bluuebunny/crossref_metadata_2025 huggingface dataset:
From Farm to Pharmacy: Strawberry-Enabled Oral Delivery of Protein Drugs
Authors: Lamson Nicholas G. , Fein Katherine C. , Gleeson John P. , Xian Sijie , Newby Alexandra , Chaudhary Namit , Melamed Jilian R. , Cochran Kyle , Ball Rebecca L. , Suri Kanika , Ahuja Vishal , Zhang Anna , Berger Adrian , Kolodieznyi Dmytro , Schmidt Brigitte F. , Silva Gloria L. , Whitehead Kathryn A.
Published: March 2020

Although oral drug delivery is preferred by patients, it is not possible for proteins because the gastrointestinal tract is not sufficiently permeable. To enable the non-toxic oral uptake of protein drugs, we investigated plant-based foods as intestinal permeation enhancers, hypothesizing that compounds found in food would be well-tolerated by the gastrointestinal tract. Following a screen of over 100 fruits, vegetables, herbs, and fungi, we identified strawberry as a potent enhancer of macromolecular permeability in vitro and in mice. Natural product chemistry techniques identified pelargonidin, an anthocyanidin, as the active compound. In mice, insulin was orally administered with pelargonidin to induce sustained pharmacodynamic effects with doses as low as 1 U/kg and bioactivity of over 100% relative to the current gold standard of subcutaneous injection. Pelargonidin-induced permeability was reversible within two hours of treatment, and one month of daily dosing did not adversely affect mice as determined by weight tracking, serum concentrations of inflammatory markers, and tight junction gene expression. Results underscore the utility of plant-based foods in biomedical applications and demonstrate pelargonidin as an especially potent enhancer for the oral delivery of biologics.
How to navigate the myosin-V motor through the actin network
Authors: Spieler Peter , Oberhofer Angela , Zimmermann Dennis , Brames Edwin , Hume Alistair N. , Ökten Zeynep
Published: March 2020

Myosin-V (MyoV) is a ubiquitous motor protein that transports an astonishingly diverse set of cargos on the actin network in eukaryotes. Phosphorylation-dependent processes often regulate MyoV-mediated cargo transport, molecular details of which remain largely unknown. We previously showed that phosphorylation regulates MyoV’s switching from microtubules onto actin filaments, not its motor activity. Regulation of switching at reconstituted microtubule-actin-crossings in fact sufficed to recapitulate the MyoVa-driven redistribution of pigment-organelles in amphibian melanophores. However, in those cells, MyoVa also encounter many actin-actin crossings. Here, we show that isolated MyoVa motors switch with equal probabilities at reconstituted actin-actin-crossings. Under the control of its adaptor-protein melanophilin (Mlph), however, the motor differentiates between the actin filaments at crossing points in a phosphorylation-regulated manner. Whereas phosphorylation of Mlph forced about ∼2/3 of MyoVa to ignore the intersections, dephosphorylation completely reversed this behavior and forced ∼2/3 to switch. We show that the filament-binding domain (FBD) of Mlph controls this switching behavior. This property evolved in amphibians, but not in the early vertebrate zebrafish. By protein engineering, we demonstrate that changes of a few residues are sufficient to impart actin-binding capability onto the zebrafish Mlph. We thus unmask the molecular beginnings of dual filament binding in Mlph that allow it to control the switching behavior of MyoVa at cytoskeletal crossings. We therefore propose a direct link between intracellular phosphorylation activity and the adaptor-protein, not to regulate MyoVa activity, but to navigate the motor through the entire cytoskeletal maze for correct positioning of cargo.

Significance statement

In virtually all eukaryotic cells, numerous myosin motors have to navigate through an elaborate actin network for timely transport of intracellular cargo. Here, we unmask an unintuitive regulation of the myosin-Va motor that is involved in pigment organelle transport. We demonstrate that myosin-Va differentiates between the same actin filaments and displays regulated switching at reconstituted actin-actin crossings, an unexpected behavior that has been predicted from previous theoretical work. We trace this regulation back to the adaptor protein of the myosin-Va motor and show that this regulation was present in amphibian but had not evolved in the early vertebrate zebrafish. Notably, we demonstrate that the evolution of actin-binding capability is achieved by changing a few residues in the adaptor protein.
Morphological profiling of tubercule bacilli identifies drug pathways of action
Authors: Smith Trever C. , Pullen Krista M. , Olson Michaela C. , McNellis Morgan E. , Richardson Ian , Hu Sophia , Larkins-Ford Jonah , Wang Xin , Freundlich Joel S. , Ando D. Michael , Aldridge Bree B.
Published: March 2020

Morphological profiling is a method to classify target pathways of antibacterials based on how bacteria respond to treatment through changes to cellular shape and spatial organization. Here, we utilized the cell-to-cell variation in morphological features ofMycobacterium tuberculosisbacilli to develop a rapid profiling platform calledMorphologicalEvaluation andUnderstanding ofStress (MorphEUS). MorphEUS classified 94% of tested drugs correctly into broad categories according to modes of action previously identified in the literature. In the other 6%, MorphEUS pointed to key off-target or secondary bactericidal activities. We observed cell-wall damaging activity induced by bedaquiline and moxifloxacin through secondary effects downstream from their main target pathways. We implemented MorphEUS to correctly classify three compounds in a blinded study and identified an off-target effect for one compound that was not readily apparent in previous studies. We anticipate that the ability of MorphEUS to rapidly identify pathways of drug action and the proximal cause of bactericidal activity in tubercule bacilli will make it applicable to other pathogens and cell types where morphological responses are subtle and heterogeneous.

Significance Statement

Tuberculosis is a leading cause of death in the world and requires treatment with an arduous multidrug regimen. Many new tuberculosis drugs are in development, and the drug development pipeline would benefit from more rapid methods to learn drug mechanism of action and off-target effects. Here, we describe a high throughput imaging method for rapidly classifying drugs into categories based on the primary and secondary cellular damage calledMorphologicalEvaluation andUnderstanding of drug-Stress (MorphEUS). We anticipate that MorphEUS will assist in rapidly pinpointing causes of cellular death in response to drug treatment in tuberculosis and other bacterial pathogens.
Dppa2/4CounteractDe NovoMethylation to Establish a Permissive Epigenome for Development
Authors: Gretarsson Kristjan H. , Hackett Jamie A.
Published: March 2020

Early mammalian development entails genome-wide epigenome remodeling, including DNA methylation erasure and reacquisition, which facilitates developmental competence. To uncover the mechanisms that orchestrate DNA methylation (DNAme) dynamics, we coupled a single-cell ratiometric DNAme reporter with unbiased CRISPR screening in ESC. We identify key genes and regulatory pathways that drive global DNA hypomethylation, and characterise roles forCop1andDusp6. We also identifyDppa2andDppa4as essential safeguards of focal epigenetic states. In their absence, developmental genes and evolutionary-young LINE1 elements, which DPPA2 specifically binds, lose H3K4me3 and gain ectopicde novoDNA methylation in pluripotent cells. Consequently, lineage-associated genes (and LINE1) acquire a repressive epigenetic memory, which renders them incompetent for activation during future lineage-specification.Dppa2/4thereby sculpt the pluripotent epigenome by facilitating H3K4me3 and bivalency to counteractde novomethylation; a function co-opted by evolutionary young LINE1 to evade epigenetic decommissioning.
Complete chloroplast genomes ofAnthurium huixtlenseandPothos scandens(Pothoideae, Araceae): unique inverted repeat expansion and contraction affect rate of evolution
Authors: Abdullah  , Henriquez Claudia L. , Mehmood Furrukh , Carlsen Monica M. , Islam Madiha , Waheed Mohammad Tahir , Poczai Peter , Croat Thomas B. , Ahmed Ibrar
Published: March 2020

The subfamily Pothoideae belongs to the ecologically important plant family Araceae. Here, we report the chloroplast genomes of two species of the subfamily Pothoideae:Anthurium huixtlense(163,116 bp) andPothos scandens(164,719 bp). The chloroplast genome ofP. scandensshowed unique inverted repeats (IRs) contraction and expansion, which increases the size of the large single copy (102,956) region and decreases the size of the small single-copy (6779 bp) region. This led to duplication of many single-copy genes due to transfer to IR regions from the small single-copy (SSC) region, whereas some duplicate genes became single copy due to transfer to large single-copy regions. The rate of evolution of protein-coding genes was affected by the contraction and expansion of IRs; we found higher mutation rates for genes that exist in single-copy regions as opposed to IRs. We found a 2.3-fold increase of oligonucleotide repeats inP. scandenswhen compared withA. huixtlense, whereas amino acid frequency and codon usage revealed similarities. We recorded higher transition substitutions than transversion substitutions. The transition/transversion ratio was 2.26 inP. scandensand 2.12 inA. huixtlense. We also found a higher rate of transversion substitutions linked with non-synonymous substitutions than synonymous substitutions. The phylogenetic inference of the limited species showed the monophyly of the Araceae subfamilies. Our study provides insight into the molecular evolution of chloroplast genomes in the subfamily Pothoideae and family Araceae.
Evidence for Elton’s diversity-invasibility hypothesis from belowground
Authors: Zhang Zhijie , Liu Yanjie , Brunel Caroline , van Kleunen Mark
Published: March 2020

Sixty year ago, Elton proposed that diverse communities are more resistant to biological invasion. However, still little is known about which processes could drive this diversity-invasibility relationship. Here we examined whether plant-soil feedback on alien invaders is more negative when the soil originates from multiple native species. We trained soils with five individually grown native species, and used amplicon sequencing to analyze the resulting bacterial and fungal soil communities. We mixed the soils to create trained soils from one, two or four native species. We then grew four alien species separately on these differently trained soils. In the soil-conditioning phase, the five native species built species-specific bacterial and fungal communities in their rhizospheres. In the test phase, it did not matter whether the soil had been trained by one or two native species. However, the alien species achieved 11.7% less aboveground biomass when grown on soils trained by four native species than on soils trained by two native species. Our results showed for the first time, that plant-soil feedback could be a process that contributes to the negative relationship between diversity and invasibility.
The RSC complex remodels nucleosomes in transcribed coding sequences and promotes transcription inSaccharomyces cerevisiae
Authors: Biernat Emily , Kinney Jeena , Dunlap Kyle , Rizza Christian , Govind Chhabi K.
Published: March 2020

RSC (Remodels theStructure ofChromatin) is a conserved ATP-dependent chromatin remodeling complex that regulates many biological processes, including transcription by RNA polymerase II (Pol II). We report that RSC contributes to generation of accessible nucleosomes in transcribed coding sequences (CDSs). RSC MNase ChIP-seq data revealed that RSC-bound nucleosome fragments were very heterogenous (~80 bp to 180 bp) compared to a sharper profile displayed by the MNase inputs (140 bp to 160 bp), supporting the idea that RSC promotes accessibility of nucleosomal DNA. Notably, RSC binding to +1 nucleosomes and CDSs, but not with −1 nucleosomes, strongly correlated with Pol II occupancies, suggesting that RSC enrichment in CDSs is linked to transcription. We also observed that Pol II associates with nucleosomes throughout transcribed CDSs, and similar to RSC, Pol II-protected fragments were highly heterogenous, consistent with the idea that Pol II interacts with remodeled nucleosome in CDSs. This idea is supported by the observation that the genes harboring high-levels of RSC in their CDSs were the most strongly affected by ablating RSC function. We also find that rapid nuclear depletion of Sth1 decreases nucleosome accessibility and results in accumulation of Pol II in highly transcribed CDSs. This is consistent with a slower clearance of elongating Pol II in cells with reduced RSC function, and is distinct from the effect of RSC depletion on PIC assembly. Altogether, our data provide evidence in support of the role of RSC in promoting Pol II elongation, in addition to its role in regulating transcription initiation.
Split-TurboID enables contact-dependent proximity labeling in cells
Authors: Cho Kelvin F. , Branon Tess C. , Rajeev Sanjana , Svinkina Tanya , Udeshi Namrata D. , Thoudam Themis , Kwak Chulhwan , Rhee Hyun-Woo , Lee In-Kyu , Carr Steven A. , Ting Alice Y.
Published: March 2020

Proximity labeling (PL) catalyzed by promiscuous enzymes such as TurboID have enabled the proteomic analysis of subcellular regions difficult or impossible to access by conventional fractionation-based approaches. Yet some cellular regions, such as organelle contact sites, remain out of reach for current PL methods. To address this limitation, we split the enzyme TurboID into two inactive fragments that recombine when driven together by a protein-protein interaction or membrane-membrane apposition. At endoplasmic reticulum (ER)-mitochondria contact sites, reconstituted TurboID catalyzed spatially-restricted biotinylation, enabling the enrichment and identification of >100 endogenous proteins, including many not previously linked to ER-mitochondria contacts. We validated eight novel candidates by biochemical fractionation and overexpression imaging. Overall, split-TurboID is a versatile tool for conditional and spatially-specific proximity labeling in cells.
A genome-scale CRISPR interference guide library enables comprehensive phenotypic profiling in yeast
Authors: McGlincy Nicholas J. , Meacham Zuriah A. , Swain Kendra , Muller Ryan , Baum Rachel , Ingolia Nicholas T.
Published: March 2020

CRISPR/Cas9-mediated transcriptional interference (CRISPRi) enables programmable gene knock-down, yielding interpretable loss-of-function phenotypes for nearly any gene. Effective, inducible CRISPRi has been demonstrated in budding yeast, but no genome-scale guide libraries have been reported. We present a comprehensive yeast CRISPRi library, based on empirical design rules, containing 10 distinct guides for most genes. Competitive growth after pooled transformation revealed strong fitness defects for most essential genes, verifying that the library provides comprehensive genome coverage. We used the relative growth defects caused by different guides targeting essential genes to further refine yeast CRISPRi design rules. In order to obtain more accurate and robust guide abundance measurements in pooled screens, we link guides with random nucleotide barcodes and carry out linear amplification by in vitro transcription. Taken together, we demonstrate a broadly useful platform for comprehensive, high-precision CRISPRi screening in yeast.
Testing the reinforcement learning hypothesis of social conformity
Authors: Levorsen Marie , Ito Ayahito , Suzuki Shinsuke , Izuma Keise
Published: March 2020

Our preferences are influenced by the opinions of others. The past human neuroimaging studies on social conformity have identified a network of brain regions related to social conformity that includes the posterior medial frontal cortex (pMFC), anterior insula, and striatum. It was hypothesized that since these brain regions are also known to play important roles in reinforcement learning (i.e., processing prediction error), social conformity and reinforcement learning have a common neural mechanism. However, these two processes have previously never been directly compared; therefore, the extent to which they shared a common neural mechanism had remained unclear. This study aimed to formally test the hypothesis. The same group of participants (n = 25) performed social conformity and reinforcement learning tasks inside a functional magnetic resonance imaging (fMRI) scanner. Univariate fMRI data analyses revealed activation overlaps in the pMFC and bilateral insula between social conflict and unsigned prediction error and in the striatum between social conflict and signed prediction error. We further conducted multi-voxel pattern analysis (MVPA) for more direct evidence of a shared neural mechanism. MVPA did not reveal any evidence to support the hypothesis in any of these regions but found that activation patterns between social conflict and prediction error in these regions were largely distinct. Taken together, the present study provides no clear evidence of a common neural mechanism between social conformity and reinforcement learning.
3D Genome Analysis Identifies Enhancer Hijacking Mechanism for High-Risk Factors in Human T-Lineage Acute Lymphoblastic Leukemia
Authors: Yang Lu , Chen Fengling , Zhu Haichuan , Chen Yang , Dong Bingjie , Shi Minglei , Wang Weitao , Jiang Qian , Zhang Leping , Huang Xiaojun , Zhang Michael Q. , Wu Hong
Published: March 2020

Recent studies have demonstrated that 3D genome alterations play important roles in tumorigenesis1–3, including the development of hematological malignancies4–7. However, how such alterations may provide key insights into T-lineage acute lymphoblastic leukemia (T-ALL) patients is largely unknown. Here, we report integrated analyses of 3D genome alterations and differentially expressed genes (DEGs) in 18 newly diagnosed T-ALL patients and 4 healthy T cell controls. We found that 3D genome organization at the compartment, topologically associated domains (TAD) and loop levels as well as the gene expression profiles could hierarchically classify different subtypes of T-ALL according to the T cell differentiation trajectory. Alterations in the 3D genome were associated with nearly 45% of the upregulated genes in T-ALL. We also identified 34 previously unrecognized translocations in the noncoding regions of the genome and 44 new loops formed between translocated chromosomes, including translocation-mediated enhancer hijacking of theHOXAcluster. Our analysis demonstrated that T-ALLs withHOXAcluster overexpression were heterogeneous clinical entities, and ectopic expressions of theHOXA11-A13genes, but not other genes in theHOXAcluster, were associated with immature phenotypes and poor outcomes. Our findings highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.
Complex interactions between DksA and stress-responsive alternative sigma factors control inorganic polyphosphate accumulation inEscherichia coli
Authors: Gray Michael J.
Published: March 2020

Bacteria synthesize inorganic polyphosphate (polyP) in response to a variety of different stress conditions. PolyP protects bacteria by acting as a protein-stabilizing chaperone, metal chelator, or regulator of protein function, among other mechanisms. However, little is known about how stress signals are transmitted in the cell to lead to increased polyP accumulation. Previous work in the model enterobacteriumEscherichia colihas indicated that the RNA polymerase-binding regulatory protein DksA is required for polyP synthesis in response to nutrient limitation stress. In this work, I set out to characterize the role of DksA in polyP regulation in more detail. I found that overexpression of DksA increases cellular polyP content (explaining the long-mysterious phenotype ofdksAoverexpression rescuing growth of adnaKmutant at high temperature) and characterized the roles of known functional residues of DksA in this process, finding that binding to RNA polymerase is required, but none of the other functions of DksA appear to be necessary. Transcriptomics revealed genome-wide transcriptional changes upon nutrient limitation, many of which were affected by DksA, and follow-up experiments identified complex interactions between DksA and the stress-sensing alternative sigma factors FliA, RpoN, and RpoE that impact polyP production, indicating that regulation of polyP synthesis is deeply entwined in the multifactorial stress response network ofE. coli.

IMPORTANCE

Inorganic polyphosphate (polyP) is an evolutionarily ancient, widely conserved biopolymer required for stress resistance and pathogenesis in diverse bacteria, but we do not understand how its synthesis is regulated. In this work, I gained new insights into this process by characterizing the role of the transcriptional regulator DksA in polyP regulation inEscherichia coliand identifying previously unknown links between polyP synthesis and the stress-responsive alternative sigma factors FliA, RpoN, and RpoE.
A Combined Evidence Approach to Prioritize Nipah Virus Inhibitors
Authors: Kumari Nishi , Upadhyay Ayush , Kalia Kishan , Kumar Rakesh , Tuteja Kanika , Paul Priyanka Rani , Covernton Eugenia , Sharma Tina , Scaria Vinod , Bhardwaj Anshu
Published: March 2020

Nipah Virus (NiV) came into limelight due to an outbreak in Kerala, India. NiV causes severe disease and death in people with over 75% case fatality rate. It is a public health concern and has the potential to become a global pandemic. Lack of treatment has forced the containment methods to be restricted to isolation and surveillance. WHO’s ‘R&D Blueprint list of priority diseases’ (2018) indicates that there is an urgent need for accelerated research & development for addressing NiV. In the quest for druglike NiV inhibitors (NVIs) a thorough literature search followed by systematic data curation was conducted. Rigorous data analysis was done with curated NVIs for prioritizing druglike compounds. For the same, more than 1800 descriptors of NVIs were computed and comparative analysis was performed with the FDA approved small molecules and antivirals. These compounds were further evaluated through PAINS filter to study their toxicity profile. Simultaneously, compounds were also prioritized based on the robustness of the assays through which they were identified. Our efforts lead to the creation of a well-curated structured knowledgebase of 182 NVIs with 98 small molecule inhibitors. The reported IC50/EC50 values for some of these inhibitors are in the nanomolar range – as low as 0.47 nM. In order to prioritize these inhibitors, we performed several tests and applied filters to identify drug-like non-toxic compounds. Of 98, a few compounds passed DruLito & PAINS filters exhibiting drug-like properties and were also prioritized in an independent screen based only the assay robustness. The NVIs have diverse structural features and offer a wide spectrum of ways in which they can be developed further as druglike molecules. We report a knowledgebase for furthering the development of NVIs. The platform has a diverse set of 98 NVIs of which a few have been prioritized based on a combined evidence strategy. The platform has the provision to submit new inhibitors as and when reported by the community for further enhancement of NiV inhibitor landscape.
Feeding-dependent tentacle development in the sea anemoneNematostella vectensis
Authors: Ikmi Aissam , Steenbergen Petrus J. , Anzo Marie , McMullen Mason R. , Stokkermans Anniek , Ellington Lacey R. , Gibson Matthew C.
Published: March 2020

In cnidarians, axial patterning is not restricted to embryonic development but continues throughout a prolonged life history filled with unpredictable environmental changes. How this developmental capacity copes with fluctuations of food availability and whether it recapitulates embryonic mechanisms remain poorly understood. To address these questions, we utilize the tentacles of the sea anemoneNematostella vectensisas a novel paradigm for developmental patterning across distinct life history stages. As a result of embryonic development,Nematostellapolyps feature four primary tentacles, while adults have 16 or more. By analyzing over 1000 growing polyps, we find that tentacle progression is remarkably stereotyped and occurs in a feeding-dependent manner. Mechanistically, we show that discreteFibroblast growth factor receptor b(Fgfrb)-positive ring muscles prefigure the sites of new tentacles in unfed polyps. In response to feeding, a Target of Rapamycin (TOR)-dependent mechanism controls the expansion ofFgfrbexpression in oral tissues which defines tentacle primordia. Using a combination of genetic, cellular and molecular approaches, we demonstrate that FGFRb regionally enhances TOR signaling activity and promotes polarized growth, a spatial pattern that is restricted to polyp but not to embryonic tentacle primordia. These findings reveal an unexpected plasticity of tentacle development, and show that the crosstalk between TOR-mediated nutrient signaling and FGFRb pathway couples post-embryonic body patterning with food availability.
A single domain shark antibody targeting the transferrin receptor 1 delivers a TrkB agonist antibody across the blood brain barrier to provide full neuroprotection in a mouse model of Parkinson’s Disease
Authors: Clarke Emily , Sinclair Liz , Fletcher Edward J R , Krawczun-Rygmaczewska Alicja , Duty Susan , Stocki Pawel , Rutowski J Lynn , Doherty Patrick , Walsh Frank S
Published: March 2020

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells can be used to shuttle antibodies and other cargos across the blood brain barrier (BBB). We have fused one of these (TXB4) to differing regions of TrkB and TrkC neurotrophin receptor agonist antibodies (AAb) and determined the effect on agonist activity, brain accumulation and engagement with neurons in the mouse brain following systemic administration. The TXB4-TrkB and TXB4-TrkC fusion proteins retain agonist activity at their respective neurotrophin receptors and in contrast to their parental AAb they rapidly accumulate in the brain reaching nM levels following a single IV injection. Following SC administration, the most active TrkB fusion protein, TXB4-TrkB1, associates with and activates ERK1/2 signalling in TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc). When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson’s disease (PD) TXB4-TrkB1, but not the parental TrkB AAb or a TXB4-TrkC1fusion protein, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 TfR1 binding module allows a TrkB AAb to reach neuroprotective concentrations in the brain parenchyma following systemic administration.
Tailored haemodynamic response function increases detection power of fMRI in awake dogs (Canis familiaris)
Authors: Boch Magdalena , Karl Sabrina , Sladky Ronald , Huber Ludwig , Lamm Claus , Wagner Isabella C.
Published: March 2020

Functional magnetic resonance imaging (fMRI) of awake and unrestrained dogs (Canis familiaris) has been established as a novel opportunity for comparative neuroimaging, promising important insights into the evolutionary roots of human brain function and cognition. However, data processing and analysis pipelines are often derivatives of methodological standards developed for human neuroimaging, which may be problematic due to profound neurophysiological and anatomical differences between humans and dogs. Here, we explore whether dog fMRI studies would benefit from a tailored dog haemodynamic response function (HRF). In two independent experiments, dogs were presented with different visual stimuli. BOLD signal changes in the visual cortex during these experiments were used for (a) the identification and estimation of a tailored dog HRF, and (b) the independent validation of the resulting dog HRF estimate. Time course analyses revealed that the BOLD signal in the primary visual cortex peaks significantly earlier in dogs compared to humans, while being comparable in shape. Deriving a tailored dog HRF significantly improved the model fit in both experiments, compared to the canonical HRF used in human fMRI. Using the dog HRF yielded significantly increased activation during visual stimulation, extending from the occipital lobe, to the caudal parietal cortex, the bilateral temporal cortex, and into bilateral hippocampal and thalamic regions. In sum, our findings provide robust evidence for an earlier onset of the dog HRF in a visual stimulation paradigm, and suggest that using such an HRF will be important to increase fMRI detection power in canine neuroimaging. By providing the parameters of the tailored dog HRF and related code, we encourage and enable other researchers to validate whether our findings generalize to other sensory modalities and experimental paradigms.

Highlights

Dog fMRI typically uses human HRF, but underlying neurophysiology might differ

V1 BOLD signal peaked earlier in dogs than predicted by the human HRF

Tailored dog HRF improved model fit when tested with independent data

Whole-brain comparisons confirmed increased detection power for tailored dog HRF

Dog fMRI will benefit from increased detection power of tailored HRF
Standardization and Harmonization of Distributed Multi-National Proteotype Analysis supporting Precision Medicine Studies
Authors: Xuan Yue , Bateman Nicholas W. , Gallien Sebastien , Goetze Sandra , Zhou Yue , Navarro Pedro , Hu Mo , Parikh Niyati , Hood Brian L. , Conrads Kelly A. , Loosse Christina , Kitata Reta Birhanu , Piersma Sander R. , Chiasserini Davide , Zhu Hongwen , Hou Guixue , Tahir Muhammad , Macklin Andrew , Khoo Amanda , Sun Xiuxuan , Crossett Ben , Sickmann Albert , Chen Yu-Ju , Jimenez Connie R. , Zhou Hu , Liu Siqi , Larsen Martin R. , Kislinger Thomas , Chen Zhinan , Parker Benjamin L. , Cordwell Stuart J. , Wollscheid Bernd , Conrads Thomas P.
Published: March 2020

Cancer has no borders: Generation and analysis of molecular data across multiple centers worldwide is necessary to gain statistically significant clinical insights for the benefit of patients. Here we conceived and standardized a proteotype data generation and analysis workflow enabling distributed data generation and evaluated the quantitative data generated across laboratories of the international Cancer Moonshot consortium. Using harmonized mass spectrometry (MS) instrument platforms and standardized data acquisition procedures, we demonstrated robust, sensitive, and reproducible data generation across eleven sites in nine countries on seven consecutive days in a 24/7 operation mode. The data presented from the high-resolution MS1-based quantitative data-independent acquisition (HRMS1-DIA) workflow shows that coordinated proteotype data acquisition is feasible from clinical specimens using such standardized strategies. This work paves the way for the distributed multi-omic digitization of large clinical specimen cohorts across multiple sites as a prerequisite for turning molecular precision medicine into reality.
Plant-derived CO2mediates long-distance host location and quality assessment by a root herbivore
Authors: Arce Carla C. M. , Theepan Vanitha , Schimmel Bernardus C. J. , Jaffuel Geoffrey , Erb Matthias , Machado Ricardo A. R.
Published: March 2020

Insect herbivores can use volatile and visual cues to locate and select suitable host plants from a distance. The importance of CO2, arguable the most conserved volatile marker of metabolic activity, is not well understood in this context, even though many herbivores are known to respond to minute differences in CO2concentrations. To address this gap of knowledge, we manipulated CO2perception of the larvae of the western corn rootworm (Diabrotica virgifera virgifera; WCR) through RNA interference and studied how CO2perception impacts their interaction with their host plant, maize (Zea mays). We show that the expression of a putative Group 2 carbon dioxide receptor,DvvGr2, is specifically required for dose-dependent larval responses to CO2in the ppm range. SilencingDvvGr2has no effect on the ability of WCR larvae to locate host plants at short distance (<9 cm), but impairs host location at greater distances. Using soil arenas and olfactometer experiments in combination withDvvGr2silencing and CO2scrubbing, we demonstrate that WCR larvae use CO2as a long-range host plant finding cue, but employ other volatiles for short-range host location. We furthermore show that the larvae use CO2as a fitness-relevant long-distance indicator of plant nutritional status: Maize plants that are well-fertilized emit more CO2from their roots and are better hosts for WCR than plants that are nutrient-deficient, and the capacity of WCR larvae to distinguish between these plants depends exclusively on their capacity to perceive CO2throughDvvGr2. This study unravels how CO2can mediate plant-herbivore interactions by serving as a distance-dependent host location and quality assessment cue.
Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement
Authors: Salta Evgenia , Walgrave Hannah , Balusu Sriram , Vanden Eynden Elke , Snoeck Sarah , Craessaerts Katleen , Thrupp Nicky , Wolfs Leen , Horré Katrien , Fourne Yannick , Ronisz Alicja , Silajdžić Edina , Callaerts-Vegh Zsuzsanna , D’Hooge Rudi , Rudolf Thal Dietmar , Zetterberg Henrik , Thuret Sandrine , Fiers Mark , Sala Frigerio Carlo , De Strooper Bart
Published: March 2020

Adult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimer’s disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic nichein vivoand in human neural stem cellsin vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.
A regulatory interface on RIPK2 is required for XIAP binding and NOD signaling activity
Authors: Heim Valentin J. , Dagley Laura F. , Stafford Che A. , Hansen Fynn M. , Clayer Elise , Bankovacki Aleksandra , Webb Andrew I. , Lucet Isabelle S. , Silke John , Nachbur Ueli
Published: March 2020

Signaling via the intracellular pathogen receptors Nucleotide-binding oligomerization domain-containing proteins NOD1 and NOD2 requires Receptor Interacting Kinase 2 (RIPK2), an adaptor kinase that can be targeted for the treatment of various inflammatory diseases. However, the molecular mechanisms of how RIPK2 contributes to NOD signaling are not completely understood. We generated FLAG-tagged RIPK2 knock-in mice using CRISPR/Cas9 technology to study NOD signaling mechanisms at the endogenous level. Using cells from these mice we were able to generate a detailed map of post-translational modifications on RIPK2 during NOD signaling and we identified a new regulatory interface on RIPK2, which dictates the crucial interaction with the E3 ligase XIAP.
RhoBAST - a rhodamine-binding aptamer for super-resolution RNA imaging
Authors: Sunbul Murat , Lackner Jens , Martin Annabell , Englert Daniel , Hacene Benjamin , Nienhaus Karin , Nienhaus G. Ulrich , Jäschke Andres
Published: March 2020

RhoBAST is a novel fluorescence light-up RNA aptamer (FLAP) that transiently binds a fluorogenic rhodamine dye. Fast dye association and dissociation result in intermittent fluorescence emission, facilitating single-molecule localization microscopy (SMLM) with an image resolution not limited by photobleaching. We demonstrate RhoBAST's excellent properties as a RNA marker by resolving subcellular and subnuclear structures of RNA in live and fixed cells by SMLM and structured illumination microscopy (SIM).
A Generalized Robust Allele-based Genetic Association Test
Authors: Zhang Lin , Sun Lei
Published: March 2020

The allele-based association test, comparing allele frequency difference between case and control groups, is locally most powerful. However, application of the classical allelic test is limited in practice, because the method is sensitive to the Hardy–Weinberg equilibrium (HWE) assumption, not applicable to continuous traits, and not easy to account for covariate effect or sample correlation. To develop a generalized robust allelic test, we propose a new allele-based regression model with individual allele as the response variable. We show that the score test statistic derived from this robust and unifying regression framework contains a correction factor that explicitly adjusts for potential departure from HWE, and encompasses the classical allelic test as a special case. When the trait of interest is continuous, the corresponding allelic test evaluates a weighted difference between individual-level allele frequency estimate and sample estimate where the weight is proportional to an individual’s trait value, and the test remains valid underY- dependent sampling. Finally, the proposed allele-based method can analyze multiple (continuous or binary) phenotypes simultaneously and multi-allelic genetic markers, while accounting for covariate effect, sample correlation and population heterogeneity. To support our analytical findings, we provide empirical evidence from both simulation and application studies.
ZIP9 is a Druggable Determinant of Sex Differences in Melanoma
Authors: Aguirre-Portolés Cristina , Payne Riley , Trautz Aspen , Foskett J. Kevin , Natale Christopher A. , Seykora John T. , Ridky Todd W.
Published: March 2020

Melanoma and most other cancers occur more frequently, and have worse prognosis, in males compared with females. Though sex steroids are thought to be involved, classical androgen and estrogen receptors are not detectable in most melanomas. Here we show that testosterone promotes melanoma proliferation by activating ZIP9 (SLC39A9), a zinc transporter that is not intentionally targeted by available therapeutics, but is widely expressed in human melanoma. This testosterone activity requires zinc influx, MAPK activation and YAP1 nuclear translocation. We demonstrate that FDA approved inhibitors of the classical androgen receptor also inhibit ZIP9, and thereby antagonize the pro-tumorigenic effects of testosterone in melanoma. In male mice, androgen receptor inhibitors suppressed growth of ZIP9-expressing melanomas, but had no effect on isogenic melanomas lacking ZIP9, nor on melanomas in females. These data suggest that ZIP9 might be effectively targeted in melanoma and other cancers by repurposing androgen receptor inhibitors that are currently approved only for prostate cancer.

Significance

Melanoma outcomes are worse in males than in females. Some of this difference is driven by testosterone signaling through ZIP9, a nonclassical testosterone receptor. Drugs that target AR can be repurposed to block ZIP9, and inhibit melanoma in males.
Deconstructing the association between abiotic factors and species assemblages in the global ocean microbiome
Authors: Shan Xiaoyu , Cordero Otto X.
Published: March 2020

Recent work on microbial communities from various environments has shown that coexisting microorganisms with similar metabolic functions can be combined into high level “functional groups”, which explain a larger proportion of variance in abiotic parameters than any individual taxon. However, the general rules by which taxa should be aggregated into functional groups remain elusive. Here, we show that two conditions are required for species-assemblages to explain a higher percentage of variance in abiotic factors than single taxa. 1) consistent taxa-environment correlations, and 2) weak or negative correlations (i.e. complementarity) between taxa. Applying this recipe to the ocean microbiome, we found that the best grouping of taxa is one that partitions it into only two groups, a core and a flexible assemblage. The core assemblage is enriched inCyanobacteriaand oligotrophic heterotrophs, and was strongly correlated to the first principal component of the taxa-sample matrix. The flexible assemblage instead was enriched in metabolically versatile copiotrophs, abundant at higher depths. This simple core / flexible bipartition explained the most variance in abiotic parameters and outperformed annotation-based functional groups as well as individual taxa. It therefore represents the simplest and best grouping of taxa that can be extracted from current ocean microbiome surveys.
Glycolysis Fuels Phosphoinositide 3-Kinase Signaling to Bolster T Cell Immunity
Authors: Xu Ke , Yin Na , Peng Min , Stamatiades Efstathios G. , Shyu Amy , Li Peng , Zhang Xian , Do Mytrang H. , Wang Zhaoquan , Capistrano Kristelle J. , Chou Chun , Levine Andrew G. , Rudensky Alexander Y. , Li Ming O.
Published: March 2020

Infection triggers clonal expansion and effector differentiation of microbial antigen-specific T cells in association with metabolic reprograming. Here, we show that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+T effector cells via phosphoinositide 3-kinase (PI3K)-dependent mechanisms. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes glycolytic adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes with glycolytic ATP serving as a rheostat to gauge PI3K/Akt/Foxo1 signaling in T cell immunity control. Such a bioenergetics mechanism of signaling regulation implies a root cause for the century-old phenomenon of Warburg effect, and could guide development of novel therapeutics for infectious diseases and cancer.

One Sentence Summary

A PI3K and LDHA circuit enables T cell immunity
Effects of the crystallographic texture on the contractile strain ratio of Ti–3Al–2.5V tubing
Authors: Wang Wenrui , Yuan Lihong , Li Yun , Zhang Hui , Zhang Wangfeng , Wang Yuhui
Published: March 2020

The contractile strain ratio (CSR) is an important property and a quality control factor of cold-worked and stress-relieved Ti–3Al–2.5V tubing. In this work, the CSR values of three thin-walled Ti–3Al–2.5V tubing samples were obtained by uniaxial tensile tests, and the crystallographic textures of the tubing samples were characterized by orientation distribution functions (ODFs) which were determined on the basis of a series of pole figures obtained by X-ray diffraction. A quantitative method is proposed for exploring the correlation between the CSR values and the ODF data of the tubing samples, including the following steps: Firstly, taking advantage of the ODF data, the volume fraction (V%) of crystallites that lie within a certain range of Euler angles (φ1, Φ, φ2) can be calculated, and the calculation is performed on each set of Euler angles (φ1, Φ, φ2). Secondly, each V% is resolved into an effective fraction in the orientation of the ideal radial texture {0002}〈10\overline 10〉 corresponding to the Euler angles of (0, 0, 0), and the equivalent radial texture (ERT) is obtained as the sum of all such effective fractions. Thirdly, similarly to the previous step, the equivalent tangential texture (ETT) is calculated. The CSR will be related to the ratio of the ERT to the ETT, named the equivalent texture ratio (ETR). The CSR values of the tubing samples are 1.38, 1.96 and 2.19 and their ETR values are 1.33, 1.72 and 1.87, respectively. In particular, the CSR and the ETR of the tubing with a random distribution of the basal poles in the radial–tangential plane are both unity. It is found from the above data that the CSR increases approximately linearly with the ETR. Since the three-dimensional orientations of crystallites and the orientation distributions throughout the Euler space are taken into account in the calculations of the ETR, the proposed method can be used for predicting and explaining the mechanical anisotropy of Ti–3Al–2.5V tubing more accurately.
High-dynamic-range transmission-mode detection of synchrotron radiation using X-ray excited optical luminescence in diamond
Authors: Stoupin Stanislav , Antipov Sergey , Zaitsev Alexander M.
Published: March 2020

Enhancement of X-ray excited optical luminescence in a 100 µm-thick diamond plate by introduction of defect states via electron beam irradiation and subsequent high-temperature annealing is demonstrated. The resulting X-ray transmission-mode scintillator features a linear response to incident photon flux in the range 7.6 × 108 to 1.26 × 1012 photons s−1 mm−2 for hard X-rays (15.9 keV) using exposure times from 0.01 to 5 s. These characteristics enable a real-time transmission-mode imaging of X-ray photon flux density without disruption of X-ray instrument operation.
Recovery, quality of life and issues in supported housing among residents with co-occurring problems: a cross-sectional study
Authors: Nesse Linda , Gonzalez Marianne Thorsen , Aamodt Geir , Raanaas Ruth Kjærsti
Published: March 2020

Purpose

Recovery for residents who experience co-occurring problems and live in supported housing takes place in everyday contexts. This study aims to explore residents’ self-reported recovery and quality of life and examine the relationships between these factors and issues in supported housing.

Design/methodology/approach

A cross-sectional study was conducted at 21 supported housing sites in six cities across Norway. A total of 104 residents (76 men and 28 women) responded to measures of recovery (Recovery Assessment Scale – Revised), life satisfaction (Manchester Short Assessment of Quality of Life), affect (single items), staff support (Brief INSPIRE) and sense of home (single items).

Findings

Linear regression analyses indicated associations between recovery and staff support (B= 0.01, 95% CI = 0.01-0.02,ß= 0.39), housing satisfaction (B= 0.15, 95% CI = 0.07-0.22,ß= 0.38), sense of home (B= 0.23, 95% CI = 0.14-0.32,ß= 0.49) and satisfaction with personal economy (B= 0.11, 95% CI = 0.05-0.17,ß= 0.33). Similarly, associations were found between life satisfaction and staff support (B= 0.03, 95% CI = 0.02-0.04,ß= 0.46), housing satisfaction (B= 0.63, 95% CI = 0.46-0.80,ß= 0.60), sense of home (B= 0.65, 95% CI = 0.42-0.87,ß= 0.51) and satisfaction with personal economy (B= 0.34, 95% CI = 0.19-0.50,ß= 0.39).

Originality/value

The findings imply that core issues in supported housing, namely, staff support, housing satisfaction, sense of home and satisfaction with personal economy, are associated with recovery and quality of life.