in broadly-integrating external granule cells in the mouse accessory olfactory bulb
Authors: Zhang Xingjian , Meeks Julian P.
Published: July 2019

The accessory olfactory bulb (AOB) is a critical circuit in the mouse accessory olfactory system (AOS), but AOB processing is poorly understood compared to the main olfactory bulb (MOB). We used 2-photon GCaMP6f Ca2+ imaging in an ex vivo preparation to study the chemosensory tuning of AOB external granule cells (EGCs), an interneuron population hypothesized to broadly integrate from mitral cells (MCs). We measured MC and EGC tuning to natural chemosignal blends and monomolecular ligands, finding that EGC tuning was far sparser than MC tuning. Simultaneous patch-clamp electrophysiology and Ca2+ imaging indicated that this was only partially explained by lower GCaMP6f-to-spiking ratios in EGCs compared to MCs. Ex vivo patch-clamp recordings revealed that EGC subthreshold responsivity was broad, but monomolecular ligand responses were insufficient to elicit spiking. These results indicate that EGC spiking is selectively engaged by chemosensory blends, suggesting different roles for EGCs than analogous interneurons in the MOB.
TraceMontage: a Method for Merging Multiple Independent Neuronal Traces
Authors: Dizaji Aslan S , Walker Logan A , Cai Dawen
Published: July 2019

Background

The ability to reconstruct neuronal networks, local microcircuits, or the entire connectome is a central goal of modern neuroscience. Recently, advancements in sample preparation (e.g., sample expansion and Brainbow labeling) and optical (e.g., confocal and light sheet) techniques have enabled the imaging of increasingly large neural systems with high contrast. Tracing neuronal structures from these images proves challenging, however, necessitating tools that integrate multiple neuronal traces, potentially derived by various methods, into one combined (montaged) result.

New Method

Here, we present TraceMontage, an ImageJ/Fiji plugin for the combination of multiple neuron traces of a single image, either redundantly or non-redundantly. Internally, it uses graph theory to connect topological patterns in the 3-D spatial coordinates of neuronal trees. The software generates a single output tracing file containing the montage traces of the input tracing files and provides several measures of consistency analysis among multiple tracers.

Results and Comparison to existing method(s)

To our knowledge, our software is the first dedicated method for the combination of tracing results. Combining multiple tracers increases the accuracy and speed of tracing of densely-labeled samples by harnessing collaborative effort. This utility is demonstrated using fluorescence microscope images from the hippocampus and primary visual cortex (V1) in Brainbow-labeled mice.

Conclusions

TraceMontageprovides researchers the ability to combine neuronal tracing data generated by either the same or different method(s). As datasets become larger, the ability to trace images in this parallel manner will help connectomics scale to increasingly larger neural systems.
Rhes, a Striatal-Enriched Protein, Promotes Mitophagy Via Nix
Authors: Sharma Manish , Ramirez Jarquin Uri Nimrod , Rivera Oscar , Karantzis Melissa , Eshraghi Mehdi , Shahani Neelam , Sharma Vishakha , Tapia Ricardo , Subramaniam Srinivasa
Published: July 2019

Elimination of dysfunctional mitochondria via mitophagy is essential for cell survival and neuronal functions. But, how impaired mitophagy participates in tissue-specific vulnerability in the brain remains unclear. Here we discovered that Rhes, a striatal-enriched protein, is a major regulator of mitophagy in the striatum. Rhes predominantly interact with dysfunctional mitochondria and degrades them via mitophagy, and this function is exacerbated by the striatal toxin, 3-nitropropionic acid (3-NP). 3-NP induces mitochondrial swelling, loss of cristae and neuronal cell death only in WT but not Rhes KO striatum. Mechanistically, Rhes disrupts the mitochondrial membrane potential (ΔΨm) and interacts with mitophagy receptor, Nix. In Nix KO cells, Rhes fails to disrupt ΔΨmor eliminate dysfunctional mitochondria. Moreover, Rhes travels to the neighboring cell and associates with dysfunctional mitochondria via Nix. Collectively, Rhes is a major regulator of mitophagy via Nix which may determine striatal vulnerability in the brain.
Standardizing the determination and interpretation ofPcritin fishes
Authors: Reemeyer Jessica E. , Rees Bernard B.
Published: July 2019

For most fishes, there is an oxygen level, the critical oxygen tension (Pcrit), below which oxygen consumption (MO2) becomes dependent upon ambient oxygen partial pressure (PO2). We compare multiple curve-fitting approaches to estimatePcritof the Gulf killifish,Fundulus grandis, during closed and intermittent-flow respirometry. The traditional approach fitting two line segments ofMO2versusPO2produced high and variable estimates ofPcrit. Nonlinear regression using hyperbolic or Weibull functions resulted in either variablePcritestimates or, in some cases, failed to converge upon meaningful solutions.Pcritdetermined as thePO2whenMO2equals standard metabolic rate (SMR) based upon a linear relationship ofMO2andPO2at lowPO2were consistent across fish and experimental trials. Therefore, we recommend that Pcrit specifically refer to thePO2below which SMR cannot be maintained. Its determination, therefore, requires accurate measurement of SMR.
Pericyte Bridges in Homeostasis and Hyperglycemia: Reconsidering Pericyte Dropout and Microvascular Structures
Authors: Corliss Bruce A. , Ray H. Clifton , Doty Richard , Mathews Corbin , Sheybani Natasha , Fitzgerald Kathleen , Prince Remi , Kelly-Goss Molly , Murfee Walter L. , Chappell John , Owens Gary , Yates Paul , Peirce Shayn M.
Published: July 2019

Diabetic retinopathy threatens the vision of a third of diabetic patients. Progression of the disease is attributed to the dropout of pericytes, a cell type that enwraps and stabilizes the microvasculature. In tandem with this presumptive pericyte dropout, there is enriched formation of structures assumed to be remnants of collapsed or regressed vessels, previously classified as acellular capillaries, string vessels, and basement membrane bridges. Instead of endothelial cells, we show that pericytes colocalize with basement membrane bridges, and both bridging structures are enriched by cell-specific knockout of KLF4 and reversibly enriched with elevation of Ang-2, PDGF-BB, and blood sugar. Our data suggests that pericyte counts from retinal digests have misclassified pericyte bridges as endothelial structures and have exaggerated the role of pericyte loss in DR progression. In vivo imaging of corneal limbal vessels demonstrates pericyte migration off-vessel, implicating pericyte movement in formation of pericyte bridges and pathogenesis of diabetic retinopathy.
Spectral cues are necessary to encode azimuthal auditory space in the mouse superior colliculus
Authors: Ito Shinya , Si Yufei , Feldheim David A. , Litke Alan M.
Published: July 2019

Sound localization plays a critical role in animal survival. Three cues can be used to compute sound direction: interaural timing differences (ITDs), interaural level differences (ILDs) and the direction-dependent spectral filtering by the head and pinnae (spectral cues). Little is known about how spectral cues contribute to the neural encoding of auditory space. Here we report on auditory space encoding in the mouse superior colliculus (SC). We show that the mouse SC contains neurons with spatially-restricted receptive fields (RFs) that form an azimuthal topographic map. We found that frontal RFs require spectral cues and lateral RFs require ILDs. The neurons with frontal RFs have frequency tunings that match the spectral structure of the specific head and pinna filter for sound coming from the front. These results demonstrate that patterned spectral cues in combination with ILDs give rise to the topographic map of azimuthal auditory space.
Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases
Authors: Dornan Gillian L. , Stariha Jordan T.B. , Rathinaswamy Manoj K. , Powell Cameron J. , Boulanger Martin J. , Burke John E.
Published: July 2019

The class IA PI3Ks are key signalling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders. Mutations in the p85α regulatory subunit encoded byPIK3R1can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations activate both the p110α/p110δ catalytic subunits. We find that the oncogenic Q572* truncation ofPIK3R1disrupts all inhibitory inputs, with p110α being hyper-activated compared to p110δ. In addition, we find that the R649W mutation in the cSH2 ofPIK3R1decreases sensitivity to activation by receptor tyrosine kinases. This work reveals novel insight into isoform specific regulation of p110s by p85α.

Highlights

- An oncogenic variant of p85α, Q572*, leads to hyper-activation of p110α compared to p110δ

- HDX-MS revealed that Q572* leads to disruption of all inhibitory interfaces in p110α

- A SHORT syndrome mutation in p85α leads to decreased sensitivity to RTKs for p110α/δ
Modeling the Interplay between Photosynthesis, CO2Fixation, and the Quinone Pool in a Purple Non-Sulfur Bacterium
Authors: Alsiyabi Adil , Immethun Cheryl , Saha Rajib
Published: July 2019

Rhodopseudomonas palustrisCGA009 is a purple non-sulfur bacterium (PNSB) that can fix CO2and nitrogen or break down organic compounds for its carbon and nitrogen requirements. Light, inorganic, and organic compounds can all be used for its source of energy. Excess electrons produced during its metabolic processes can be exploited to produce hydrogen gas or biodegradable polyesters (polyhydroxybutyrate). A genome-scale metabolic model of the bacterium was reconstructed to study the interactions between photosynthesis, carbon dioxide fixation, and the redox state of the quinone pool. A comparison of model-predicted flux values with publishedin vivoMFA fluxes resulted in predicted errors of 5-19% across four different growth substrates. The model predicted the presence of an unidentified sink responsible for the oxidation of excess quinols generated by the TCA cycle. Furthermore, light-dependent energy production was found to be highly dependent on the rate of quinol oxidation. Finally, the extent of CO2fixation was predicted to be dependent on the amount of ATP generated through the electron transport cycle, with excess ATP going toward the energy-demanding CBB pathway. Based on this analysis, it is hypothesized that the quinone redox state acts as a feed-forward controller of the CBB pathway, signaling the amount of ATP available.
Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago
Authors: Natri Heini , Bobowik Katalina S. , Kusuma Pradiptajati , Darusallam Chelzie Crenna , Jacobs Guy S. , Hudjashov Georgi , Lansing J. Stephen , Sudoyo Herawati , Banovich Nicholas E. , Cox Murray P. , Gallego Romero Irene
Published: July 2019

Indonesia is the world’s fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10% of tested genes are differentially expressed between the islands of Mentawai (Sumatra) and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.7% of genes strongly correlating with nearby CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by very local environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.
The herpes simplex virus type I deamidase enhances propagation but is dispensable for retrograde axonal transport into the nervous system
Authors: Stults Austin M. , Smith Gregory A.
Published: July 2019

Upon replication in mucosal epithelia and transmission to nerve endings, capsids of herpes simplex virus type I (HSV-1) travel retrograde within axons to peripheral ganglia where life-long latent infections are established. A capsid-bound tegument protein, pUL37, is an essential effector of retrograde axonal transport and also houses a deamidase activity that antagonizes innate immune signaling. In this report, we examined whether the deamidase of HSV-1 pUL37 contributes to the neuroinvasive retrograde axonal transport mechanism. We conclude that neuroinvasion is enhanced by the deamidase, but the critical contribution of pUL37 to retrograde axonal transport functions independently of this activity.

IMPORTANCE

Herpes simplex virus type 1 invades the nervous system by entering nerve endings and sustaining long-distance retrograde axonal transport to reach neuronal nuclei in ganglia of the peripheral nervous system. The incoming viral particle carries a deamidase activity on its surface that antagonizes antiviral responses. We examined the contribution of the deamidase to the hallmark neuroinvasive property of this virus.
Fast, 3D isotropic imaging of whole mouse brain using multi-angle-resolved subvoxel SPIM
Authors: Nie Jun , Liu Sa , Yu Tingting , Li Yusha , Ping Junyu , Zhao Fang , Huang Yujie , Mei Wei , Zeng Shaoqun , Zhu Dan , Fei Peng
Published: July 2019

This manuscript has been withdrawn by the authors because some descriptions of other techniques (line 47-50) in the current version of manuscript are inaccurate. Therefore, the authors request that this version of the manuscript is not cited as reference for the project. Please contact the corresponding author if you have any questions.
Effects of long-term warming and enhanced nitrogen and sulfur deposition on microbial communities in a boreal peatland
Authors: Martí Magalí , Eiler Alexander , Buck Moritz , Bertilsson Stefan , Al-Soud Waleed Abu , Sørensen Søren , Nilsson Mats B. , Svensson Bo H.
Published: July 2019

With ongoing environmental change, it is important to understand ecosystem responses to multiple perturbations over long time scales atin situconditions. Here, we investigated the individual and combined effects of 18 years of warming and enhanced nitrogen and sulfate deposition on peat microbial communities in a nutrient-poor boreal mire. The three perturbations individually affected prokaryotic community composition, where nitrogen addition had the most pronounced effect, and its combination with the other perturbations led to additive effects. The functional potential of the community, characterized by shotgun metagenomics, was strongly affected by the interactive effects in the combined treatments. The responses in composition were also partly reflected in the functional gene repertoire and in altered carbon turnover, i.e. an increase of methane production rates as a result of nitrogen addition and a decrease with warming. Long-term nitrogen addition and warming-induced changes caused a shift fromSphagnum-dominated plant communities to vascular plant dominance, which likely transact with many of the observed microbial responses. We conclude that simultaneous perturbations do not always lead to synergistic effects, but can also counteract and even neutralize one another, and thus must be studied in combination when attempting to predict future characteristics and services of peatland ecosystems.