bluuebunny/crossref_metadata_2025 huggingface dataset:
IFN-λ4 is associated with increased risk and earlier occurrence of several common infections in African children
Authors: Prokunina-Olsson Ludmila , Morrison Robert D. , Obajemu Adeola , Mahamar Almahamoudou , Kim Sungduk , Attaher Oumar , Florez-Vargas Oscar , Sidibe Youssoufa , Onabajo Olusegun O. , Hutchinson Amy A. , Manning Michelle , Kwan Jennifer , Brand Nathan , Dicko Alassane , Fried Michal , Albert Paul S. , Mbulaiteye Sam M. , Duffy Patrick E.
Published: April 2021

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), rs368234815-dG allele was most strongly associated with an earlier time-to-first episode of gastrointestinal infections (p = 0.003). The risk of experiencing an infection episode during the follow-up was also significantly increased with rs368234815-dG allele, with OR = 1.53, 95%CI (1.13–2.07), p = 0.005 for gastrointestinal infections and OR = 1.30, 95%CI (1.02–1.65), p = 0.033 for malaria. All the associations for the moderately linked rs4803217 (r2 = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-λ4-P70S groups. Our results implicate IFN-λ4 and not IFN-λ3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.
Identifying therapeutic drug targets using bidirectional effect genes
Authors: Estrada Karol , Froelich Steven , Wuster Arthur , Bauer Christopher R. , Sterling Teague , Clark Wyatt T. , Ru Yuanbin , Trinidad Marena , Nguyen Hong Phuc , Luu Amanda R. , Wendt Daniel J. , Yogalingam Gouri , Yu Guoying Karen , LeBowitz Jonathan H. , Cardon Lon R.
Published: April 2021

Prioritizing genes for translation to therapeutics for common diseases has been challenging. Here, we propose an approach to identify drug targets with high probability of success by focusing on genes with both gain of function (GoF) and loss of function (LoF) mutations associated with opposing effects on phenotype (Bidirectional Effect Selected Targets, BEST). We find 98 BEST genes for a variety of indications. Drugs targeting those genes are 3.8-fold more likely to be approved than non-BEST genes. We focus on five genes (IGF1R, NPPC, NPR2, FGFR3, and SHOX) with evidence for bidirectional effects on stature. Rare protein-altering variants in those genes result in significantly increased risk for idiopathic short stature (ISS) (OR = 2.75, p = 3.99 × 10−8). Finally, using functional experiments, we demonstrate that adding an exogenous CNP analog (encoded by NPPC) rescues the phenotype, thus validating its potential as a therapeutic treatment for ISS. Our results show the value of looking for bidirectional effects to identify and validate drug targets.
Fermi surface in La-based cuprate superconductors from Compton scattering imaging
Authors: Yamase Hiroyuki , Sakurai Yoshiharu , Fujita Masaki , Wakimoto Shuichi , Yamada Kazuyoshi
Published: April 2021

Compton scattering provides invaluable information on the underlying Fermi surface (FS) and is a powerful tool complementary to angle-resolved photoemission spectroscopy and quantum oscillation measurements. Here we perform high-resolution Compton scattering measurements for La2−xSrxCuO4 with x = 0.08 (Tc = 20 K) at 300 K and 150 K, and image the momentum distribution function in the two-dimensional Brillouin zone. We find that the observed images cannot be reconciled with the conventional hole-like FS believed so far. Instead, our data imply that the FS is strongly deformed by the underlying nematicity in each CuO2 plane, but the bulk FSs recover the fourfold symmetry. We also find an unusually strong temperature dependence of the momentum distribution function, which may originate from the pseudogap formation in the presence of the reconstructed FSs due to the underlying nematicity. Additional measurements for x = 0.15 and 0.30 at 300 K suggest similar FS deformation with weaker nematicity, which nearly vanishes at x = 0.30.
2D vanadium carbide MXenzyme to alleviate ROS-mediated inflammatory and neurodegenerative diseases
Authors: Feng Wei , Han Xiuguo , Hu Hui , Chang Meiqi , Ding Li , Xiang Huijing , Chen Yu , Li Yuehua
Published: April 2021

Reactive oxygen species (ROS) are generated and consumed in living organism for normal metabolism. Paradoxically, the overproduction and/or mismanagement of ROS have been involved in pathogenesis and progression of various human diseases. Here, we reported a two-dimensional (2D) vanadium carbide (V2C) MXene nanoenzyme (MXenzyme) that can mimic up to six naturally-occurring enzymes, including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione peroxidase (GPx), thiol peroxidase (TPx) and haloperoxidase (HPO). Based on these enzyme-mimicking properties, the constructed 2D V2C MXenzyme not only possesses high biocompatibility but also exhibits robust in vitro cytoprotection against oxidative stress. Importantly, 2D V2C MXenzyme rebuilds the redox homeostasis without perturbing the endogenous antioxidant status and relieves ROS-induced damage with benign in vivo therapeutic effects, as demonstrated in both inflammation and neurodegeneration animal models. These findings open an avenue to enable the use of MXenzyme as a remedial nanoplatform to treat ROS-mediated inflammatory and neurodegenerative diseases.
Stabilization of supramolecular membrane protein–lipid bilayer assemblies through immobilization in a crystalline exoskeleton
Authors: Herbert Fabian C. , Abeyrathna Sameera S. , Abeyrathna Nisansala S. , Wijesundara Yalini H. , Brohlin Olivia R. , Carraro Francesco , Amenitsch Heinz , Falcaro Paolo , Luzuriaga Michael A. , Durand-Silva Alejandra , Diwakara Shashini D. , Smaldone Ronald A. , Meloni Gabriele , Gassensmith Jeremiah J.
Published: April 2021

Artificial native-like lipid bilayer systems constructed from phospholipids assembling into unilamellar liposomes allow the reconstitution of detergent-solubilized transmembrane proteins into supramolecular lipid-protein assemblies called proteoliposomes, which mimic cellular membranes. Stabilization of these complexes remains challenging because of their chemical composition, the hydrophobicity and structural instability of membrane proteins, and the lability of interactions between protein, detergent, and lipids within micelles and lipid bilayers. In this work we demonstrate that metastable lipid, protein-detergent, and protein-lipid supramolecular complexes can be successfully generated and immobilized within zeolitic-imidazole framework (ZIF) to enhance their stability against chemical and physical stressors. Upon immobilization in ZIF bio-composites, blank liposomes, and model transmembrane metal transporters in detergent micelles or embedded in proteoliposomes resist elevated temperatures, exposure to chemical denaturants, aging, and mechanical stresses. Extensive morphological and functional characterization of the assemblies upon exfoliation reveal that all these complexes encapsulated within the framework maintain their native morphology, structure, and activity, which is otherwise lost rapidly without immobilization.
On the limitations in assessing stability of oxygen evolution catalysts using aqueous model electrochemical cells
Authors: Knöppel Julius , Möckl Maximilian , Escalera-López Daniel , Stojanovski Kevin , Bierling Markus , Böhm Thomas , Thiele Simon , Rzepka Matthias , Cherevko Serhiy
Published: April 2021

Recent research indicates a severe discrepancy between oxygen evolution reaction catalysts dissolution in aqueous model systems and membrane electrode assemblies. This questions the relevance of the widespread aqueous testing for real world application. In this study, we aim to determine the processes responsible for the dissolution discrepancy. Experimental parameters known to diverge in both systems are individually tested for their influence on dissolution of an Ir-based catalyst. Ir dissolution is studied in an aqueous model system, a scanning flow cell coupled to an inductively coupled plasma mass spectrometer. Real dissolution rates of the Ir OER catalyst in membrane electrode assemblies are measured with a specifically developed, dedicated setup. Overestimated acidity in the anode catalyst layer and stabilization over time in real devices are proposed as main contributors to the dissolution discrepancy. The results shown here lead to clear guidelines for anode electrocatalyst testing parameters to resemble realistic electrolyzer operating conditions.
Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters
Authors: Pidathala Shabareesh , Mallela Aditya Kumar , Joseph Deepthi , Penmatsa Aravind
Published: April 2021

Norepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters.
Interacting with volatile environments stabilizes hidden-state inference and its brain signatures
Authors: Weiss Aurélien , Chambon Valérian , Lee Junseok K. , Drugowitsch Jan , Wyart Valentin
Published: April 2021

Making accurate decisions in uncertain environments requires identifying the generative cause of sensory cues, but also the expected outcomes of possible actions. Although both cognitive processes can be formalized as Bayesian inference, they are commonly studied using different experimental frameworks, making their formal comparison difficult. Here, by framing a reversal learning task either as cue-based or outcome-based inference, we found that humans perceive the same volatile environment as more stable when inferring its hidden state by interaction with uncertain outcomes than by observation of equally uncertain cues. Multivariate patterns of magnetoencephalographic (MEG) activity reflected this behavioral difference in the neural interaction between inferred beliefs and incoming evidence, an effect originating from associative regions in the temporal lobe. Together, these findings indicate that the degree of control over the sampling of volatile environments shapes human learning and decision-making under uncertainty.
Metabolic pathways inferred from a bacterial marker gene illuminate ecological changes across South Pacific frontal boundaries
Authors: Raes Eric J. , Karsh Kristen , Sow Swan L. S. , Ostrowski Martin , Brown Mark V. , van de Kamp Jodie , Franco-Santos Rita M. , Bodrossy Levente , Waite Anya M.
Published: April 2021

Global oceanographic monitoring initiatives originally measured abiotic essential ocean variables but are currently incorporating biological and metagenomic sampling programs. There is, however, a large knowledge gap on how to infer bacterial functions, the information sought by biogeochemists, ecologists, and modelers, from the bacterial taxonomic information (produced by bacterial marker gene surveys). Here, we provide a correlative understanding of how a bacterial marker gene (16S rRNA) can be used to infer latitudinal trends for metabolic pathways in global monitoring campaigns. From a transect spanning 7000 km in the South Pacific Ocean we infer ten metabolic pathways from 16S rRNA gene sequences and 11 corresponding metagenome samples, which relate to metabolic processes of primary productivity, temperature-regulated thermodynamic effects, coping strategies for nutrient limitation, energy metabolism, and organic matter degradation. This study demonstrates that low-cost, high-throughput bacterial marker gene data, can be used to infer shifts in the metabolic strategies at the community scale.
Mediator subunit Med15 dictates the conserved “fuzzy” binding mechanism of yeast transcription activators Gal4 and Gcn4
Authors: Tuttle Lisa M. , Pacheco Derek , Warfield Linda , Wilburn Damien B. , Hahn Steven , Klevit Rachel E.
Published: April 2021

The acidic activation domain (AD) of yeast transcription factor Gal4 plays a dual role in transcription repression and activation through binding to Gal80 repressor and Mediator subunit Med15. The activation function of Gal4 arises from two hydrophobic regions within the 40-residue AD. We show by NMR that each AD region binds the Mediator subunit Med15 using a “fuzzy” protein interface. Remarkably, comparison of chemical shift perturbations shows that Gal4 and Gcn4, two intrinsically disordered ADs of different sequence, interact nearly identically with Med15. The finding that two ADs of different sequence use an identical fuzzy binding mechanism shows a common sequence-independent mechanism for AD-Mediator binding, similar to interactions within a hydrophobic cloud. In contrast, the same region of Gal4 AD interacts strongly with Gal80 via a distinct structured complex, implying that the structured binding partner of an intrinsically disordered protein dictates the type of protein–protein interaction.
Timely and atomic-resolved high-temperature mechanical investigation of ductile fracture and atomistic mechanisms of tungsten
Authors: Zhang Jianfei , Li Yurong , Li Xiaochen , Zhai Yadi , Zhang Qing , Ma Dongfeng , Mao Shengcheng , Deng Qingsong , Li Zhipeng , Li Xueqiao , Wang Xiaodong , Liu Yinong , Zhang Ze , Han Xiaodong
Published: April 2021

Revealing the atomistic mechanisms for the high-temperature mechanical behavior of materials is important for optimizing their properties for service at high-temperatures and their thermomechanical processing. However, due to materials microstructure’s dynamic recovery and the absence of available in situ techniques, the high-temperature deformation behavior and atomistic mechanisms of materials are difficult to evaluate. Here, we report the development of a microelectromechanical systems-based thermomechanical testing apparatus that enables mechanical testing at temperatures reaching 1556 K inside a transmission electron microscope for in situ investigation with atomic-resolution. With this unique technique, we first uncovered that tungsten fractures at 973 K in a ductile manner via a strain-induced multi-step body-centered cubic (BCC)-to-face-centered cubic (FCC) transformation and dislocation activities within the strain-induced FCC phase. Both events reduce the stress concentration at the crack tip and retard crack propagation. Our research provides an approach for timely and atomic-resolved high-temperature mechanical investigation of materials at high-temperatures.
A compendium and comparative epigenomics analysis of cis-regulatory elements in the pig genome
Authors: Zhao Yunxia , Hou Ye , Xu Yueyuan , Luan Yu , Zhou Huanhuan , Qi Xiaolong , Hu Mingyang , Wang Daoyuan , Wang Zhangxu , Fu Yuhua , Li Jingjin , Zhang Saixian , Chen Jianhai , Han Jianlin , Li Xinyun , Zhao Shuhong
Published: April 2021

Although major advances in genomics have initiated an exciting new era of research, a lack of information regardingcis-regulatory elements has limited the genetic improvement or manipulation of pigs as a meat source and biomedical model. Here, we systematically characterizecis-regulatory elements and their functions in 12 diverse tissues from four pig breeds by adopting similar strategies as the ENCODE and Roadmap Epigenomics projects, which include RNA-seq, ATAC-seq, and ChIP-seq. In total, we generate 199 datasets and identify more than 220,000cis-regulatory elements in the pig genome. Surprisingly, we find higher conservation ofcis-regulatory elements between human and pig genomes than those between human and mouse genomes. Furthermore, the differences of topologically associating domains between the pig and human genomes are associated with morphological evolution of the head and face. Beyond generating a major new benchmark resource for pig epigenetics, our study provides basic comparative epigenetic data relevant to using pigs as models in human biomedical research.
B1a and B2 cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers
Authors: Mahajan Vinay S. , Mattoo Hamid , Sun Na , Viswanadham Vinayak , Yuen Grace J. , Allard-Chamard Hugues , Ahmad Maimuna , Murphy Samuel J. H. , Cariappa Annaiah , Tuncay Yesim , Pillai Shiv
Published: April 2021

The B1 and B2 lineages of B cells contribute to protection from pathogens in distinct ways. The role of the DNA CpG methylome in specifying these two B-cell fates is still unclear. Here we profile the CpG modifications and transcriptomes of peritoneal B1a and follicular B2 cells, as well as their respective proB cell precursors in the fetal liver and adult bone marrow from wild-type and CD19-Cre Dnmt3a floxed mice lacking DNMT3A in the B lineage. We show that an underlying foundational CpG methylome is stably established during B lineage commitment and is overlaid with a DNMT3A-maintained dynamic methylome that is sculpted in distinct ways in B1a and B2 cells. This dynamic DNMT3A-maintained methylome is composed of novel enhancers that are closely linked to lineage-specific genes. While DNMT3A maintains the methylation state of these enhancers in both B1a and B2 cells, the dynamic methylome undergoes a prominent programmed demethylation event during B1a but not B2 cell development. We propose that the methylation pattern of DNMT3A-maintained enhancers is determined by the coincident recruitment of DNMT3A and TET enzymes, which regulate the developmental expression of B1a and B2 lineage-specific genes.
Spreading depression as an innate antiseizure mechanism
Authors: Tamim Isra , Chung David Y. , de Morais Andreia Lopes , Loonen Inge C. M. , Qin Tao , Misra Amrit , Schlunk Frieder , Endres Matthias , Schiff Steven J. , Ayata Cenk
Published: April 2021

Spreading depression (SD) is an intense and prolonged depolarization in the central nervous systems from insect to man. It is implicated in neurological disorders such as migraine and brain injury. Here, using an in vivo mouse model of focal neocortical seizures, we show that SD may be a fundamental defense against seizures. Seizures induced by topical 4-aminopyridine, penicillin or bicuculline, or systemic kainic acid, culminated in SDs at a variable rate. Greater seizure power and area of recruitment predicted SD. Once triggered, SD immediately suppressed the seizure. Optogenetic or KCl-induced SDs had similar antiseizure effect sustained for more than 30 min. Conversely, pharmacologically inhibiting SD occurrence during a focal seizure facilitated seizure generalization. Altogether, our data indicate that seizures trigger SD, which then terminates the seizure and prevents its generalization.
EpCAM promotes endosomal modulation of the cortical RhoA zone for epithelial organization
Authors: Gaston Cécile , De Beco Simon , Doss Bryant , Pan Meng , Gauquelin Estelle , D’Alessandro Joseph , Lim Chwee Teck , Ladoux Benoit , Delacour Delphine
Published: April 2021

At the basis of cell shape and behavior, the organization of actomyosin and its ability to generate forces are widely studied. However, the precise regulation of this contractile network in space and time is unclear. Here, we study the role of the epithelial-specific protein EpCAM, a contractility modulator, in cell shape and motility. We show that EpCAM is required for stress fiber generation and front-rear polarity acquisition at the single cell level. In fact, EpCAM participates in the remodeling of a transient zone of active RhoA at the cortex of spreading epithelial cells. EpCAM and RhoA route together through the Rab35/EHD1 fast recycling pathway. This endosomal pathway spatially organizes GTP-RhoA to fine tune the activity of actomyosin resulting in polarized cell shape and development of intracellular stiffness and traction forces. Impairment of GTP-RhoA endosomal trafficking either by silencing EpCAM or by expressing Rab35/EHD1 mutants prevents proper myosin-II activity, stress fiber formation and ultimately cell polarization. Collectively, this work shows that the coupling between co-trafficking of EpCAM and RhoA, and actomyosin rearrangement is pivotal for cell spreading, and advances our understanding of how biochemical and mechanical properties promote cell plasticity.
Incommensurate smectic phase in close proximity to the high-Tc superconductor FeSe/SrTiO3
Authors: Yuan Yonghao , Fan Xuemin , Wang Xintong , He Ke , Zhang Yan , Xue Qi-Kun , Li Wei
Published: April 2021

Superconductivity is significantly enhanced in monolayer FeSe grown on SrTiO3, but not for multilayer films, in which large strength of nematicity develops. However, the link between the high-transition temperature superconductivity in monolayer and the correlation related nematicity in multilayer FeSe films is not well understood. Here, we use low-temperature scanning tunneling microscopy to study few-layer FeSe thin films grown by molecular beam epitaxy. We observe an incommensurate long-range smectic phase, which solely appears in bilayer FeSe films. The smectic order still locally exists and gradually fades away with increasing film thickness, while it suddenly vanishes in monolayer FeSe, indicative of an abrupt smectic phase transition. Surface alkali-metal doping can suppress the smectic phase and induce high-Tc superconductivity in bilayer FeSe. Our observations provide evidence that the monolayer FeSe is in close proximity to the smectic phase, and its superconductivity is likely enhanced by this electronic instability as well.
Considerations for bioanalytical characterization and batch release of COVID-19 vaccines
Authors: Sanyal Gautam , Särnefält Anna , Kumar Arun
Published: April 2021

The COVID-19 pandemic has prompted hundreds of laboratories around the world to employ traditional as well as novel technologies to develop vaccines against SARS-CoV-2. The hallmarks of a successful vaccine are safety and efficacy. Analytical evaluation methods, that can ensure the high quality of the products and that can be executed speedily, must be in place as an integral component of Chemistry, Manufacturing, and Control (CMC). These methods or assays are developed to quantitatively test for critical quality attributes (CQAs) of a vaccine product. While clinical (human) efficacy of a vaccine can never be predicted from pre-clinical evaluation of CQA, precise and accurate measurements of antigen content and a relevant biological activity (termed “potency”) elicited by the antigen allow selection of potentially safe and immunogenic doses for entry into clinical trials. All available vaccine technology platforms, novel and traditional, are being utilized by different developers to produce vaccines against SARS-CoV-2. It took less than a year from the publication of SARS-CoV-2 gene sequence to Emergency Use Authorization (EUA) of the first vaccine, setting a record for speed in the history of vaccine development. The largest ever global demand for vaccines has prompted some vaccine developers to enter multiple manufacturing partnerships in different countries in addition to implementing unprecedented scale-up plans. Quantitative, robust, and rapid analytical testing for CQA of a product is essential in ensuring smooth technology transfer between partners and allowing analytical bridging between vaccine batches used in different clinical phases leading up to regulatory approvals and commercialization. We discuss here opportunities to improve the speed and quality of the critical batch release and characterization assays.
Autofluorescence enhancement for label-free imaging of myelinated fibers in mammalian brains
Authors: Costantini Irene , Baria Enrico , Sorelli Michele , Matuschke Felix , Giardini Francesco , Menzel Miriam , Mazzamuto Giacomo , Silvestri Ludovico , Cicchi Riccardo , Amunts Katrin , Axer Markus , Pavone Francesco Saverio
Published: April 2021

Analyzing the structure of neuronal fibers with single axon resolution in large volumes is a challenge in connectomics. Different technologies try to address this goal; however, they are limited either by the ineffective labeling of the fibers or in the achievable resolution. The possibility of discriminating between different adjacent myelinated axons gives the opportunity of providing more information about the fiber composition and architecture within a specific area. Here, we propose MAGIC (Myelin Autofluorescence imaging by Glycerol Induced Contrast enhancement), a tissue preparation method to perform label-free fluorescence imaging of myelinated fibers that is user friendly and easy to handle. We exploit the high axial and radial resolution of two-photon fluorescence microscopy (TPFM) optical sectioning to decipher the mixture of various fiber orientations within the sample of interest. We demonstrate its broad applicability by performing mesoscopic reconstruction at a sub-micron resolution of mouse, rat, monkey, and human brain samples and by quantifying the different fiber organization in control and Reeler mouse's hippocampal sections. Our study provides a novel method for 3D label-free imaging of nerve fibers in fixed samples at high resolution, below micrometer level, that overcomes the limitation related to the myelinated axons exogenous labeling, improving the possibility of analyzing brain connectivity.
Integrated transcription factor profiling with transcriptome analysis identifies L1PA2 transposons as global regulatory modulators in a breast cancer model
Authors: Jiang Jiayue-Clara , Rothnagel Joseph A. , Upton Kyle R.
Published: April 2021

While transposons are generally silenced in somatic tissues, many transposons escape epigenetic repression in epithelial cancers, become transcriptionally active and contribute to the regulation of human gene expression. We have developed a bioinformatic pipeline for the integrated analysis of transcription factor binding and transcriptomic data to identify transposon-derived promoters that are activated in specific diseases and developmental states. We applied this pipeline to a breast cancer model, and found that the L1PA2 transposon subfamily contributes abundant regulatory sequences to co-ordinated transcriptional regulation in breast cancer. Transcription factor profiling demonstrates that over 27% of L1PA2 transposons harbour co-localised binding sites of functionally interacting, cancer-associated transcription factors in MCF7 cells, a cell line used to model breast cancer. Transcriptomic analysis reveals that L1PA2 transposons also contribute transcription start sites to up-regulated transcripts in MCF7 cells, including some transcripts with established oncogenic properties. In addition, we verified the utility of our pipeline on other transposon subfamilies, as well as on leukemia and lung carcinoma cell lines. We demonstrate that the normally quiescent regulatory activities of transposons can be activated and alter the cancer transcriptome. In particular, the L1PA2 subfamily contributes abundant regulatory sequences, and likely plays a global role in modulating breast cancer transcriptional regulation. Understanding the regulatory impact of L1PA2 on breast cancer genomes provides additional insights into cancer genome regulation, and may provide novel biomarkers for disease diagnosis, prognosis and therapy.
Multi-modal nonlinear optical and thermal imaging platform for label-free characterization of biological tissue
Authors: Adams Wilson R. , Mehl Brian , Lieser Eric , Wang Manqing , Patton Shane , Throckmorton Graham A. , Jenkins J. Logan , Ford Jeremy B. , Gautam Rekha , Brooker Jeff , Jansen E. Duco , Mahadevan-Jansen Anita
Published: April 2021

The ability to characterize the combined structural, functional, and thermal properties of biophysically dynamic samples is needed to address critical questions related to tissue structure, physiological dynamics, and disease progression. Towards this, we have developed an imaging platform that enables multiple nonlinear imaging modalities to be combined with thermal imaging on a common sample. Here we demonstrate label-free multimodal imaging of live cells, excised tissues, and live rodent brain models. While potential applications of this technology are wide-ranging, we expect it to be especially useful in addressing biomedical research questions aimed at the biomolecular and biophysical properties of tissue and their physiology.
Role of interferon therapy in severe COVID-19: the COVIFERON randomized controlled trial
Authors: Alavi Darazam Ilad , Shokouhi Shervin , Pourhoseingholi Mohamad Amin , Naghibi Irvani Seyed Sina , Mokhtari Majid , Shabani Minoosh , Amirdosara Mahdi , Torabinavid Parham , Golmohammadi Maryam , Hashemi SayedPayam , Azimi Arsalan , Jafarazadeh Maivan Mohammad Hossein , Rezaei Omidvar , Zali Alireza , Hajiesmaeili Mohammadreza , Shabanpour Dehbsneh Hadiseh , Hoseyni Kusha Akram , Taleb Shoushtari Maryam , Khalili Negar , Soleymaninia Azam , Gachkar Latif , Khoshkar Ali
Published: April 2021

Type 1 Interferons (IFNs) have been associated with positive effects on Coronaviruses. Previous studies point towards the superior potency of IFNβ compared to IFNα against viral infections. We conducted a three-armed, individually-randomized, open-label, controlled trial of IFNβ1a and IFNβ1b, comparing them against each other and a control group. Patients were randomly assigned in a 1:1:1 ratio to IFNβ1a (subcutaneous injections of 12,000 IU on days 1, 3, 6), IFNβ1b (subcutaneous injections of 8,000,000 IU on days 1, 3, 6), or the control group. All three arms orally received Lopinavir/Ritonavir (400 mg/100 mg twice a day for ten days) and a single dose of Hydroxychloroquine 400 mg on the first day. Our utilized primary outcome measure was Time To Clinical Improvement (TTCI) defined as the time from enrollment to discharge or a decline of two steps on the clinical seven-step ordinal scale, whichsoever came first. A total of 60 severely ill patients with positive RT-PCR and Chest CT scans underwent randomization (20 patients to each arm). In the Intention-To-Treat population, IFNβ1a was associated with a significant difference against the control group, in the TTCI; (HR; 2.36, 95% CI 1.10–5.17, P-value = 0.031) while the IFNβ1b indicated no significant difference compared with the control; HR; 1.42, (95% CI 0.63–3.16, P-value = 0.395). The median TTCI for both of the intervention groups was five days vs. seven days for the control group. The mortality was numerically lower in both of the intervention groups (20% in the IFNβ1a group and 30% in the IFNβ1b group vs. 45% in the control group). There were no significant differences between the three arms regarding the adverse events. In patients with laboratory-confirmed SARS-CoV-2 infection, as compared with the base therapeutic regiment, the benefit of a significant reduction in TTCI was observed in the IFNβ1a arm. This finding needs further confirmation in larger studies.

Trial Registration Number: ClinicalTrials.gov, NCT04343768. (Submitted: 08/04/2020; First Online: 13/04/2020) (Registration Number: NCT04343768).
The morphology, biomechanics, and physiological function of the suboccipital myodural connections
Authors: Ma Yue , Tang Wei , Gong De-Zheng , Li Xing-Yi , Zhang Jing-Hui , Sun Jia-Hui , Wang Bing , Zhang Ying , Chen Yu-Xiao , Zhang Zhi-Hong , Zheng Nan , Okoye Chukwuemeka Samuel , Chi Yan-Yan , Wu Cheng-Wei , Yu Sheng-Bo , Sui Hong-Jin
Published: April 2021

The myodural bridge (MDB) connects the suboccipital musculature to the spinal dura mater (SDM) as it passed through the posterior atlanto-occipital and the atlanto-axial interspaces. Although the actual function of the MDB is not understood at this time, it has recently been proposed that head movement may assist in powering the movement of cerebrospinal fluid (CSF) via muscular tension transmitted to the SDM via the MDB. But there is little information about it. The present study utilized dogs as the experimental model to explore the MDB’s effects on the CSF pressure (CSFP) during stimulated contractions of the suboccipital muscles as well as during manipulated movements of the atlanto-occiptal and atlanto-axial joints. The morphology of MDB was investigated by gross anatomic dissection and by histological observation utilizing both light microscopy and scanning electron microscopy. Additionally biomechanical tensile strength tests were conducted. Functionally, the CSFP was analyzed during passive head movements and electrical stimulation of the suboccipital muscles, respectively. The MDB was observed passing through both the dorsal atlanto-occipital and the atlanto-axial interspaces of the canine and consisted of collagenous fibers. The tensile strength of the collagenous fibers passing through the dorsal atlanto-occipital and atlanto-axial interspaces were 0.16 ± 0.04 MPa and 0.82 ± 0.57 MPa, respectively. Passive head movement, including lateral flexion, rotation, as well as flexion–extension, all significantly increased CSFP. Furthermore, the CSFP was significantly raised from 12.41 ± 4.58 to 13.45 ± 5.16 mmHg when the obliques capitis inferior (OCI) muscles of the examined specimens were electrically stimulated. This stimulatory effect was completely eliminated by severing the myodural bridge attachments to the OCI muscle. Head movements appeared to be an important factor affecting CSF pressure, with the MDB of the suboccipital muscles playing a key role this process. The present study provides direct evidence to support the hypothesis that the MDB may be a previously unappreciated significant power source (pump) for CSF circulation.
Identification of extremely hard coke generation by low-temperature reaction on tungsten catalysts via Operando and in situ techniques
Authors: Takkawatakarn Thotsatham , Praserthdam Supareak , Wannakao Sippakorn , Panpranot Joongjai , Praserthdam Piyasan
Published: April 2021

The coke formation in the catalytic system mainly cause to the catalyst deactivate resulting the dramatic decreasing of the catalyst performance then the catalyst regeneration was required. In this study, adding MgO physically mixed with WO3/SiO2 catalysts were prepared and compared with the ones prepared by physically mixing with SiO2. Adding MgO affected the generation of new species of coke deposited on WO3/SiO2 and MgO itself. Comparing the reaction temperature when adding MgO between at 300 and 450 °C, the different pathway of reaction and the coke formation were found. At 450 °C, the metathesis reaction was more pronounced and the lower temperature of coke deposited on WOx/SiO2 was found. Surprisingly, the extremely hard coke occurred during reaction at 300 °C that the maxima of coke formation was found over 635 °C. This due to the fact that the reduction of reaction temperature from 450 to 300 °C affected the decreasing of the metathesis activity. Conversely, the increasing of dimerization and isomerization of butenes-isomer was observed especially 1-butene and iso-butene. Thus, it could suggest that those quantity of them play the important role to generate the charged monoenyl or cyclopentenyl species by participating with ethene through the dimerization, resulting in the formation of extremely hard coke.
Humic + Fulvic acid mitigated Cd adverse effects on plant growth, physiology and biochemical properties of garden cress
Authors: Yildirim Ertan , Ekinci Melek , Turan Metin , Ağar Güleray , Dursun Atilla , Kul Raziye , Alim Zeynep , Argin Sanem
Published: April 2021

Cadmium (Cd) is a toxic and very mobile heavy metal that can be adsorbed and uptaken by plants in large quantities without any visible sign. Therefore, stabilization of Cd before uptake is crucial to the conservation of biodiversity and food safety. Owing to the high number of carboxyl and phenolic hydroxyl groups in their structure, humic substances form strong bonds with heavy metals which makes them perfect stabilizing agents. The aim of this study was to determine the effects of humic and fulvic acid (HA + FA) levels (0, 3500, 5250, and 7000 mg/L) on alleviation of Cadmium (Cd) toxicity in garden cress (Lepidium sativum) contaminated with Cd (CdSO4.8H2O) (0, 100, and 200 Cd mg/kg) under greenhouse conditions. Our results showed that, Cd stress had a negative effect on the growth of garden cress, decreased leaf fresh, leaf dry, root fresh and root dry weights, leaf relative water content (LRWC), and mineral content except for Cd, and increased the membrane permeability (MP) and enzyme (CAT, SOD and POD) activity. However, the HA + FA applications decreased the adverse effects of the Cd pollution. At 200 mg/kg Cd pollution, HA + FA application at a concentration of 7000 mg/L increased the leaf fresh, leaf dry, root fresh, root dry weights, stem diameter, leaf area, chlorophyll reading value (CRV), MP, and LRWC values by 262%, 137%, 550%,133%, 92%, 104%, 34%, 537%, and 32% respectively, compared to the control. Although the highest H2O2, MDA, proline and sucrose values were obtained at 200 mg/L Cd pollution, HA + FA application at a concentration of 7000 mg/L successfully alleviated the deleterious effects of Cd stress by decreasing H2O2, MDA, proline, and sucrose values by 66%, 68%, 70%, and 56%, respectively at 200 mg/kg Cd pollution level. HA + FA application at a concentration of 7000 mg/L successfully mitigated the negative impacts of Cd pollution by enhanced N, P, K, Ca, Mg, Fe, Mn, Cu, Mn, Zn, and B by 75%, 23%, 84%, 87%, 40%, 85%, 143%, 1%, 65%, and 115%, respectively. In addition, HA + FA application at a concentration of 7000 mg/L successfully reduced Cd uptake by 95% and Cl uptake by 80%. Considering the plant growth parameters, the best results were determined when HA + FA concentration was 7000 mg/L. We have shown that, it is critical to apply a humic substance with high percentage of FA, which was 10% in this study, to mitigate the adverse effects of heavy metal stress on plant growth. In conclusion, the application of HA + FA may be suggested as an effective solution for reducing the Cd uptake of the plants by stabilizing Cd in soil and preventing translocation of Cd from the roots of plant to its shoot and leaves.
Comprehensive comparative genomics reveals over 50 phyla of free-living and pathogenic bacteria are associated with diverse members of the amoebozoa
Authors: Tekle Yonas I. , Lyttle Janae M. , Blasingame Maya G. , Wang Fang
Published: April 2021

The Amoebozoa, a group containing predominantly amoeboid unicellular protists has been shown to play an important ecological role in controlling environmental bacteria. Amoebozoans not only graze bacteria but also serve as a safe niche for bacterial replication and harbor endosymbiotic bacteria including dangerous human pathogens. Despite their importance, only a few lineages of Amoebozoa have been studied in this regard. In this research, we conducted a comprehensive genomic and transcriptomic study with expansive taxon sampling by including representatives from the three known clades of the Amoebozoa. We used culture independent whole culture and single cell genomics/transcriptomics to investigate the association of bacteria with diverse amoebozoans. Relative to current published evidence, we recovered the largest number of bacterial phyla (64) and human pathogen genera (51) associated with the Amoebozoa. Using single cell genomics/transcriptomics we were able to determine up to 24 potential endosymbiotic bacterial phyla, some potentially endosymbionts. This includes the majority of multi-drug resistant pathogens designated as major public health threats. Our study demonstrates amoebozoans are associated with many more phylogenetically diverse bacterial phyla than previously recognized. It also shows that all amoebozoans are capable of harboring far more dangerous human pathogens than presently documented, making them of primal public health concern.
Prognosis of nontuberculous mycobacterial pulmonary disease according to the method of microbiologic diagnosis
Authors: Sin Sooim , Han Seungchul , Lee Yeon Joo , Cho Young-jae , Park Jong Sun , Yoon Ho Il , Lee Choon-Taek , Lee Jae Ho
Published: April 2021

Microbiological criteria for nontuberculous mycobacterial pulmonary disease (NTM-PD) require cultures from two separate sputum or one non-sputum specimen. However, there is limited data on the progression of NTM-PD following non-sputum culture-based diagnosis. We compared the disease progression of NTM-PD diagnosed with non-sputum vs sputum cultures. We included 833 patients and divided them into sputum NTM isolation (n = 123), sputum NTM-PD (n = 558), and non-sputum NTM-PD groups (n = 152). Disease progression, defined as radiographic aggravation and therapy initiation, was compared between groups. The median observation time was 60.5 months (interquartile range, 31.4–96.0). The non-sputum NTM-PD group showed longer treatment-free survival (log-rank test; p = 0.009) and lower risk of treatment (adjusted hazard ratio [aHR] of sputum NTM-PD group, 1.36; 95% confidence interval (CI), 1.01–1.84) than the sputum NTM-PD group. The non-sputum NTM-PD group showed longer radiographic aggravation-free survival (Log-rank test; p = 0.015) and lower risk of radiographic aggravation (aHR of sputum NTM-PD group, 1.52; 95% CI, 1.06–2.19) than the sputum NTM-PD group. NTM-PD diagnosed using methods other than sputum culture showed a low risk of disease progression and progressed slower than NTM-PD diagnosed from a sputum culture. NTM-PD diagnosed using methods other than sputum culture may be a mild disease, not equivalent to NTM-PD diagnosed from sputum culture.
Machine learning, transcriptome, and genotyping chip analyses provide insights into SNP markers identifying flower color in Platycodon grandiflorus
Authors: Yu Go-Eun , Shin Younhee , Subramaniyam Sathiyamoorthy , Kang Sang-Ho , Lee Si-Myung , Cho Chuloh , Lee Seung-Sik , Kim Chang-Kug
Published: April 2021

Bellflower is an edible ornamental gardening plant in Asia. For predicting the flower color in bellflower plants, a transcriptome-wide approach based on machine learning, transcriptome, and genotyping chip analyses was used to identify SNP markers. Six machine learning methods were deployed to explore the classification potential of the selected SNPs as features in two datasets, namely training (60 RNA-Seq samples) and validation (480 Fluidigm chip samples). SNP selection was performed in sequential order. Firstly, 96 SNPs were selected from the transcriptome-wide SNPs using the principal compound analysis (PCA). Then, 9 among 96 SNPs were later identified using the Random forest based feature selection method from the Fluidigm chip dataset. Among six machines, the random forest (RF) model produced higher classification performance than the other models. The 9 SNP marker candidates selected for classifying the flower color classification were verified using the genomic DNA PCR with Sanger sequencing. Our results suggest that this methodology could be used for future selection of breeding traits even though the plant accessions are highly heterogeneous.
Cardiolipin enhances the enzymatic activity of cytochrome bd and cytochrome bo3 solubilized in dodecyl-maltoside
Authors: Asseri Amer H. , Godoy-Hernandez Albert , Goojani Hojjat Ghasemi , Lill Holger , Sakamoto Junshi , McMillan Duncan G. G. , Bald Dirk
Published: April 2021

Cardiolipin (CL) is a lipid that is found in the membranes of bacteria and the inner membranes of mitochondria. CL can increase the activity of integral membrane proteins, in particular components of respiratory pathways. We here report that CL activated detergent-solubilized cytochrome bd, a terminal oxidase from Escherichia coli. CL enhanced the oxygen consumption activity ~ twofold and decreased the apparent KM value for ubiquinol-1 as substrate from 95 µM to 35 µM. Activation by CL was also observed for cytochrome bd from two Gram-positive species, Geobacillus thermodenitrificans and Corynebacterium glutamicum, and for cytochrome bo3 from E. coli. Taken together, CL can enhance the activity of detergent-solubilized cytochrome bd and cytochrome bo3.
Sustained sustainable development actions of China from 1986 to 2020
Authors: Liu Bingsheng , Wang Tao , Zhang Jiaming , Wang Xiaoming , Chang Yuan , Fang Dongping , Yang Mengjun , Sun Xinzhang
Published: April 2021

Achieving the Sustainable Development Goals (SDGs) is a long-term task, which puts forward high requirements on the sustainability of related policies and actions. Using the text analysis method, we analyze the China National Sustainable Communities (CNSCs) policy implemented over 30 years and its effects on achieving SDGs. We find that the national government needs to understand the scope of sustainable development more comprehensively, the sustained actions can produce positive effects under the right goals. The SDGs selection of local governments is affected by local development levels and resource conditions, regions with better economic foundations tend to focus on SDGs on human well-being, regions with weaker foundations show priority to basic SDGs on the economic development, infrastructures and industrialization.
A psychometric and validity study of callous-unemotional traits in 2.5 year old children
Authors: Wright Nicola , Pickles Andrew , Sharp Helen , Hill Jonathan
Published: April 2021

Callous-unemotional (CU) traits are associated with severe and stable antisocial behaviour in childhood and adolescence. In order to understand the earliest origins of CU traits we need first to know whether measurement is reliable and valid in young children. This study evaluated the psychometric properties and validity of a CU traits measure generated from existing child problem behaviour scales at age 2.5 years. The participants were members of an epidemiological longitudinal study starting in pregnancy. Items from the Antisocial Process Screening Device and other problem behaviour scales were subjected to exploratory and confirmatory factor analysis. Structural equation modelling was used to test whether age 2.5 CU traits showed incremental validity in predicting aggression at age 5. The CU measure showed acceptable psychometric properties, factorial invariance by sex and good stability. Incremental prediction to later aggression was evident in girls, whereas boys showed strong continuity in aggression not found for girls.
Humans rely more on algorithms than social influence as a task becomes more difficult
Authors: Bogert Eric , Schecter Aaron , Watson Richard T.
Published: April 2021

Algorithms have begun to encroach on tasks traditionally reserved for human judgment and are increasingly capable of performing well in novel, difficult tasks. At the same time, social influence, through social media, online reviews, or personal networks, is one of the most potent forces affecting individual decision-making. In three preregistered online experiments, we found that people rely more on algorithmic advice relative to social influence as tasks become more difficult. All three experiments focused on an intellective task with a correct answer and found that subjects relied more on algorithmic advice as difficulty increased. This effect persisted even after controlling for the quality of the advice, the numeracy and accuracy of the subjects, and whether subjects were exposed to only one source of advice, or both sources. Subjects also tended to more strongly disregard inaccurate advice labeled as algorithmic compared to equally inaccurate advice labeled as coming from a crowd of peers.