bluuebunny/crossref_metadata_2025 huggingface dataset:
Extratropical Low‐Frequency Variability With ENSO Forcing: A Reduced‐Order Coupled Model Study
Authors: Vannitsem Stéphane , Demaeyer Jonathan , Ghil Michael
Published: May 2021

The impact of the El Niño‐Southern Oscillation (ENSO) on the extratropics is investigated in an idealized, reduced‐order model that has a tropical and an extratropical module. Unidirectional ENSO forcing is used to mimick the atmospheric bridge between the tropics and the extratropics. The variability of the coupled ocean‐atmosphere extratropical module is then investigated through the analysis of its pullback attractors (PBAs). This analysis focuses on two types of ENSO forcing generated by the tropical module, one periodic and the other aperiodic. For a substantial range of the ENSO forcing, two chaotic PBAs are found to coexist for the same set of parameter values. Different types of extratropical low‐frequency variability (LFV) are associated with either PBA over the parameter ranges explored. For periodic ENSO forcing, the coexisting PBAs exhibit only weak nonlinear instability. For chaotic forcing, though, they are quite unstable and certain extratropical perturbations induce transitions between the two PBAs. These distinct stability properties may have profound consequences for extratropical climate predictions: in particular, ensemble averaging may no longer help isolate the LFV signal.
The balance between the intronic miR-342 and its host gene Evl determines hematopoietic cell fate decision
Authors: Herbst Friederike , Lang Tonio J. L. , Eckert Elias S. P. , Wünsche Peer , Wurm Alexander A. , Kindinger Tim , Laaber Karin , Hemmati Shayda , Hotz-Wagenblatt Agnes , Zavidij Oksana , Paruzynski Anna , Lu Junyan , von Kalle Christof , Zenz Thorsten , Klein Christoph , Schmidt Manfred , Ball Claudia R. , Glimm Hanno
Published: May 2021

Protein-coding and non-coding genes like miRNAs tightly control hematopoietic differentiation programs. Although miRNAs are frequently located within introns of protein-coding genes, the molecular interplay between intronic miRNAs and their host genes is unclear. By genomic integration site mapping of gamma-retroviral vectors in genetically corrected peripheral blood from gene therapy patients, we identified theEVL/MIR342gene locus as a hotspot for therapeutic vector insertions indicating its accessibility and expression in human hematopoietic stem and progenitor cells. We therefore asked if and how EVL and its intronic miRNA-342 regulate hematopoiesis. Here we demonstrate that overexpression (OE) of Evl in murine primary Lin−Sca1+cKit+cells drives lymphopoiesis whereas miR-342 OE increases myeloid colony formation in vitro and in vivo, going along with a profound upregulation of canonical pathways essential for B-cell development or myelopoietic functions upon Evl or miR-342 OE, respectively. Strikingly, miR-342 counteracts its host gene by targeting lymphoid signaling pathways, resulting in reduced pre-B-cell output. Moreover, EVL overexpression is associated with lymphoid leukemia in patients. In summary, our data show that one common gene locus regulates distinct hematopoietic differentiation programs depending on the gene product expressed, and that the balance between both may determine hematopoietic cell fate decision.
Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq
Authors: Saygin Caner , Hu Eileen , Zhang Pu , Sher Steven , Lozanski Arletta , Doong Tzyy-Jye , Nicolet Deedra , Orwick Shelley , Labanowska Jadwiga , Skinner Jordan N. , Cempre Casey , Kauffman Tierney , Goettl Virginia M. , Heerema Nyla A. , Abruzzo Lynne , Miller Cecelia , Lapalombella Rosa , Behbehani Gregory , Mims Alice S. , Larkin Karilyn , Grieselhuber Nicole , Walker Alison , Bhatnagar Bhavana , Bloomfield Clara D. , Byrd John C. , Lozanski Gerard , Blachly James S.
Published: May 2021

Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease.
SFRP2 induces a mesenchymal subtype transition by suppression of SOX2 in glioblastoma
Authors: Guo Min , Goudarzi Kaveh M. , Abedi Shiva , Pieber Melanie , Sjöberg Elin , Behnan Jinan , Zhang Xing-Mei , Harris Robert A. , Bartek Jiri , Lindström Mikael S. , Nistér Monica , Hägerstrand Daniel
Published: May 2021

Intratumoral heterogeneity is a characteristic of glioblastomas that contain an intermixture of cell populations displaying different glioblastoma subtype gene expression signatures. Proportions of these populations change during tumor evolution, but the occurrence and regulation of glioblastoma subtype transition is not well described. To identify regulators of glioblastoma subtypes we utilized a combination of in vitro experiments and in silico analyses, using experimentally generated as well as publicly available data. Through this combined approach SOX2 was identified to confer a proneural glioblastoma subtype gene expression signature. SFRP2 was subsequently identified as aSOX2-antagonist, able to induce a mesenchymal glioblastoma subtype signature. A subset of patient glioblastoma samples with highSFRP2and lowSOX2expression was particularly enriched with mesenchymal subtype samples. Phenotypically, SFRP2 decreased tumor sphere formation, stemness as assessed by limiting dilution assay, and overall cell proliferation but increased cell motility, whereas SOX2 induced the opposite effects. Furthermore, an SFRP2/non-canonical-WNT/KLF4/PDGFR/phospho-AKT/SOX2 signaling axis was found to be involved in the mesenchymal transition. Analysis of human tumor tissue spatial gene expression patterns showed distinct expression ofSFRP2- and SOX2-correlated genes in vascular and cellular areas, respectively. Finally, conditioned media from SFRP2 overexpressing cells increased CD206 on macrophages. Together, these findings present SFRP2 as a SOX2-antagonist with the capacity to induce a mesenchymal subtype transition in glioma cells located in vascular tumor areas, highlighting its role in glioblastoma tumor evolution and intratumoral heterogeneity.
Facilitating improvements in young people’s social relationships to prevent or treat depression: A review of empirically supported interventions
Authors: Filia Kate , Eastwood Oliver , Herniman Sarah , Badcock Paul
Published: May 2021

Interpersonal difficulties are often implicated in the onset of depressive disorders, and typically exacerbate depressive symptoms. This is particularly true for young people, given rapid changes in, and the increased importance of, their social relationships. The purpose of this narrative review was to identify empirically supported interventions that aim to prevent or treat depression in young people by facilitating improvements in their social environment. We conducted a search of controlled trials, systematic reviews and meta-analyses of such interventions, published between 1980 and June 2020. Our literature search and interpretation of results was informed by consultations with clinical experts and youth consumers and advocates. A number of promising approaches were identified with respect to prevention and treatment. Preliminary evidence was identified suggesting that school- and Internet-based approaches present a viable means to prevent the worsening of depressive symptoms in young people. Notably, delivering interpersonal psychotherapy—adolescent skills training (IPT-AST) in schools appears to be a promising early intervention strategy for young people at risk of full-threshold depressive disorder. In terms of treating depressive disorders in young people, there is strong evidence for the efficacy of interpersonal psychotherapy for adolescents (IPT-A), and preliminary evidence in favour of attachment-based family therapy (ABFT). Results are discussed with respect to recommendations for future research and practice.
Increased GFAP concentrations in the cerebrospinal fluid of patients with unipolar depression
Authors: Michel Maike , Fiebich Bernd L. , Kuzior Hanna , Meixensberger Sophie , Berger Benjamin , Maier Simon , Nickel Kathrin , Runge Kimon , Denzel Dominik , Pankratz Benjamin , Schiele Miriam A. , Domschke Katharina , van Elst Ludger Tebartz , Endres Dominique
Published: May 2021

Inflammatory processes involving altered microglial activity may play a relevant role in the pathophysiology of depressive disorders. Glial fibrillary acidic protein (GFAP) and calcium-binding protein S100B are considered microglial markers. To date, their role has been studied in the serum and tissue material of patients with unipolar depression but not in the cerebrospinal fluid (CSF). Therefore, the aim of the current study was to examine GFAP and S100B levels in the CSF of patients with major depression to better understand their role in affective disorders. In this retrospective study, 102 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension were investigated. GFAP and S100B levels were measured using commercially available ELISA kits. CSF routine parameters were collected during routine clinical care. The mean values of GFAP and S100B were compared using age (and sex) corrected ANOVAs. Matched subgroups were analyzed by using an independent sample t-test. In addition, correlation analyses between GFAP/S100B levels and CSF routine parameters were performed within the patient group. Patients with unipolar depression had significantly higher levels of GFAP than controls (733.22 pg/ml vs. 245.56 pg/ml, p < 0.001). These results remained significant in a sub-analysis in which all controls were compared with patients suffering from depression matched 1:1 by age and sex (632.26 pg/ml vs. 245.56 pg/ml, p < 0.001). Levels of S100B did not differ significantly between patients and controls (1.06 ng/ml vs. 1.17 ng/ml, p = 0.385). GFAP levels correlated positively with albumin quotients (p < 0.050), S100B levels correlated positively with white blood cell counts (p = 0.001), total protein concentrations (p < 0.001), and albumin quotients (p = 0.001) in the CSF. The significance of the study is limited by its retrospective and open design, methodological aspects, and the control group with idiopathic intracranial hypertension. In conclusion, higher GFAP levels in patients with depression may be indicative of altered microglia activity, especially in astrocytes, in patients with unipolar depression. In addition, correlation analyses support the idea that S100B levels could be related to the integrity of the blood–brain/CSF barrier. Further multimodal and longitudinal studies are necessary to validate these findings and clarify the underlying biological processes.
Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial
Authors: Puig Noemi , Hernández Miguel T. , Rosiñol Laura , González Esther , de Arriba Felipe , Oriol Albert , González-Calle Verónica , Escalante Fernando , de la Rubia Javier , Gironella Mercedes , Ríos Rafael , García-Sánchez Ricarda , Arguiñano José M. , Alegre Adrián , Martín Jesús , Gutiérrez Norma. C. , Calasanz María J. , Martín María L. , Couto María del Carmen , Casanova María , Arnao Mario , Pérez-Persona Ernesto , Garzón Sebastián , González Marta S. , Martín-Sánchez Guillermo , Ocio Enrique M. , Coleman Morton , Encinas Cristina , Vale Ana M. , Teruel Ana I. , Cortés-Rodríguez María , Paiva Bruno , Cedena M. Teresa , San-Miguel Jesús F. , Lahuerta Juan J. , Bladé Joan , Niesvizky Ruben , Mateos María-Victoria
Published: May 2021

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0–54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3–4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene.
IL-26 mediates epidermal growth factor receptor-tyrosine kinase inhibitor resistance through endoplasmic reticulum stress signaling pathway in triple-negative breast cancer cells
Authors: Itoh Takumi , Hatano Ryo , Horimoto Yoshiya , Yamada Taketo , Song Dan , Otsuka Haruna , Shirakawa Yuki , Mastuoka Shuji , Iwao Noriaki , Aune Thomas M. , Dang Nam H. , Kaneko Yutaro , Okumura Ko , Morimoto Chikao , Ohnuma Kei
Published: May 2021

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other breast cancer subtypes. Although epidermal growth factor receptor (EGFR) is overexpressed in TNBC, clinical trials with EGFR inhibitors including tyrosine kinase inhibitors (EGFR-TKI) in TNBC have heretofore been unsuccessful. To develop effective EGFR-targeted therapy for TNBC, the precise mechanisms of EGFR-TKI resistance in TNBC need to be elucidated. In this study, to understand the molecular mechanisms involved in the differences in EGFR-TKI efficacy on TNBC between human and mouse, we focused on the effect of IL-26, which is absent in mice. In vitro analysis showed that IL-26 activated AKT and JNK signaling of bypass pathway of EGFR-TKI in both murine and human TNBC cells. We next investigated the mechanisms involved in IL-26-mediated EGFR-TKI resistance in TNBC. We identified EphA3 as a novel functional receptor for IL-26 in TNBC. IL-26 induced dephosphorylation and downmodulation of EphA3 in TNBC, which resulted in increased phosphorylation of AKT and JNK against EGFR-TKI-induced endoplasmic reticulum (ER) stress, leading to tumor growth. Meanwhile, the blockade of IL-26 overcame EGFR-TKI resistance in TNBC. Since the gene encoding IL-26 is absent in mice, we utilized humanIL-26transgenic (hIL-26Tg) mice as a tumor-bearing murine model to characterize the role of IL-26 in the differential effect of EGFR-TKI in human and mice and to confirm our in vitro findings. Our findings indicate that IL-26 activates the bypass pathway of EGFR-TKI, while blockade of IL-26 overcomes EGFR-TKI resistance in TNBC via enhancement of ER stress signaling. Our work provides novel insights into the mechanisms of EGFR-TKI resistance in TNBC via interaction of IL-26 with its newly identified receptor EphA3, while also suggesting IL-26 as a possible therapeutic target in TNBC.
Intrinsic luminescence blinking from plasmonic nanojunctions
Authors: Chen Wen , Roelli Philippe , Ahmed Aqeel , Verlekar Sachin , Hu Huatian , Banjac Karla , Lingenfelder Magalí , Kippenberg Tobias J. , Tagliabue Giulia , Galland Christophe
Published: May 2021

Plasmonic nanojunctions, consisting of adjacent metal structures with nanometre gaps, can support localised plasmon resonances that boost light matter interactions and concentrate electromagnetic fields at the nanoscale. In this regime, the optical response of the system is governed by poorly understood dynamical phenomena at the frontier between the bulk, molecular and atomic scales. Here, we report ubiquitous spectral fluctuations in the intrinsic light emission from photo-excited gold nanojunctions, which we attribute to the light-induced formation of domain boundaries and quantum-confined emitters inside the noble metal. Our data suggest that photoexcited carriers and gold adatom - molecule interactions play key roles in triggering luminescence blinking. Surprisingly, this internal restructuring of the metal has no measurable impact on the Raman signal and scattering spectrum of the plasmonic cavity. Our findings demonstrate that metal luminescence offers a valuable proxy to investigate atomic fluctuations in plasmonic cavities, complementary to other optical and electrical techniques.
Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
Authors: Scekic-Zahirovic Jelena , Sanjuan-Ruiz Inmaculada , Kan Vanessa , Megat Salim , De Rossi Pierre , Dieterlé Stéphane , Cassel Raphaelle , Jamet Marguerite , Kessler Pascal , Wiesner Diana , Tzeplaeff Laura , Demais Valérie , Sahadevan Sonu , Hembach Katharina M. , Muller Hans-Peter , Picchiarelli Gina , Mishra Nibha , Antonucci Stefano , Dirrig-Grosch Sylvie , Kassubek Jan , Rasche Volker , Ludolph Albert , Boutillier Anne-Laurence , Roselli Francesco , Polymenidou Magdalini , Lagier-Tourenne Clotilde , Liebscher Sabine , Dupuis Luc
Published: May 2021

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex ofFusknock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization.
Prevalence of SARS-CoV-2 antibodies in France: results from nationwide serological surveillance
Authors: Le Vu Stéphane , Jones Gabrielle , Anna François , Rose Thierry , Richard Jean-Baptiste , Bernard-Stoecklin Sibylle , Goyard Sophie , Demeret Caroline , Helynck Olivier , Escriou Nicolas , Gransagne Marion , Petres Stéphane , Robin Corinne , Monnet Virgile , Perrin de Facci Louise , Ungeheuer Marie-Noelle , Léon Lucie , Guillois Yvonnick , Filleul Laurent , Charneau Pierre , Lévy-Bruhl Daniel , van der Werf Sylvie , Noel Harold
Published: May 2021

Assessment of the cumulative incidence of SARS-CoV-2 infections is critical for monitoring the course and extent of the COVID-19 epidemic. Here, we report estimated seroprevalence in the French population and the proportion of infected individuals who developed neutralising antibodies at three points throughout the first epidemic wave. Testing 11,000 residual specimens for anti-SARS-CoV-2 IgG and neutralising antibodies, we find nationwide seroprevalence of 0.41% (95% CI: 0.05–0.88) mid-March, 4.14% (95% CI: 3.31–4.99) mid-April and 4.93% (95% CI: 4.02–5.89) mid-May 2020. Approximately 70% of seropositive individuals have detectable neutralising antibodies. Infection fatality rate is 0.84% (95% CI: 0.70–1.03) and increases exponentially with age. These results confirm that the nationwide lockdown substantially curbed transmission and that the vast majority of the French population remained susceptible to SARS-CoV-2 in May 2020. Our study shows the progression of the first epidemic wave and provides a framework to inform the ongoing public health response as viral transmission continues globally.
Diffusion dynamics controlled colloidal synthesis of highly monodisperse InAs nanocrystals
Authors: Kim Taewan , Park Seongmin , Jeong Sohee
Published: May 2021

Highly monodisperse colloidal InAs quantum dots (QDs) with superior optoelectronic properties are promising candidates for various applications, including infrared photodetectors and photovoltaics. Recently, a synthetic process involving continuous injection has been introduced to synthesize uniformly sized InAs QDs. Still, synthetic efforts to increase the particle size of over 5 nm often suffer from growth suppression. Secondary nucleation or interparticle ripening during the growth accompanies the inhomogeneity in size as well. In this study, we propose a growth model for the continuous synthetic processing of colloidal InAs QDs based on molecular diffusion. The experimentally validated model demonstrates how precursor solution injection reduces monomer flux, limiting particle growth during synthesis. As predicted by our model, we control the diffusion dynamics by tuning reaction volume, precursor concentration, and injection rate of precursor. Through diffusion-dynamics-control in the continuous process, we synthesize the InAs QDs with a size over 9.0-nm (1Smax of 1600 nm) with a narrow size distribution (12.2%). Diffusion-dynamics-controlled synthesis presented in this study effectively manages the monomer flux and thus overcome monomer-reactivity-originating size limit of nanocrystal growth in solution.
Shape control of size-selected naked platinum nanocrystals
Authors: Xia Yu , Nelli Diana , Ferrando Riccardo , Yuan Jun , Li Z. Y.
Published: May 2021

Controlled growth of far-from-equilibrium-shaped nanoparticles with size selection is essential for the exploration of their unique physical and chemical properties. Shape control by wet-chemistry preparation methods produces surfactant-covered surfaces with limited understanding due to the complexity of the processes involved. Here, we report the controlled production and transformation of octahedra to tetrahedra of size-selected platinum nanocrystals with clean surfaces in an inert gas environment. Molecular dynamics simulations of the growth reveal the key symmetry-breaking atomic mechanism for this autocatalytic shape transformation, confirming the experimental conditions required. In-situ heating experiments demonstrate the relative stability of both octahedral and tetrahedral Pt nanocrystals at least up to 700 °C and that the extended surface diffusion at higher temperature transforms the nanocrystals into equilibrium shape.
Peripheral and lung resident memory T cell responses against SARS-CoV-2
Authors: Grau-Expósito Judith , Sánchez-Gaona Nerea , Massana Núria , Suppi Marina , Astorga-Gamaza Antonio , Perea David , Rosado Joel , Falcó Anna , Kirkegaard Cristina , Torrella Ariadna , Planas Bibiana , Navarro Jordi , Suanzes Paula , Álvarez-Sierra Daniel , Ayora Alfonso , Sansano Irene , Esperalba Juliana , Andrés Cristina , Antón Andrés , Ramón y Cajal Santiago , Almirante Benito , Pujol-Borrell Ricardo , Falcó Vicenç , Burgos Joaquín , Buzón María J. , Genescà Meritxell
Published: May 2021

Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.
Trabecular bone organoids: a micron-scale ‘humanised’ prototype designed to study the effects of microgravity and degeneration
Authors: Iordachescu Alexandra , Hughes Erik A. B. , Joseph Stephan , Hill Eric J. , Grover Liam M. , Metcalfe Anthony D.
Published: May 2021

Bone is a highly responsive organ, which continuously adapts to the environment it is subjected to in order to withstand metabolic demands. These events are difficult to study in this particular tissue in vivo, due to its rigid, mineralised structure and inaccessibility of the cellular component located within. This manuscript presents the development of a micron-scale bone organoid prototype, a concept that can allow the study of bone processes at the cell-tissue interface. The model is constructed with a combination of primary female osteoblastic and osteoclastic cells, seeded onto femoral head micro-trabeculae, where they recapitulate relevant phenotypes and functions. Subsequently, constructs are inserted into a simulated microgravity bioreactor (NASA-Synthecon) to model a pathological state of reduced mechanical stimulation. In these constructs, we detected osteoclastic bone resorption sites, which were different in morphology in the simulated microgravity group compared to static controls. Once encapsulated in human fibrin and exposed to analogue microgravity for 5 days, masses of bone can be observed being lost from the initial structure, allowing to simulate the bone loss process further. Constructs can function as multicellular, organotypic units. Large osteocytic projections and tubular structures develop from the initial construct into the matrix at the millimetre scale. Micron-level fragments from the initial bone structure are detected travelling along these tubules and carried to sites distant from the native structure, where new matrix formation is initiated. We believe this model allows the study of fine-level physiological processes, which can shed light into pathological bone loss and imbalances in bone remodelling.
Enhanced dengue vaccine virus replication and neutralizing antibody responses in immune primed rhesus macaques
Authors: McCracken Michael K. , Kuklis Caitlin H. , Kannadka Chandrika B. , Barvir David A. , Sanborn Mark A. , Waickman Adam T. , Siegfried Hayden C. , Victor Kaitlin A. , Hatch Kristin L. , De La Barrera Rafael , Walls Shannon D. , Rutvisuttinunt Wiriya , Currier Jeffrey R. , Friberg Heather , Jarman Richard G. , Gromowski Gregory D.
Published: May 2021

Antibody-dependent enhancement (ADE) is suspected to influence dengue virus (DENV) infection, but the role ADE plays in vaccination strategies incorporating live attenuated virus components is less clear. Using a heterologous prime-boost strategy in rhesus macaques, we examine the effect of priming with DENV purified inactivated vaccines (PIVs) on a tetravalent live attenuated vaccine (LAV). Sera exhibited low-level neutralizing antibodies (NAb) post PIV priming, yet moderate to high in vitro ADE activity. Following LAV administration, the PIV primed groups exhibited DENV-2 LAV peak viremias up to 1,176-fold higher than the mock primed group, and peak viremia correlated with in vitro ADE. Furthermore, PIV primed groups had more balanced and higher DENV-1–4 NAb seroconversion and titers than the mock primed group following LAV administration. These results have implications for the development of effective DENV vaccine prime-boost strategies and for our understanding of the role played by ADE in modulating DENV replication.
GWAS of allometric body-shape indices in UK Biobank identifies loci suggesting associations with morphogenesis, organogenesis, adrenal cell renewal and cancer
Authors: Christakoudi Sofia , Evangelou Evangelos , Riboli Elio , Tsilidis Konstantinos K.
Published: May 2021

Genetic studies have examined body-shape measures adjusted for body mass index (BMI), while allometric indices are additionally adjusted for height. We performed the first genome-wide association study of A Body Shape Index (ABSI), Hip Index (HI) and the new Waist-to-Hip Index and compared these with traditional indices, using data from the UK Biobank Resource for 219,872 women and 186,825 men with white British ancestry and Bayesian linear mixed-models (BOLT-LMM). One to two thirds of the loci identified for allometric body-shape indices were novel. Most prominent was rs72959041 variant in RSPO3 gene, expressed in visceral adipose tissue and regulating adrenal cell renewal. Highly ranked were genes related to morphogenesis and organogenesis, previously additionally linked to cancer development and progression. Genetic associations were fewer in men compared to women. Prominent region-specific associations showed variants in loci VEGFA and HMGA1 for ABSI and KLF14 for HI in women, and C5orf67 and HOXC4/5 for ABSI and RSPO3, VEGFA and SLC30A10 for HI in men. Although more variants were associated with waist and hip circumference adjusted for BMI compared to ABSI and HI, associations with height had previously been reported for many of the additional variants, illustrating the importance of adjusting correctly for height.
Morphological convergence and adaptation in cave and pelagic scale worms (Polynoidae, Annelida)
Authors: Gonzalez Brett C. , Martínez Alejandro , Worsaae Katrine , Osborn Karen J.
Published: May 2021

Across Annelida, accessing the water column drives morphological and lifestyle modifications—yet in the primarily “benthic” scale worms, the ecological significance of swimming has largely been ignored. We investigated genetic, morphological and behavioural adaptations associated with swimming across Polynoidae, using mitogenomics and comparative methods. Mitochondrial genomes from cave and pelagic polynoids were highly similar, with non-significant rearrangements only present in caveGesiella.Gene orders of the new mitogenomes were highly similar to shallow water species, suggestive of an underlying polynoid ground pattern. Being the first phylogenetic analyses to include the holopelagicDrieschia,we recovered this species nested among shallow water terminals, suggesting a shallow water ancestry. Based on these results, our phylogenetic reconstructions showed that swimming evolved independently three times in Polynoidae, involving convergent adaptations in morphology and motility patterns across the deep sea (Branchipolynoe), midwater (Drieschia) and anchialine caves (PelagomacellicephalaandGesiella). Phylogenetic generalized least-squares (PGLS) analyses showed that holopelagic and anchialine cave species exhibit hypertrophy of the dorsal cirri, yet, these morphological modifications are achieved along different evolutionary pathways, i.e., elongation of the cirrophore versus style. Together, these findings suggest that a water column lifestyle elicits similar morphological adaptations, favouring bodies designed for drifting and sensing.
Classification of directionally specific vagus nerve activity using an upper airway obstruction model in anesthetized rodents
Authors: Sabetian P. , Sadat-Nejad Y. , Yoo Paul B.
Published: May 2021

Electrical signals from the peripheral nervous system have the potential to provide the necessary motor, sensory or autonomic information for implementing closed-loop control of neuroprosthetic or neuromodulatory systems. However, developing methods to recover information encoded in these signals is a significant challenge. Our goal was to test the feasibility of measuring physiologically generated nerve action potentials that can be classified as sensory or motor signals. A tetrapolar recording nerve cuff electrode was used to measure vagal nerve (VN) activity in a rodent model of upper airway obstruction. The effect of upper airway occlusions on VN activity related to respiration (RnP) was calculated and compared for 4 different cases: (1) intact VN, (2) VN transection only proximal to recording electrode, (3) VN transection only distal to the recording electrode, and (4) transection of VN proximal and distal to electrode. We employed a Support Vector Machine (SVM) model with Gaussian Kernel to learn a model capable of classifying efferent and afferent waveforms obtained from the tetrapolar electrode. Invivoresults showed that the RnP values decreased significantly during obstruction by 91.7% ± 3.1%, and 78.2% ± 3.4% for cases of intact VN or proximal transection, respectively. In contrast, there were no significant changes for cases of VN transection at the distal end or both ends of the electrode. The SVM model yielded an 85.8% accuracy in distinguishing motor and sensory signals. The feasibility of measuring low-noise directionally-sensitive neural activity using a tetrapolar nerve cuff electrode along with the use of an SVM classifier was shown. Future experimental work in chronic implant studies is needed to support clinical translatability.
The novel immune-related genes predict the prognosis of patients with hepatocellular carcinoma
Authors: Li Lunxu , Xia Shilin , Shi Xueying , Chen Xu , Shang Dong
Published: May 2021

Hepatocellular carcinoma (HCC) is one of the main causes of cancer deaths globally. Immunotherapy is becoming increasingly important in the cure of advanced HCC. Thus it is essential to identify biomarkers for treatment response and prognosis prediction. We searched publicly available databases and retrieved 465 samples of genes from The Cancer Genome Atlas (TCGA) database and 115 tumor samples from Gene Expression Omnibus (GEO). Meanwhile, we used the ImmPort database to determine the immune-related genes as well. Weighted gene correlation network analysis, Cox regression analysis and least absolute shrinkage and selection operator (LASSO) analysis were used to identify the key immune related genes (IRGs) which are closely related to prognosis. Gene set enrichment analysis (GSEA) was implemented to explore the difference of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway between Immune high- and low-risk score groups. Finally, we made a prognostic nomogram including Immune-Risk score and other clinicopathologic factors. A total of 318 genes from prognosis related modules were identified through weighted gene co-expression network analysis (WGCNA). 46 genes were strongly linked to prognosis after univariate Cox analysis. We constructed a seven genes prognostic signature which showed powerful prediction ability in both training cohort and testing cohort. 16 significant KEGG pathways were identified between high- and low- risk score groups using GSEA analysis. This study identified and verified seven immune-related prognostic biomarkers for the patients with HCC, which have potential value for immune modulatory and therapeutic targets.
Machine learning-based microstructure prediction during laser sintering of alumina
Authors: Tang Jianan , Geng Xiao , Li Dongsheng , Shi Yunfeng , Tong Jianhua , Xiao Hai , Peng Fei
Published: May 2021

Predicting material’s microstructure under new processing conditions is essential in advanced manufacturing and materials science. This is because the material’s microstructure hugely influences the material’s properties. We demonstrate an elegant machine learning algorithm that faithfully predicts the microstructure under new conditions, without the need of knowing the governing laws. We name this algorithm, RCWGAN-GP, which is regression-based conditional generative adversarial networks with Wasserstein loss function and gradient penalty. This algorithm was trained with experimental SEM micrographs from laser-sintered alumina under various laser powers. The RCWGAN-GP realistically regenerates the SEM micrographs under the trained laser powers. Impressively, it also faithfully predicts the alumina’s microstructure under unexplored laser powers. The predicted microstructure features, including the morphology of the sintered particles and the pores, match the experimental SEM micrographs very well. We further quantitatively examined the prediction accuracy of the RCWGAN-GP. We trained the algorithm with computer-created micrograph datasets of secondary-phase growth governed by the well-known Johnson–Mehl–Avrami (JMA) equation. The RCWGAN-GP accurately regenerates the micrographs at the trained time series, in terms of the grains’ shapes, sizes, and spatial distributions. More importantly, the predicted secondary phase fraction accurately follows the JMA curve.
Mesenchymal stromal cell mitochondrial transfer to human induced T-regulatory cells mediates FOXP3 stability
Authors: Do Jeong-su , Zwick Daniel , Kenyon Jonathan D. , Zhong Fei , Askew David , Huang Alex Y. , Van’t Hof Wouter , Finney Marcie , Laughlin Mary J.
Published: May 2021

The key obstacle to clinical application of human inducible regulatory T cells (iTreg) as an adoptive cell therapy in autoimmune disorders is loss of FOXP3 expression in an inflammatory milieu. Here we report human iTreg co-cultured with bone marrow-derived mesenchymal stromal cells (MSCs) during short-term ex vivo expansion enhances the stability of iTreg FOXP3 expression and suppressive function in vitro and in vivo, and further that a key mechanism of action is MSC mitochondrial (mt) transfer via tunneling nanotubules (TNT). MSC mt transfer is driven by mitochondrial metabolic function (CD39/CD73 signaling) in proliferating iTreg and promotes iTreg expression of FOXP3 stabilizing factors BACH2 and SENP3. These results elucidate cellular and molecular mechanisms underlying human MSC mt transfer to proliferating cells. MSC mt transfer stabilizes FOXP3 expression in iTregs, thereby enhancing and sustaining their suppressive function in inflammatory conditions in vitro and in vivo.
Author Correction: Nonalcoholic fatty liver disease accelerates kidney function decline in patients with chronic kidney disease: a cohort study
Authors: Jang Hye Ryoun , Kang Danbee , Sinn Dong Hyun , Gu Seonhye , Cho Soo Jin , Lee Jung Eun , Huh Wooseong , Paik Seung Woon , Ryu Seungho , Chang Yoosoo , Shafi Tariq , Lazo Mariana , Guallar Eliseo , Cho Juhee , Gwak Geum-Youn
Published: May 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Microbial sulfate reduction by Desulfovibrio is an important source of hydrogen sulfide from a large swine finishing facility
Authors: Karnachuk Olga V. , Rusanov Igor I. , Panova Inna A. , Grigoriev Mikhail A. , Zyusman Viacheslav S. , Latygolets Elena A. , Kadyrbaev Maksat K. , Gruzdev Eugeny V. , Beletsky Alexey V. , Mardanov Andrey V. , Pimenov Nikolai V. , Ravin Nikolai V.
Published: May 2021

There is still a lack of understanding of H2S formation in agricultural waste, which leads to poor odour prevention and control. Microbial sulfate reduction is a major process contributing to sulfide formation in natural and technogenic environments with high sulfate and low oxygen concentration. Agricultural waste can be considered a low-sulfate system with no obvious input of oxidised sulfur compounds. The purpose of this study was to characterise a microbial community participating in H2S production and estimate the microbial sulfate reduction rate (SRR) in manure slurry from a large-scale swine finishing facility in Western Siberia. In a series of manure slurry microcosms, we identified bacterial consortia by 16S rRNA gene profiling and metagenomic analysis and revealed that sulfate-reducing Desulfovibrio were key players responsible for H2S production. The SRR measured with radioactive sulfate in manure slurry was high and comprised 7.25 nmol S cm−3 day−1. Gypsum may be used as a solid-phase electron acceptor for sulfate reduction. Another plausible source of sulfate is a swine diet, which often contains supplements in the form of sulfates, including lysine sulfate. Low-sulfur diet, manure treatment with iron salts, and avoiding gypsum bedding are possible ways to mitigate H2S emissions from swine manure.
SARS-CoV-2 and other human coronavirus show genome patterns previously associated to reduced viral recognition and altered immune response
Authors: Franzo Giovanni
Published: May 2021

A new pandemic caused by the betacoronavirus SARS-CoV-2 originated in China in late 2019. Although often asymptomatic, a relevant percentage of affected people can develop severe pneumonia. Initial evidence suggests that dysregulation of the immune response could contribute to the pathogenesis, as previously demonstrated for SARS-CoV. The presence of genome composition features involved in delaying viral recognition is herein investigated for human coronaviruses (HCoVs), with a special emphasis on SARS-CoV-2. A broad collection of HCoVs polyprotein, envelope, matrix, nucleocapsid and spike coding sequences was downloaded and several statistics representative of genome composition and codon bias were investigated. A model able to evaluate and test the presence of a significant under- or over-representation of dinucleotide pairs while accounting for the underlying codon bias and protein sequence was also implemented. The study revealed the significant under-representation of CpG dinucleotide pair in all HcoV, but especially in SARS-CoV and even more in SARS-CoV-2. The presence of forces acting to minimize CpG content was confirmed by relative synonymous codon usage pattern. Codons containing the CpG pair were severely under-represented, primarily in the polyprotein and spike coding sequences of SARS-CoV-2. Additionally, a significant under-representation of the TpA pair was observed in the N and S region of SARS-CoV and SARS-CoV-2. Increasing experimental evidence has proven that CpG and TpA are targeted by innate antiviral host defences, contributing both to RNA degradation and RIG-1 mediated interferon production. The low content of these dinucleotides could contribute to a delayed interferon production, dysregulated immune response, higher viral replication and poor outcome. Significantly, the RIG-1 signalling pathway was proven to be defective in elderlies, suggesting a likely interaction between limited viral recognition and lower responsiveness in interferon production that could justify the higher disease severity and mortality in older patients.
Ocean fertilization by pyrogenic aerosol iron
Authors: Ito Akinori , Ye Ying , Baldo Clarissa , Shi Zongbo
Published: May 2021

Aerosols supply bioaccessible iron to marine biota which could affect climate through biogeochemical feedbacks. This paper review progresses in research on pyrogenic aerosol iron. Observations and laboratory experiments indicate that the iron solubility of pyrogenic aerosol can be considerably higher than lithogenic aerosol. Aerosol models highlight a significant contribution of pyrogenic aerosols (~20%) to the atmospheric supply of dissolved iron into the ocean. Some ocean models suggest a higher efficiency of pyrogenic iron in enhancing marine productivity than lithogenic sources. It is, however, challenging to quantitatively estimate its impact on the marine biogeochemical cycles under the changing air quality and climate.
Common DNA methylation dynamics in endometriod adenocarcinoma and glioblastoma suggest universal epigenomic alterations in tumorigenesis
Authors: Karlow Jennifer A. , Miao Benpeng , Xing Xiaoyun , Wang Ting , Zhang Bo
Published: May 2021

Trends in altered DNA methylation have been defined across human cancers, revealing global loss of methylation (hypomethylation) and focal gain of methylation (hypermethylation) as frequent cancer hallmarks. Although many cancers share these trends, little is known about the specific differences in DNA methylation changes across cancer types, particularly outside of promoters. Here, we present a comprehensive comparison of DNA methylation changes between two distinct cancers, endometrioid adenocarcinoma (EAC) and glioblastoma multiforme (GBM), to elucidate common rules of methylation dysregulation and changes unique to cancers derived from specific cells. Both cancers exhibit significant changes in methylation over regulatory elements. Notably, hypermethylated enhancers within EAC samples contain several transcription factor binding site clusters with enriched disease ontology terms highlighting uterine function, while hypermethylated enhancers in GBM are found to overlap active enhancer marks in adult brain. These findings suggest that loss of original cellular identity may be a shared step in tumorigenesis.
Deep ocean metagenomes provide insight into the metabolic architecture of bathypelagic microbial communities
Authors: Acinas Silvia G. , Sánchez Pablo , Salazar Guillem , Cornejo-Castillo Francisco M. , Sebastián Marta , Logares Ramiro , Royo-Llonch Marta , Paoli Lucas , Sunagawa Shinichi , Hingamp Pascal , Ogata Hiroyuki , Lima-Mendez Gipsi , Roux Simon , González José M. , Arrieta Jesús M. , Alam Intikhab S. , Kamau Allan , Bowler Chris , Raes Jeroen , Pesant Stéphane , Bork Peer , Agustí Susana , Gojobori Takashi , Vaqué Dolors , Sullivan Matthew B. , Pedrós-Alió Carlos , Massana Ramon , Duarte Carlos M. , Gasol Josep M.
Published: May 2021

The deep sea, the largest ocean’s compartment, drives planetary-scale biogeochemical cycling. Yet, the functional exploration of its microbial communities lags far behind other environments. Here we analyze 58 metagenomes from tropical and subtropical deep oceans to generate the Malaspina Gene Database. Free-living or particle-attached lifestyles drive functional differences in bathypelagic prokaryotic communities, regardless of their biogeography. Ammonia and CO oxidation pathways are enriched in the free-living microbial communities and dissimilatory nitrate reduction to ammonium and H2oxidation pathways in the particle-attached, while the Calvin Benson-Bassham cycle is the most prevalent inorganic carbon fixation pathway in both size fractions. Reconstruction of the Malaspina Deep Metagenome-Assembled Genomes reveals unique non-cyanobacterial diazotrophic bacteria and chemolithoautotrophic prokaryotes. The widespread potential to grow both autotrophically and heterotrophically suggests that mixotrophy is an ecologically relevant trait in the deep ocean. These results expand our understanding of the functional microbial structure and metabolic capabilities of the largest Earth aquatic ecosystem.