bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1
Authors: Casalino-Matsuda S. Marina , Chen Fei , Gonzalez-Gonzalez Francisco J. , Nair Aisha , Dib Sandra , Yemelyanov Alex , Gates Khalilah , Budinger G. R. Scott , Beitel Greg J. , Sporn Peter H. S.
Published: February 2020

Hypercapnia, elevation of the partial pressure of CO2in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. We previously showed that hypercapnia inhibits multiple macrophage and neutrophil antimicrobial functions, and that it increases the mortality of bacterial pneumonia in mice. Here, we show that normoxic hypercapnia increases viral replication, lung injury and mortality in mice infected with influenza A virus (IAV). Elevated CO2increased IAV replication and inhibited antiviral gene and protein expression in macrophagesin vivoandin vitro. Hypercapnia potentiated IAV-induced activation of Akt, while specific pharmacologic inhibition or shRNA knockdown of Akt1 in alveolar macrophages blocked hypercapnia’s effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or downstream pathways through which elevated CO2signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.
Genome-wide identification of binding sites of GRHL2 in luminal-like and basal A subtypes of breast cancer
Authors: Wang Zi , Wu Haoyu , Daxinger Lucia , Danen Erik HJ
Published: February 2020

Grainyhead like 2 (GRHL2) is one of three mammalian homologues of the grainyhead (GRH) gene. It suppresses the oncogenic epithelial-mesenchymal transition (EMT), acting as a tumor suppressor. On the other hand, GHRL2 promotes cell proliferation by increasing human telomerase reverse transcriptase (hTERT) activity, serving as a tumor promoter. According to gene expression profiling, breast cancer can be divided into basal-like (basal A and basal B), luminal-like, HER2 enriched, claudin-low and normal-like subtypes. To identify common and subtype-specific genomic binding sites of GRHL2 in breast cancer, GRHL2 ChIP-seq was performed in three luminal-like and three basal A human breast cancer cell lines. Most binding sites of GRHL2 were found in intergenic and intron regions. 13,351 common binding sites were identified in basal A cells, which included 551 binding sites in gene promoter regions. For luminal-like cells, 6,527 common binding sites were identified, of which 208 binding sites were found in gene promoter regions. Basal A and luminal-like breast cancer cells shared 4711 GRHL2 binding sites, of which 171 binding sites were found in gene promoter regions. The identified GRHL2-binding motifs are all identical to a motif reported for human ovarian cancer, indicating conserved GRHL2 DNA-binding among human cancer cells. Notably, no binding sites of GRHL2 were detected in the promoter regions of several established EMT-related genes, including CDH1, ZEB1, ZEB2 and CDH2 genes. Collectively, this study provides a comprehensive overview of interactions of GRHL2 with DNA and lays the foundation for further understanding of common and subtype-specific signaling pathways regulated by GRHL2 in breast cancer.
mzMLb: a future-proof raw mass spectrometry data format based on standards-compliant mzML and optimized for speed and storage requirements
Authors: Bhamber Ranjeet S. , Jankevics Andris , Deutsch Eric W , Jones Andrew R , Dowsey Andrew W
Published: February 2020

With ever-increasing amounts of data produced by mass spectrometry (MS) proteomics and metabolomics, and the sheer volume of samples now analyzed, the need for a common open format possessing both file size efficiency and faster read/write speeds has become paramount to drive the next generation of data analysis pipelines. The Proteomics Standards Initiative (PSI) has established a clear and precise XML representation for data interchange, mzML, receiving substantial uptake; nevertheless, storage and file access efficiency has not been the main focus. We propose an HDF5 file format ‘mzMLb’ that is optimised for both read/write speed and storage of the raw mass spectrometry data. We provide extensive validation of write speed, random read speed and storage size, demonstrating a flexible format that with or without compression is faster than all existing approaches in virtually all cases, while with compression, is comparable in size to proprietary vendor file formats. Since our approach uniquely preserves the XML encoding of the metadata, the format implicitly supports future versions of mzML and is straightforward to implement: mzMLb’s design adheres to both HDF5 and NetCDF4 standard implementations, which allows it to be easily utilised by third parties due to their widespread programming language support. A reference implementation within the established ProteoWizard toolkit is provided.
Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo
Authors: Abulizi Abudukadier , Stark Romana , Cardone Rebecca L. , Lewandowski Sophie L. , Zhao Xiaojian , Alves Tiago C. , Thomas Craig , Kung Charles , Wang Bei , Siebel Stephan , Andrews Zane B. , Merrins Matthew J. , Kibbey Richard G.
Published: February 2020

The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle is an anaplerotic-cataplerotic mitochondrial shuttle utilizing mitochondrial PEPCK (PCK2) and pyruvate kinase (PK). PEP cycling stimulates insulin secretion via OxPhos-independent lowering of ADP by PK. We assessin vivowhether islet PCK2 is necessary for glucose sensing and if speeding the PEP cycle via pharmacological PK activators amplifies insulin secretion.Pck2-/-mice had severely impaired insulin secretion during islet perifusion, oral glucose tolerance tests and hyperglycemic clamps. Acute and chronic pharmacologic PK activator therapy improved islet insulin secretion from normal, high-fat diet (HFD) fed, or Zucker diabetic fatty (ZDF) rats, and glucolipotoxic or diabetic humans. A similar improvement in insulin secretion was observed in regular chow and HFD ratsin vivo. Insulin secretion and cytosolic Ca2+during PK activation were dependent on PCK2. These data provide a preclinical rationale for strategies, such as PK activation, that target the PEP cycle to improve glucose homeostasis.

Highlights

Loss of mitochondrial phosphoenolpyruvate (PEP) impairs insulin releasein vivo.

Pyruvate kinase (PK) activators stimulate beta-cells in preclinical diabetes models.

PEP cyclingin vivodepends on PK and mitochondrial PEPCK (PCK2) for insulin release.

Acute and 3-week oral PK activator amplifies insulin release during hyperglycemia.

eTOC Blurb

Abudukadier et al. show that small molecule pyruvate kinase activationin vivoandin vitroincreases insulin secretion in rodent and human models of diabetes. The phosphoenolpyruvate (PEP) cycling mechanism and its amplification are dependent on mitochondrial PEPCK (PCK2).
Photoreceptor progenitor dynamics in the zebrafish embryo retina and its modulation by primary cilia and N-cadherin
Authors: Aparicio Gonzalo , Rodao Magela , Badano José L. , Zolessi Flavio R.
Published: February 2020

Background

Photoreceptors of the vertebrate neural retina are originated from the neuroepithelium, and like other neurons, must undergo cell body translocation and polarity transitions to acquire their final functional morphology, which includes features of neuronal and epithelial cells.

Methods

We analyzed this process in detail on zebrafish embryos usingin vivoconfocal microscopy and electron microscopy. Photoreceptor progenitors were labeled by the transgenic expression of EGFP under the regulation of the photoreceptor-specific promotercrx, and genes of interest were knocked-down using morpholino oligomers.

Results

Photoreceptor progenitors detached from the basal retina at pre-mitotic stages, rapidly retracting a short basal process as the cell body translocated apically. They remained at an apical position indefinitely to form the outer nuclear layer (ONL), initially extending and retracting highly dynamic neurite-like processes, tangential to the apical surface. Many photoreceptor progenitors presented a short apical primary cilium. The number and length of these cilia was gradually reduced until nearly disappearing around 60 hpf. Their disruption by knocking-down IFT88 and Elipsa caused a notorious defect on basal process retraction. Time-lapse analysis of N-cadherin knock-down, a treatment known to cause a severe disruption of the ONL, showed that the ectopic photoreceptor progenitors initially migrated in an apparent random manner, profusely extending cell processes, until they encountered other cells to establish cell rosettes in which they stayed acquiring the photoreceptor-like polarity.

Conclusion

Altogether, our observations indicate a complex regulation of photoreceptor progenitor dynamics to form the retinal ONL, previous to the post-mitotic maturation stages.
G4C2repeat RNA mediates the disassembly of the nuclear pore complex in C9orf72 ALS/FTD
Authors: Coyne Alyssa N , Zaepfel Benjamin L , Hayes Lindsey , Fitchman Boris , Salzberg Yuval , Bowen Kelly , Trost Hannah , Rigo Frank , Harel Amnon , Svendsen Clive N , Sareen Dhruv , Rothstein Jeffrey D
Published: February 2020

Nucleocytoplasmic transport, controlled by the nuclear pore complex, has recently emerged as a pathomechanism underlying neurodegenerative diseases including C9orf72 ALS/FTD. However, little is known about the underlying molecular events and the underlying biology in human neurons. Using super resolution structured illumination microscopy of twenty three nucleoporins in nuclei from C9orf72 iPSC derived neurons and postmortem human tissue we identify a unique subset of eight nucleoporins lost from human neuronal nuclei. POM121, an integral transmembrane nucleoporin, appears to coordinate the composition of the nucleoporins within human neuronal nuclei ultimately impacting nucleocytoplasmic transport, and subsequent cellular toxicity in C9orf72 iPSNs. These data suggest that POM121 is a critical nucleoporin in the maintenance of the nuclear localization of specific nucleoporins in human neurons. Moreover, loss of nuclear POM121, as a result of expanded C9orf72 ALS/FTD repeat RNA, initiates a pathological cascade affecting nucleoporin composition within neuronal nuclei, nuclear pore complex function, and overall downstream neuronal survival.
β-L-1-[5-(E-2-Bromovinyl)-2-(hydroxymethyl)-1,3-dioxolan-4-yl)] uracil (L-BHDU) effectiveness against varicella-zoster virus and herpes simplex virus type 1 depends on thymidine kinase activity
Authors: De Chandrav , Liu Dongmei , Depledge Daniel , Breuer Judith , Singh Uma S. , Hartline Caroll , Prichard Mark N. , Chu Chung K. , Moffat Jennifer F.
Published: February 2020

ß-L-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (L-BHDU) prevents varicella-zoster virus (VZV) replication in cultured cells andin vivo. Its mechanism of action was investigated by evaluating its activity against related herpesviruses and by analyzing resistant VZV strains. L-BHDU was effective against herpes simplex virus type 1 (HSV-1) with an EC50of 0.22µM in human foreskin fibroblast (HFF) cells. L-BHDU also inhibited HSV-2 and simian varicella virus (SVV) to a lesser extent. VZV mutants resistant to L-BHDU and other antiviral compounds were obtained by serial passage of the wild type VZV pOka and VZV Ellen strains in the presence of increasing drug concentrations. VZV strains resistant to L-BHDU (L-BHDUR) were cross-resistant to acyclovir (ACV) and brivudin (BVdU) but not to foscarnet (PFA) and cidofovir (CDV). Conversely, ACV-resistant strains were also resistant to L-BHDU. Whole genome sequencing of L-BHDURstrains identified mutations in ATP-binding (G22R) and nucleoside binding (R130Q) domains of VZV thymidine kinase (TK). The wild type and mutant forms of VZV TK were cloned as GST fusion proteins and expressed inE. coli. The partially purified TKG22R-GST and TKR130Q- GST proteins failed to convert thymidine to thymidine monophosphate whereas the wild type TK-GST protein was enzymatically active. Similarly, L-BHDURvirus TK did not phosphorylate the drug. As expected, wild type VZV converted L-BHDU to L-BHDU monophosphate and diphosphate forms. In conclusion, L-BHDU effectiveness against VZV and HSV-1 depends on thymidine kinase activity.
Phenotypic associations among cell cycle genes inSaccharomyces cerevisiae
Authors: Bermudez-Cruz María , Wu Peter I. , Callerame Deanna , Hammer Staci , Hu James C. , Polymenis Michael
Published: February 2020

A long-standing effort in biology is to precisely define and group phenotypes that characterize a biological process, and the genes that underpin them. InSaccharomyces cerevisiaeand other organisms, functional screens have generated rich lists of phenotypes associated with individual genes. However, it is often challenging to identify sets of phenotypes and genes that are most closely associated with a given biological process. Here, we focused on the 166 phenotypes arising from loss-of-function and the 86 phenotypes from gain-of-function mutations in 571 genes currently assigned to cell cycle-related ontologies inS. cerevisiae. To reduce this complexity, we applied unbiased, computational approaches of correspondence analysis to identify a minimum set of phenotypic variables that accounts for as much of the variability in the data as possible. Loss-of-function phenotypes can be reduced to 20 dimensions, while gain-of-function ones to 14 dimensions. We also pinpoint the contributions of phenotypes and genes in each set. The approach we describe not only simplifies the categorization of phenotypes associated with cell cycle progression but can also serve as a discovery tool for gene function.
Chronic wireless streaming of invasive neural recordings at home for circuit discovery and adaptive stimulation
Authors: Gilron Ro’ee , Little Simon , Perrone Randy , Wilt Robert , de Hemptinne Coralie , Yaroshinsky Maria S. , Racine Caroline A. , Wang Sarah , Ostrem Jill L. , Larson Paul S. , Wang Doris D. , Galifianakis Nick B. , Bledsoe Ian , San Luciano Marta , Dawes Heather E. , Worrell Gregory A. , Kremen Vaclav , Borton David , Denison Timothy , Starr Philip A.
Published: February 2020

Invasive neural recording in humans shows promise for understanding the circuit basis of brain disorders. Most recordings have been done for short durations from externalized brain leads in hospital settings, or from first-generation implantable sensing devices that offer only intermittent brief streaming of time series data. Here we report the first human use of an implantable neural interface for wireless multichannel streaming of field potentials over long periods, with and without simultaneous therapeutic neurostimulation, untethered to receiving devices. Four Parkinson’s disease patients streamed bilateral 4-channel motor cortical and basal ganglia field potentials at home for over 500 hours, paired with wearable monitors that behaviorally categorize states of inadequate or excessive movement. Motor state during normal home activities was efficiently decoded using either supervised learning or unsupervised clustering algorithms. This platform supports adaptive deep brain stimulation, and may be widely applicable to brain disorders treatable by invasive neuromodulation.
Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy
Authors: Madar A.D. , Pfammatter J.A. , Bordenave J. , Plumley E.I. , Ravi S. , Cowie M. , Wallace E.P. , Hermann B.P. , Maganti R.K. , Jones M.V.
Published: February 2020

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is due to a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.

Significance Statement

People with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathological bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE and supports a long-standing hypothesis of episodic memory theories.
β-catenin-Mediated Wnt Signal Transduction Proceeds Through an Endocytosis-Independent Mechanism
Authors: Rim Ellen Youngsoo , Kinney Leigh Katherine , Nusse Roel
Published: February 2020

The Wnt pathway is a key intercellular signaling cascade that regulates development, tissue homeostasis, and regeneration. However, gaps remain in our understanding of the molecular events that take place between ligand-receptor binding and target gene transcription. Here we used a novel tool for quantitative, real-time assessment of endogenous pathway activation, measured in single cells, to answer an unresolved question in the field – whether receptor endocytosis is required for Wnt signal transduction. We combined knockdown or knockout of essential components of Clathrin-mediated endocytosis with quantitative assessment of Wnt signal transduction in mouse embryonic stem cells (mESCs). Disruption of Clathrin-mediated endocytosis did not affect accumulation and nuclear translocation ofβ-catenin, as measured by single-cell live imaging of endogenousβ-catenin, and subsequent target gene transcription. Disruption of another receptor endocytosis pathway, Caveolin-mediated endocytosis, did not affect Wnt pathway activation either. These results, confirmed in multiple cell lines, suggest that endocytosis is not a general requirement for Wnt signal transduction. We show that off-target effects of a drug used to inhibit endocytosis may be one source of the discrepancy among reports on the role of endocytosis in Wnt signaling.
Machine Learning Algorithms for Predicting Coronary Artery Disease: Efforts Toward an Open Source Solution
Authors: Akella Aravind , Kaushik Vibhor
Published: February 2020

The development of Coronary Artery Disease (CAD), one of the most prevalent diseases in the world, is heavily influenced by several modifiable risk factors. Predictive models built using machine learning (ML) algorithms may assist healthcare practitioners in timely detection of CAD, and ultimately, may improve outcomes. In this study, we have applied six different ML algorithms to predict the presence of CAD amongst patients listed in an openly available dataset provided by the University of California Irvine (UCI) Machine Learning Repository, named “the Cleveland dataset.” All six ML algorithms achieved accuracies greater than 80%, with the “Neural Network” algorithm achieving accuracy greater than 93%. The recall achieved with the “Neural Network” model is also highest of the six models (0.93). Additionally, five of the six algorithms resulted in very similar AUC-ROC curves. The AUC-ROC curve corresponding to the “Neural Network” algorithm is slightly steeper implying higher “true positive percentage” achieved with this model. We also extracted the variables of importance in the “Neural Network” model to help in the risk assessment. We have released the full computer code generated in this study in the public domain as a preliminary effort toward developing an open solution for predicting the presence of coronary artery disease in a given population and present a workflow model for implementing a possible solution.
A one-tube method for rapid and reliable plant genomic DNA isolation for PCR analysis
Authors: Hu Wei , Lagarias J. Clark
Published: February 2020

Background

Consistent isolation of high quality plant genomic DNA is a prerequisite for successful PCR analysis. Time consumption, ease of operation and procedure cost are important secondary considerations for selecting an effective DNA extraction method. The simple, reliable and rapid DNA extraction method developed by Edwards and colleagues in 1991 [1] has proven to be the gold standard.

Results

Through modification of the Edwards method of extraction, we have developed a one-tube protocol that greatly improves the efficiency of plant DNA extraction and reduces the potential for sample contamination while simultaneously yielding high quality DNA suitable for PCR analysis. We further show that DNA extracts prepared with this method are stable at room temperature for at least three months.

Conclusion

The one-tube extraction method yields high quality plant DNA with improved efficiency while greatly minimizing the potential for cross contamination. This low-cost and environment-friendly method is widely applicable for plant molecular biology research.
Comparison of the two up-to-date sequencing technologies for genome assembly: HiFi reads of Pacbio Sequel II system and ultralong reads of Oxford Nanopore
Authors: Lang Dandan , Zhang Shilai , Ren Pingping , Liang Fan , Sun Zongyi , Meng Guanliang , Tan Yuntao , Hu Jiang , Li Xiaokang , Lai Qihua , Han Lingling , Wang Depeng , Hu Fengyi , Wang Wen , Liu Shanlin
Published: February 2020

The availability of reference genomes has revolutionized the study of biology. Multiple competing technologies have been developed to improve the quality and robustness of genome assemblies during the last decade. The two widely-used long read sequencing providers – Pacbio (PB) and Oxford Nanopore Technologies (ONT) – have recently updated their platforms: PB enable high throughput HiFi reads with base-level resolution with >99% and ONT generated reads as long as 2 Mb. We applied the two up-to-date platforms to one single rice individual, and then compared the two assemblies to investigate the advantages and limitations of each. The results showed that ONT ultralong reads delivered higher contiguity producing a total of 18 contigs of which 10 were assembled into a single chromosome compared to that of 394 contigs and three chromosome-level contigs for the PB assembly. The ONT ultralong reads also prevented assembly errors caused by long repetitive regions for which we observed a total 44 genes of false redundancies and 10 genes of false losses in the PB assembly leading to over/under-estimations of the gene families in those long repetitive regions. We also noted that the PB HiFi reads generated assemblies with considerably less errors at the level of single nucleotide and small InDels than that of the ONT assembly which generated an average 1.06 errors per Kb assembly and finally engendered 1,475 incorrect gene annotations via altered or truncated protein predictions.
Reconstruction of cell spatial organization based on ligand-receptor mediated self-assembly
Authors: Ren Xianwen , Zhong Guojie , Zhang Qiming , Zhang Lei , Sun Yujie , Zhang Zemin
Published: February 2020

Single-cell RNA sequencing (scRNA-seq) has revolutionized transcriptomic studies by providing unprecedented cellular and molecular throughputs, but spatial information of individual cells is lost during tissue dissociation. While imaging-based technologies such asin situsequencing show great promise, technical difficulties currently limit their wide usage. Since cellular spatial organization is inherently encoded by cell identity and can be reconstructed, at least in part, by ligand-receptor interactions, here we present CSOmap, a computational strategy to infer cellular interaction from scRNA-seq. We show that CSOmap can successfully recapitulate the spatial organization of tumor microenvironments for multiple cancers and reveal molecular determinants of cellular interactions. Further, CSOmap readily simulates perturbation of genes or cell types to gain novel biological insights, especially into how immune cells interact in the tumor microenvironment. CSOmap can be widely applicable to interrogate cellular organizations based on scRNA-seq data for various tissues in diverse systems.
Bile acid supplementation improves murine pancreatitis in association with the gut microbiota
Authors: Wan You-Dong , Zhu Rui-Xue , Pan Xin-Ting
Published: February 2020

Disorders of bile acids (BAs) are closely related to the development of liver and intestinal diseases, including acute pancreatitis (AP). However, the mechanism underlying the involvement of BAs in AP development remains unclear. We used intraperitoneal injection of cerulein to construct AP mouse models. These mice had significantly reduced tauroursodeoxycholic acid (TUDCA) and an imbalance of intestinal microbiota, based on 16S rDNA gene sequencing. To explore the role of AP-induced intestinal microbiota changes in the development of AP, we transplanted stool obtained from AP mice to antibiotic-treated, microbiota-depleted healthy mice. Microbiota-depleted mice presented injury to the intestinal barrier function and pancreas. Additionally, microbiota depletion reduced AP-associated pancreatic injury. This indicated that the gut microbiota may worsen AP. As TUDCA was deficient in AP mice, we gavaged AP mice with it, and evaluated subsequent expression changes in the bile acid signaling receptors farnesoid-x-receptor (FXR) and its target gene fibroblast growth factor (FGF) 15. These were downregulated, and pancreatic and intestinal barrier function injury were mitigated. Similar results were found in microbiota-depleted AP without BA treatment. However, we did not observe further downregulation of the FXR signaling pathway in microbiota-depleted AP mice given TUDCA, indicating that improvement of pancreatitis by TUDCA may be associated with gut microbiota. Our analysis of changes to the gut microbiota in AP indicated thatLactobacillimay be the key contributors. Taken together, our study shows that supplementation with BAs could improve bile acid-FXR-FGF15 signaling, and reduce pancreatic and intestinal injury, and that this effect may be associated with the gut microbiota.
A new member in the Argonaute crew: the mt-miRNAs
Authors: Pozzi Andrea , Dowling Damian K.
Published: February 2020

Mutations within the mitochondrial genome have been linked to many diverse phenotypes. Moreover, the effects of these mutations have been shown to differ across sexes and environments. The mechanisms that explain the manifold array of mitochondrial genotypic effects on organismal function, and their context-dependency, have however remained a mystery. Here, we present evidence that mitochondria are involved in nuclear gene regulation via RNA interference; transcribing mitochondrial (mt-)miRNAs that may repress the transcription of nuclear genes that previously had no known involvement in mitochondrial function. Our findings uncover a new mechanism by which mitochondria may shape the expression of animal life-histories and health components; implying that the influence of the mitochondria in regulating organismal function extends well beyond the process of energy production.
Distinct regionalization patterns of cortical morphology are associated with cognitive performance across different domains
Authors: Palmer C E , Zhao W , Loughnan R , Zou J , Fan C C , Thompson W K , Dale A M , Jernigan T L
Published: February 2020

Cognitive performance in children is predictive of academic and social outcomes; therefore, understanding neurobiological mechanisms underlying individual differences in cognition during development may be important for improving quality of life. The belief that a single, psychological construct underlies many cognitive processes is pervasive throughout society. However, it is unclear if there is a consistent neural substrate underlying many cognitive processes. Here we show that a distributed configuration of cortical surface area and apparent thickness, when controlling for global imaging measures, is differentially associated with cognitive performance on different types of tasks in a large sample (N=10,145) of 9-11 year old children from the Adolescent Brain and Cognitive DevelopmentSM(ABCD) study. The minimal overlap in these regionalization patterns of association has implications for competing theories about developing intellectual functions. Surprisingly,notcontrolling for sociodemographic factors increased the similarity between these regionalization patterns. This highlights the importance of understanding the shared variance between sociodemographic factors, cognition and brain structure, particularly with a population-based sample such as ABCD.
Maternal antibodies to gliadin and autism spectrum disorders in offspring - A population-based case-control study in Sweden
Authors: Gardner Renee , Samuelsson Ida , Severance Emily G. , Sjöqvist Hugo , Yolken Robert H. , Dalman Christina , Karlsson Håkan
Published: February 2020

Objective

Individuals diagnosed with autism spectrum disorders (ASD) are reported to have higher levels of antibodies directed towards gliadin, a component of wheat gluten. However, no study has examined such antibodies in etiologically-relevant periods before diagnosis. The objective of this study is to investigate if maternal levels of immunoglobulin G antibodies directed at gliadin, during pregnancy and at the time of birth, are associated with ASD in offspring.

Methods

In this population-based study set in Sweden with 921 ASD cases and 1090 controls, we analyzed levels of anti-gliadin antibodies (AGA) in archived neonatal dried blood spots (NDBS, as maternal IgG is transferred to the fetus) and in paired maternal sera collected earlier in pregnancy for a subset of 547 cases and 428 controls. We examined associations to any ASD diagnosis and considering common comorbidities (i.e. intellectual disability [ID] and attention-deficit/hyperactivity disorder [ADHD]). We compared 206 ASD cases to their unaffected siblings to examine the potential for confounding by shared familial factors.

Results

High levels (≥90thpercentile) of maternal AGA were associated with decreased odds of ASD, particularly ASD with comorbid ID, when measured in NDBS (OR 0.51, 95% CI 0.30–0.87) with a similar trend in maternal sera (0.55, 0.24-1.29). High levels of maternal AGA were similarly associated with lower odds of ASD with ID in the sibling comparison.

Conclusions

This first study of exposure to AGA in the pre- and perinatal periods suggests that high levels of maternal AGA are associated with lower odds of ASD with ID.
Quantifying microbially mediated fitness differences reveals the tendency for plant-soil feedbacks to drive species exclusion among California annual plants
Authors: Kandlikar Gaurav S. , Yan Xinyi , Levine Jonathan M. , Kraft Nathan J.B.
Published: February 2020

Soil microorganisms influence a variety of processes in plant communities. Many the-oretical and empirical studies have shown that dynamic feedbacks between plants and soil microbes can stabilize plant coexistence by generating negative frequency-dependent plant population dynamics. However, inferring the net effects of soil microbes on plant coexistence requires also quantifying the degree to which they provide one species an average fitness advantage, an effect that has received little empirical attention. We conducted a greenhouse study to quantify microbially mediated stabilization and fitness differences among fifteen pairs of annual plants that co-occur in southern California grasslands. We found that although soil microbes frequently generate negative frequency-dependent dynamics that stabilize plant interactions, they simultaneously mediate large average fitness differences between species. The net result is that if the plant species are otherwise competitively equivalent, the impact of plant-soil feedbacks is often to favor species exclusion over coexistence, a result that only becomes evident by quantifying the microbially mediated fitness difference. Our work highlights that comparing the stabilizing effects of plant-soil feedbacks to the fitness difference they generate is essential for understanding the influence of soil microbes on plant diversity.
THEHOK/SOKTOXIN/ANTITOXIN LOCUS ENHANCES BACTERIAL SUSCEPTIBILITY TO DOXYCYCLINE
Authors: Chukwudi Chinwe U. , Good Liam
Published: February 2020

The antibacterial efficacy of the tetracycline antibiotics has been greatly reduced by the development of resistance, hence a decline in their clinical use as antibiotics. Thehok/soklocus is a type I toxin/antitoxin plasmid stability element, often associated with multi-drug resistance plasmids, especially ESBL-encoding plasmids. It enhances host cell survivability and pathogenicity in stressful growth conditions, and particularly increases bacterial tolerance to β-lactam antibiotics. Thehok/soklocus forms dsRNA by RNA:RNA interactions of the toxin and antitoxin, and doxycycline has been reported to bind and inhibit dsRNA cleavage/processing. This study investigated the antibacterial efficacy of doxycycline in hok/sok host bacteria cells, the effect onhok/sok-induced growth changes and the potential mechanism of the observed changes. Different strains ofE. coliwith growth characteristics affected by thehok/soklocus were transformed withhok/sokplasmids, and assessed for doxycycline susceptibility and growth changes. The results show that thehok/soklocus increases bacterial susceptibility to doxycycline, especially in strains with more pronouncedhok/sokgrowth effects. The increased doxycycline susceptibility occurs despite β-lactam resistance imparted byhok/sok. Doxycycline was found to induce bacterial death in a manner phenotypically characteristic of Hok toxin expression, suggesting that it inhibits the toxin/antitoxin dsRNA degradation, leading to Hok toxin expression and cell death. In this way, doxycycline could be used to counteract the multi-drug resistance plasmid maintenance/propagation and pathogenicity mechanisms associated with thehok/soklocus. This has great potentials in the global war to contain the rise in antimicrobial resistance.
Tol-Pal system and Rgs proteins interact to promote unipolar growth and cell division inSinorhizobium meliloti
Authors: Krol Elizaveta , Yau Hamish C. L. , Lechner Marcus , Schäper Simon , Bange Gert , Vollmer Waldemar , Becker Anke
Published: February 2020

Sinorhizobium melilotiis an α-proteobacterium belonging to the Rhizobiales. Bacteria from this order elongate their cell wall at the new cell pole, generated by cell division. Screening for protein interaction partners of the previously characterized polar growth factors RgsP and RgsM, we identified the inner membrane components of the Tol-Pal system (TolQ and TolR) and novel Rgs (rhizobial growth and septation) proteins with unknown functions. TolQ, Pal and all Rgs proteins, except for RgsE, were indispensable forS. meliloticell growth. Six of the Rgs proteins, TolQ and Pal localized to the growing cell pole in the cell elongation phase and to the septum in pre-divisional cells, and three Rgs proteins localized to growing cell pole only. The FtsN-like protein RgsS contains a conserved SPOR domain and is indispensable at the early stages of cell division. The components of the Tol-Pal system were required at the late stages of cell division. RgsE, a homolog of theAgrobacterium tumefaciensgrowth pole ring protein GPR, has an important role in maintaining the normal growth rate and rod cell shape. RgsD is a novel periplasmic protein with the ability to bind peptidoglycan. Analysis of the phylogenetic distribution of novel Rgs proteins showed that they are conserved in Rhizobiales and mostly absent from other α-proteobacterial orders, suggesting a conserved role of these proteins in polar growth.

IMPORTANCE

Bacterial cell proliferation involves cell growth and septum formation followed by cell division. For cell growth, bacteria have evolved different complex mechanisms. The most prevalent growth mode of rod shaped bacteria is cell elongation by incorporating new peptidoglycan in a dispersed manner along the sidewall. A small share of rod-shaped bacteria, including the α-proteobacterial Rhizobiales, grow unipolarly. Here, we identified and initially characterized a set of Rgs (rhizobial growth and septation) proteins, which are involved in cell division and unipolar growth ofSinorhizobium melilotiand highly conserved in Rhizobiales. Our data expand the knowledge of components of the polarly localized machinery driving cell wall growth and suggest a complex of Rgs proteins with components of the divisome, differing in composition between the polar cell elongation zone and the septum.
A resurrection study reveals limited evolution of thermal performance in response to recent climate change across the geographic range of the scarlet monkeyflower
Authors: Wooliver Rachel , Tittes Silas B. , Sheth Seema N.
Published: February 2020

Evolutionary rescue can prevent populations from declining under climate change, and should be more likely at high-latitude, “leading” edges of species’ ranges due to greater temperature anomalies and gene flow from warm-adapted populations. Using a resurrection study with seeds collected before and after a seven-year period of record warming, we tested for thermal adaptation in the scarlet monkeyflowerMimulus cardinalis. We grew ancestors and descendants from northern-edge, central, and southern-edge populations across eight temperatures. Despite recent climate anomalies, populations showed limited evolution of thermal performance curves. However, one southern population evolved a narrower thermal performance breadth by 1.25 °C, which matches the direction and magnitude of the average decrease in seasonality experienced. Consistent with the climate variability hypothesis, thermal performance breadth increased with temperature seasonality across the species’ geographic range. Inconsistent with performance trade-offs between low and high temperatures across populations, we did not detect a positive relationship between thermal optimum and mean temperature. These findings fail to support the hypothesis that evolutionary response to climate change is greatest at the leading edge, and suggest that the evolution of thermal performance is unlikely to rescue most populations from the detrimental effects of rapidly changing climate.
Unified Methods for Feature Selection in Large-Scale Genomic Studies with Censored Survival Outcomes
Authors: Spirko-Burns Lauren , Devarajan Karthik
Published: February 2020

One of the major goals in large-scale genomic studies is to identify genes with a prognostic impact on time-to-event outcomes which provide insight into the disease’s process. With rapid developments in high-throughput genomic technologies in the past two decades, the scientific community is able to monitor the expression levels of tens of thousands of genes and proteins resulting in enormous data sets where the number of genomic features is far greater than the number of subjects. Methods based on univariate Cox regression are often used to select genomic features related to survival outcome; however, the Cox model assumes proportional hazards (PH), which is unlikely to hold for each feature. When applied to genomic features exhibiting some form of non-proportional hazards (NPH), these methods could lead to an under- or over-estimation of the effects. We propose a broad array of marginal screening techniques that aid in feature ranking and selection by accommodating various forms of NPH. First, we develop an approach based on Kullback-Leibler information divergence and the Yang-Prentice model that includes methods for the PH and proportional odds (PO) models as special cases. Next, we proposeR2indices for the PH and PO models that can be interpreted in terms of explained randomness. Lastly, we propose a generalized pseudo-R2measure that includes PH, PO, crossing hazards and crossing odds models as special cases and can be interpreted as the percentage of separability between subjects experiencing the event and not experiencing the event according to feature expression. We evaluate the performance of our measures using extensive simulation studies and publicly available data sets in cancer genomics. We demonstrate that the proposed methods successfully address the issue of NPH in genomic feature selection and outperform existing methods. The proposed information divergence,R2and pseudo-R2measures were implemented in R (www.R-project.org) and code is available upon request.
PhyRepID: a comparative phylogenomics approach for large-scale quantification of protein repeat evolution
Authors: van Belzen I.A.E.M. , Deutekom E. S. , Snel B.
Published: February 2020

Protein repeats consisting of domains or motifs are involved in key biological processes such as neural development, host-pathogen interactions, and speciation. Expansion and contraction of these repeats can strongly impact protein function as was shown for KNL1 and PRDM9. However, these known cases could only be identified manually and were previously incorrectly reported as conserved in large-scale analyses, because signatures of repeat evolution are difficult to resolve automatically.

We developed PhyRepID to compare protein domain repeat evolution and analysed 4939 groups of orthologous proteins (OGs) from 14 vertebrate species. Our main contributions are 1) detecting a wide scope of repeats consisting of Pfam structural domains and motifs, 2) improving sensitivity and precision of repeat unit detection through optimization for the OGs, 3) using phylogenetic analysis to detect evolution within repeat regions. From these phylogenetic signals, we derived a “protein repeat duplication” (PRD) score that quantifies evolution in repeat regions and thereby enables large-scale comparison of protein families. Zinc finger repeats show remarkably fast evolution, comprising 25 of 100 fastest evolving proteins in our dataset, whilst cooperatively-folding domain repeats like beta-propellers are mostly conserved. Motif repeats have a similar PRD score distribution as domain repeats and also show a large diversity in evolutionary rates. A ranking based on the PRD score reflects previous manual observations of both highly conserved (CDC20) and rapidly evolving repeats (KNL1, PRDM9) and proposes novel candidates (e.g. AHNAK, PRX, SPATA31) showing previously undescribed rapid repeat evolution. PhyRepID is available onhttps://github.com/ivanbelzen/PhyRepID/.
HIV-1-infected human macrophages, by secreting RANKL, contribute to enhanced osteoclastogenesis
Authors: Mascarau Rémi , Bertrand Florent , Labrousse Arnaud , Gennero Isabelle , Poincloux Renaud , Maridonneau-Parini Isabelle , Raynaud-Messina Brigitte , Vérollet Christel
Published: February 2020

HIV-1 infection is frequently associated with low bone density, which can progress to osteoporosis leading to a high risk of fractures. Only a few mechanisms have been proposed to explain the enhanced osteolysis in the context of HIV-1 infection. As macrophages are involved in bone homeostasis and are critical cell hosts for HIV-1, we asked whether HIV-1-infected macrophages could participate in bone degradation. Upon infection, human macrophages acquired some osteoclast features: they became multinucleated, upregulated the osteoclast markers RhoE and β3 integrin, and organized their podosomes as ring superstructures resembling osteoclast sealing zones. However, HIV-1 infected macrophages were not fully differentiated in osteoclasts as they did not upregulate NFATc-1 transcription factor and were unable to degrade bone. Investigating whether infected macrophages participate indirectly to virus-induced osteolysis, we showed that they produce RANKL, the key osteoclastogenic cytokine. RANK-L secreted by HIV-1-infected macrophages was not sufficient to stimulate multinucleation, but promoted the protease-dependent migration of osteoclast precursors. In conclusion, we propose that, by stimulating RANKL secretion, HIV-1-infected macrophages contribute to create a microenvironment that favors the recruitment of osteoclasts, participating to bone disorders observed in HIV-1+patients.
Fine-scale computations for adaptive processing in the human brain
Authors: Zamboni E , Kemper VG , Goncalves NR , Jia K , Karlaftis VM , Bell SJ , Giorgio JJ , Rideaux R , Goebel R , Kourtzi Z
Published: February 2020

Adapting to the environment statistics by reducing brain responses to repetitive sensory information is key for efficient information processing. Yet, the fine-scale computations that support this adaptive processing in the human brain remain largely unknown. Here, we capitalize on the sub-millimetre resolution afforded by ultra-high field imaging to examine BOLD-fMRI signals across cortical depth and discern competing hypotheses about the brain mechanisms (feedforward vs. feedback) that mediate adaptive visual processing. We demonstrate suppressive recurrent processing within visual cortex, as indicated by stronger BOLD decrease in superficial than middle and deeper layers for gratings that were repeatedly presented at the same orientation. Further, we show dissociable connectivity mechanisms for adaptive processing: enhanced feedforward connectivity within visual cortex, while feedback occipito-parietal connectivity, reflecting top-down influences on visual processing. Our findings provide evidence for a circuit of local recurrent and feedback interactions that mediate rapid brain plasticity for adaptive information processing.
Conditional Analysis Cakewalk
Authors: French Jennifer N. , Gaynor Brady J. , Perry James A.
Published: February 2020

Sequential conditional analysis is an important tool for identifying the unique signals in single-variant association analysis between genomic variants and various phenotypic outcomes. With large datasets, it is tedious and time-consuming to manually run the sequential steps which require the association analysis, computation of linkage disequilibrium (LD) between the variants, generation of a visualization graphic, and identification of the “top hit” to be inserted as an additional covariate for the next iteration. The Conditional Analysis Cakewalk automates this process, making it easy and fast, while only requiring user input in the initial configuration steps.

Availability and Implementation

The Conditional Analysis Cakewalk is implemented as a Linux shell script utilizing MMAP or PLINK and LocusZoom. Source code and documentation are available athttps://github.com/jennetics/Cakewalk.