bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lineages derived from Cryptococcus neoformans type strain H99 support a link between the capacity to be pleomorphic and virulence
Authors: Fernandes Kenya E. , Fraser James A. , Carter Dee A. 
Published: February 2022

ABSTRACTThe pathogenic yeast Cryptococcus neoformans causes nearly 200,000 deaths annually in immunocompromised individuals. Cryptococcus cells can undergo substantial morphological change during mammalian infection, including increased capsule and cell size, the release of shed capsule, and the production of titan (> 10 μm), micro (< 2 μm) and irregular cells. We examined phenotypic variation under conditions designed to simulate in vivo stress in a collection of nine lineages derived from the C. neoformans type strain H99. These lineages are highly genetically similar but have a range of virulence levels. Strains from hypervirulent lineages had a larger average capsule size, greater variation in cell size, and an increased production of micro cells and shed capsule. We tested whether disruption of SGF29, which encodes a component of the SAGA histone acetylation complex that has previously been implicated in the hypervirulence of some lineages, might also have a role in the production of morphological variants. Deletion of SGF29 in a lineage with intermediate virulence substantially increased its production of micro cells and released capsule, consistent with a switch to hypervirulence. We further examined SGF29 in a set of 52 clinical isolates and found loss-of-function mutations were significantly correlated with patient death. Expansion of a TA repeat in the second intron of SGF29 was positively correlated with cell and capsule size, suggesting it may also affect Sgf29 function. This study extends the evidence for a link between pleomorphism and virulence in Cryptococcus, with a likely role for epigenetic mechanisms mediated by SAGA-induced histone acetylation.IMPORTANCECryptococcosis is a devastating cause of death and disease worldwide. During infection, Cryptococcus cells can undergo substantial changes to their size and shape. In this study, we used a collection C. neoformans strains that are highly genetically similar but possess differing levels of virulence to investigate how morphological variation aligns with virulence. We found hypervirulent strains on average had larger capsules and greater variation in cell size, and also produced more micro cells and shed capsule. These hypervirulent strains possessed a mutation in SGF29, which encodes a component of the SAGA complex involved in epigenetic regulation. Analysis of the SGF29 gene in a set of clinical isolates found strains with loss-of-function mutations were associated with higher patient death rates. The capacity to vary appears to be linked with virulence in Cryptococcus, and this can occur in the absence of genetic variation via epigenetic mechanisms.
Single-cell molecular characterization to partition the human glioblastoma tumor microenvironment (TME) genetic background
Authors: Lessi Francesca , Franceschi Sara , Morelli Mariangela , Menicagli Michele , Pasqualetti Francesco , Santonocito Orazio , Gambacciani Carlo , Pieri Francesco , Aquila Filippo , Aretini Paolo , Mazzanti Chiara Maria 
Published: February 2022

AbstractGlioblastoma (GB) is a devastating primary brain malignancy. Recurrence of GB is inevitable despite the standard treatment of surgery, chemotherapy, and radiation, and the median survival is limited to around 15 months. Barriers to treatment include the complex interactions among the different cellular components inhabitant of the tumor microenvironment. These challenges are further compounded by extensive inter- and intra-tumor heterogeneity and by the dynamic plasticity of GB cells. The complex heterogeneous nature of GB cells is helped by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. More effective therapy development heavily depends on higher resolution molecular subtype signatures. All cellular components of a GB tumor are subjected to a continuous pressure inducing proliferation that might favor the accumulation of genetic mutations. Understanding the genetic background of several cellular component s belonging to a GB microenvironment could give insights into tumor behavior and progression. In the present study by using fluorescent multiple labeling and DEPArray cell separator, we recovered several single cells or groups of single cells from populations of different origins from IDH-WT GB samples. From each GB sample, we collected astrocytes (GFAP+), microglia (IBA+), stem cells (CD133+), and endothelial cells (CD105+) and performed Copy Number Aberration (CNA) analysis with a low sequencing depth. The same tumors were subjected to a bulk CNA analysis. The tumor partition in its single components allowed single-cell molecular subtyping which revealed new aspects of GB altered genetic background. Nowadays, single-cell approaches are leading to a new understanding of GB physiology and disease. Moreover, single-cell CNAs resource will permit new insights into genome heterogeneity, mutational processes, and clonal evolution in malignant tissues.
Conformational switch in the alpha-synuclein C-terminus domain directs its fibril polymorphs
Authors: Aguirre Cesar , Miyanoiri Yohei , So Masatomo , Tamaki Hajime , Maruno Takahiro , Doi Junko , Wang Nan , Yamaguchi Keiichi , Nakajima Kichitaro , Yamamori Yu , Inoura Hiroko , Choong Chi-Jing , Kakuda Keita , Ajiki Takahiro , Kimura Yasuyoshi , Ozono Tatsuhiko , Baba Kousuke , Nagano Seiichi , Nagai Yoshitaka , Ogi Hirotsugu , Uchiyama Susumu , Matsuki Yoh , Tomii Kentaro , Goto Yuji , Ikenaka Kensuke , Mochizuki Hideki 
Published: February 2022

Abstractα-Synuclein (αSyn) inclusions are a pathological hallmark of several neurodegenerative disorders. While cryo-electron microscopy studies have revealed distinct fibril polymorphs across different synucleinopathies, the molecular switches controlling polymorphism remained unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric αSyn. Through systematic manipulation of the ionic strength and temperature, we pinpoint two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Most strikingly, we found that a specific conformational change in the C-terminal domain of the monomeric αSyn serves as the master switch for the formation of polymorphs. Interestingly, this conformational change can be triggered by calcium binding to the C-terminus, connecting environmental factors to specific fibril architectures. Our results unmask the C-terminal domain as a key player for orchestrating αSyn fibril morphology, providing significant insights into the fibrogenesis of αSyn.Significance StatementThe αSyn C-terminus domain acts as the master switch programming its fibril polymorphism.
Identification and characterization of the HERV-K (HML-8) group of human endogenous retroviruses in the genome
Authors: Liu Mengying , Jia Lei , Li Hanping , Liu Yongjian , Han Jingwan , Zhai Xiuli , Wang Xiaolin , Li Tianyi , Li Jingyun , Zhang Bohan , Yu Changyuan , Li Lin 
Published: February 2022

AbstractHuman endogenous retroviruses (HERV) could vertically transmit in a Mendelian fashion and stable maintenance in the human genome which are estimated to comprise about 8%. HERVs affect human physiology and pathology based on the effect of the provirus-encoded protein or LTR elements. The characterization of the genomic distribution is an essential step to understanding the relationship between endogenous retrovirus expression and diseases. However, the poorly characterization of HML-8 hinders a detailed understanding of the expression regulation of this family in human health and its actual impact on host genomes. In the light of this, the definition of a precise and updated HERV-K HML-8 genomic map is urgently needed. Here we report a comprehensive analysis of HERV-K HML-8 sequences presence and distribution within the human genome, with a detailed description of the different structural and phylogenetic aspects characterizing the group. A total of 40 proviruses and 5 solo LTR elements were characterized with a detailed description of provirus structure, integration time, potentially regulated genes, transcription factor binding sites, and primer binding site feature. The integration time results showed that the HML-8 elements found in the human genome have been integrated in the primate lineage between 23.5 and 52 million years ago (mya). Overall, the results have finally clarified the composition of HML-8, providing an exhaustive background for subsequent functional studies.Highlights➢A comprehensive characterization of the HERV-K (HML-8) in human genome.➢There is an apparent preference of HML-8 into intergenic regions and introns.➢There are two distinct clusters for the env region of the HML-8 elements.➢The average time of HML-8 integration in human is 37.1 mya.
GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming
Authors: Duan Suzann , Sawyer Travis W. , Sontz Ricky A. , Wieland Bradley A. , Diaz Andres F. , Merchant Juanita L. 
Published: February 2022

ABSTRACTBACKGROUND & AIMSEfforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive model systems that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a role for enteric glia in neuroendocrine cell specification. Here we investigated the hypothesis that loss of menin in glial cells stimulated neuroendocrine differentiation and tumorigenesis.METHODSUsing Cre-lox technology, we generated a conditional glial fibrillary acidic protein-directed Men1 knockout (GFAPΔMen1) mouse model. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. siRNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel.RESULTSGFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Mechanistically, Men1 deletion induced reprogramming from a mature glial phenotype toward a neuroendocrine lineage. Furthermore, blockade of Hedgehog signaling in enteric glia attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate.CONCLUSIONSGFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.GRAPHICAL ABSTRACT
Modelling the spread of resistance to Varroa in Australian feral honeybee populations
Authors: Owen Robert , Scheerlinck Jean-Pierre , Stevenson Mark 
Published: February 2022

AbstractAustralia is the only country where Western honeybees, Apis mellifera, are not infested with the mite Varroa destructor. Hence, a collapse in the feral honeybee population, brought about by an incursion and spread of V. destructor, would have serious consequences for Australian horticulture given its dependence on managed and feral honeybees for pollination. Managing Varroa in commercial colonies is well understood and can be achieved, although at significant bee-health costs, by using miticides. Protecting the feral population in the event of a Varroa incursion is much more difficult, but nevertheless imperative. One way to mitigate against collapse of the feral population is to seed it with Varroa-resistant queens, so as to accelerate the spread of resistance. We developed a simulation model of the spread of Varroa-resistance in feral honeybee populations following the introduction of Varroa-resistant queens into the managed population.We show that, compared with a do-nothing scenario, seeding the managed honeybee population with Varroa-resistant queens was only effective in decreasing the length of time for the feral honeybee population to recover when the size of the managed resistant population was large compared to the size of the feral population. This situation may be achievable in some urban areas where numbers of managed colonies are high and habitat for feral colonies is limited.
High sorbic acid resistance ofPenicillium roquefortiis mediated by the SORBUS gene cluster
Authors: Punt Maarten , Seekles Sjoerd J. , van Dam Jisca L. , de Adelhart Toorop Connor , Martina Raithel R , Houbraken Jos , Ram Arthur F. J. , Wösten Han A. B. , Ohm Robin A. 
Published: February 2022

AbstractPenicillium roquefortiis a major food-spoilage fungus known for its high resistance to the food preservative sorbic acid. Here, we demonstrate that the minimum inhibitory concentration of undissociated sorbic acid (MICu) ranges between 4.2 and 21.2 mM when 34P. roquefortistrains were grown on malt extract broth. A genome-wide association study revealed that the six most resistant strains contained the 180 kbp gene cluster SORBUS, which was absent in the other 28 strains. In addition, a SNP analysis revealed five genes outside the SORBUS cluster that may be linked to sorbic acid resistance. A partial SORBUS knock-out (>100 of 180 kbp) in a resistant strain reduced sorbic acid resistance to similar levels as observed in the sensitive strains. Whole genome transcriptome analysis revealed a small set of genes present in both resistant and sensitiveP. roquefortistrains that were differentially expressed in the presence of the weak acid. These genes could explain whyP. roquefortiis more resistant to sorbic acid when compared to other fungi, even in the absence of the SORBUS cluster. Together, the MICuof 21.2 mM makesP. roquefortiamong the most sorbic acid-resistant fungi, if not the most resistant fungus, which is mediated by the SORBUS gene cluster.Author summaryChemical preservatives, such as sorbic acid, are often used in food to prevent spoilage by fungi, yet some fungi are particularly well-suited to deal with these preservatives. First, we investigated the resistance of 34Penicillium roquefortistrains to various food preservatives. This revealed that some strains were highly resistant to sorbic acid, while others are more sensitive. Next, we used DNA sequencing to compare the genetic variation between these strains and discovered a specific genetic region (SORBUS) that is unique to the resistant strains. Through comparative analysis with other fungal species the SORBUS region was studied in more detail and with the use of genetic engineering tools we removed this unique region. Finally, the mutant lacking the SORBUS region was confirmed to have lost its sorbic acid resistance. This finding is of particular interest as it suggests that only some, not all,P. roquefortistrains are potent spoilers and that specific genetic markers could help in the identification of resistant strains.
Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis
Authors: Mijnheer Gerdien , Servaas Nila H. , Leong Jing Yao , Boltjes Arjan , Spierings Eric , Chen Phyllis , Lai Liyun , Petrelli Alessandra , Vastert Sebastiaan , de Boer Rob J. , Albani Salvatore , Pandit Aridaman , van Wijk Femke 
Published: February 2022

ABSTRACTAutoimmune inflammation is characterized by tissue infiltration and expansion of antigen-specific T cells. Although this inflammation is often limited to specific target tissues, it remains yet to be explored whether distinct affected sites are infiltrated with the same, persistent T cell clones. Here we performed CyTOF analysis and T cell receptor (TCR) sequencing to study immune cell composition and (hyper-)expansion of circulating and joint-derived Tregs and non-Tregs in Juvenile Idiopathic Arthritis (JIA). We studied different joints affected at the same time, as well as over the course of relapsing-remitting disease. We found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient, and observed a strong overlap between dominant T cell clones, especially Treg, of which some could also be detected in circulation and persisted over the course of relapsing remitting disease. Moreover, these T cell clones were characterized by a high degree of sequence similarity, indicating the presence of TCR clusters responding to the same antigens. These data suggest that in localized autoimmune disease there is auto-antigen driven expansion of both Teffector and Treg clones, that are highly persistent and are (re)circulating. These dominant clones might represent interesting therapeutic targets.
Generating Functional Cells Through Enhanced Interspecies Chimerism with Human Pluripotent Stem Cells
Authors: Zhu Yanling , Zhang Zhishuai , Fan Nana , Huang Ke , Li Hao , Gu Jiaming , Zhang Quanjun , Ouyang Zhen , Zhang Tian , Tang Jun , Zhang Yanqi , Suo Yangyang , Lai Chengdan , Wang Jiaowei , Wang Junwei , Shan Yongli , Wang Mingquan , Chen Qianyu , Zhou Tiancheng , Lai Liangxue , Pan Guangjin 
Published: February 2022

AbstractObtaining functional human cells through interspecies chimerism with human pluripotent stem cells (hPSCs) remains unsuccessful due to its extreamly low efficiency. Here, we show that hPSCs failed to differentiate and contribute teratoma in presence of mouse PSCs (mPSCs). While, MYCN, a pro-growth factor dramatically promotes hPSC contribution in teratoma co-formation by hPSCs/mPSCs. MYCN combined with BCL2 (M/B) greatly enhanced conventional hPSCs to integrate into preimplantation embryos of different species, such as mice, rabbits and pigs and substrantially contributed to mouse post-implantation chimera in embryonic and extra-embyonic tissues. Strikingly, M/B-hPSCs injected into preimplantation Flk-1+/- mouse embryos show further enhanced chimerism that allows obtaining live human CD34+ blood progenitor cells from chimeras through cell sorting. The chimera derived human CD34+ cells further gave rise to various subtype blood cells in typical colony forming unit(CFU) assay. Thus, we proof the concept to obtain functional human cells through enchanced interspecies chimerism with hPSCs.
Mitonuclear interactions produce extreme differences in response to redox stress
Authors: Camus M. Florencia , Kotiadis Vassilios , Carter Hugh , Rodriguez Enrique , Lane Nick 
Published: February 2022

AbstractIncompatibilities between mitochondrial and nuclear genes can perturb respiration, biosynthesis, signalling and gene expression. Here we investigate whether mild mitonuclear incompatibilities alter response to redox stress induced by N-acetyl cysteine (NAC). We studied threeDrosophila melanogasterlines with mitochondrial genomes either coevolved (WT) or mildly mismatched (BAR, COX) to an isogenic nuclear background. Responses to NAC varied substantially with mitonuclear genotype, sex, tissue and dose. NAC caused infertility and high mortality in some groups but not others. Using tissue-specific fluorespirometry, we show that NAC did not alter H2O2flux but suppressed complex I-linked respiration in female flies, maintaining a reduced glutathione pool. High mortality in BAR females was associated with severe suppression of complex I-linked respiration, rising H2O2flux in ovaries and oxidation of the glutathione pool. Our results suggest that redox stress is attenuated by suppression of complex-I linked respiration, to the point of death in some mitonuclear lines.
Selective effects of a short transient environmental fluctuation on a natural population
Authors: Pfenninger Markus , Foucault Quentin , Waldvogel Ann-Marie , Feldmeyer Barbara 
Published: February 2022

AbstractNatural populations experience continuous and often transient changes of environmental conditions. These in turn may result in fluctuating selection pressures leading to variable demographic and evolutionary population responses. Rapid adaptation as short-term response to a sudden environmental change has in several cases been attributed to polygenic traits, but the underlying genomic dynamics and architecture are poorly understood. In this study, took advantage of a natural experiment in an insect population by monitoring genome-wide allele frequencies before and after a cold snap event. Whole genome pooled sequencing of time series samples revealed ten selected haplotypes carrying ancient polymorphisms, partially with signatures of balancing selection. By constantly cold exposing genetically variable individuals in the laboratory, we could demonstrate with whole genome resequencing i) among the survivors, the same alleles rose in frequency as in the wild and ii) that the identified variants additively predicted fitness (survival time) of its bearers. Finally, by simultaneously sequencing the genome and the transcriptome of cold exposed individuals we could tentatively link some of the selected SNPs to thecis- andtrans-regulation of genes and pathways known to be involved in cold response of insects, likeCytochrome P450and fatty acid metabolism. Altogether, our results shed light on the strength and speed of selection in natural populations and the genomic architecture of its underlying polygenic trait. Population genomic time series data thus appear as promising tool for measuring the selective tracking of fluctuating selection in natural populations.
Disconnectedness in a connected world: why people ignore messages and calls
Authors: Agarwal Naresh Kumar , Mitiku Tenbit , Lu Wenqing 
Published: February 2022

PurposePeople are living in a world where they maintain connectivity through sending and receiving messages and calls. Yet, almost daily, people choose not to respond to certain messages or calls, which can make the sender anxious, and adversely affect their communication. The aim of this study was to investigate the receivers' reasons for not responding.Design/methodology/approachThe authors used theories related to information avoidance, power, interpersonal deception and emotions and conducted interviews of smartphone users.FindingsThe study found that the receiver’s physical and psychological state, the time of the day and the content of the message impacted non-response. The findings suggest that the non-response behavior is moderated by the power relationship between the sender and the receiver. The receiver’s state of mind will determine the likelihood of non-response, while the sender’s state of mind will determine how the sender deals with non-response.Research limitations/implicationsThe study contributes to research in mobile information behavior, and the wider fields of information science, sociology and communication.Practical implicationsThe process of interviewing itself helped raise awareness about these issues with the people who were interviewed.Social implicationsThe findings shed light on the current communicative practices and ways to overcome the disconnectedness and stress suffered by people regularly using smartphones.Originality/valueThe study provides recommendations for healthy communication between the sender and the receiver using their smartphones.