bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mineral crystal thickness in calcified cartilage and subchondral bone in healthy and osteoarthritic knees
Authors: Finnilä Mikko A.J. , Das Gupta Shuvashis , Turunen Mikael J. , Kestilä Iida , Turkiewicz Aleksandra , Lutz-Bueno Viviane , Folkesson Elin , Holler Mirko , Ali Neserin , Hughes Velocity , Isaksson Hanna , Tjörnstrand Jon , Önnerfjord Patrik , Guizar-Sicairos Manuel , Saarakkala Simo , Englund Martin 
Published: June 2021

AbstractOsteoarthritis (OA) is the most common joint disease globally. In OA, articular cartilage degradation is often accompanied with sclerosis of the subchondral bone. However, the association between OA and tissue mineralization at the nanostructural level is currently not understood. Especially, it is technically challenging to identify calcified cartilage, where relevant but poorly understood pathological processes like tidemark multiplication and advancement occur. Here, we used state-of-the-art micro-focus small-angle X-ray scattering with high 5µm spatial resolution to determine mineral crystal thickness in human subchondral bone and calcified cartilage. Specimens with a wide spectrum of OA severities were acquired from the medial and lateral compartments of medial compartment knee OA patients (n=15) and cadaver knees (n=10). For the first time, we identified a well-defined layer of calcified cartilage associated with pathological tidemark multiplication, containing 0.32nm thicker crystals compared to the rest of calcified cartilage. In addition, we found 0.2nm thicker mineral crystals in both tissues of the lateral compartment in OA compared with healthy knees, indicating a loading-related disease process since the lateral compartment is typically less loaded in medial compartment knee OA. Furthermore, the crystal thickness of the subchondral bone was lower with increasing histopathological OA severity. In summary, we report novel changes in mineral crystal thickness during OA. Our data suggest that unloading in the knee is associated with the growth of mineral crystals, which is especially evident in the calcified cartilage. In the subchondral bone, mineral crystals become thinner with increasing OA severity, which indicates new bone formation with sclerosis.One Sentence SummaryMineral crystal thickness increases with osteoarthritis in the lateral condyle that is typically unloaded.
Honey bees cannot sense harmful concentrations of metal pollutants in food
Authors: Monchanin Coline , de Brito Sanchez Maria Gabriela , Lecouvreur Loreleï , Boidard Océane , Méry Grégoire , Silvestre Jérôme , Roux Gaël Le , Baqué David , Elger Arnaud , Barron Andrew B. , Lihoreau Mathieu , Devaud Jean-Marc 
Published: June 2021

AbstractWhether animals can actively avoid food contaminated with harmful compounds through taste is key to understand their ecotoxicological risks. Here, we investigated the ability of honey bees to perceive and avoid food resources contaminated with common metal pollutants known to impair their cognition at low concentrations (lead, zinc and arsenic). In behavioural assays, bees did not discriminate food contaminated with field-realistic concentrations of these metals. Bees only reduced their food consumption and displayed aversive behaviours at very high, unrealistic concentrations of lead and zinc that they perceived through their antennae and proboscis. Electrophysiological analyses confirmed that high concentrations of the three metals in sucrose solution induced a reduced neural response to sucrose in their antennae. Our results thus show that honey bees can avoid metal pollutants in their food, but only at very high concentrations above regulatory levels. Their inability to detect lower, yet harmful, concentrations in a field-realistic range suggests that metal pollution is a major threat for pollinators.
Phosphatidylserine Receptors Enhance SARS-CoV-2 Infection: AXL as a Therapeutic Target for COVID-19
Authors: Bohan Dana , Van Ert Hanora , Ruggio Natalie , Rogers Kai J. , Badreddine Mohammad , Aguilar Briseño José A. , Chavez Roberth Anthony Rojas , Gao Boning , Stokowy Tomasz , Christakou Eleni , Micklem David , Gausdal Gro , Haim Hillel , Minna John , Lorens James B. , Maury Wendy 
Published: June 2021

AUTHOR SUMMARYPhosphatidylserine (PS) receptors are PS binding proteins that mediate uptake of apoptotic bodies. Many enveloped viruses utilize this PS/PS receptor mechanism to adhere to and internalize into the endosomal compartment of cells and this is termed apoptotic mimicry. For viruses that have a mechanism(s) of endosomal escape, apoptotic mimicry is a productive route of virus entry. We evaluated if PS receptors serve as cell surface receptors for SARS-CoV-2 and found that the PS receptors, AXL, TIM-1 and TIM-4, facilitated virus infection when low concentrations of the SARS-CoV-2 cognate receptor, ACE2, was present. Consistent with the established mechanism of PS receptor utilization by other viruses, PS liposomes competed with SARS-CoV-2 for binding and entry. We demonstrated that this PS receptor enhances SARS-CoV-2 binding to and infection of an array of human lung cell lines and is an under-appreciated but potentially important host factor facilitating SARS-CoV-2 entry.
Derlin rhomboid pseudoproteases employ substrate engagement and lipid distortion function for retrotranslocation of ER multi-spanning membrane substrates
Authors: Nejatfard Anahita , Wauer Nicholas , Bhaduri Satarupa , Conn Adam , Gourkanti Saroj , Singh Narinderbir , Kuo Tiffany , Kandel Rachel , Amaro Rommie E. , Neal Sonya E. 
Published: June 2021

SummaryNearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane where they are correctly folded, assembled, and then delivered to their final cellular destinations. In order to prevent the accumulation of misfolded membrane proteins, ER associated degradation (ERAD) moves these clients from the ER membrane to the cytosol; a process known as retrotranslocation. Our recent work in S. cerevisiae has revealed a derlin rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study, we sought to understand the mechanism associated with Dfm1’s actions and found that Dfm1’s conserved rhomboid residues are critical for membrane protein retrotranslocation. Specifically, we identified several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 has retained the lipid thinning functions of its rhomboid protease predecessors to facilitate in the removal of ER membrane substrates. We find this substrate engagement and lipid thinning feature is conserved in its human homolog, Derlin-1. Utilizing interaction studies and molecular dynamics simulations, this work reveals that derlin rhomboid pseudoproteases employ novel mechanisms of substrate engagement and lipid thinning for catalyzing extraction of multi-spanning membrane substrates.
Accurate and fast cell marker gene identification with COSG
Authors: Dai Min , Pei Xiaobing , Wang Xiu-Jie 
Published: June 2021

AbstractAccurate cell classification is the groundwork for downstream analysis of single-cell sequencing data, yet how to identify marker genes to distinguish different cell types still remains as a big challenge. We developed COSG as a cosine similarity-based method for more accurate and scalable marker gene identification. COSG is applicable to single-cell RNA sequencing data, single-cell ATAC sequencing data and spatially resolved transcriptome data. COSG is fast and scalable for ultra-large datasets of million-scale cells. Application on both simulated and real experimental datasets demonstrates the superior performance of COSG in terms of both accuracy and efficiency as compared with other available methods. Marker genes or genomic regions identified by COSG are more indicative and with greater cell-type specificity.
Tracking SARS-CoV-2 Spike Protein Mutations in the United States (2020/01 – 2021/03) Using a Statistical Learning Strategy
Authors: Zhao Lue Ping , Lybrand Terry P. , Gilbert Peter B. , Hawn Thomas R. , Schiffer Joshua T. , Stamatatos Leonidas , Payne Thomas H. , Carpp Lindsay N. , Geraghty Daniel E. , Jerome Keith R. 
Published: June 2021

AbstractThe emergence and establishment of SARS-CoV-2 variants of interest (VOI) and variants of concern (VOC) highlight the importance of genomic surveillance. We propose a statistical learning strategy (SLS) for identifying and spatiotemporally tracking potentially relevant Spike protein mutations. We analyzed 167,893 Spike protein sequences from US COVID-19 cases (excluding 21,391 sequences from VOI/VOC strains) deposited at GISAID from January 19, 2020 to March 15, 2021. Alignment against the reference Spike protein sequence led to the identification of viral residue variants (VRVs), i.e., residues harboring a substitution compared to the reference strain. Next, generalized additive models were applied to model VRV temporal dynamics, to identify VRVs with significant and substantial dynamics (false discovery rate q-value <0.01; maximum VRV proportion > 10% on at least one day).Unsupervised learning was then applied to hierarchically organize VRVs by spatiotemporal patterns and identify VRV-haplotypes. Finally, homology modelling was performed to gain insight into potential impact of VRVs on Spike protein structure. We identified 90 VRVs, 71 of which have not previously been observed in a VOI/VOC, and 35 of which have emerged recently and are durably present. Our analysis identifies 17 VRVs ∼91 days earlier than their first corresponding VOI/VOC publication. Unsupervised learning revealed eight VRV-haplotypes of 4 VRVs or more, suggesting two emerging strains (B1.1.222 and B.1.234). Structural modeling supported potential functional impact of the D1118H and L452R mutations. The SLS approach equally monitors all Spike residues over time, independently of existing phylogenic classifications, and is complementary to existing genomic surveillance methods.
APRIL drives a co-ordinated but diverse response as a foundation for plasma cell longevity
Authors: Stephenson Sophie , Care Matthew A , Doody Gina M , Tooze Reuben M 
Published: June 2021

AbstractAntibody secreting cells (ASCs) survive in niche microenvironments, but cellular responses driven by particular niche signals are incompletely defined. The TNF superfamily member APRIL provides a niche signal that can support the transition of transitory plasmablasts into long-lived plasma cells. Here we explore how APRIL helps to establish the biological programs that promote life in the niche, by studying the initial response of primary human plasmablast to APRIL. Under conditions allowing the maturation of ex vivo or in vitro generated plasmablasts, we find that APRIL drives activation of ERK, p38 and JNK. This is accompanied by a classical NFκB response. Under these conditions induction of AKT phosphorylation is also observed with similar kinetics, paralleled by FOXO1 phosphorylation and nuclear exclusion. Time course gene expression data resolve the downstream co-ordinated transcriptional response. The APRIL-signal propagates via immediate early genes and classical NFκB responsive targets to converge onto modules of MYC- and OCT2-regulated gene expression linked to cell growth, as well as leading to enhanced expression of ICAM1 and SQSTM1 associated with adhesion and metabolic/stress responses. Thus, APRIL drives a combination of multiple transcriptional programs that co-ordinate cell growth, stress response and adhesion in human ASCs, providing a broad foundation to support plasma cell longevity.
Genome instability drives epistatic adaptation in the human pathogen Leishmania
Authors: Bussotti Giovanni , Piel Laura , Pescher Pascale , Domagalska Malgorzata A. , Shanmugha Rajan K. , Cohen-Chalamish Smadar , Doniger Tirza , Hiregange Disha-Gajanan , Myler Peter J , Unger Ron , Michaeli Shulamit , Späth Gerald F. 
Published: June 2021

AbstractHow genome instability is harnessed for fitness gain despite its potential deleterious effects is largely elusive. An ideal system to address this important open question is provided by the protozoan pathogen Leishmania, which exploits frequent variations in chromosome and gene copy number to regulate expression levels. Using ecological genomics and experimental evolution approaches we provide first evidence that Leishmania adaptation relies on epistatic interactions between functionally associated gene copy number variations in pathways driving fitness gain in a given environment. We further uncover post-transcriptional regulation as a key mechanism that compensates for deleterious gene dosage effects and provides phenotypic robustness to genetically heterogenous parasite populations. Finally, we correlate dynamic variations in snoRNA gene dosage with changes in rRNA 2’-O-methylation and pseudouridylation, suggesting translational control is an additional layer of parasite adaptation. Leishmania genome instability is thus harnessed for fitness gain by genome-dependent variations in gene expression, and genome-independent, compensatory mechanisms. This allows for polyclonal adaptation and maintenance of genetic heterogeneity despite strong selective pressure. The epistatic adaptation described here needs to be considered in Leishmania epidemiology and biomarker discovery, and may be relevant to other fast evolving, eukaryotic cells that exploit genome instability for adaptation, such as fungal pathogens or cancer.One Sentence SummaryEpistatic interactions harness genome instability for Leishmania fitness gain.
Freely-moving mice visually pursue prey using a retinal area with least optic flow
Authors: Holmgren Carl D. , Stahr Paul , Wallace Damian J. , Voit Kay-Michael , Matheson Emily J. , Sawinski Juergen , Bassetto Giacomo , Kerr Jason N. D. 
Published: June 2021

AbstractMice have a large visual field that is constantly stabilized by vestibular ocular reflex driven eye rotations that counter head-rotations. While maintaining their extensive visual coverage is advantageous for predator detection, mice also track and capture prey using vision. However, in the freely moving animal quantifying object location in the field of view is challenging. Here, we developed a method to digitally reconstruct and quantify the visual scene of freely moving mice performing a visually based prey capture task. By isolating the visual sense and combining amouse eye optic model with the head and eye rotations, the detailed reconstruction of the digital environment and retinal features were projected onto the corneal surface for comparison, and updated throughout the behavior. By quantifying the spatial location of objects in the visual scene and their motion throughout the behavior, we show that the image of the prey is maintained within a small area, the functional focus, in the upper-temporal part of the retina. This functional focus coincides with a region of minimal optic flow in the visual field and consequently minimal motion-induced image blur during pursuit, as well as the reported high density-region of Alpha-ON sustained retinal ganglion cells.
Carbonyl Post-Translational Modification Associated with Early Onset Type 1 Diabetes Autoimmunity
Authors: Yang Mei-Ling , Connolly Sean E. , Gee Renelle , Lam TuKiet , Kanyo Jean , Clarke Steven G. , Clarke Catherine F. , James Eddie A. , Speake Cate , Evans-Molina Carmella , Wen Li , Herold Kevan C. , Mamula Mark J. 
Published: June 2021

AbstractInflammation and oxidative stress in pancreatic islets amplify the appearance of various post-translational modifications (PTMs) to self-proteins. Herein, we identified a select group of carbonylated islet proteins arising before the onset of hyperglycemia in non-obese diabetic (NOD) mice. Of particular interest, we identified carbonyl modification of the prolyl-4-hydroxylase beta subunit (P4Hb) that is responsible for proinsulin folding and trafficking as an autoantigen in both human and murine type 1 diabetes. We found the carbonylated-P4Hb is amplified in stressed islets coincident with decreased glucose-stimulated insulin secretion and altered proinsulin to insulin ratios. Moreover, circulating autoantibodies against P4Hb were detected in prediabetic NOD mice and in early human type 1 diabetes prior to the onset of anti-insulin autoimmunity. Our studies provide mechanistic insight into the pathways of proinsulin metabolism and those creating autoantigenic forms of insulin in type 1 diabetes.
Frequency chasing of individual megadalton ions in an Orbitrap analyzer improves precision of analysis in single molecule mass spectrometry
Authors: Wörner Tobias P. , Aizikov Konstantin , Snijder Joost , Fort Kyle L. , Makarov Alexander A. , Heck Albert J.R. 
Published: June 2021

AbstractTo enhance the performance of charge detection mass spectrometry, we investigated the behavior of macromolecular single ions on their paths towards and within the Orbitrap analyzer. We discovered that ions in mass beyond one megadalton reach a plateau of stability and can be successfully trapped for seconds, travelling a path length of multiple kilometers, thereby enabling precise mass analysis with an effective resolution of greater than 100,000 at m/z 35,000. Through monitoring the frequency of individual ions, we show that these high mass ions, rather than being lost from the trap, can gradually lose residual solvent molecules and, in rare cases, a single elementary charge. Our observations highlight the importance of efficient desolvation for optimal charge detection mass spectrometry and inspired us to implement multiple improved data acquisition strategies. We demonstrate that the frequency drift of single ions due to desolvation and charge stripping can be corrected, which improves the effective ion sampling 23-fold and gives a two-fold improvement in mass precision and resolution, as demonstrated in the analysis of various viral particles.
Targeting Gi/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy
Authors: Lyu Cancan , Ye Yuanchao , Lensing Maddison M , Wagner Kay-Uwe , Weigel Ronald J. , Chen Songhai 
Published: June 2021

AbstractG protein coupled receptors (GPCRs) are among the most desirable drug targets for human disease. Although GPCR dysfunction drives the development and progression of many tumors including breast cancer (BC), targeting individual GPCRs has limited efficacy as a cancer therapy because numerous GPCRs are activated. In this study, we sought a new way of blocking GPCR activation in HER2+-BC by targeting a subgroup of GPCRs that couple to Gi/o proteins (Gi/o-GPCRs). Using cell lines and transgenic mouse models, we showed in mammary epithelial cells, HER2 hyperactivation altered GPCR expression, particularly, Gi/o-GPCRs. Gi/o-GPCR stimulation transactivated EGFR and HER2, which in turn activated the PI3K/AKT and Src pathways. Uncoupling Gi/o-GPCRs from cognate Gi/o proteins by pertussis toxin (PTx) inhibited BC cell proliferation and migration in vitro and suppressed HER2-driven tumor formation and metastasis in vivo. Moreover, targeting Gi/o-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that HER2 hyperactivation in BC cells drives aberrant Gi/o-GPCR signaling, and Gi/o-GPCR signals converge on PI3K/AKT and Src signaling pathways to promote cancer progression and the development of resistance to HER2-targeted therapy. Our findings suggest a new way to pharmacologically deactivate GPCR signaling to block tumor growth and enhance therapeutic efficacy.
Novel Role of UHRF1 in DNA methylation-mediated repression of latent HIV-1
Authors: Verdikt Roxane , Bouchat Sophie , Pasternak Alexander O. , Nestola Lorena , Darcis Gilles , Avettand-Fenoel Véronique , Vanhulle Caroline , Aït-Ammar Amina , Bendoumou Maryam , Plant Estelle , Douce Valentin Le , Delacourt Nadège , Cicilionytė Aurelija , Necsoi Coca , Corazza Francis , Bittencourt Passaes Caroline Pereira , Schwartz Christian , Bizet Martin , Fuks François , Sáez-Cirión Asier , Rouzioux Christine , Wit Stéphane De , Berkhout Ben , Gautier Virginie , Rohr Olivier , Lint Carine Van 
Published: June 2021

ABSTRACTThe multiplicity, heterogeneity and dynamic nature of HIV-1 latency mechanisms are reflected in the current lack of functional cure for HIV-1 and in the various reported ex vivo potencies of latency- reversing agents. Here, we investigated the molecular mechanisms underlying the potency of the DNA methylation inhibitor 5-aza-2’-deoxycytidine (5-AzadC) in HIV-1 latency reversal. Doing so, we uncovered specific demethylation CpG signatures induced by 5-AzadC in the HIV-1 promoter. By analyzing the binding modalities to these CpG, we revealed the recruitment of the epigenetic integrator UHRF1 to the HIV-1 promoter. We further demonstrated the role of UHRF1 in DNA methylation- mediated silencing of the latent HIV-1 promoter. As a proof-of-concept to this molecular characterization, we showed that pharmacological downregulation of UHRF1 in ex vivo HIV+ patient cell cultures resulted in potent reactivation of latent HIV-1. Together, we identify UHRF1 as a novel actor in HIV-1 gene silencing and highlight that it constitutes a new molecular target for HIV-1 curative strategies.
Mechanistic Insights Revealed by YbtPQ in the Occluded State
Authors: Hu Wenxin , Parkinson Chance , Zheng Hongjin 
Published: June 2021

AbstractRecently, several ATP-binding cassette (ABC) importers have been found to adopt the typical fold of type IV ABC exporters. Presumably, these importers would function under the transport scheme of “alternating access” like those exporters: cycling through conformations of inward-open, occluded, and outward-open. Understanding how the exporter-like importers move substrates in the opposite direction requires structural studies in all the major conformations. To shed light on that, here we report the structure of yersiniabactin importer YbtPQ from uropathogenic Escherichia coli in the occluded conformation trapped by ADP-vanadate (ADP.Vi) at 3.1Å resolution determined by cryo electron microscopy. The structure shows unusual local rearrangements in multiple helices and loops in its transmembrane domains (TMDs). In addition, the dimerization of nucleotide-binding domains (NBDs) promoted by the vanadate trapping is highlighted by the “screwdriver” action happening at one of the two hinge points. These structural observations are rare and thus provide valuable information to understand the structural plasticity of the exporter-like ABC importers.
Mapping Activity-Dependent Quasi-Stationary States of Mitochondrial Membranes with Graphene-Induced Energy Transfer Imaging
Authors: Raja Sufi Oasim , Chizhik Alexey I. , Schmidt Christoph F. , Enderlein Jörg , Ghosh Arindam 
Published: June 2021

AbstractGraphene-induced energy transfer (GIET) was recently introduced for the precise localization of fluorescent molecules along the optical axis of a microscope. GIET is based on near-field energy transfer from an optically excited fluorophore to a single sheet of graphene. As a proof-of-concept, we demonstrated its potential by determining the distance between the two leaflets of supported lipid bilayers (SLBs) with sub-nanometer accuracy. Here, we use GIET imaging for three-dimensional reconstruction of the mitochondrial membrane architecture. We map two quasi-stationary states of the inner and outer mitochondrial membranes before and during adenosine tri-phosphate (ATP) synthesis. We trigger the ATP synthesis state in vitro by activating mitochondria with precursor molecules. Our results demonstrate that the inner membrane (IM) approaches the outer membrane (OM) while the outer membrane (OM) does not show a measurable change in average axial position upon activation. As a result, the inter-membrane space (IM-OM distance) is reduced by ∼2 nm upon activation of the mitochondria. This direct experimental observation of the subtle dynamics of mitochondrial membranes and the change in inter-membrane distance induced by ATP synthesis is relevant for our understanding of the physical functioning of mitochondria.