bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of the COVID-19 pandemic on health related quality of life in head and neck cancer survivors: an observational cohort study
Authors: Lissenberg-Witte B.I. , Jansen F. , de Jong R.J. Baatenburg , Lamers F. , Leemans C.R. , Oosting S.F. , Takes R.P. , Leeuw I.M. Verdonck-de 
Published: January 2023

AbstractBackgroundPhysical, psychological, and social aspects of health-related quality of life (HRQOL) among head and neck cancer (HNC) survivors may be more affected during the COVID-19 pandemic than before the pandemic. However, the impact is not yet understood well.MethodsProspectively collected data from the NETherlands QUality of life and BIomedical Cohort study in HNC were used. All patients were diagnosed and treated before the COVID-19 pandemic. Patient reported outcome measures (PROMs) collected 24 and 36 months after treatment (M24 and M36) were compared between survivors who completed both assessments before the COVID-19 pandemic and those who completed M24 before but M36 during the pandemic. Personal, clinical, physical, psychological, social, and lifestyle characteristics of the survivors assessed at baseline or M24 were investigated as potential effect modifiers.ResultsIn total, 318 HNC survivors were included, of which 199 completed both M24 and M36 before the COVID-19 pandemic and 119 completed M24 before but M36 during the pandemic. Changes in HRQOL between 24 and 36 months follow-up did not differ between the two groups for any of the PROMs. However, in some subgroups of HNC survivors the COVID-19 pandemic negatively affected the course of HRQOL for several PROMs while it positively affected the course of HRQOL for other PROMs.ConclusionsThe COVID-19 pandemic did not affect HRQOL in HNC survivors in general, but some subgroups were affected in a positive and others in a negative way.FundingThis work was supported by the Dutch Cancer Society [grant number VU 2013–5930] and the Dutch Cancer Society, Alpe Young Investigator Grant [grant number 12820].
Physical Activity Delays Obesity-Associated Pancreatic Ductal Adenocarcinoma in Mice and Decreases Inflammation
Authors: Pita-Grisanti Valentina , Dubay Kelly , Lahooti Ali , Badi Niharika , Ueltschi Olivia , Gumpper-Fedus Kristyn , Hsueh Hsiang-Yin , Lahooti Ila , Chavez-Tomar Myrriah , Terhorst Samantha , Knoblaugh Sue E. , Cao Lei , Huang Wei , Coss Christopher C. , Mace Thomas A. , Choueiry Fouad , Hinton Alice , Mitchell Jennifer M , Schmandt Rosemarie , Grinsfelder Michaela Onstad , Basen-Engquist Karen , Cruz-Monserrate Zobeida 
Published: January 2023

ABSTRACTBACKGROUND & AIMSObesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity might prevent obesity-associated PDAC. Here, we examined whether decreasing obesity by increased physical activity (PA) and/or dietary changes would decrease inflammation in humans and prevent PDAC in mice.METHODSCirculating inflammatory-associated cytokines of overweight and obese subjects before and after a PA intervention were compared. PDAC pre-clinical models were exposed to PA and/or dietary interventions after obesity-associated cancer initiation. Body composition, tumor progression, growth, fibrosis, inflammation, and transcriptomic changes in the adipose tissue were evaluated.RESULTSPA decreased the levels of systemic inflammatory cytokines in overweight and obese subjects. PDAC mice on a diet-induced obesity (DIO) and PA intervention, had delayed weight gain, decreased systemic inflammation, lower grade pancreatic intraepithelial neoplasia lesions, reduced PDAC incidence, and increased anti-inflammatory signals in the adipose tissue compared to controls. PA had additional cancer prevention benefits when combined with a non-obesogenic diet after DIO. However, weight loss through PA alone or combined with a dietary intervention did not prevent tumor growth in an orthotopic PDAC model. Adipose-specific targeting of interleukin (IL)-15, an anti-inflammatory cytokine induced by PA in the adipose tissue, slowed PDAC growth.CONCLUSIONSPA alone or combined with diet-induced weight loss delayed the progression of PDAC and reduced systemic and adipose inflammatory signals. Therefore, obesity management via dietary interventions and/or PA, or modulating weight loss related pathways could prevent obesity-associated PDAC in high-risk obese individuals.Graphical Abstract
mRNA delivery of dimeric human IgA protects mucosal tissues from bacterial infection
Authors: Deal Cailin E. , Richards Angelene F. , Yeung Tracy , Maron Max J. , Wang Ziqiu , Lai Yen-Ting , Fritz Brian R. , Himansu Sunny , Narayanan Elisabeth , Liu Ding , Koleva Rositsa , Licht Stuart , Hsiao Chiaowen J. , Rajlic Ivana L. , Koch Hillary , Kleyman Michael , Pulse Mark E. , Weiss William J. , Doering Jennifer E. , Lindberg Samantha K. , Mantis Nicholas J. , Carfi Andrea , Plante Obadiah J. 
Published: January 2023

AbstractMonoclonal antibody (mAb) therapy is a promising infectious disease intervention strategy but is limited to IgG1 isotypes that have restricted access to mucosal sites. IgA is well-established as the predominant antibody isotype in mucosal secretions but is clinically underutilized. To enable development of IgA-based mAbs, we exploited mRNA platform technology and demonstrated expression of functional, antigen-specific IgA (IgAmRNA) that can limit bacterial invasion in the intestine and prevent colonization in the lung. Moreover,in vivoIgAmRNAhad enhanced serum half-life and a greater degree of sialylation than a recombinantly produced IgA. The results underscore the potential of mRNA-based platforms to deliver protective human mAbs to mucosal surfaces and open new avenues to combat infectious diseases in the face of pervasive antibiotic resistance.One Sentence SummarymRNA-encoded human monoclonal IgA traffics to mucosal tissues and provides protection against bacterial challenge
An Automated Scientist to Design and Optimize Microbial Strains for the Industrial Production of Small Molecules
Authors: Singh Amoolya H. , Kaufmann-Malaga Benjamin B. , Lerman Joshua A. , Dougherty Daniel P. , Zhang Yang , Kilbo Alexander L. , Wilson Erin H. , Ng Chiam Yu , Erbilgin Onur , Curran Kate A. , Reeves Christopher D. , Hung John E. , Mantovani Simone , King Zachary A. , Ayson Marites J. , Denery Judith R. , Lu Chia-Wei , Norton Phillip , Tran Carol , Platt Darren M. , Cherry Joel R. , Chandran Sunil S. , Meadows Adam L. 
Published: January 2023

AbstractEngineering microbes to synthesize molecules of societal value has historically been a time consuming and artisanal process, with the synthesis of each new non-native molecule typically warranting its own separate publication. Because most microbial strain engineering efforts leverage a finite number of common metabolic engineering design tactics, we reasoned that automating these design steps would help create a pipeline that can quickly, cheaply, and reliably generate so-called microbial factories. In this work we describe the design and implementation of a computational system, an Automated Scientist we call Lila, which handles all metabolic engineering design and optimization through the design-build-test-learn (DBTL) paradigm. Lila generates metabolic routes, identifies relevant genetic elements for perturbation, and specifies the design and re-design of microbial strains in a matter of seconds to minutes. Strains specified by Lila are then built and subsequently phenotyped as part of a largely automated in-house pipeline. Humans remain in-the-loop to curate choices made by the system, helping for example to refine the metabolic model or suggest custom protein modifications. Lila attempted to build strains that could produce 454 biochemically diverse molecules with precursors located broadly throughout the metabolism of two microbial hosts,Saccharomyces cerevisiaeandEscherichia coli. Notably, we observed the highest published titers for the molecule naringenin, the metabolic precursor to flavonoids. In total we created hundreds of thousands of microbial strains capable of overproducing 242 molecules, of which 180 are not native toS. cerevisiaeorE. coli.
Human embryonic tanycyte: heterogeneity and developmental trajectory
Authors: Li Yuan 
Published: January 2023

AbstractDisruption of energy homeostasis may cause diseases such as obesity and diabetes that affect millions of people every year. The adult hypothalamic stem cells, tanycytes, play critical roles in helping hypothalamic neurons maintain energy homeostasis, however the developmental trajectory of tanycytes especially in human still awaits to be discovered. In the current study, we for the first time use human embryonic single cell transcriptomics data to distinguish RAX+tanycytes from RAX+neural progenitors, explore human embryonic tanycyte heterogeneity, and unravel their developing trajectories. We found human embryonic tanycytes share similar subtypes with adult rodent tanycytes (α and β). We also discovered that radial glia markersFABP7as well as astrocyte marker (e.g.AQP4) etc, are characteristics of tanycytes that distinguish them from RAX+neural progenitors, and the α and β tanycytes follow different developmental trajectories. Our study represents a pioneer work on human embryonic tanycytes.
Control of atypical PKCι membrane dissociation by tyrosine phosphorylation within a PB1-C1 interdomain interface
Authors: Cobbaut Mathias , McDonald Neil Q. , Parker Peter J. 
Published: January 2023

AbstractAtypical PKCs are cell polarity kinases that operate at the plasma membrane where they function within multiple molecular complexes to contribute to the establishment and maintenance of polarity. In contrast to the classical and novel PKCs, atypical PKCs do not respond to diacylglycerol cues to bind the membrane compartment. Until recently it was not clear how aPKCs are recruited; whether aPKCs can directly interact with membranes or whether they are dependent on other protein interactors to do so. Two recent studies identified the pseudo-substrate region and the C1 domain as direct membrane interaction modules, however their relative importance and coupling are unknown. We combined molecular modelling and functional assays to show that the regulatory module of aPKCι, comprising the PB1 pseudo-substrate and C1 domains, forms a cooperative and spatially continuous invariant membrane interaction platform. Furthermore, we show the coordinated orientation of membrane-binding elements within the regulatory module requires a key PB1-C1 interfacial β-strand (BSL). We show this element contains a highly conserved Tyr residue that can be phosphorylated and that negatively regulates the integrity of the regulatory module, leading to membrane release. We thus expose a novel regulatory mechanism of aPKCι membrane binding and release during cell polarization.
Structural insights into ion conduction by novel cation channel, TMEM87A, in Golgi apparatus
Authors: Han Ah-reum , Zhang Aihua , Kang Hyunji , Maria-Solano Miguel A. , Yang Jimin , Lee C. Justin , Choi Sun , Kim Ho Min 
Published: January 2023

AbstractTMEM87 family is evolutionarily conserved eukaryotic transmembrane proteins residing in the Golgi1. TMEM87 members play a role in retrograde transport in Golgi and are also proposed mechanosensitive ion channel implicated in cancer and heart disease2–7. In an accompanying study, TMEM87A is described as a voltage-gated, pH-sensitive, non-selective cation channel whose genetic ablation in mice disrupts Golgi morphology, alters glycosylation and protein trafficking, and impairs hippocampal memory. Despite the pivotal functions of TMEM87s in Golgi, underlying molecular mechanisms of channel gating and ion conduction have remained unknown. Here, we present a high-resolution cryo-electron microscopy structure of human TMEM87A (hTMEM87A). Compared with typical ion channels, the architecture of hTMEM87A is unique: a monomeric cation channel consisting of a globular extracellular/luminal domain and a seven-transmembrane domain (TMD) with close structural homology to channelrhodopsin. The central cavity within TMD is occupied by endogenous phosphatidylethanolamine, which seals a lateral gap between two TMs exposed to the lipid bilayer. By combining electrophysiology and molecular dynamics analysis, we identify a funnel-shaped electro-negative luminal vestibule that effectively attracts cations, and phosphatidylethanolamine occludes ion conduction. Our findings suggest that a conformational switch of highly conserved positively-charged residues on TM3 and displacement of phosphatidylethanolamine are opening mechanisms for hTMEM87A, providing an unprecedented insight into the molecular basis for voltage-gated ion conduction in Golgi.
Multi-omics analysis reveals the regulatory mechanism of flavonol biosynthesis during the formation of petal color inCamellia nitidissima
Authors: Feng Yi , Li Jiyuan , Chu Xian , Yin Hengfu , Fan Zhengqi , Yu Suhang , Wang Minyan , Li Xinlei , Liu Weixin 
Published: January 2023

AbstractCamellia nitidissimais a prized woody flower with golden-yellow flowers, and has high ornamental, medicinal and economic value. Previous works indicated that the content of flavonol accumulated greatly during golden petal formation. However, the molecular mechanism of golden flower formation inC. nitidissimaremains largely unknown. In this study, we performed an integrative anlysis of transcriptome, proteome and metablome of petals at five developmental stages to construct the regulatory network during golden flower formation inC. nitidissima. Metablome anlysis showed that two flavonols, the quercetin and kaempferol glycosides, were highly accumulated in the golden petals. Furthermore, transcriptome and proteome sequencing suggested that the expression of flavonol biosynthesis genes or proteins was increased in golden petal stage, whereas expression of anthocyanin and proanthocyanidin genes or proteins were decreased. SixMYBand 20bHLHgenes were identified as potentially involved in flavonoid biosynthesis, and the brassinosteroid (BR) and jasmonate (JA) pathways were positively and negatively corretated with flavonol biosynthesis, respectively. Network correlation analysis suggested close relationships among BR and JA, MYB and bHLH, and the flavonoid pathway and flavonoid metabolites. Overall, this study shows a potential regulatory mechanism of flavonol biosynthesis duing golden petal formation inC. nitidissima.HighlightThe BR and JA pathway may positively and negatively regulate flavonol synthesis inCamellia nitidissima, respectively.
HERC5-catalyzed ISGylation potentiates cGAS-mediated innate immunity
Authors: Chu Lei , Chen Yu , Qian Li , Meng Wei , Zhu Juanjuan , Wang Quanyi , Wang Chen , Cui Shufang 
Published: January 2023

AbstractThe key cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) is essential to elicit anti-infection innate immunity whereas aberrant activation of cGAS by endogenous DNA promotes severe autoimmune diseases, thus the activity of cGAS must be strictly regulated to maintain immune homeostasis. Here we report that the E3 ISG15-protein ligase HERC5 interacts with and catalyzes the cGAS ISGylation robustly, whereas the deconjugating enzyme USP18 removes the ISG15 conjugation of cGAS. The interaction of cGAS and HERC5 depends on the cGAS N-terminal domain and the RRC1-4 and HECT domain of HERC5. Mass spectrometry reveals that the Lys21,187,219,458 are the potential ISGylation sites in human cGAS. Deficiency of ISG15 or the E1 ubiquitin-activating enzyme UBA7 greatly attenuate the downstream gene expression induced by cGAS-STING axis and the antiviral ability in mouse and human cells. Collectively, our study uncovered an important role of the HERC5-facilitated cGAS ISGylaion in promoting antiviral defense.
Glycoprofiling of Cartilage Matrix-Forming Tumours
Authors: McClure John , McClure Sheena F 
Published: January 2023

ABSTRACTLectin staining of benign and malignant cartilage proliferations indicates restricted glycoprofiles and significant differences. In general terms benign lesions show less cellular binding and more matrical binding than malignant lesions. This suggests that in the benign category cells are less metabolically active and the matrix more structurally stable. Chondrosarcoma cells stain with the lectin lPHA indicating increased β1-6 branching linkages in complex N-linked glycans which is also a known feature of carcinoma cells. Increased angiogenesis and increased mast cell numbers are present in the connective tissue septa separating lobules of chondrosarcoma. The blood vessels stain with the lectins PTL-II and lPHA. Mast cells stain with lPHA.β 1-6 linkage is initiated by the Golgi-bound glycosyltransferase GnTase V. Increased β1-6 linkages are believed to enhance the metastatic potential of a malignant cell by angiogenesis. LPHA ligand is present not only in chondrosarcoma cells but also in endothelial cells and mast cells of the septa.The ligand for the lectin PTL-II is a core 1 O-linked glycans produced under the auspices of the galactosyltransferase T synthase. Production of this glycans by endothelial cells is believed to be obligatory for the formation of these cells into tubes as part of the construction of functioning blood vessels.There are, therefore, two candidate genes in chondrosarcoma worthy of further study viz those for GnTase V and T synthase. Targeted disruption of the activities of these genes has therapeutic possibilities.
Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor
Authors: Buigues Pedro J. , Gehrke Sascha , Badaoui Magd , Mandana Gaurav , Qi Tianyun , Bottegoni Giovanni , Rosta Edina 
Published: January 2023

ABSTRACTPatient symptom relief is often heavily influenced by the residence time of the inhibitor-target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodylator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights of this inhibitor remain unclear, specifically, elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide show a consistent qualitative mechanism and allowed us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved at the transition state. Additionally, our results point at relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3’s activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid towards drug design and lead optimization.DescriptionGraphical abstract of the work, showing the unbinding for ligands1(tiotropium, TTP),2(N-methylscopolamin, NMS) and3(homatropine methylbromide, CPD2). Using TTP’s downhill simulations from its unbinding transition state, different protein-ligand and proteinprotein interactions were analyzed with MLTSA to find relevant CVs driving the different outcomes.
Comprehensive locus-specific L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites
Authors: Lanciano Sophie , Philippe Claude , Sarkar Arpita , Pratella David , Domrane Cécilia , Doucet Aurélien J. , Essen Dominic van , Saccani Simona , Ferry Laure , Defossez Pierre-Antoine , Cristofari Gael 
Published: January 2023

SUMMARYLong interspersed element-1 (L1) retrotransposons play important roles in human disease and evolution. Their global activity is repressed by DNA methylation, but studying the regulation of individual copies has been difficult. Here, we combine short- and long-read sequencing to resolve the DNA methylation profiles of these repeated sequences in a panel of normal and cancer cells genome-wide at single-locus resolution. We unveil key principles underpinning L1 methylation heterogeneity among cell-types, families and integration sites. First, intronic L1 methylation is intimately associated with gene transcription. Conversely, L1s can influence the methylation status of the upstream region over short distances (300 bp). This phenomenon is accompanied by the binding of specific transcription factors, which drive the expression of L1 and chimeric transcripts. Finally, L1 hypomethylation alone is generally insufficient to trigger L1 expression due to redundant silencing pathways. Our results illuminate the epigenetic and transcriptional interplay between retrotransposons and their host genome.GRAPHICAL ABSTRACTHIGHLIGHTSBs-ATLAS-seq profiles L1 position and methylation genome-wideL1 has a frequent but short-range (300 bp) influence on the DNA methylation status of the upstream sequenceHypomethylated L1s are bound by tissue-specific transcription factors which drive L1 and chimeric transcripts synthesisL1 hypomethylation alone is insufficient to enable its transcription at most loci
Epithelioids: Self-sustaining 3D epithelial cultures to study long-term processes
Authors: Herms Albert , Fernandez-Antoran David , Alcolea Maria P. , Kalogeropoulou Argyro , Banerjee Ujjwal , Piedrafita Gabriel , Abby Emilie , Valverde-Lopez Jose Antonio , Ferreira Inês S. , Dentro Stefan C. , Ong Swee Hoe , Colom Bartomeu , Murai Kasumi , King Charlotte , Mahbubani Krishnaa , Saeb-Parsy Kourosh , Lowe Alan R , Gerstung Moritz , Jones Philip H 
Published: January 2023

ABSTRACTStudying long-term biological processes such as the colonization of aging epithelia by somatic mutant clones has been slowed by the lack of suitable culture systems. Here we describe epithelioids, a facile, cost-effective method of culturing multiple mouse and human epithelia. Esophageal epithelioids self-maintain without passaging for at least a year, recapitulating the 3D structure, cell dynamics, transcriptome, and genomic stability of the esophagus. Live imaging over 5 months showed epithelioids replicatein vivocell dynamics. Epithelioids enable the study of cell competition and mutant selection in 3D epithelia, and how anti-cancer treatments modulate the competition between transformed and wild type cells. Epithelioids are a novel method with a wide range of applications in epithelial tissues, particularly the study of long term processes, that cannot be accessed using other culture models.