bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental safety testing shows that the NSAID tolfenamic acid is not toxic to Gyps vultures in India at concentrations likely to be encountered in cattle carcasses
Authors: Chandramohan S , Mallord John W. , Manickam Kesavan , Sharma A. K. , Mahendran K. , Gupta Reena , Chutia Krishna , Mathes Karikalan , Pawde Abhijit , Prakash Nikita V. , Ravichandran P. , Saikia Debasish , Shringarpure Rohan , Timung Avinash , Galligan Toby H. , Green Rhys E. , Prakash Vibhu M. 
Published: August 2021

AbstractPopulation declines of Gyps vultures across the Indian subcontinent were caused by unintentional poisoning by the non-steroidal anti-inflammatory drug (NSAID) diclofenac. Subsequently, a number of other NSAIDs have been identified as toxic to vultures, while one, meloxicam, is safe at concentrations likely to be encountered by vultures in the wild. Other vulture-safe drugs need to be identified to reduce the use of those toxic to vultures. We report on safety-testing experiments on the NSAID tolfenamic acid on captive vultures of three Gyps species, all of which are susceptible to diclofenac poisoning. Firstly, we estimated the maximum level of exposure (MLE) of wild vultures and gave this dose to 38 Near Threatened G. himalayensis by oral gavage, with 15 control birds dosed with benzyl alcohol (the carrier solution for tolfenamic acid). Two birds given tolfenamic acid died with elevated uric acid levels and severe visceral gout, while the remainder showed no adverse clinical or biochemical signs. Secondly, four G. himalayensis were fed tissues from water buffaloes which had been treated with double the recommended veterinary dose of tolfenamic acid prior to death and compared to two birds fed uncontaminated tissue; none suffered any clinical effects. Finally, two captive Critically Endangered vultures, one G. bengalensis and one G. Indicus, were given the MLE dose by gavage and compared to two control birds; again, none suffered any clinical effects. The death of two G. himalayensis may have been an anomaly due to i) the high dose level used and ii) the high ambient temperatures at the time of the experiment. Tolfenamic acid is likely to be safe to Gyps vultures at concentrations encountered by wild birds and could therefore be promoted as a safe alternative to toxic NSAIDs. It is manufactured in the region, and is increasingly being used to treat livestock.
Cyclic loading regime considered beneficial does not protect injured and interleukin-1-inflamed cartilage from post-traumatic osteoarthritis
Authors: Eskelinen ASA , Florea C , Tanska P , Hung HK , Frank EH , Mikkonen S , Nieminen P , Julkunen P , Grodzinsky AJ , Korhonen RK 
Published: August 2021

AbstractPost-traumatic osteoarthritis is a degenerative musculoskeletal condition where homeostasis of articular cartilage is perturbated by lesions and inflammation, leading to abnormal tissue-level loading. These mechanisms have rarely been included simultaneously inin vitroosteoarthritis models. We modeled the early disease progression in bovine cartilage regulated by the coaction of(1)mechanical injury,(2)pro-inflammatory interleukin-1α challenge, and(3)cyclic loading mimicking walking and considered beneficial (15% strain, 1 Hz). Surprisingly, cyclic loading did not protect cartilage from accelerated glycosaminoglycan loss over 12 days of interleukin-1-culture despite promoting aggrecan biosynthesis. Our time-dependent data suggest that this loading regime could be beneficial in the first days following injury but later turn detrimental in interleukin-1-inflamed cartilage. Consequently, early anti-catabolic drug intervention may inhibit, whereas cyclic loading during chronic inflammation may promote osteoarthritis progression. Our data on the early stages of post-traumatic osteoarthritis could be utilized in the development of countermeasures for disease progression.
Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection
Authors: Iida Kei , Ajiro Masahiko , Muramoto Yukiko , Takenaga Toru , Denawa Masatsugu , Kurosawa Ryo , Noda Takeshi , Hagiwara Masatoshi 
Published: August 2021

AbstractBackgroundThe rapidly accumulating disease susceptibility information collected from coronavirus disease (COVID-19) patient genomes must be urgently utilized to develop therapeutic interventions for SARS-CoV-2 infection. Chromosome 12q24.13, which encodes the 2’-5’-oligoadenylate synthetase (OAS) family of proteins that sense viral genomic RNAs and trigger an antiviral response, is identified as one of the genomic regions that contains SNPs associated with COVID-19 severity. A high-risk SNP identified at the splice acceptor site of OAS1 exon 6 is known to change the proportions of the various splicing isoforms and the activity of the enzyme.MethodsWe employed in-silico motif search and RNA pull-down assay to define a factor responsible for the OAS1 splicing. Next, we rationally selected a candidate for slicing modulator to modulate this splicing.ResultsWe found that inhibition of CDC-like kinase with a small chemical compound induces switching of OAS1 splice isoforms in human lung cells. In this condition, increased resistance to SARS-CoV-2 infection, enhanced RNA degradation, and transcriptional activation of interferon β1, were also observed.ConclusionsThe results indicate the possibility of using chemical splicing modifiers aided by genome-based precision medicine to boost the innate immune response against SARS-CoV-2 infection.
An NLR Integrated Domain toolkit to identify plant pathogen effector targets
Authors: Landry David , Mila Isabelle , Sabbagh Cyrus Raja Rubenstein , Zaffuto Matilda , Pouzet Cécile , Tremousaygue Dominique , Dabos Patrick , Deslandes Laurent , Peeters Nemo 
Published: August 2021

SUMMARYPlant resistance genes (or NLR “Nod-like Receptors”) are known to contain atypical domains procuring them with a decoy capacity. Some of these integrated domains (or ID) allow the plant to lure the virulence determinants (“effectors”) of pathogens and triggering a specific NLR immune reaction.In this work, our goal was to generate a library of known IDs that could be screened with plant pathogen effectors in order to identify putative new effector virulence targets and NLR-effector pairs.We curated the IDs contained in NLRs from seven model and crop plant species. We cloned 52 IDs representing 31 distinct Pfam domains. This library was screened for interaction by yeast-two-hybrid with a set of 31 conservedRalstonia solanacearumtype III effectors. This screening and the furtherin plantainteraction assay allowed us to identify three interactions, involving different IDs (kinase, DUF3542, WRKY) and two type III effectors (RipAE and PopP2).PopP2 was found to physically interact with ID#85, an atypical WRKY domain integrated in the GmNLR-ID85 NLR protein from Soybean. Using a imaging method in living plant cells, we showed that PopP2 associates with ID#85 in the nucleus. But unlike the known WRKY-containing Arabidopsis RRS1-R NLR receptor, this newly identified soybean WRKY domain could not be acetylated by PopP2 and its atypical sequence (WRKYGKR) also probably renders it inefficient in plant immunity triggering.This ID toolkit is available for screening with other plant pathogen effectors and should prove useful to discover new effectors targets and potentially engineer new plant resistance genes.
Presence and Stability of SARS-CoV-2 on Environmental Currency and Money Cards
Authors: Newey Colleen , Olausson Abigail T , Applegate Alyssa , Reid Ann Aubrey , Robison Richard A , Grose Julianne H. 
Published: August 2021

The highly contagious nature of SARS-CoV-2 has led to several studies on the transmission of the virus. A little studied potential fomite of great concern in the community is currency, which has been shown to harbor microbial pathogens in several studies. Since the onset of the COVID-19 pandemic, many businesses in the United States have limited the use of banknotes in favor of credit cards. However, SARS-CoV-2 has shown greater stability on plastic in several studies. Herein, the stability of SARS-CoV-2 at room temperature on banknotes, money cards and coins was investigated. In vitro studies with live virus suggested SARS-CoV-2 was highly unstable on banknotes, showing an initial rapid reduction in viable virus and no viral detection by 24 hours. In contrast, SARS-CoV-2 was far more stable on money cards with live virus detected after 48 hours. Environmental swabbing of currency and money cards on and near the campus of Brigham Young University supported these results, with no detection of SARS-CoV-2 RNA on banknotes, and a low level on money cards. No viable virus was detected on either. These preliminary results suggest that the use of money cards over banknotes in order to slow the spread of this virus may be ill-advised. These findings should be investigated further through larger environmental studies involving more locations.
Thiol and Disulfide Containing Vancomycin Derivatives Against Bacterial Resistance and Biofilm Formation
Authors: Shchelik Inga S. , Gademann Karl 
Published: August 2021

AbstractAntibiotic-resistant and biofilm-associated infections constitute a rapidly growing issue. Use of the last resort antibiotic vancomycin is under threat, due to the increasing appearance of vancomycin resistant bacteria as well as the formation of biofilms. Herein, we report a series of novel vancomycin derivatives carrying thiol- and disulfide-containing moieties. The new compounds exhibited enhanced antibacterial activity against a broad range of bacterial strains, including vancomycin resistant microbes and Gram-negative bacteria. Moreover, all obtained derivatives demonstrated improved antibiofilm formation activity against VanB resistant Enterococcus compared to vancomycin. This work established a promising strategy for combating drug-resistant bacterial infections or disrupting biofilm formation and advances the knowledge on structural optimization of antibiotics with sulfur-containing modifications.
Repurposing melanoma chemotherapy to activate inflammasomes in treatment of BRAF/MAPK inhibitor resistant melanoma
Authors: Ahmed Farzana , Tseng Hsin-Yi , Ahn Antonio , Gunatilake Dilini , Alavi Sara , Eccles Michael , Rizos Helen , Gallagher Stuart , Tiffen Jessamy , Hersey Peter , Emran Abdullah Al 
Published: August 2021

AbstractThe development of resistance to treatments of melanoma is commonly associated with upregulation of the MAPK pathway and development of an undifferentiated state. Prior studies have suggested that melanoma with these resistance characteristics may be susceptible to innate death mechanisms such as pyroptosis triggered by activation of inflammasomes. In the present studies we have taken cell lines from patients before and after development of resistance to BRAF V600 inhibitors and exposed the resistant melanoma to temozolomide (a commonly used chemotherapy) with and without chloroquine to inhibit autophagy. It was found that melanoma with an inflammatory undifferentiated state appeared susceptible to this combination when tested in vitro and in vivo against xenografts in NSG mice. Translation of the latter results into patients would promise durable responses in patients treated by the combination. The inflammasome and death mechanism involved appeared to vary between melanoma and involved either AIM2, NLRP3 or NLRC4 inflammasomes and gasdermin D or E. These preliminary studies have raised questions as to the selectivity for different inflammasomes in different melanoma and their selective targeting by chemotherapy. They also question whether the inflammatory state of melanoma may be used as biomarkers to select patients for inflammasome targeted therapy.
A Recurring Chemogenetic Switch for Chimeric Antigen Receptor T Cells
Authors: Cao Wenyue , Geng Zhi Z. , Wang Na , Pan Quan , Guo Shaodong , Xu Shiqing , Zhou Jianfeng , Liu Wenshe Ray 
Published: August 2021

AbstractAs a revolutionary cancer treatment, the chimeric antigen receptor (CAR) T cell therapy suffers from complications such as cytokine release syndromes and T cell exhaustion. Their mitigation desires controllable activation of CAR-T cells that is achievable through regulatory display of CARs on the T cell surface. By embedding the hepatitis C virus NS3 protease (HCV-NS3) in an anti-CD19 CAR between the anti-CD19 single-chain variable fragment (scFv) and the hinge domain, we showed that the display of anti-CD19 scFv on CAR-T cells was positively correlated to the presence of a clinical HCV-NS3 inhibitor asunaprevir (ASV). This novel CAR design that allows the display of anti- CD19 scFv on the T cell surface in the presence of ASV and its removal in the absence of ASV effectuates a practically recurring chemical switch for CAR-T cells. We demonstrated that the intact CAR on T cells was repeatedly turn on and off by controlling the presence of ASV. The dose dependent manner of the intact CAR display on T cells with regard to the ASV concentration enables delicate modulation of CAR-T cell activation during cancer treatment. In a mouse model, we showed different treatment prospects when ASV was provided at different doses to mice that were infused with both human CD19+ lymphoma and the switchable CAR-T cells.
Neuronal control of suppression, initiation and completion of egg deposition in Drosophila melanogaster
Authors: Oliveira-Ferreira Cristina , Gaspar Miguel , Vasconcelos Maria Luísa 
Published: August 2021

AbstractEgg-laying in Drosophila is the product of post-mating physiological and behavioural changes that culminate in a stereotyped sequence of actions. While egg-laying behaviour has been mostly used as a system to understand the neuronal basis of decision making in the context of site selection, it harbours a great potential as a paradigm to uncover how, once a site is selected, the appropriate motor circuits are organized and activated to deposit an egg. To study this programme, we first describe the different stages of the egg-laying programme and the specific actions associated with each stage. Using a combination of neuronal activation and silencing experiments we characterize the role of three distinct neuronal populations in the abdominal ganglion with different contributions to the egg deposition motor elements. Specifically, we identify a subset of glutamatergic neurons and a subset of cholinergic neurons that promote the initiation and completion of egg expulsion respectively, while a subset of GABAergic neurons suppresses egg-laying. This study provides insight into the organization of neuronal circuits underlying complex motor behaviour.
Comparison of Single-Trait and Multi-Trait Genome-Wide Association Models and Inclusion of Correlated Traits in the Dissection of the Genetic Architecture of a Complex Trait in a Breeding Program
Authors: Merrick Lance F. , Burke Adrienne B. , Zhang Zhiwu , Carter Arron H. 
Published: August 2021

AbstractTraits with an unknown genetic architecture make it difficult to create a useful bi-parental mapping population to characterize the genetic basis of the trait due to a combination of complex and pleiotropic effects. Seedling emergence of wheat (Triticum aestivumL.) from deep planting is a vital factor affecting stand establishment and grain yield, has a poorly understood genetic architecture, and is historically correlated with coleoptile length. The creation of bi-parental mapping populations can be overcome by using genome-wide association studies (GWAS). This study aimed to dissect the genetic architecture of seedling emergence while accounting for correlated traits using one multi-trait GWAS model (MT-GWAS) and three single-trait GWAS models (ST-GWAS) with the inclusion of covariates for correlated traits. The ST-GWAS models included one single locus model (MLM), and two multiple loci models (FarmCPU and BLINK). We conducted the GWAS using two populations, the first consisting of 473 varieties from a diverse association mapping panel (DP) phenotyped from 2015-2019, and the other population used as a validation population consisting of 279 breeding lines (BL) phenotyped in 2015 in Lind, WA, with 40,368 markers. We also compared the inclusion of coleoptile length and markers associated with reduced height as covariates in our ST-GWAS models for the DP. ST-GWAS found 107 significant markers across 19 chromosomes, while MT-GWAS found 82 significant markers across 14 chromosomes. MT-GWAS models were able to identify large-effect markers on chromosome 5A. FarmCPU and BLINK models were able to identify many small effect markers, and the inclusion of covariates helped to identify the large effect markers on chromosome 5A. Therefore, by using multi-locus models combined with pleiotropic covariates, breeding programs can uncover the complex nature of traits to help identify candidate genes and the underlying architecture of a trait, such as seedling emergence of deep-sown winter wheat.
LRRK2 causes centrosomal deficits via phosphorylated Rab10 and RILPL1 at centriolar subdistal appendages
Authors: Ordóñez Antonio Jesús Lara , Fernández Belén , Fasiczka Rachel , Naaldijk Yahaira , Fdez Elena , Ramírez Marian Blanca , Phan Sébastien , Boassa Daniela , Hilfiker Sabine 
Published: August 2021

AbstractThe Parkinson’s disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases including Rab8 and Rab10, which enhances their binding to RILPL1 and RILPL2. The nascent interaction between phospho-Rab10 and RILPL1 blocks ciliogenesis in vitro and in the intact brain, and interferes with the cohesion of duplicated centrosomes in dividing cells. We show here that various LRRK2 risk variants and all currently described regulators of the LRRK2 signaling pathway converge upon causing centrosomal cohesion deficits. The cohesion deficits do not require the presence of RILPL2 or of other LRRK2 kinase substrates including Rab12, Rab35 and Rab43. Rather, they depend on the RILPL1-mediated centrosomal accumulation of phosphorylated Rab10. RILPL1 localizes to the subdistal appendages of the mother centriole, followed by recruitment of the LRRK2-phosphorylated Rab protein to cause the centrosomal defects. These data reveal a common molecular pathway by which alterations in the LRRK2 kinase activity impact upon centrosome-related events.
Superovulation does not alter calcium oscillations following fertilization
Authors: Savy Virginia , Stein Paula , Shi Min , Williams Carmen J. 
Published: August 2021

AbstractSuperovulation is a common approach to maximize the number of eggs available for either clinical assisted reproductive technologies or experimental animal studies. This procedure provides supraphysiological amounts of gonadotropins to promote continued growth and maturation of ovarian follicles that otherwise would undergo atresia. There is evidence in mice, cows, sheep and humans that superovulation has a detrimental impact on the quality of the resulting ovulated eggs or embryos. Here we tested the hypothesis that eggs derived from superovulation have a reduced capacity to support calcium oscillations following fertilization, which is a critical factor in the success of embryo development. Eggs were obtained from mice that were either naturally cycling or underwent a standard superovulation protocol. Naturally cycling mice were mated to vasectomized males and vaginal plugs were checked to assure ovulation had occurred. The superovulated mice were also mated to vasectomized males for consistency of treatment across groups. The eggs were fertilized in vitro while undergoing monitoring of calcium oscillatory patterns. There were no differences in any measures of calcium oscillatory behavior, including length of the first oscillation, area under the curve of calcium signal, or frequency or persistence of oscillations. These findings indicate that superovulation does not disrupt calcium signaling at fertilization, supporting the use of this method for both clinical and experimental purposes.
CRISPRi screens in human astrocytes elucidate regulators of distinct inflammatory reactive states
Authors: Leng Kun , Rose Indigo V.L. , Kim Hyosung , Xia Wenlong , Romero-Fernandez Wilber , Rooney Brendan , Koontz Mark , Li Emmy , Ao Yan , Wang Shinong , Krawczyk Mitchell , TCW Julia , Goate Alison , Zhang Ye , Ullian Erik M. , Sofroniew Michael V. , Fancy Stephen P.J. , Schrag Matthew S. , Lippmann Ethan S. , Kampmann Martin 
Published: August 2021

ABSTRACTIn response to central nervous system injury or disease, astrocytes become reactive, adopting context-dependent states and functional outputs. Certain inflammatory insults induce reactive astrocytes that lose homeostatic functions and gain harmful outputs through cellular pathways that are not fully understood. Here, we combined single-cell transcriptomics with CRISPRi screening in human iPSC-derived astrocytes to systematically interrogate inflammatory astrocyte reactivity. We found that autocrine-paracrine IL-6 and interferon signaling downstream of canonical NF-κB activation drove two distinct inflammatory reactive signatures – one promoted by and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in the human brain in Alzheimer’s disease and hypoxic ischemic encephalopathy. Furthermore, we validated that these signatures were regulated by Stat3in vivo.These results and the platform we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.
Genome assembly, annotation and comparative analysis of the cattail Typha latifolia
Authors: Widanagama Shane D. , Freeland Joanna R. , Xu Xinwei , Shafer Aaron B.A. 
Published: August 2021

ABSTRACTCattails (Typha species) comprise a genus of emergent wetland plants with a global distribution. Typha latifolia and T. angustifolia are two of the most widespread species, and in areas of sympatry can interbreed to produce the hybrid Typha x glauca. In some regions the relatively high fitness of T. x glauca allows it to outcompete and displace both parent species, while simultaneously reducing plant and invertebrate biodiversity, and modifying nutrient and water cycling. We generated a high-quality whole genome assembly of T. latifolia using PacBio long-read and high coverage Illumina sequences that will facilitate evolutionary and ecological studies in this hybrid zone. Genome size was 287 Mb and consisted of 1,189 scaffolds, with an N50 of 8.706 Mb; 43.84% of the genome were identified as repetitive elements. The assembly has a BUSCO score of 96.03%, and 27,432 genes and 2,700 RNA sequences were putatively identified. Comparative analysis detected over 9,000 shared orthologues with related taxa and phylogenomic analysis supporting Typha latifolia as a divergent lineage within Poales. This high-quality scaffold-level reference genome will provide a useful resource for future population genomic analyses and improve our understanding of Typha hybrid dynamics.