bluuebunny/crossref_metadata_2025 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

Background

Physical, 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.

Methods

Prospectively 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.

Results

In 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.

Conclusions

The 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.

Funding

This 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

BACKGROUND & AIMS

Obesity 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.

METHODS

Circulating 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.

RESULTS

PA 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.

CONCLUSIONS

PA 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

Monoclonal 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 Summary

mRNA-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

Engineering 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

Disruption 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

Atypical 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

TMEM87 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

Camellia 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.

Highlight

The 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

The 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

Lectin 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

Patient 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.

Description

Graphical 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

Long 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 ABSTRACT

HIGHLIGHTS

Bs-ATLAS-seq profiles L1 position and methylation genome-wide

L1 has a frequent but short-range (300 bp) influence on the DNA methylation status of the upstream sequence

Hypomethylated L1s are bound by tissue-specific transcription factors which drive L1 and chimeric transcripts synthesis

L1 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

Studying 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.
A step towards measuring connectivity in the deep sea: elemental fingerprints of mollusk larval shells discriminate hydrothermal vent sites
Authors: Mouchi Vincent , Pecheyran Christophe , Claverie Fanny , Cathalot Cécile , Matabos Marjolaine , Germain Yoan , Rouxel Olivier , Jollivet Didier , Broquet Thomas , Comtet Thierry
Published: January 2023

Deep-sea hydrothermal-vent systems are under investigation for base and precious metal exploitations. The impact of mining will depend critically on the ability of larval dispersal to connect and replenish endemic populations. However, assessing connectivity is extremely challenging, especially in the deep sea. Here, we investigate the potential of elemental fingerprinting of mollusc larval shells to discriminate larval origins between multiple hydrothermal sites in the Southwest Pacific Ocean. The gastropodShinkailepas tollmannirepresents a suitable candidate as it uses capsules to hold larvae before dispersal, which facilitates sampling and ensures mineralization occurs on the site of origin. Multielemental microchemistry was performed using cutting-edge femtosecond laser ablation Inductively Coupled Plasma Mass Spectrometry analysis to obtain individual measurements on 600 encapsulated larval shells. We used classification methods to discriminate the origin of individuals from 14 hydrothermal sites spanning over 3,500 km, with an overall success rate of 70%. When considering less sites within more restricted areas, reflecting dispersal distances reported by genetic and modelling approaches, the success rate increased up to 86%. We conclude that individual larval shells register site-specific elemental signatures that can be used to assess their origin. These results open new perspectives to get direct estimates on population connectivity from the geochemistry of pre-dispersal shell of recently settled juveniles.
Molecular architecture of the ciliary tip revealed by cryo-electron tomography
Authors: Legal T. , Tong M. , Black C. , Valente Paterno M. , Gaertig J. , Bui K.H.
Published: January 2023

Cilia are essential organelles that protrude from the cell body. Cilia are made of a microtubule-based structure called the axoneme. In most types of cilia, the ciliary tip is distinct from the rest of the cilium. Here, we used cryo-electron tomography and subtomogram averaging to obtain the structure of the ciliary tip of the ciliateTetrahymena thermophila. We show the microtubules in the tip are highly cross-linked with each other and stabilised by luminal proteins, plugs and cap proteins at the plus ends. In the tip region, the central pair lacks the typical projections and twists significantly. By analysing cells lacking a ciliary tip-enriched proteinCEP104/FAP256by cryo-electron tomography and proteomics, we discovered candidates for the central pair cap complex and explain potential functions ofCEP104/FAP256. These data provide new insights into the function of the ciliary tip and inform about the mechanisms of ciliary assembly and length regulation.
Structural mechanism ofLIN28Bnucleosome targeting by OCT4 for pluripotency
Authors: Guan Ruifang , Lian Tengfei , Zhou Bing-Rui , Bai Yawen
Published: January 2023

Pioneer transcription factors are essential for cell fate changes by targeting closed chromatin. OCT4 is a crucial pioneer factor that can induce cell reprogramming. However, the structural basis of how pioneer factors recognize thein vivonucleosomal DNA targets is unknown. Here, we determine the high-resolution structures of the nucleosome containing humanLIN28BDNA and its complexes with the OCT4 DNA binding region. Three OCT4s bind the pre-positioned nucleosome by recognizing non-canonical DNA motifs. Two use their POUS domains by forming extensive hydrogen bonds. The other uses the POUS-loop-POUHD region; POUHD serves as a wedge to unwrap ∼25 base pair DNA. Biochemical studies suggest that multiple OCT4s cooperatively open the H1-condensed nucleosome array containing theLIN28Bnucleosome. Our study suggests a mechanism whereby OCT4s target theLIN28Bnucleosome by forming multivalent interactions with nucleosomal motifs, unwrapping nucleosomal DNA, evicting H1, and cooperatively open closed chromatin to initiate cell reprogramming.
MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis
Authors: Cazarin Juliana , DeRollo Rachel E. , Ahmad Shahidan Siti Noor Ain Binti , Burchett Jamison B. , Mwangi Daniel , Krishnaiah Saikumari , Hsieh Annie L. , Walton Zandra E. , Brooks Rebekah , Mello Stephano S. , Weljie Aalim M. , Dang Chi V. , Altman Brian J.
Published: January 2023

The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites in healthy tissues, is disrupted across many human cancers. Deregulated expression of the MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC or its paralog N-MYC (collectively termed MYC herein) suppress oscillation of gene expression and metabolism to upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC were examined, using time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression pathways, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter proteins while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.
Application of nanopore sequencing for accurate identification of bacterial colonies
Authors: Marshall Austin , Fuller Daniel T. , Dougall Paul , Kumaragama Kavindra , Dhaniyala Suresh , Sur Shantanu
Published: January 2023

Culture based detection remains to be one of the most reliable and acceptable techniques to detect extremely low quantity pathogens present in a sample. The process typically involves inoculating the sample on an agar plate to allow growth of the microorganisms to form colonies, followed by the identification of the individual colonies, commonly by DNA sequencing of a PCR-amplified targeted gene. Sanger method is often the default choice of sequencing as it offers affordable and accurate results for a single species. However, the technique could pose limitations in certain situations such as identification of multi-species microbial colonies. In this work, we compared the performance of Sanger sequencing with MinION nanopore sequencing in identifying bacterial colonies derived from bioaerosol samples. We conducted Sanger and nanopore sequencing of full-length 16S rRNA genes from seven bacterial colonies derived from bioaerosol samples and compared the outcome by alignment against NCBI 16S reference database. We found that for five out of seven colonies both techniques indicated the presence of the same bacterial genus. For one of the remaining colonies, a noisy Sanger electropherogram failed to generate a meaningful sequence, but nanopore sequencing identified it to be a mix of two bacterial generaAlkalihalobacillusandKocuria. For the other remaining colony, the Sanger sequencing suggestedMicrococcuswith a clean electropherogram, however, the nanopore sequencing suggested the presence of an additional genusParaburkholderia. Further corroborating these findings with mock multispecies colonies from pure bacterial DNA samples, we confirm that nanopore sequencing is comparable to the Sanger method in identifying colonies with single bacterial species but is the superior method in classifying individual bacterial components with their relative abundances in multispecies colonies. Our results suggest that nanopore sequencing could be advantageous over Sanger sequencing for colony identification in culture-based analysis of environmental samples such as bioaerosol where direct inoculation of the sample to culture plate might lead to formation of multispecies colonies.
EpiMix: an integrative tool for epigenomic subtyping using DNA methylation
Authors: Zheng Yuanning , Jun John , Brennan Kevin , Gevaert Olivier
Published: January 2023

DNA methylation (DNAme) is a major epigenetic factor influencing gene expression with alterations leading to cancer, immunological, and cardiovascular diseases. Recent technological advances enable genome-wide quantification of DNAme in large human cohorts. So far, existing methods have not been evaluated to identify differential DNAme present in large and heterogeneous patient cohorts. We developed an end-to-end analytical framework named “EpiMix” for population-level analysis of DNAme and gene expression. Compared to existing methods, EpiMix showed higher sensitivity in detecting abnormal DNAme that was present in only small patient subsets. We extended the model-based analyses of EpiMix to cis-regulatory elements within protein-coding genes, distal enhancers, and genes encoding microRNAs and lncRNAs. Using cell-type specific data from two separate studies, we discovered novel epigenetic mechanisms underlying childhood food allergy and survival-associated, methylation-driven non-coding RNAs in non-small cell lung cancer.
Small cell lung cancer co-culture organoids provide insights into cancer cell survival after chemotherapy
Authors: Sen Chandani , Koloff Caroline , Kundu Souvik , Wilkinson Dan C , Yang Juliette , Shia David W , Meneses Luisa K , Rickabaugh Tammy M , Gomperts Brigitte N
Published: January 2023

Small-cell-lung-cancer (SCLC) has the worst prognosis of all lung cancers because of a high incidence of relapse after therapy. We developed a bioengineered 3-dimensional (3D) SCLC co-culture organoid as a phenotypic tool to study SCLC tumor kinetics and SCLC-fibroblast interactions during relapse. We used functionalized alginate microbeads as a scaffold to mimic lung alveolar architecture and co-cultured SCLC cell lines with primary adult lung fibroblasts (ALF). We found that SCLCs in the model proliferated extensively, invaded the microbead scaffold and formed tumors within just 7 days. We compared the bioengineered tumors with patient tumors and found them to recapitulate the pathology and immunophenotyping of the patient tumors better than the PDX model developed from the same SCLC cell line. When treated with standard chemotherapy drugs, etoposide and cisplatin, the organoid recapitulated relapse after chemotherapy. Co-culture of the SCLC cells with ALFs revealed that the fibroblasts play a key role in inducing faster and more robust SCLC cell regrowth in the model. This was a paracrine effect as conditioned medium from the same fibroblasts was responsible for this accelerated cell regrowth. This model is also amenable to high throughput phenotypic or targeted drug screening to find new therapeutics for SCLC.
Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake
Authors: Fozzato Arianna , New Lauryn E. , Griffiths Joanne C. , Patel Bianca , Deuchars Susan A. , Filippi Beatrice M.
Published: January 2023

Brown adipose tissue (BAT) uptakes and metabolises both glucose and triglycerides to produce heat and is activated by the central nervous system (CNS) through direct noradrenergic sympathetic innervation. Dysregulation of signalling modules in selective CNS areas such as the nucleus of tractus solitarius (NTS) are linked with altered BAT activity, obesity and diabetes. High-fat diet (HFD)-feeding increases mitochondrial fragmentation in the NTS triggering insulin resistance, hyperphagia and weight gain. Here we sought to determine whether changes in mitochondrial dynamics in the NTS can affect BAT glucose uptake. Our findings demonstrated that short-term HFD feeding reduces BAT’s ability to take up glucose, as measured by PET/CT scan. However, inhibiting mitochondrial fragmentation in NTS-astrocytes of HFD-fed rats improved BAT glucose uptake while lowering blood glucose and insulin levels. Compared with HFD-fed rats, HFD fed animals, where mitochondrial fragmentation was inhibited in the NTS-astrocytes, had higher levels of catecholaminergic innervation of BAT, and did not present HFD-dependent infiltration of enlarged white fat droplets in the BAT. In regular chow-fed rats, increasing mitochondrial fragmentation in the NTS-astrocytes reduced BAT glucose uptake, catecholaminergic innervation and β3-adrenergic receptor levels. Our data suggest that targeting mitochondrial dynamics in the NTS-astrocytes could be a beneficial strategy to increase glucose utilization and protect from developing obesity and diabetes.
A fluorogenic chemically induced dimerization technology for controlling, imaging and sensing protein proximity
Authors: Bottone Sara , Cakil Zeyneb Vildan , Joliot Octave , Boncompain Gaelle , Perez Franck , Gautier Arnaud
Published: January 2023

Proximity between proteins plays an essential and ubiquitous role in many biological processes. Molecular tools enabling to control and observe the proximity of proteins are essential for studying the functional role of physical distance between two proteins. Here we present CATCHFIRE (Chemically Assisted Tethering of CHimera by Fluorogenic Induced REcognition), a chemically induced proximity technology with intrinsic fluorescence imaging and sensing capabilities. CATCHFIRE relies on genetic fusion to small dimerizing domains that interact upon addition of fluorogenic inducers of proximity that fluoresce upon formation of the ternary assembly, allowing real-time monitoring of the chemically induced proximity. CATCHFIRE is rapid and fully reversible, and allows the control and tracking of protein localization, protein trafficking, organelle transport and cellular processes, opening new avenues for studying or controlling biological processes with high spatiotemporal resolution. Its fluorogenic nature allowed furthermore the design of innovative biosensors for the study of various processes, such as signal transduction and apoptosis.
Activity of Sotrovimab against BQ.1.1 and XBB.1 Omicron sublineages in a hamster model
Authors: Driouich Jean-Sélim , Bernadin Ornéllie , Touret Franck , de Lamballerie Xavier , Nougairède Antoine
Published: January 2023

The successive emergence of SARS-CoV-2 Omicron variants has completely changed the modalities of use of therapeutic monoclonal antibodies. Recent in vitro studies indicated that only Sotrovimab has maintained partial activity against BQ.1.1 and XBB.1. In the present study, we used the hamster model to determine whether Sotrovimab retains antiviral activity against these Omicron variants in vivo. Our results show that at exposures consistent with those observed in humans, Sotrovimab remains active against BQ.1.1 and XBB.1, although for BQ.1.1 the efficacy is lower than that observed against the first globally dominant Omicron sublineages BA.1 and BA.2.
Calmness instead of panicking: re-thinking the resource allocation strategies in an era of uncertainty: a case of a developing country
Authors: Blouch Riffat , Khan Muhammad Majid
Published: January 2023

Purpose

Drawing on the concept of superior resource, capability and processes of the resource-based theory of the firm, the purpose of the current study is to analyze the influence of firms’ winner-picking strategic approach on firm performance (FP) via a direct and indirect mechanism.

Design/methodology/approach

Using survey data of 104 diversified manufacturing firms, the current study analyzed the conditional indirect effect of firms’ strategic approach on efficient resource allocation with the help of Statistical Analysis Software (SAS) process macros.

Findings

The study found that firms’ choices of winner-picking approach can undermine the resource allocation efficiency when not perfectly blended with firms’ access to the resource. Furthermore, the effect of winner-picking strategy (WPS) on resource allocation efficiency via firms’ competitive advantage (CA) can be greater when both strategic choice and resources are employed adequately.

Research limitations/implications

Despite making a unique contribution, the present study has a few limitations requiring researchers’ attention to be tackled in the forthcoming. This includes a little amount of data, a self-reporting technique and failure to include all the possible reasons that could lead to inefficient resource allocation.

Practical implications

The present research has potential applications for managers of the manufacturing industry in a period of sheer uncertainty [coronavirus disease 2019 (COVID-19)]. First, the study alerts managers about the challenges of underinvestment and overinvestment while allocating resources. At the same time, this study provides an important implication for managing the importance of firms’ access to capital (AC).

Originality/value

The current study has made a sizeable impression in the literature on internal resource allocation and resource-based theory of the firm by recommending a model that augments the theoretical foundation of strategic management of the firms. As there are only a handful of studies on this grave issue in the context of developing economies, thus, closely considering these insights would be helping for the firms for allocating resources efficiently in the manufacturing industry.
A survey of corporate communication professionals' perspective on social listening and analytics
Authors: Yavuz Şenay , Tire Engin
Published: January 2023

Purpose

The present research aimed to identify the motivations, needs, wants, preferences and limitations of corporate professionals with regard to business social analytics.

Design/methodology/approach

Online interviews were conducted with 26 professionals the majority of whom work at the management level at 20 reputable corporations in Turkey. Both qualitative and quantitative data was collected during these interviews, which lasted an average of one hour.

Findings

The findings shed light on the motivations of corporate professionals for monitoring social media and other digital media, their perceived capability and limitations in doing so, the media that they monitor and wanted to monitor if possible, their criteria and processes for working with service providers in the field of business social analytics, their needs which are not fully met by service providers, their suggestions on service improvement and their reflections on how internal and external customer data can be analyzed with an integrated approach.

Originality/value

This research is an attempt to bridge the gap between the priorities of engineers who generate artificial intelligence for the purposes of social listening and analytics and the end users, e.g. corporate communication professionals. Only by doing so, this field, which is getting more and more important as people spend more time online, will reach its full potential and benefit corporations by providing fruitful insight upon which strategic steps can be taken.
International human rights law and the intangible face of ageism
Authors: Mikołajczyk Barbara
Published: January 2023

Purpose

The purpose of this paper is to show the potential of international human rights law to raise awareness of the international community about ageism and its three aspects – old age discrimination, stereotyping and prejudices against older persons. The author evaluates the ability of international human rights law to encourage states to take action against these phenomena and looks for new solutions. The author also intends to examine if there are international law instruments compelling states to reject stereotypes and prejudices on older persons if there is no treaty devoted to them.

Design/methodology/approach

The author applies methods relevant to legal science. The core human rights treaties, soft law documents and activities of human rights bodies are selected, analysed and interpreted.

Findings

The core human rights treaties require going beyond their literal interpretation to observe older persons' rights. States should interpret them in good faith, relying on the ageing mainstreaming approach. Instruction to states on how to do so lies in the soft law and output of the international human rights bodies. However, there is also room for improvement. Therefore, the author proposes adopting a targeted resolution on counteracting ageism and its components, updating positions by international treaty bodies, and involving various human rights procedures and specialised agencies in the fight against intangible dimensions of ageism.

Originality/value

It is the first study analysing awareness about stereotyping and prejudices against older persons from international human rights law. The author indicates untapped possibilities of the fight against ageism and its intangible dimensions under international law.
Adaptation re-use of traditional cafés in Erbil, Iraq
Authors: Agha Rand H.M. , Hussein Amna Nassir
Published: January 2023

Purpose

This paper aims to shed light on adaptive reuse in traditional architecture (TA) in Erbil, Iraq.

Design/methodology/approach

An inductive approach and qualitative method were used in this study. The inductive research approach was used because there was no clear image of adaptive reuse in traditional cafés (TCs) in Erbil. Besides, there are no studies of TCs in Erbil particularly. Thus, there is a lack of knowledge about what adaptations took place in TCs in Erbil. The qualitative method extracted themes and issues from case studies of four TCs in Erbil citadel's buffer zone. This included a physical survey and observation of the TCs in Erbil and 18 semi-structured interviews with the owners, servers and visitors.

Findings

The analysis shows the flexibility of the TCs in Erbil as a face of adaptive re-use (AR) which is explained through the capacity linked to space modifications, the addition of modern devices, the function linked to space modifications, service addition, the condition linked to space modifications and the addition of modern devices. Also, TCs in Erbil has a spatial identity and architectural value that proves it is worthy enough to be preserved through unique spirituality linked to preserving the place.

Research limitations/implications

The findings are limited to the cases of TCs in mountain regain and may not be applicable or appropriate to other cafés in other different countries.

Originality/value

There are three aspects of authenticity in the current research. Firstly, the TCs in Erbil have not been studied before. Secondly, TCs that have been discovered have made AR of themselves whilst maintaining their original function-serving beverages, to stimulate creativity. Thirdly, most of the studies of AR have dealt with historical and heritage architecture, whilst the current research paper is dealing with TA.
Relationship of abusive supervision and employees’ helping behaviors: moderated-mediation perspective
Authors: Asim Muhammad , Liu Zhiying , Nadeem Muhammad Athar , Ghani Usman , Khalid Junaid , Xu Yi
Published: January 2023

Purpose

This study, based on the conservation of resource theory, aims to investigate the negative impacts of abusive supervision on helping behaviors among employees by examining the mediating role of rumination and the moderating role of psychological flexibility.

Design/methodology/approach

A total sample of 282 reliable questionnaires are collected from 282 employees working in education and banking sectors of Pakistan. SPSS and AMOS are used for data analysis of the proposed model.

Findings

The findings reveal that rumination mediates the relationship between abusive supervision and employees’ helping behavior. In addition, the results show that higher levels of psychological flexibility negatively moderate the relationship between abusive supervision and employees’ helping behaviors through mediation.

Practical implications

This study elucidates how and when abusive supervision deters helping behavior among employees and provides useful guidelines for banking/university’s administration to understand harmful consequences of abusive supervision and take appropriate policy measures to lessen their harmful effects upon employees.

Originality/value

By proposing a moderated mediation model, this study discovers rumination as a key mediator that links abusive supervision to employees’ helping behaviors and identifies the role of psychological flexibility in diminishing the negative impacts of abusive supervision upon employees’ helping behaviors through rumination.