bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Machine Learning to Estimate Statistics of the Posterior Distribution in Probabilistic Inverse Problems—An Application to Airborne EM Data
Authors: Hansen T. M. , Finlay C. C.
Published: October 2022

The solution to a probabilistic inverse problem is the posterior probability distribution for which a full analytic expression is rarely possible. Sampling methods are therefore often used to generate a sample from the posterior. Decision‐makers may be interested in the probability of features related to model parameters (e.g., existence of pollution or the cumulative clay thickness) rather than the individual realizations themselves. Such features and their associated uncertainty, are simple to compute once a sample from the posterior distribution has been generated. However, sampling methods are often associated with high computational costs, especially when the prior and posterior distribution is non‐trivial (non‐Gaussian), and when the inverse problem is non‐linear. Here we demonstrate how to use a neural network to directly estimate posterior statistics of continuous or discrete features of the posterior distribution. The method is illustrated on a probabilistic inversion of airborne EM data from Morrill Nebraska, where the forward problem is nonlinear and the prior information is non‐Gaussian. Once trained the application of the network is fast, with results similar to those obtained using much slower sampling methods.
Assimilation of Remotely Sensed Leaf Area Index Enhances the Estimation of Anthropogenic Irrigation Water Use
Authors: Nie Wanshu , Kumar Sujay V. , Peters‐Lidard Christa D. , Zaitchik Benjamin F. , Arsenault Kristi R. , Bindlish Rajat , Liu Pang‐Wei
Published: October 2022

Representation of irrigation in Earth System Models has advanced over the past decade, yet large uncertainties persist in the effective simulation of irrigation practices, particularly over locations where the on‐ground practices and climate impacts are less reliably known. Here we investigate the utility of assimilating remotely sensed vegetation data for improving irrigation water use and associated fluxes within a land surface model. We show that assimilating optical sensor‐based leaf area index estimates significantly improves the simulation of irrigation water use when compared to the USGS ground reports. For heavily irrigated areas, assimilation improves the evaporative fluxes and gross primary production (GPP) simulations, with the median correlation increasing by 0.1–1.1 and 0.3–0.6, respectively, as compared to the reference datasets. Further, bias improvements in the range of 14–35 mm mo−1 and 10–82 g m−2 mo−1 are obtained in evaporative fluxes and GPP as a result of incorporating vegetation constraints, respectively. These results demonstrate that the use of remotely sensed vegetation data is an effective, observation‐informed, globally applicable approach for simulating irrigation and characterizing its impacts on water and carbon states.
METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4
Authors: Li Mingying , Ye Jingjing , Xia Yuan , Li Meng , Li Guosheng , Hu Xiang , Su Xiuhua , Wang Dongmei , Zhao Xin , Lu Fei , Li Jingxin , Ma Daoxin , Sun Tao , Ji Chunyan
Published: October 2022

Chemoresistant leukemia relapse is one of the most common causes of death for acute myeloid leukemia (AML) patients and the homing/engraftment in bone marrow (BM) are crucial steps for AML cells to acquire chemoresistance by interacting with stromal cell components. No crosstalk between m6A modification and homing/engraftment has been reported. Here, we performed comprehensive high-throughput analyses, including RNA sequencing of CR (complete remission) and relapsed AML patients, and reverse-phase protein arrays of chemoresistant cells to identify METTL3 as a key player regulating AML chemoresistance. Then, METTL3-mediated m6A modification was proved to induce the chemoresistance in vitro and in vivo. Furthermore, AML homing/engraftment was discovered being enhanced by upregulated-METTL3 in chemoresistant cells. And the homing/engraftment and drug-resistance associated phenotypes of chemoresistant cells could be reversed by a METTL3 inhibitor. Mechanistically, METTL3 extended the half-life of ITGA4 mRNA by m6A methylation, and then, increased expression of ITGA4 protein to enhance homing/engraftment of AML cells. The results provide insights into the function of m6A modification on the interaction between AML cells and BM niches and clarify the relationship between METTL3 and AML homing/engraftment, suggesting a therapeutic strategy for the treatment of refractory/relapsed AML with METTL3 inhibitors.
Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions
Authors: Thastrup Maria , Duguid Alasdair , Mirian Christian , Schmiegelow Kjeld , Halsey Christina
Published: October 2022

Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2–3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear – we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires; (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade.
Zymosan-A promotes the regeneration of intestinal stem cells by upregulating ASCL2
Authors: Du Jicong , Fang Lan , Zhao Jianpeng , Yu Yike , Feng Zhenlan , Wang Yuedong , Cheng Ying , Li Bailong , Gao Fu , Liu Cong
Published: October 2022

Intestinal stem cells (ISCs) are responsible for intestinal tissue homeostasis and are important for the regeneration of the damaged intestinal epithelia. Through the establishment of ionizing radiation (IR) induced intestinal injury model, we found that a TLR2 agonist, Zymosan-A, promoted the regeneration of ISCs in vivo and in vitro. Zymosan-A improved the survival of abdominal irradiated mice (81.82% of mice in the treated group vs. 30% of mice in the PBS group), inhibited the radiation damage of intestinal tissue, increased the survival rate of intestinal crypts and the number of ISCs after lethal IR in vivo. Through organoid experiments, we found that Zymosan-A promoted the proliferation and differentiation of ISCs after IR. Remarkably, the results of RNA sequencing and Western Blot (WB) showed that Zymosan-A reduced IR-induced intestinal injury via TLR2 signaling pathway and Wnt signaling pathway and Zymosan-A had no radioprotection on TLR2 KO mice, suggesting that Zymosan-A may play a radioprotective role by targeting TLR2. Moreover, our results revealed that Zymosan-A increased ASCL2, a transcription factor of ISCs, playing a core role in the process of Zymosan-A against IR-induced intestinal injury and likely contributing to the survival of intestinal organoids post-radiation. In conclusion, we demonstrated that Zymosan-A promotes the regeneration of ISCs by upregulating ASCL2.
Atomic resolution protein allostery from the multi-state structure of a PDZ domain
Authors: Ashkinadze Dzmitry , Kadavath Harindranath , Pokharna Aditya , Chi Celestine N. , Friedmann Michael , Strotz Dean , Kumari Pratibha , Minges Martina , Cadalbert Riccardo , Königl Stefan , Güntert Peter , Vögeli Beat , Riek Roland
Published: October 2022

Recent methodological advances in solution NMR allow the determination of multi-state protein structures and provide insights into structurally and dynamically correlated protein sites at atomic resolution. This is demonstrated in the present work for the well-studied PDZ2 domain of protein human tyrosine phosphatase 1E for which protein allostery had been predicted. Two-state protein structures were calculated for both the free form and in complex with the RA-GEF2 peptide using the exact nuclear Overhauser effect (eNOE) method. In the apo protein, an allosteric conformational selection step comprising almost 60% of the domain was detected with an “open” ligand welcoming state and a “closed” state that obstructs the binding site by changing the distance between the β-sheet 2, α-helix 2, and sidechains of residues Lys38 and Lys72. The observed induced fit-type apo-holo structural rearrangements are in line with the previously published evolution-based analysis covering ~25% of the domain with only a partial overlap with the protein allostery of the open form. These presented structural studies highlight the presence of a dedicated highly optimized and complex dynamic interplay of the PDZ2 domain owed by the structure-dynamics landscape.
Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape
Authors: Mangolini Maurizio , Maiques-Diaz Alba , Charalampopoulou Stella , Gerhard-Hartmann Elena , Bloehdorn Johannes , Moore Andrew , Giachetti Giorgia , Lu Junyan , Roamio Franklin Valar Nila , Chilamakuri Chandra Sekkar Reddy , Moutsopoulos Ilias , Rosenwald Andreas , Stilgenbauer Stephan , Zenz Thorsten , Mohorianu Irina , D’Santos Clive , Deaglio Silvia , Hodson Daniel J. , Martin-Subero Jose I. , Ringshausen Ingo
Published: October 2022

Hotspot mutations in the PEST-domain of NOTCH1 and NOTCH2 are recurrently identified in B cell malignancies. To address how NOTCH-mutations contribute to a dismal prognosis, we have generated isogenic primary human tumor cells from patients with Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL), differing only in their expression of the intracellular domain (ICD) of NOTCH1 or NOTCH2. Our data demonstrate that both NOTCH-paralogs facilitate immune-escape of malignant B cells by up-regulating PD-L1, partly dependent on autocrine interferon-γ signaling. In addition, NOTCH-activation causes silencing of the entire HLA-class II locus via epigenetic regulation of the transcriptional co-activator CIITA. Notably, while NOTCH1 and NOTCH2 govern similar transcriptional programs, disease-specific differences in their expression levels can favor paralog-specific selection. Importantly, NOTCH-ICD also strongly down-regulates the expression of CD19, possibly limiting the effectiveness of immune-therapies. These NOTCH-mediated immune escape mechanisms are associated with the expansion of exhausted CD8+ T cells in vivo.
Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function
Authors: Ainsworth Richard I. , Hammaker Deepa , Nygaard Gyrid , Ansalone Cecilia , Machado Camilla , Zhang Kai , Zheng Lina , Carrillo Lucy , Wildberg Andre , Kuhs Amanda , Svensson Mattias N. D. , Boyle David L. , Firestein Gary S. , Wang Wei
Published: October 2022

Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease. To tackle this challenge, we develop and apply a systems biology approach to identify important transcription factors (TFs) in individual RA fibroblast-like synoviocyte (FLS) cell lines by integrating transcriptomic and epigenomic information. Based on the relative importance of the identified TFs, we stratify the RA FLS cell lines into two subtypes with distinct phenotypes and predicted active pathways. We biologically validate these predictions for the top subtype-specific TF RARα and demonstrate differential regulation of TGFβ signaling in the two subtypes. This study characterizes clusters of RA cell lines with distinctive TF biology by integrating transcriptomic and epigenomic data, which could pave the way towards a greater understanding of disease heterogeneity.
Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression
Authors: Li Zhongchi , Low Vivien , Luga Valbona , Sun Janet , Earlie Ethan , Parang Bobak , Shobana Ganesh Kripa , Cho Sungyun , Endress Jennifer , Schild Tanya , Hu Mengying , Lyden David , Jin Wenbing , Guo Chunjun , Dephoure Noah , Cantley Lewis C. , Laughney Ashley M. , Blenis John
Published: October 2022

The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.
Low-bias photoelectrochemical water splitting via mediating trap states and small polaron hopping
Authors: Wu Hao , Zhang Lei , Du Aijun , Irani Rowshanak , van de Krol Roel , Abdi Fatwa F. , Ng Yun Hau
Published: October 2022

Metal oxides are promising for photoelectrochemical (PEC) water splitting due to their robustness and low cost. However, poor charge carrier transport impedes their activity, particularly at low-bias voltage. Here we demonstrate the unusual effectiveness of phosphorus doping into bismuth vanadate (BiVO4) photoanode for efficient low-bias PEC water splitting. The resulting BiVO4 photoanode shows a separation efficiency of 80% and 99% at potentials as low as 0.6 and 1.0 VRHE, respectively. Theoretical simulation and experimental analysis collectively verify that the record performance originates from the unique phosphorus-doped BiVO4 configuration with concurrently mediated carrier density, trap states, and small polaron hopping. With NiFeOx cocatalyst, the BiVO4 photoanode achieves an applied bias photon-to-current efficiency of 2.21% at 0.6 VRHE. The mechanistic understanding of the enhancement of BiVO4 properties provides key insights in trap state passivation and polaron hopping for most photoactive metal oxides.
Synthetic five-wave mixing in an integrated microcavity for visible-telecom entanglement generation
Authors: Wang Jia-Qi , Yang Yuan-Hao , Li Ming , Zhou Haiqi , Xu Xin-Biao , Zhang Ji-Zhe , Dong Chun-Hua , Guo Guang-Can , Zou C.-L.
Published: October 2022

Nonlinear optics processes lie at the heart of photonics and quantum optics for their indispensable role in light sources and information processing. During the past decades, the three- and four-wave mixing (χ(2) and χ(3)) effects have been extensively studied, especially in the micro-/nano-structures by which the photon-photon interaction strength is greatly enhanced. So far, the high-order nonlinearity beyond the χ(3) has rarely been studied in dielectric materials due to their weak intrinsic nonlinear susceptibility, even in high-quality microcavities. Here, an effective five-wave mixing process (χ(4)) is synthesized by incorporating χ(2) and χ(3) processes in a single microcavity. The coherence of the synthetic χ(4) is verified by generating time-energy entangled visible-telecom photon pairs, which requires only one drive laser at the telecom waveband. The photon-pair generation rate from the synthetic process shows an estimated enhancement factor over 500 times upon intrinsic five-wave mixing. Our work demonstrates a universal approach of nonlinear synthesis via photonic structure engineering at the mesoscopic scale rather than material engineering, and thus opens a new avenue for realizing high-order optical nonlinearities and exploring functional photonic devices.
Cross-linking of the endolysosomal system reveals potential flotillin structures and cargo
Authors: Singh Jasjot , Elhabashy Hadeer , Muthukottiappan Pathma , Stepath Markus , Eisenacher Martin , Kohlbacher Oliver , Gieselmann Volkmar , Winter Dominic
Published: October 2022

Lysosomes are well-established as the main cellular organelles for the degradation of macromolecules and emerging as regulatory centers of metabolism. They are of crucial importance for cellular homeostasis, which is exemplified by a plethora of disorders related to alterations in lysosomal function. In this context, protein complexes play a decisive role, regulating not only metabolic lysosomal processes but also lysosome biogenesis, transport, and interaction with other organelles. Using cross-linking mass spectrometry, we analyze lysosomes and early endosomes. Based on the identification of 5376 cross-links, we investigate protein-protein interactions and structures of lysosome- and endosome-related proteins. In particular, we present evidence for a tetrameric assembly of the lysosomal hydrolase PPT1 and a heterodimeric structure of FLOT1/FLOT2 at lysosomes and early endosomes. For FLOT1-/FLOT2-positive early endosomes, we identify >300 putative cargo proteins and confirm eleven substrates for flotillin-dependent endocytosis, including the latrophilin family of adhesion G protein-coupled receptors.
Blood monocyte-derived CD169+ macrophages contribute to antitumor immunity against glioblastoma
Authors: Kim Hyun-Jin , Park Jang Hyun , Kim Hyeon Cheol , Kim Chae Won , Kang In , Lee Heung Kyu
Published: October 2022

Infiltrating tumor-associated macrophages (TAM) are known to impede immunotherapy against glioblastoma (GBM), however, TAMs are heterogeneous, and there are no clear markers to distinguish immunosuppressive and potentially immune-activating populations. Here we identify a subset of CD169+ macrophages promoting an anti-tumoral microenvironment in GBM. Using single-cell transcriptome analysis, we find that CD169+ macrophages in human and mouse gliomas produce pro-inflammatory chemokines, leading to the accumulation of T cells and NK cells. CD169 expression on macrophages facilitates phagocytosis of apoptotic glioma cells and hence tumor-specific T cell responses. Depletion of CD169+ macrophages leads to functionally impaired antitumor lymphocytes and poorer survival of glioma-bearing mice. We show that NK-cell-derived IFN-γ is critical for the accumulation of blood monocyte-derived CD169+ macrophages in gliomas. Our work thus identifies a well-distinguished TAM subset promoting antitumor immunity against GBM, and identifies key factors that might shift the balance from immunosuppressive to anti-tumor TAM.
Large area polymer semiconductor sub-microwire arrays by coaxial focused electrohydrodynamic jet printing for high-performance OFETs
Authors: Wang Dazhi , Lu Liangkun , Zhao Zhiyuan , Zhao Kuipeng , Zhao Xiangyu , Pu Changchang , Li Yikang , Xu Pengfei , Chen Xiangji , Guo Yunlong , Suo Liujia , Liang Junsheng , Cui Yan , Liu Yunqi
Published: October 2022

Large area and highly aligned polymer semiconductor sub-microwires were fabricated using the coaxial focused electrohydrodynamic jet printing technology. As indicated by the results, the sub-microwire arrays have smooth morphology, well reproducibility and controllable with a width of ~110 nm. Analysis shows that the molecular chains inside the sub-microwires mainly exhibited edge-on arrangement and the π-stacking direction (010) of the majority of crystals is parallel to the long axis of the sub-microwires. Sub-microwires based organic field effect transistors showed high mobility with an average of 1.9 cm2 V−1 s−1, approximately 5 times higher than that of thin film based organic field effect transistors. In addition, the number of sub-microwires can be conveniently controlled by the printing technique, which can subsequently concisely control the performance of organic field effect transistors. This work demonstrates that sub-microwires fabricated by the coaxial focused electrohydrodynamic jet printing technology create an alternative path for the applications of high-performance organic flexible device.
RNA G-quadruplex structure contributes to cold adaptation in plants
Authors: Yang Xiaofei , Yu Haopeng , Duncan Susan , Zhang Yueying , Cheema Jitender , Liu Haifeng , Benjamin Miller J. , Zhang Jie , Kwok Chun Kit , Zhang Huakun , Ding Yiliang
Published: October 2022

Nucleotide composition is suggested to infer gene functionality and ecological adaptation of species to distinct environments. However, the underlying biological function of nucleotide composition dictating environmental adaptations is largely unknown. Here, we systematically analyze the nucleotide composition of transcriptomes across 1000 plants (1KP) and their corresponding habitats. Intriguingly, we find that plants growing in cold climates have guanine (G)-enriched transcriptomes, which are prone to forming RNA G-quadruplex structures. Both immunofluorescence detection and in vivo structure profiling reveal that RNA G-quadruplex formation in plants is globally enhanced in response to cold. Cold-responsive RNA G-quadruplexes strongly enhanced mRNA stability, rather than affecting translation. Disruption of individual RNA G-quadruplex promotes mRNA decay in the cold, leading to impaired plant cold response. Therefore, we propose that plants adopted RNA G-quadruplex structure as a molecular signature to facilitate their adaptation to the cold during evolution.
The salivary microbiome shows a high prevalence of core bacterial members yet variability across human populations
Authors: Ruan Xinwei , Luo Jiaqiang , Zhang Pangzhen , Howell Kate
Published: October 2022

Human saliva contains diverse bacterial communities, reflecting health status, dietary patterns and contributing to variability in the sensory perception of food. Many descriptions of the diversity of the salivary microbiome have focused on the changes induced by certain diseased states, but the commonalities and differences within healthy saliva have not been fully described. Here, we define and explore the core membership of the human salivary microbial community by collecting and re-analysing raw 16S rRNA amplicon sequencing data from 47 studies with 2206 saliva samples. We found 68 core bacterial taxa that were consistently detected. Differences induced by various host intrinsic and behaviour factors, including gender, age, geographic location, tobacco usage and alcohol consumption were evident. The core of the salivary microbiome was verified by collecting and analysing saliva in an independent study. These results suggest that the methods used can effectively define a core microbial community in human saliva. The core salivary microbiome demonstrated both stability and variability among populations. Geographic location was identified as the host factor that is most associated with the structure of salivary microbiota. The independent analysis confirmed the prevalence of the 68 core OTUs we defined from the global data and provides information about how bacterial taxa in saliva varies across human populations.
Biallelic variants in coenzyme Q10 biosynthesis pathway genes cause a retinitis pigmentosa phenotype
Authors: Jurkute Neringa , Cancellieri Francesca , Pohl Lisa , Li Catherina H. Z. , Heaton Robert A. , Reurink Janine , Bellingham James , Quinodoz Mathieu , Yioti Georgia , Stefaniotou Maria , Weener Marianna , Zuleger Theresia , Haack Tobias B. , Stingl Katarina ,   Genomics England Research Consortium, Ambrose J. C. , Arumugam P. , Bevers R. , Bleda M. , Boardman-Pretty F. , Boustred C. R. , Brittain H. , Brown M. A. , Caulfield M. J. , Chan G. C. , Giess A. , Griffin J. N. , Hamblin A. , Henderson S. , Hubbard T. J. P. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Kousathanas A. , Lahnstein L. , Lakey A. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , McEntagart M. , Minneci F. , Mitchell J. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , O‘Donovan P. , Odhams C. A. , Patch C. , Perez-Gil D. , Pereira M. B. , Pullinger J. , Rahim T. , Rendon A. , Rogers T. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smith S. C. , Sosinsky A. , Stuckey A. , Tanguy M. , Taylor Tavares A. L. , Thomas E. R. A. , Thompson S. R. , Tucci A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Zarowiecki M. , Hoyng Carel B. , Mahroo Omar A. , Hargreaves Iain , Raymond F. Lucy , Michaelides Michel , Rivolta Carlo , Kohl Susanne , Roosing Susanne , Webster Andrew R. , Arno Gavin
Published: October 2022

The aim of this study was to investigate coenzyme Q10 (CoQ10) biosynthesis pathway defects in inherited retinal dystrophy. Individuals affected by inherited retinal dystrophy (IRD) underwent exome or genome sequencing for molecular diagnosis of their condition. Following negative IRD gene panel analysis, patients carrying biallelic variants in CoQ10 biosynthesis pathway genes were identified. Clinical data were collected from the medical records. Haplotypes harbouring the same missense variant were characterised from family genome sequencing (GS) data and direct Sanger sequencing. Candidate splice variants were characterised using Oxford Nanopore Technologies single molecule sequencing. The CoQ10 status of the human plasma was determined in some of the study patients. 13 individuals from 12 unrelated families harboured candidate pathogenic genotypes in the genes: PDSS1, COQ2, COQ4 and COQ5. The PDSS1 variant c.589 A > G was identified in three affected individuals from three unrelated families on a possible ancestral haplotype. Three variants (PDSS1 c.468-25 A > G, PDSS1 c.722-2 A > G, COQ5 c.682-7 T > G) were shown to lead to cryptic splicing. 6 affected individuals were diagnosed with non-syndromic retinitis pigmentosa and 7 had additional clinical findings. This study provides evidence of CoQ10 biosynthesis pathway gene defects leading to non-syndromic retinitis pigmentosa in some cases. Intronic variants outside of the canonical splice-sites represent an important cause of disease. RT-PCR nanopore sequencing is effective in characterising these splice defects.
Diverse MarR bacterial regulators of auxin catabolism in the plant microbiome
Authors: Conway Jonathan M. , Walton William G. , Salas-González Isai , Law Theresa F. , Lindberg Chloe A. , Crook Laura E. , Kosina Suzanne M. , Fitzpatrick Connor R. , Lietzan Adam D. , Northen Trent R. , Jones Corbin D. , Finkel Omri M. , Redinbo Matthew R. , Dangl Jeffery L.
Published: October 2022

Chemical signalling in the plant microbiome can have drastic effects on microbial community structure, and on host growth and development. Previously, we demonstrated that the auxin metabolic signal interference performed by the bacterial genus Variovorax via an auxin degradation locus was essential for maintaining stereotypic root development in an ecologically relevant bacterial synthetic community. Here, we dissect the Variovorax auxin degradation locus to define the genes iadDE as necessary and sufficient for indole-3-acetic acid (IAA) degradation and signal interference. We determine the crystal structures and binding properties of the operon’s MarR-family repressor with IAA and other auxins. Auxin degradation operons were identified across the bacterial tree of life and we define two distinct types on the basis of gene content and metabolic products: iac-like and iad-like. The structures of MarRs from representatives of each auxin degradation operon type establish that each has distinct IAA-binding pockets. Comparison of representative IAA-degrading strains from diverse bacterial genera colonizing Arabidopsis plants show that while all degrade IAA, only strains containing iad-like auxin-degrading operons interfere with auxin signalling in a complex synthetic community context. This suggests that iad-like operon-containing bacterial strains, including Variovorax species, play a key ecological role in modulating auxins in the plant microbiome.
Improved AlphaFold modeling with implicit experimental information
Authors: Terwilliger Thomas C. , Poon Billy K. , Afonine Pavel V. , Schlicksup Christopher J. , Croll Tristan I. , Millán Claudia , Richardson Jane. S. , Read Randy J. , Adams Paul D.
Published: October 2022

Machine-learning prediction algorithms such as AlphaFold and RoseTTAFold can create remarkably accurate protein models, but these models usually have some regions that are predicted with low confidence or poor accuracy. We hypothesized that by implicitly including new experimental information such as a density map, a greater portion of a model could be predicted accurately, and that this might synergistically improve parts of the model that were not fully addressed by either machine learning or experiment alone. An iterative procedure was developed in which AlphaFold models are automatically rebuilt on the basis of experimental density maps and the rebuilt models are used as templates in new AlphaFold predictions. We show that including experimental information improves prediction beyond the improvement obtained with simple rebuilding guided by the experimental data. This procedure for AlphaFold modeling with density has been incorporated into an automated procedure for interpretation of crystallographic and electron cryo-microscopy maps.
The Immune Signatures data resource, a compendium of systems vaccinology datasets
Authors: Diray-Arce Joann , Miller Helen E. R. , Henrich Evan , Gerritsen Bram , Mulè Matthew P. , Fourati Slim , Gygi Jeremy , Hagan Thomas , Tomalin Lewis , Rychkov Dmitry , Kazmin Dmitri , Chawla Daniel G. , Meng Hailong , Dunn Patrick , Campbell John ,   The Human Immunology Project Consortium (HIPC), Deckhut-Augustine Alison , Gottardo Raphael , Haddad Elias K. , Hafler David A. , Harris Eva , Farber Donna , Levy Ofer , McElrath Julie , Montgomery Ruth R. , Peters Bjoern , Rahman Adeeb , Reed Elaine F. , Rouphael Nadine , Fernandez-Sesma Ana , Sette Alessandro , Stuart Ken , Togias Alkis , Tsang John S. , Sarwal Minnie , Tsang John S. , Levy Ofer , Pulendran Bali , Sekaly Rafick , Floratos Aris , Gottardo Raphael , Kleinstein Steven H. , Suárez-Fariñas Mayte
Published: October 2022

Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern ‘omic profiling techniques and computational modeling to promote rapid and transformative advances in vaccinology and vaccine discovery. The NIH/NIAID Human Immunology Project Consortium (HIPC) has leveraged systems immunology approaches to identify molecular signatures associated with the immunogenicity of many vaccines. However, comparative analyses have been limited by the distributed nature of some data, potential batch effects across studies, and the absence of multiple relevant studies from non-HIPC groups in ImmPort. To support comparative analyses across different vaccines, we have created the Immune Signatures Data Resource, a compendium of standardized systems vaccinology datasets. This data resource is available through ImmuneSpace, along with code to reproduce the processing and batch normalization starting from the underlying study data in ImmPort and the Gene Expression Omnibus (GEO). The current release comprises 1405 participants from 53 cohorts profiling the response to 24 different vaccines. This novel systems vaccinology data release represents a valuable resource for comparative and meta-analyses that will accelerate our understanding of mechanisms underlying vaccine responses.
Novel metallomic profiling and non-carcinogenic risk assessment of botanical ingredients for use in herbal, phytopharmaceutical and dietary products using HR-ICP-SFMS
Authors: Kenny Ciara-Ruth , Ring Gavin , Sheehan Aisling , Mc Auliffe Michael A. P. , Lucey Brigid , Furey Ambrose
Published: October 2022

Knowledge of element concentrations in botanical extracts is relevant to assure consumer protection given the increased interest in plant-based ingredients. This study demonstrates successful multi-element investigations in order to address the lack of comprehensive profiling data for botanical extracts, while reporting for the first time the metallomic profile(s) of arnica, bush vetch, sweet cicely, yellow rattle, bogbean, rock-tea and tufted catchfly. Key element compositions were quantified using a validated HR-ICP-SFMS method (µg kg−1) and were found highly variable between the different plants: Lithium (18–3964); Beryllium (3–121); Molybdenum (75–4505); Cadmium (5–325); Tin (6–165); Barium (747–4646); Platinum (2–33); Mercury (5–30); Thallium (3–91); Lead (12–4248); Bismuth (2–30); Titanium (131–5827); Vanadium (15–1758); Chromium (100–4534); Cobalt (21–652); Nickel (230–6060) and Copper (1910–6340). Compendial permissible limits were not exceeded. Overall, no evidence of a health risk to consumers could be determined from consumption of the investigated plants at reasonable intake rates. Mathematical risk modelling (EDI, CDI, HQ, HI) estimated levels above safe oral thresholds only for Cd (16%) and Pb (8%) from higher intakes of the respective plant-derived material. Following high consumption of certain plants, 42% of the samples were categorised as potentially unsafe due to cumulative exposure to Cu, Cd, Hg and Pb. PCA suggested a potential influence of post-harvest processing on Cr, Ti and V levels in commercially-acquired plant material compared to wild-collected and farm-grown plants. Moreover, a strong correlation was observed between Pb-Bi, Be-V, Bi-Sn, and Tl-Mo occurrence. This study may support future research by providing both robust methodology and accompanying reference profile(s) suitable for the quality evaluation of essential elements and/or metal contaminants in botanical ingredients.
Abstract and concrete concepts in conversation
Authors: Villani Caterina , Orsoni Matteo , Lugli Luisa , Benassi Mariagrazia , Borghi Anna M.
Published: October 2022

Concepts allow us to make sense of the world. Most evidence on their acquisition and representation comes from studies of single decontextualized words and focuses on the opposition between concrete and abstract concepts (e.g., “bottle” vs. “truth”). A significant step forward in research on concepts consists in investigating them in online interaction during their use. Our study examines linguistic exchanges analyzing the differences between sub-kinds of concepts. Participants were submitted to an online task in which they had to simulate a conversational exchange by responding to sentences involving sub-kinds of concrete (tools, animals, food) and abstract concepts (PS, philosophical-spiritual; EMSS, emotional-social, PSTQ, physical-spatio-temporal-quantitative). We found differences in content: foods evoked interoception; tools and animals elicited materials, spatial, auditive features, confirming their sensorimotor grounding. PS and EMSS yielded inner experiences (e.g., emotions, cognitive states, introspections) and opposed PSTQ, tied to visual properties and concrete agency. More crucially, the various concepts elicited different interactional dynamics: more abstract concepts generated higher uncertainty and more interactive exchanges than concrete ones. Investigating concepts in situated interactions opens new possibilities for studying conceptual knowledge and its pragmatic and social aspects.
Remnant cholesterol levels are associated with severity and death in COVID-19 patients
Authors: Fabre Bibiana , Fernandez Machulsky Nahuel , Olano Carolina , Jacobsen Darío , Gómez María Eugenia , Perazzi Beatriz , Zago Valeria , Zopatti Damián , Ferrero Andrés , Schreier Laura , Berg Gabriela
Published: October 2022

Coronavirus disease-19 (COVID-19) patients with severe complications present comorbidities like cardiovascular-disease, hypertension and type-2 diabetes mellitus (DM), sharing metabolic alterations like insulin resistance (IR) and dyslipidemia. Our objective was to evaluate the association among different components of the lipid-lipoprotein profile, such as remnant lipoprotein (RLP)-cholesterol, in patients with COVID-19, and to analyze their associations with the severity of the disease and death. We studied 193 patients (68 (29–96) years; 49.7% male) hospitalized for COVID-19 and 200 controls (46 (18–79) years; 52.5% male). Lipoprotein profile, glucose and procalcitonin were assessed. Patients presented higher glucose, TG, TG/HDL-cholesterol and RLP-cholesterol levels, but lower total, LDL, HDL and no-HDL-cholesterol levels (p < 0.001). When a binary logistic regression was performed, age, non-HDL-cholesterol, and RLP-cholesterol were associated with death (p = 0.005). As the COVID-19 condition worsened, according to procalcitonin tertiles, a decrease in all the cholesterol fractions (p < 0.03) was observed with no differences in TG, while levels of RLP-cholesterol and TG/HDL-cholesterol increased (p < 0.001). Lower levels of all the cholesterol fractions were related with the presence and severity of COVID-19, except for RLP-cholesterol levels and TG/HDL-cholesterol index. These alterations indicate a lipid metabolic disorder, characteristic of IR states in COVID-19 patients. RLP-cholesterol levels predicted severity and death in these patients.
Angiogenic stem cell delivery platform to augment post-infarction neovasculature and reverse ventricular remodeling
Authors: Shin Hye Sook , Thakore Akshara , Tada Yuko , Pedroza Albert J. , Ikeda Gentaro , Chen Ian Y. , Chan Doreen , Jaatinen Kevin J. , Yajima Shin , Pfrender Eric M. , Kawamura Masashi , Yang Phillip C. , Wu Joseph C. , Appel Eric A. , Fischbein Michael P. , Woo YJoseph , Shudo Yasuhiro
Published: October 2022

Many cell-based therapies are challenged by the poor localization of introduced cells and the use of biomaterial scaffolds with questionable biocompatibility or bio-functionality. Endothelial progenitor cells (EPCs), a popular cell type used in cell-based therapies due to their robust angiogenic potential, are limited in their therapeutic capacity to develop into mature vasculature. Here, we demonstrate a joint delivery of human-derived endothelial progenitor cells (EPC) and smooth muscle cells (SMC) as a scaffold-free, bi-level cell sheet platform to improve ventricular remodeling and function in an athymic rat model of myocardial infarction. The transplanted bi-level cell sheet on the ischemic heart provides a biomimetic microenvironment and improved cell–cell communication, enhancing cell engraftment and angiogenesis, thereby improving ventricular remodeling. Notably, the increased density of vessel-like structures and upregulation of biological adhesion and vasculature developmental genes, such as Cxcl12 and Notch3, particularly in the ischemic border zone myocardium, were observed following cell sheet transplantation. We provide compelling evidence that this SMC-EPC bi-level cell sheet construct can be a promising therapy to repair ischemic cardiomyopathy.
The nephroprotective action of Passiflora edulis in streptozotocin-induced diabetes
Authors: Araújo Galdino Ony , de Souza Gomes Iago , Ferreira de Almeida Júnior Renato , Conceição Ferreira de Carvalho Maria Imaculada , Abreu Bento João , Abbott Galvão Ururahy Marcela , Cabral Barbara , Zucolotto Langassner Silvana Maria , Costa de Souza Karla Simone , Augusto de Rezende Adriana
Published: October 2022

In the present study, we aimed to evaluate the therapeutic effect of Passiflora edulis fruit peel aqueous (AFA) extract as an adjuvant to insulin to confer nephroprotection against streptozotocin-induced diabetes. Male Wistar rats were divided into four groups based on treatment received for 60 days: diabetic (DB), control (CTL), insulin (INS), and insulin + AFA extract (INS + AFA). mRNA and protein expression levels of podocyte (nephrin, podocin, and WT1) and tubular (megalin) proteins were measured in kidney tissue specimens and urine. Biochemical parameters and kidney histopathology were also examined. Herein, the INS + AFA group showed superior glycemic control, which resulted in the reduction of urinary albumin/creatinine ratio, maintenance of baseline levels of Nphs1, Nphs2, Wt1, and Lrp2 mRNA expression, prevention of protein loss from the kidney tissue into the urinary space, along with the maintenance of glomerular basement membrane thickness, hyalinization, glomerular and tubulointerstitial fibrosis at values approximating those of the CTL group and significantly lower than those in the DB group. Therefore, these results suggest that, as an anti-diabetic agent, the AFA extract adjuvant to insulin could reduce and potentially prevent diabetic kidney disease.
Tactile facilitation during actual and mere expectation of object reception
Authors: Manzone Damian M. , Tremblay Luc , Chua Romeo
Published: October 2022

During reaching and grasping movements tactile processing is typically suppressed. However, during a reception or catching task, the object can still be acquired but without suppressive processes related to movement execution. Rather, tactile information may be facilitated as the object approaches in anticipation of object contact and the utilization of tactile feedback. Therefore, the current study investigated tactile processing during a reception task. Participants sat with their upper limb still as an object travelled to and contacted their fingers. At different points along the object’s trajectory and prior to contact, participants were asked to detect tactile stimuli delivered to their index finger. To understand if the expectation of object contact contributed to any modulation in tactile processing, the object stopped prematurely on 20% of trials. Compared to a pre-object movement baseline, relative perceptual thresholds were decreased throughout the object’s trajectory, and even when the object stopped prematurely. Further, there was no evidence for modulation when the stimulus was presented shortly before object contact. The former results suggest that tactile processing is facilitated as an object approaches an individual’s hand. As well, we purport that the expectation of tactile feedback drives this modulation. Finally, the latter results suggest that peripheral masking may have reduced/abolished any facilitation.
Comparison of the inhibitory effect of tocilizumab and etanercept on the progression of joint erosion in rheumatoid arthritis treatment
Authors: Hayashi Shinya , Matsubara Tsukasa , Maeda Toshihisa , Fukuda Koji , Funahashi Keiko , Hashimoto Marowa , Tsumiyama Ken , Kamenaga Tomoyuki , Takashima Yoshinori , Matsumoto Tomoyuki , Tachibana Shotaro , Kuroda Ryosuke
Published: October 2022

We compared the efficacy of tocilizumab and etanercept in inhibiting radiographic progression of joint destruction in rheumatoid arthritis. Overall, 187 patients treated with etanercept or tocilizumab were selected. To adjust for baseline patient characteristics between the tocilizumab and etanercept treatment groups, a propensity score matching was performed. Radiographic progression of joint destruction was compared between patients treated with tocilizumab or etanercept. Clinical disease activity index (CDAI) and modified health assessment questionnaire (mHAQ) scores at the administration of biologic treatment and after 12 months of tocilizumab and etanercept therapy were measured and compared to radiographical parameters between the groups. Levels of C-reactive protein (CRP), matrix metalloproteinase-3 (MMP-3), CDAI, and mHAQ scores improved after 12 months of treatment in the two groups. Proportion of patients with no Sharp erosion score progression was significantly higher with tocilizumab treatment than with etanercept treatment (p = 0.032). Multivariate analysis demonstrated that Sharp erosion score was significantly associated with baseline CDAI (odds ratio, 1.05; 95% confidence interval, 1.003–1.099, p = 0.037). Tocilizumab treatment suppressed joint erosion progression compared to etanercept, and the progression correlated with baseline CDAI.
Seismic velocity changes in the Groningen reservoir associated with distant drilling
Authors: Zhou Wen , Paulssen Hanneke
Published: October 2022

In this study, we show that passively recorded data of nearby passing trains by a deep borehole geophone array could be linked to fluctuations of the gas-water contact in the Groningen reservoir in The Netherlands. During a period of 1.5 months, changes of inter-geophone P-wave travel times were detected by deconvolution interferometry of the recorded train signals. P-to-S converted waves, obtained by deconvolution of the horizontal component by the vertical component at individual geophones, showed simultaneous variations. The observed travel-time changes could be related to fluctuations of the gas-water contact in the observation well caused by pressure variations at a well drilling 4.5 km away. The $$\sim$$
∼
3.5 day delay between drilling in the reservoir and the seismic response yields a hydraulic diffusivity of approximately 5 m$$^2$$

2

/s and suggests that the pressure front is effectively propagated over such a long distance. Our observations illustrate that downhole geophone arrays can be used to monitor changes in the subsurface if repeating noise sources are available, and that unexpected effects may occur due to drilling.