bluuebunny/crossref_metadata_2025_split huggingface dataset:
The grape MYB24 mediates the coordination of light-induced terpene and flavonol accumulation in response to berry anthocyanin sunscreen depletion
Authors: Chen Zhang , Zhanwu Dai , Thilia Ferrier , Luis Orduña , Antonio Santiago , Arnau Peris , Darren Wong , Christian Kappel , Stefania Savoi , Rodrigo Loyola , Alessandra Amato , Bartosz Kozak , Miaomiao Li , David Carrasco , Carlos Meyer , Carmen Espinoza , Ghislaine Hilbert , Rosa Figueroa-Balderas , Dario Cantu , Rosa Arroyo , Patricio Arce-Johnson , Patricia Claudel , Eric Duchêne , Carol Huang Shao-shan , Diego Castellarin Simone , Battista Tornielli Giovanni , Francois Barrieu , Tomás Matus J. 
Published: December 2021

AbstractThe presence of naturally-occurring color mutants in plants has permitted the identification of many regulatory genes implicated in the synthesis of discrete metabolic compounds, mostly anthocyanins and carotenoids. Conversely, transcription factors that coordinate more than one specialized metabolic pathway seem challenging to screen from a forward genetics’ perspective. We explored the relationship between different branches of the phenylpropanoid and isoprenoid pathways while examining an infrequent berry skin color variegation in grapevine. Red and white berry skin sections were compared at the genetic, transcriptomic and metabolomic levels showing that, as in most cultivated white grape varieties, the uncolored skin section convened the non-functional alleles of the anthocyanin regulators MYBA1 and MYBA2, explaining the lack of pigments. In contrast, light-responsive flavonols and monoterpenes increased in anthocyanin-depleted areas. We disclosed an enrichment of the flavonol, terpene and carotenoid pathways among up-regulated genes from white-skin sections, accompanied by increased expressions of flavonol regulators and the still uncharacterized MYB24 gene. We used DAP-seq to examine the in vitro binding of affinity-purified MYB24 protein to genomic DNA and demonstrated its binding in the promoter regions of terpene (22) and carotenoid (6) genes, in addition to more than 30 photosynthesis and light-response genes, including the flavonol-regulator HY5 homologue (HYH). We confirmed the activation of TPS35 and HYH promoter:luciferase reporters in the presence of MYB24 and the grape bHLH MYC2, all of which correlate in their higher expression in white skin variegated sections. The integration of several datasets allowed to define a list of high confidence targets, suggesting MYB24 as a modulator of light responses including the synthesis of flavonoids (flavonols) and isoprenoids (terpenes, and putatively carotenoids). The correspondence between MYB24 and monoterpenes in all conditions surveyed implies that this regulatory network is broadly triggered towards berry ripening, and that the absence of anthocyanin sunscreens accelerates its activation most likely in a dose-dependent manner due to increased radiation exposure.
Diverse and rapidly evolving viral strategies modulate arthropod vector gene expression
Authors: Eliash Nurit , Suenaga Miyuki , Mikheyev Alexander S. 
Published: December 2021

AbstractVector-borne viral diseases threaten human and wildlife worldwide. Vectors are often viewed as a passive syringe injecting the virus, however to survive, replicate and spread, viruses must manipulate vector biology. While most vector-borne viral research focuses on vectors transmitting a single virus, in reality vectors often carry diverse viruses. Yet how viruses affect the vectors remains poorly understood. Here we focused on the varroa mite, an emergent parasite that vectors over 20 honey bee viruses, and has been responsible for colony collapses worldwide, as well as changes in global viral populations. Co-evolution of the varroa and the viral community makes it possible to investigate whether viruses affect vector gene expression, and whether these interactions affect viral epidemiology. Using a large set of available varroa transcriptomes we identified how abundances of individual viruses affect the vector’s transcriptional network. Perhaps surprisingly, we found no evidence of competition between viruses, but rather that some virus abundances are positively correlated. Furthermore, we found a strong correlation between the extent to which a virus interacts with the vector’s gene expression and co-occurrence with other viruses, suggesting that interactions with the vector affect epidemiology. We experimentally validated this observation by silencing candidate genes using RNAi and found that reduction in varroa gene expression was accompanied by a change in viral load. Combined, the meta-transcriptomic analysis and experimental results shed light on the mechanism by which viruses interact with each other and with their vector to shape the disease course.
Effects of ozone on sickness and depressive-like behavioral and biochemical phenotypes and their relations to serum amyloid A and kynurenine in blood
Authors: Baumann Kristen K. , Liang W. Sandy , Quaranta Daniel V. , Wilson Miranda L. , Asrat Helina S. , Thysell Jarl A. , Sarchi Angelo V. , Banks William A. , Erickson Michelle A. 
Published: December 2021

AbstractOzone (O3) is an air pollutant which primarily damages the lungs, but growing evidence supports that O3exposure can also affect the brain. Serum amyloid A (SAA) and kynurenine have been identified as circulating factors that are upregulated by O3, and both can contribute to depressive-like behaviors in mice. However, little is known about the relations of O3exposure to sickness and depressive-like behaviors in experimental settings. In this study, we evaluated O3dose-, time- and sex-dependent changes in circulating SAA in context of pulmonary inflammation and damage, sickness and depressive-like behavioral changes, and systemic changes in kynurenine and indoleamine 2,3-dioxygenase (IDO), an enzyme that regulates kynurenine production and contributes to inflammation-induced depressive-like behaviors. Our results in Balb/c and CD-1 mice showed that 3ppm O3, but not 2 or 1ppm O3, caused elevations in serum SAA and pulmonary neutrophils, and these responses resolved by 48 hours. Sickness and depressive-like behaviors were observed at all O3doses (1-3ppm), although the detection of certain behavioral changes varied by dose. We also found thatIdo1mRNA expression was increased in the brain and spleen 24 hours after 3ppm O3, and that kynurenine was increased in blood. Together, these findings indicate that acute O3exposure induces transient symptoms of sickness and depressive-like behaviors which may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. We also present evidence that the IDO/kynurenine pathway is upregulated systemically following an acute exposure to O3in mice.
Disrupting ATXN1 Nuclear Localization in a Knock-in SCA1 Mouse Model Improves a Spectrum of SCA1-Like Phenotypes and their Brain Region Associated Transcriptomic Profiles
Authors: Handler Hillary P. , Duvick Lisa , Mitchell Jason , Cvetanovic Marija , Reighard Molly , Soles Alyssa , Rainwater Orion , Serres Shannah , Nichols-Meade Tessa , Coffin Stephanie L. , You Yun , Ruis Brian , O’Callaghan Brennon , Henzler Christine , Zoghbi Huda Y. , Orr Harry T. 
Published: December 2021

SUMMARYSpinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with the amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein.Characterization of these mice indicates proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes whose expression was corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.
Dopamine and GPCR-mediated modulation of DN1 clock neurons gates the circadian timing of sleep
Authors: Schlichting M. , Richhariya S. , Herndon N. , Ma D. , Xin J. , Lenh W. , Abruzzi K. , Rosbash M. 
Published: December 2021

AbstractThe metronome-like circadian regulation of sleep timing must still adapt to an uncertain environment. Recent studies in Drosophila indicate that neuromodulation not only plays a key role in clock neuron synchronization but also affects interactions between the clock network and brain sleep centers. We show here that the targets of neuromodulators, G-Protein Coupled Receptors (GPCRs), are highly enriched in the fly brain circadian clock network. Single cell sequencing indicates that they are not only differentially expressed but also define clock neuron identity. We generated a comprehensive guide library to mutagenize individual GPCRs in specific neurons and verified the strategy with a targeted sequencing approach. Combined with a behavioral screen, the mutagenesis strategy revealed a novel role of dopamine in sleep regulation by identifying two dopamine receptors and a clock neuron subpopulation that gate the timing of sleep.
Conditions for maintaining and eroding pseudo-overdominance and its contribution to inbreeding depression
Authors: Awad Diala Abu , Waller Donald 
Published: December 2021

AbstractClassical models that ignore linkage predict that deleterious recessive mutations should purge or fix within inbred populations, yet inbred populations often retain moderate to high segregating load. True overdominance could generate balancing selection strong enough to sustain inbreeding depression even within inbred populations, but this is considered rare. However, arrays of deleterious recessives linked in repulsion could generate appreciable pseudo-overdominance that would also sustain segregating load. We used simulations to explore how long pseudo-overdominant (POD) zones persist once created (e.g., by hybridization between populations fixed for alternative mildly deleterious mutations). Balanced haplotype loads, tight linkage, and moderate to strong cumulative selective effects all serve to maintain POD zones. Tight linkage is key, suggesting that such regions are most likely to arise and persist in low recombination regions (like inversions). Selection and drift unbalance the load, eventually eliminating POD zones, but this process is quite slow under strong pseudo-overdominance. Background selection accelerates the loss of weak POD zones but reinforces strong ones in inbred populations by disfavoring homozygotes. Models and empirical studies of POD dynamics within populations help us understand how POD zones may allow the load to persist, greatly affecting load dynamics and mating systems evolution.
Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones
Authors: Koppes Erik A. , Johnson Marie A. , Moresco James J. , Luppi Patrizia , Lewis Dale W. , Stolz Donna B. , Diedrich Jolene K. , Yates John R. , Wek Ronald C. , Watkins Simon C. , Gollin Susanne M. , Park Hyun J. , Drain Peter , Nicholls Robert D. 
Published: December 2021

ABSTRACTPrader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged insulin and deficient insulin secretion. To determine the collective roles of PWS genes in β-cell biology, we used genome-editing to generate isogenic, clonal INS-1 insulinoma lines having 3.16 Mb deletions of the silent, maternal (control) or active, paternal PWS-alleles. PWS β-cells demonstrated a significant cell-autonomous reduction in basal and glucose-stimulated insulin secretion. Further, proteomic analyses revealed reduced levels of cellular and secreted hormones, including all insulin peptides and amylin, concomitant with reduction of at least ten endoplasmic reticulum (ER) chaperones, including GRP78 and GRP94. Critically, transcriptomic studies demonstrated that the broad reduction of ER chaperones originated from transcriptional downregulation without corresponding changes for Ins1 and Ins2. In contrast to the dosage compensation previously seen for ER chaperones in Grp78 or Grp94 gene knockouts or knockdown, compensation is precluded by the stress-independent deficiency of ER chaperones in PWS β-cells. Consistent with reduced ER chaperones levels, PWS INS-1 β-cells are more sensitive to ER stress, leading to earlier activation of all three arms of the unfolded protein response. These findings suggest that a chronic shortage of ER chaperones in PWS β-cells leads to a deficiency of protein folding and/or delay in ER transit of insulin and other cargo. In summary, our results illuminate the pathophysiological basis of pancreatic β-cell hormone deficits in PWS, with evolutionary implications for the multigenic PWS-domain, and indicate that PWS-imprinted genes coordinate concerted regulation of ER chaperone biosynthesis and β-cell secretory pathway function.
Superinfection Exclusion of Alphaherpesviruses Interferes with Virion Trafficking
Authors: Cwick James P. , Owen Jonathan I. , Kochetkova Irina , Van Horssen Nick , Taylor Matthew P. 
Published: December 2021

ABSTRACTSuperinfection exclusion (SIE) is a phenomenon in which a primary viral infection interferes with secondary viral infections within that same cell. Although SIE has been observed across many viruses, it has remained relatively understudied. A recently characterized glycoprotein D (gD) -independent SIE of alphaherpesviruses presents a novel mechanism of co-infection restriction for Herpes Simplex Virus Type 1 (HSV-1) and Pseudorabies virus (PRV). In this study, we evaluated the role of multiplicity of infection (MOI), receptor expression, and trafficking of virions to gain greater insight into potential mechanisms of alphaherpesvirus SIE.We observed that high MOI secondary viral infections were able to overcome SIE in a manner that was independent of receptor availability. Utilizing recombinant viruses expressing fluorescent protein fusions, we assessed virion localization during SIE through live fluorescent microscopy of dual-labeled virions and localization of capsid assemblies. Analysis of these assemblies confirmed changes in the distribution of capsids during SIE. These results indicate that SIE during PRV infection inhibits viral entry or fusion while HSV-1 SIE inhibits infection through a post-entry mechanism. Although the timing and phenotype of SIE is similar between alphaherpesviruses, the related viruses implement different mechanisms to restrict coinfection.IMPORTANCEMost viruses utilize a form of superinfection exclusion to conserve resources and control population dynamics. gD-dependent superinfection exclusion in alphaherpesviruses is well-documented. However, the under-characterized gD-independent SIE provides new insight into how alphaherpesviruses limit sequential infection. The observations described here demonstrate that gD-independent SIE differs between PRV and HSV-1. Comparing these differences provide new insights into the underlying mechanisms of SIE implemented by two related viruses.
eXNVerify: coverage analysis for long and short-read sequencing data in clinical context
Authors: Porebski Sebastian , Stokowy Tomasz 
Published: December 2021

AbstractAccurate identification of genetic variants to a large extent is based on type of experimental technology, quality of the material and coverage of obtained sequencing data. Our motivation was to create a tool that will evaluate genome coverage and accelerate the introduction of long-read sequencing to medical diagnostics and clinical practice. Here we present eXNVerify: a tool for inspection of clinical data in the context of pathogenic variants. The tool calculates Clinical Depth Coverage – a measure of coverage which we introduce to evaluate loci with pathogenic germline and somatic variants reported in ClinVar. The tool additionally provides visualization options for user-defined genes of interest. Finally, we present an examples of BRCA1, TP53, CFTR application and results of a test conducted in the Extensive Sequence Dataset of Gold-Standard Samples for Benchmarking and Development. eXNVerify is available at https://github.com/porebskis/eXNVerify and can be directly pulled from the DockerHub repository: docker pull porebskis/exnverify:1.0.
Structural, functional and computational studies of membrane recognition by Plasmodium Perforin-Like Proteins 1 and 2
Authors: Williams Sophie I. , Yu Xiulian , Ni Tao , Gilbert Robert J. C. , Stansfeld Phillip J. 
Published: December 2021

AbstractPerforin-like proteins (PLPs) play key roles in the mechanisms associated with parasitic disease caused by apicomplexans such as Plasmodium (malaria) and Toxoplasma. The T. gondii PLP1 (TgPLP1) mediates tachyzoite egress from cells, while the five Plasmodium PLPs carry out various roles in the life cycle of the parasite and with respect to the molecular basis of disease. Here we focus on Plasmodium vivax PLP1 and PLP2 (PvPLP1 and PvPLP2) compared to TgPLP1; PvPLP1 is important for invasion of mammalian hosts by the parasite and establishment of a chronic infection, PvPLP2 is important during the symptomatic blood stage of the parasite life cycle. Determination of the crystal structure of the membrane-binding APCβ domain of PvPLP1 reveals notable differences with that of TgPLP1, which are reflected in its inability to bind lipid bilayers in the way that TgPLP1 and PvPLP2 can be shown to. Molecular dynamics simulations combined with site-directed mutagenesis and functional assays allow a dissection of the binding interactions of TgPLP1 and PvPLP2 on lipid bilayers, and reveal a similar tropism for lipids found enriched in the inner leaflet of the mammalian plasma membrane. In addition to this shared mode of membrane binding PvPLP2 displays a secondary synergistic interaction side-on from its principal bilayer interface. This study underlines the substantial differences between the biophysical properties of the APCβ domains of Apicomplexan PLPs, which reflect their significant sequence diversity. Such differences will be important factors in determining the cell targeting and membrane-binding activity of the different proteins, in their different developmental roles within parasite life cycles.
False-positive detection of Group B Streptococcus (GBS) in chromogenic media due to presence of Enterococcus faecalis in High Vaginal Swabs
Authors: Singh Abhishek , Husein Atahar , Singh Salomi , Ghattargi Vikas , Dhotre Dhiraj , Shouche Yogesh S. , Colaco Stacy , Abhyankar Vivek , Patekar Suyash , Chhabria Karisma , Kumar Sushil , Urhekar A.D. , Modi Deepak 
Published: December 2021

AbstractVaginal colonization of Group B Streptococcus (GBS) is associated with preterm births and neonatal sepsis. Thus, routine screening of GBS in prenatal care is recommended. Chromogenic media are useful in rapid and sensitive screening for GBS. herein, we evaluated the performance of Carrot broth for the detection of GBS in vaginal swabs of pregnant women. In all 20/201 (9.9%) vaginal swab samples were positive in the carrot broth. 17/20 (85%) and 19/20 (95%) samples yielded colonies on Blood agar and Crome agar respectively. However, 16s rRNA sequencing revealed that none of the carrot broth positive cultures had sequence similarities to the Enterococcus faecalis and not GBS. Furthermore, Enterococcus faecalis was detected by PCR in DNA isolated from the corresponding uncultured vaginal swabs samples, while GBS could be detected by PCR only in 4 samples. Thus carrot broth-based culture can lead to false-positive detection due to the presence of Enterococcus faecalis.
Reduced sensitivity of SARS-CoV-2 Omicron variant to booster-enhanced neutralization
Authors: Yu Xiaoqi , Wei Dong , Xu Wenxin , Li Yulong , Li Xinxin , Zhang Xinxin , Qu Jieming , Yang Zhitao , Chen Erzhen 
Published: December 2021

AbstractThe Omicron Variant of Concern (B.1.1.529) has spread internationally and is raising serious concerns about reduced vaccine efficacy and the increased risk of reinfection. We assessed the serum neutralizing activity using a pseudovirus-based neutralization assay in 292 healthcare workers who had received a homologous booster dose of BBIBP-CorV vaccine, 8 to 9 months after completing the priming two-dose vaccination schedule, to investigate whether the newly identified Omicron variant can escape serum antibody neutralization induced by the booster vaccination. The booster dose of BBIBP-CorV rapidly induced a significantly high level of humoral immune response, and the neutralization geometric mean titer (GMT) against the wild-type strain on day 28 after the booster dose was 294.85 (252.99-343.65), 6.1 times higher than the level on day 28 after the second dose. The neutralization against the Omicron variant was also improved by the booster vaccination, although the GMT showed an approximately 20.1-fold reduction to 14.66 (12.30-17.48) when compared with the wild-type strain. This study demonstrated that a booster dose of BBIBP-CorV led to a significant rebound in neutralizing immune response against SARS-CoV-2, while the Omicron variant showed partial resistance to neutralizing antibodies induced by the booster vaccination.
Magnitude, global variation, and temporal development of the COVID-19 infection fatality burden
Authors: Bohk-Ewald Christina , Acosta Enrique , Riffe Tim , Dudel Christian , Myrskylä Mikko 
Published: December 2021

AbstractHow deadly is an infection with SARS-CoV-2 worldwide over time? This information is critical for developing and assessing public health responses on the country and global levels. However, imperfect data have been the most limiting factor for estimating the COVID-19 infection fatality burden during the first year of the pandemic. Here we leverage recently emerged compelling data sources and broadly applicable modeling strategies to estimate the crude infection fatality rate (cIFR) in 77 countries from 28 March 2020 to 31 March 2021, using 2.4 million reported deaths and estimated 435 million infections by age, sex, country, and date. The global average of all cIFR estimates is 1.2% (10th to 90th percentile: 0.2% to 2.4%). The cIFR varies strongly across countries, but little within countries over time, and it is often lower for women than men. Cross-country differences in cIFR are largely driven by the age structures of both the general and the truly infected population. While the broad trends and patterns of the cIFR estimates are more robust, we show that their levels are uncertain and sensitive to input data and modeling choices. In consequence, increased efforts at collecting high-quality data are essential for accurately estimating the cIFR, which is a key indicator for better understanding the health and mortality consequences of this pandemic.