bluuebunny/crossref_metadata_2025_split huggingface dataset:
Merkel cell polyomavirus regulates miR183 cluster and piR62011 in Merkel cell carcinoma
Authors: Arora Reety , Dohadwala Lamiya , Nanavati Bageshri Naimish , Lakshmanan Vairavan , Mukherjee Sanjukta 
Published: January 2022

ABSTRACTMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer, a major subset of which is caused by the clonal integration of Merkel Cell Polyomavirus (MCV). Recent studies by Cheng et al. (2017) reported that virus-derived small T antigen protein-bound EP400 complex drives expression of genes essential for cellular transformation. On close analysis of their ChIP-Seq data, we uncovered that the complex binds to the promoter region of the microRNA-183 cluster. The miRNA183 cluster is a cluster of 3 miRNAs (miR183, 182 & 96) expressed and regulated together. These miRNAs are conserved across species, highly expressed in human embryonic stem cells and necessary for sensory/ mechanosensory organ development. We hypothesized that the MCV oncoproteins regulate host miRNA expression directly; an interaction novel in polyomaviruses. We tested miRNA expression via qPCR in both virus positive and negative MCC cell lines and found the former showed a much higher level. Further, fibroblasts expressing T antigens displayed an increase in miR182 expression in comparison to control. Knock-down of T antigens in MCC cells correspondingly decreased miR182 levels. To investigate its regulation we performed luciferase assays for the miRNA predicted promoter that showed increased activity in the presence of T antigens. Intriguingly, the seed sequence of miR182 completely matches to a piRNA called piR62011. Upon reanalysis of a MCC small RNA library, piR62011 emerged as the highest expressed. We found it expressed in MKL-1, a MCV positive cell line as well. Finally, to translate our findings into therapy for MCC, we screened small molecule (CMBL) library by performing surface plasmon resonance (SPR) assay and identified small molecules that binds to pre-miRNA182 and are testing them for their activity to kill MCC.
SARS-CoV-2 infection results in lasting and systemic perturbations post recovery
Authors: Frere Justin J. , Serafini Randal A. , Pryce Kerri D. , Zazhytska Marianna , Oishi Kohei , Golynker Ilona , Panis Maryline , Zimering Jeffrey , Horiuchi Shu , Hoagland Daisy A. , Møller Rasmus , Ruiz Anne , Overdevest Jonathan B. , Kodra Albana , Canoll Peter D. , Goldman James E. , Borczuk Alain C. , Chandar Vasuretha , Bram Yaron , Schwartz Robert , Lomvardas Stavros , Zachariou Venetia , tenOever Benjamin R. 
Published: January 2022

SUMMARYSARS-CoV-2 has been found capable of inducing prolonged pathologies collectively referred to as Long-COVID. To better understand this biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. While SARS-CoV-2 exceeded IAV in its capacity to cause injury to the lung and kidney, the most significant changes were observed in the olfactory bulb (OB) and olfactory epithelium (OE) where inflammation was visible beyond one month post SARS-CoV-2 infection. Despite a lack of detectable virus, OB/OE demonstrated microglial and T cell activation, proinflammatory cytokine production, and interferon responses that correlated with behavioral changes. These findings could be corroborated through sequencing of individuals who recovered from COVID-19, as sustained inflammation in OB/OE tissue remained evident months beyond disease resolution. These data highlight a molecular mechanism for persistent COVID-19 symptomology and characterize a small animal model to develop future therapeutics.
Broad-host-range mutagenesis with CRISPR-associated transposase
Authors: Rodríguez Lidimarie Trujillo , Ellington Adam J. , Reisch Christopher R. 
Published: January 2022

AbstractTransposons have been instrumental tools in microbiology enabling random mutagenesis, with transposons like Tn5 and Mariner, and site-specific DNA integrations with Tn7. However, programmable targeting of transposons was impossible until CRISPR-associated transposase (CasTn) systems were described. Like other CRISPR-derived systems, CasTn can be programmed with a short DNA encoded sequence that is transcribed into a guide-RNA. Here we describe a broad-host-range CasTn system and demonstrate its function in bacteria from three classes of the Proteobacteria. The CasTn genes are expressed from a broad-host-range replicative plasmid, while the guide-RNA and transposon are provided on a high-copy pUC plasmid that is suicidal in most bacteria outside of E. coli. Using our CasTn system, single-gene disruptions were performed with on-target efficiencies approaching 100% in the Beta- and Gammaproteobacteria, Burkholderia thailandensis, and Pseudomonas putida, respectively. The results were more modest in the Alphaproteobacterium Agrobacterium fabrum, with a peak efficiency of 45%, though for routine single-gene disruptions, this efficiency is adequate. In B. thailandensis, the system allowed simultaneous co-integration of transposons at two different target sites. The CasTn system is also capable of high-efficiency large transposon insertion totaling over 11 kbp in P. putida. Given the iterative capabilities and large payload size, this system will be helpful for genome engineering experiments across several fields of research.SignificanceThe genetic modification of bacteria to disrupt native genes and integrate recombinant genes is necessary for basic and applied research. Traditional methods for targeted disruptions and insertions are often cumbersome and inefficient, limiting experiments' scale and throughput. This work developed a system for targeted transposon mutagenesis that is easy to use, iterative, and efficient. We demonstrate that the system functions across three different classes of the Proteobacteria in species widely used in research and biotechnology. Moreover, the framework of the system and accompanying plasmids that we developed will facilitate porting the system to other bacteria. Our system provides a fast and efficient protocol to genetically modify these bacteria by inserting desired genetic cargo into specific genomic targets.
Lamin A/C phosphorylation at serine 22 is a conserved heat shock response to regulate nuclear adaptation during stress
Authors: Virtanen Laura , Holm Emilia , Halme Mona , West Gun , Lindholm Fanny , Gullmets Josef , Irjala Juho , Heliö Tiina , Padzik Artur , Meinander Annika , Eriksson John E. , Taimen Pekka 
Published: January 2022

ABSTRACTThe heat shock (HS) response is crucial for cell survival in harmful environments. Nuclear lamin A/C, encoded by LMNA gene, has been shown to contribute towards altered gene expression during heat shock, but the underlying mechanisms are poorly understood. Here we show that reversible lamin A/C phosphorylation at Ser22 upon HS is an evolutionary conserved stress response that is triggered in concert with HSF1 activation in human and mouse cells and can also be observed in D. melanogaster in vivo. Consequently, the phosphorylation increase facilitated nucleoplasmic localization of lamin A/C and nuclear rounding in response to HS. The importance of lamin phosphorylation equilibria in HS was confirmed by lamin A/C knock-out (KO) cells that showed deformed nuclei after HS and were rescued by ectopic expression of wild-type, but not by a phosphomimetic (S22D) lamin A mutant. Furthermore, HS triggered release of lamina-associated protein 2α (Lap2α) from its association with lamin A/C and concurrently its downregulation, a response that was perturbed in lamin A/C KO cells and in LMNA mutant patient fibroblasts. The abrogated Lap2α response resulted in impaired cell cycle arrest under HS and compromised survival at the recovery. Taken together, our results suggest that the altered phosphorylation stoichiometry of lamin A/C provides an evolutionary conserved mechanism to regulate lamin structure and serve nuclear adaptation and cell survival during HS.
Macroscopic control of synchronous electrical signaling with chemically-excited gene expression
Authors: García-Navarrete M. , Avdovic Merisa , Pérez García S. , Ruiz Sanchis D. , Wabnik K. 
Published: January 2022

AbstractExcitable cells can convert electrical signals into chemical outputs to facilitate the active transport of information across larger distances. This electrical-to-chemical conversion requires a tightly regulated expression of ion channels. Alterations of ion channel expression provide landmarks of numerous pathological diseases, such as cardiac arrhythmia, epilepsy, or cancer. Although the activity of ion channels can be locally regulated by external light or chemical stimulus, it remains challenging to coordinate the expression of ion channels on extended spatial-temporal scales in a non-invasive manner. Here, we have engineered yeast S. cerevisiae to read and convert local chemical concentrations into a dynamic electrical field distributed across cell populations. The core mechanism encodes a chemically-excitable dual-feedback gene circuit that precisely tunes the expression domain of potassium channels, globally coordinating cyclic firing of the plasma membrane potential (PMP). We demonstrate that this mechanism leverages an engineered constitutively open bacterial potassium channel KcsA to directly couple chemical stimuli with ion flux through gene expression and it can interface with the host ion channels through the pulsatile production of toxins. Our study provides a robust synthetic transcriptional toolbox underlying the conversion of local chemical environments into spatiotemporally organized electrical impulses for various cellular engineering, synthetic biology, and potential therapeutic applications.
Structural features of Dnase1L3 responsible for serum antigen clearance
Authors: McCord Jon J. , Engavale Minal , Masoumzadeh Elahe , Villarreal Johanna , Mapp Britney , Latham Michael P. , Keyel Peter A. , Sutton R. Bryan 
Published: January 2022

ABSTRACTAutoimmunity develops when extracellular DNA released from dying cells is not cleared from serum. While serum DNA is primarily digested by Dnase1 and Dnase1L3, Dnase1 does not rescue autoimmunity arising from Dnase1L3 deficiencies. Dnase1L3 uniquely degrades antigenic forms of cell-free DNA, including DNA complexed with lipids and proteins. The distinct activity of Dnase1L3 relies on its unique C-terminal Domain (CTD), but the mechanism is unknown. We used multiple biophysical techniques and functional assays to study the interplay between the core catalytic domain and the CTD. While the core domain resembles Dnase1, there are several key differences between the two enzymes. Dnase1L3 is not inhibited by actin due to multiple differences in the actin recognition site. The CTD augments the ability of the core to bind DNA, thereby facilitating the degradation of complexed DNA to prevent autoimmune pathology. Together, these structural insights will inform the development of Dnase1L3-based therapies for autoimmunity.
Linking Dynamic DNA Secondary Structures to Genome Instability
Authors: Matos-Rodrigues Gabriel , van Wietmarschen Niek , Wu Wei , Tripathi Veenu , Koussa Natasha , Pavani Raphael , Nathan William , Belinky Frida , Mohammed Ashraf , Napierala Marek , Usdin Karen , Ansari Aseem Z. , Mirkin Sergei M. , Nussenzweig André 
Published: January 2022

SummaryGenomic double-stranded DNA (dsDNA) becomes single-stranded (ssDNA) during replication, transcription, and DNA repair. ssDNA is therefore believed to be transient, occurring in only a fraction of the genome at a given time, and variable amongst a population of cells. These transiently formed ssDNA segments can also adopt alternative, dynamic DNA conformations, such as cruciform DNA, triplexes, quadruplexes and others. To determine whether there are stable and conserved regions of ssDNA, we utilized our previously developed method S1-END-seq 1 to convert ssDNA to DNA double strand breaks (DSBs), which are then processed for high-throughput sequencing. This approach revealed two predominant dynamic DNA structures: cruciform DNA formed by expanded (TA)n repeats that accumulated uniquely in microsatellite unstable human cancer cell lines, and DNA triplexes (H-DNA) formed by homopurine/homopyrimidine (hPu/hPy) mirror repeats common across a variety of human cell lines. Triplex-forming repeats accumulated during replication, blocked DNA synthesis and were hotspots of somatic mutation. In contrast, pathologically expanded (hPu/hPy) repeats in Friedreich’s ataxia patient cells formed a replication-independent and transcription-inducible DNA secondary structure. Our results identify dynamic DNA secondary structures in vivo that contribute to elevated genome instability.
Sustainability performance disclosures: the impact of gender diversity and intellectual capital on GRI standards compliance in Uganda
Authors: Bananuka Juma , Nkundabanyanga Stephen Korutaro , Kaawaase Twaha Kigongo , Mindra Rachel Katoroogo , Kayongo Isaac Newton 
Published: January 2022

PurposeThe purpose of this study is to examine the extent of and impact of gender diversity and intellectual capital on compliance with Global Reporting Initiative (GRI) sustainability reporting standards by Uganda manufacturing companies.Design/methodology/approachData were collected from manufacturing firms in Uganda using a questionnaire survey to find out their perception of compliance with the GRI standards. Data were analyzed using statistical package for social sciences, Microsoft Excel and smart partial least squares structural equation modeling (PLS–SEM).FindingsThe results indicate that on average, manufacturing firms in Uganda comply with GRI sustainability reporting standards to the extent of 59%. The results further indicate that manufacturing companies comply more with the GRI 200 (economic performance disclosures) to the extent of 63% as compared with 55% for GRI 300 (environmental performance disclosures) and 58% for GRI 400 (social performance disclosures). The results also indicate that intellectual capital has a significant impact on the GRI-based sustainability performance disclosures in Uganda. However, board gender diversity has no significant effect. In terms of the control variables, only firm size is significant, while firm age, capital structure and auditor type are not.Originality/valueThis study provides first time evidence of the extent of compliance with the GRI sustainability reporting standards using evidence from Uganda – an African developing country. This study widens the understanding of the usage of GRI standards in the preparation of sustainability reports by manufacturing firms in an emerging economy. This study also provides first-time evidence on the role of gender diversity and intellectual capital in GRI-based sustainability performance disclosures using evidence from Uganda's manufacturing sector.
Ancient routes, new gateways: a systematic literature review of China's cultural route heritage
Authors: Zhang Ke , González del Valle-Brena Almudena , Ramos Riera Ignacio , Zhao Jingli 
Published: January 2022

PurposeThe study aims to understand how cultural route heritage is conceptualized and managed in China by systematically reviewing the research literature on Chinese cultural route heritage (CRH). The study intends to inspire further discussion on the theoretical and practical development of cultural routes since the development is still at a liminal stage in China.Design/methodology/approachA total of 253 research articles related to Chinese cultural rote heritage from major Chinese and English research databases China National Knowledge Infrastructure (CNKI), Web of Science (WOS) and Scopus have been comprehensively identified and reviewed for the purpose of the study.FindingsFour major themes of research on Chinese CRH have been identified: conceptual evaluation, list of the routes and characteristics of the routes, conservation and utilization. The results revealed that China has very rich resources in CRH, many of which were formed a long time ago, which exist across vast geographic regions and have assumed multiple functions and undergone dynamic reciprocal exchanges among diverse cultures and ethnicities.Practical implicationsThe paper summarizes some major obstacles faced by CRH in China and proposes a strategic model to address the need for a more sustainable development of CRH in the Chinese context.Originality/valueThe paper offers a comprehensive overview of CRH in China and discusses practical issues in management and development of heritage great in size, number and complexity.
Prevalence of genetically similar Flavobacterium columnare phages across aquaculture environments reveals a strong potential for pathogen control
Authors: Runtuvuori‐Salmela Anniina , Kunttu Heidi M. T. , Laanto Elina , Almeida Gabriel M. F. , Mäkelä Kati , Middelboe Mathias , Sundberg Lotta‐Riina 
Published: January 2022

SummaryIntensive aquaculture conditions expose fish to bacterial infections, leading to significant financial losses, extensive antibiotic use and risk of antibiotic resistance in target bacteria. Flavobacterium columnare causes columnaris disease in aquaculture worldwide. To develop a bacteriophage‐based control of columnaris disease, we isolated and characterized 126 F. columnare strains and 63 phages against F. columnare from Finland and Sweden in 2017. Bacterial isolates were virulent on rainbow trout (Oncorhynchus mykiss) and fell into four previously described genetic groups A, C, E and G, with genetic groups C and E being the most virulent. Phage host range studied against a collection of 227 bacterial isolates (from 2013 to 2017) demonstrated modular infection patterns based on host genetic group. Phages infected contemporary and previously isolated bacterial hosts, but bacteria isolated most recently were generally resistant to previously isolated phages. Despite large differences in geographical origin, isolation year or host range of the phages, whole‐genome sequencing of 56 phages showed high level of genetic similarity to previously isolated F. columnare phages (Ficleduovirus, Myoviridae). Altogether, this phage collection demonstrates a potential for use in phage therapy.
Respectability and boundary making on a superdiverse housing estate: The cross‐racial deployment of intra‐ethnic stereotypes
Authors: Rosbrook‐Thompson James , Armstrong Gary 
Published: January 2022

AbstractThis article examines how white British residents of a superdiverse London housing estate learn about—and subsequently deploy—the intra‐ethnic stereotypes used by their British Pakistani and British Bangladeshi neighbours/flatmates. Building on recent attempts to bring together conviviality and boundary making, along with insights into intra‐ethnic othering, we show how, for white British residents, these stereotypes offered the chance to add detail and authenticity to judgements about the “unrespectable” behaviour of British Asian residents and/or visitors. Ultimately, however, white British residents' inappropriate and/or imprecise deployment of these stereotypes in relation to British Bangladeshis and British Pakistanis led to the misidentification of low‐status people and the unfair extension of discrimination faced by low‐status individuals and families. Furthermore, the combination of clumsy application and the positioning of “respectable” British Bangladeshis and British Pakistanis as purveyors of “insider knowledge” about intra‐ethnic stereotypes led to the reinscribing of boundaries between racial groups. We conclude that studying the cross‐racial use of intra‐ethnic stereotypes allows for a subtler appreciation of the complex dynamics of inclusion and exclusion in superdiverse areas.
Seasonal variations in the composition and functional profiles of gut microbiota reflect dietary changes in plateau pikas
Authors: FAN Chao , ZHANG Liangzhi , JIA Shangang , TANG Xianjiang , FU Haibo , LI Wenjing , LIU Chuanfa , ZHANG He , CHENG Qi , ZHANG Yanming 
Published: January 2022

AbstractSeasonal variations in gut microbiota of small mammals and how they are influenced by environmental variables are relatively poorly understood. We sampled 162 wild plateau pikas (Ochotona curzoniae) in 4 seasons over 2 and a half years and recorded the air temperature, precipitation, and nutrient content in edible vegetation at the sampling site. After conducting 16S rRNA and shotgun metagenomic sequencing, we found that the highest alpha diversity, the relative abundance of Firmicutes, and the simplest co‐occurrence network occurred in winter, whereas the highest relative abundance of Proteobacteria and the most complex network structure were observed in spring. The highest relative abundance of Verrucomicrobiota and Spirochaetota was seen in summer and autumn, respectively. Air temperature, precipitation, and the contents of crude protein, crude fiber, and polysaccharide in vegetation had significant effects on the seasonal changes in gut microbiota. Diet contributed more to microbial variation than climatic factors. Metagenomic analysis revealed that the amino acid metabolism pathway and axillary activity enzymes were most abundant in summer, while abundance of carbohydrate‐binding modules and carbohydrate esterases was highest in spring. These microbial variations were related to the changes in dietary nutrition, indicating that gut microbiota of plateau pika contribute to the efficient use of food resources. This study provides new evidence of how external environmental factors affect the intestinal environment of small mammals.
Pixantrone in patients with relapsed/refractory diffuse large B‐cell lymphoma: A real‐life, retrospective, multicenter trial on behalf of the “RTL” (Regional Tuscan Lymphoma network)
Authors: Cencini Emanuele , Mecacci Bianca , Rocco Melania , Innocenti Fabio , Ghio Francesco , Puccini Benedetta , Della Seta Roberta , Simonetti Federico , Mannelli Lara , Cuccaro Annarosa , Bocchia Monica , Fabbri Alberto 
Published: January 2022

AbstractIntroductionPixantrone is a novel aza‐anthracenedione with antineoplastic activity, currently approved for multiply relapsed/refractory diffuse large B‐cell lymphoma (DLBCL), even if real‐life data are limited.MethodsWe investigated pixantrone efficacy and safety in clinical practice, as 3rd or 4th line therapy. We retrospectively analyzed a cohort of 37 R/R DLBCL patients managed in 8 Tuscan onco‐hematological centers. Pixantrone, 50 mg/m2, was administered on days 1, 8, 15 of a 28 days cycle for up to 6 cycles. Response to therapy was evaluated according to the Lugano 2014 classification.ResultsPixantrone was administered as 3rd or 4th line in 24/37 (64.9%) and 13/37 (35.1%) cases. Overall response rate and CR rate were 43.2% and 32.4%. After a median follow‐up of 6 months, 17/37 patients (46%) were alive, the main cause of death was progressive disease (14/37 cases, 37.9%).Median PFS was 3 months, median DOR was 17.9 months, and median OS was 9.7 months. A significant proportion of patients achieved a long‐lasting response >12 months (8/37 cases). IPI>2 showed a trend toward inferior PFS.ConclusionIn this real‐life setting, pixantrone demonstrated appreciable efficacy in a population with poor prognosis; in a small proportion of cases, it can be associated with long‐term remission.