bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondria preserve an autarkic one-carbon cycle to confer growth-independent cancer cell migration and metastasis
Authors: Kiweler Nicole , Delbrouck Catherine , Pozdeev Vitaly I. , Neises Laura , Soriano-Baguet Leticia , Eiden Kim , Xian Feng , Benzarti Mohaned , Haase Lara , Koncina Eric , Schmoetten Maryse , Jaeger Christian , Noman Muhammad Zaeem , Vazquez Alexei , Janji Bassam , Dittmar Gunnar , Brenner Dirk , Letellier Elisabeth , Meiser Johannes 
Published: May 2021

AbstractProgression of primary cancer to metastatic disease is the most common cause of death in cancer patients with minimal treatment options available. Canonical drugs target mainly the proliferative capacity of cancer cells, which often leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions supporting resistance and metastatic dissemination are still poorly understood.In the present study, we revealed that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism allowing sustained serine catabolism and formate overflow when cytosolic 1C metabolism is impaired. Interestingly, antifolate dependent growth-arrest did not correlate with decreased migration capacity. Therefore, using the antifolate Methotrexate as a tool compound allowed us to disentangle proliferation and migration to profile the metabolic phenotype of migrating (growth-arrested) cells. Supported by an increased NAD/NADH ratio, we observed increased serine de novo synthesis and increased serine catabolism to formate.Consequently, inhibition of serine de novo synthesis using the competitive PHGDH-inhibitor BI-4916 or direct inhibition of mitochondrial 1C metabolism reduced cancer cell migration. Using an orthotopic breast cancer model, we show that sole inhibition of mitochondrial serine catabolism does not affect primary tumor growth but strongly inhibits pulmonary metastasis.We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential.Our results improve our understanding of 1C metabolism and of metabolic determinants that support the process of cancer cell migration and metastasis.
NaturalizedDolichogenidea gelechiidivorisMarsh (Hymenoptera: Braconidae) complement the resident parasitoid complex ofTuta absoluta(Meyrick) (Lepidopera:Gelechiidae) in Spain
Authors: Denis Carmen , Riudavets Jordi , Alomar Oscar , Agustí Nuria , Gonzalez-Valero Helena , Cubí Martina , Matas Montserrat , Rodríguez David , van Achterberg Kees , Arnó Judit 
Published: May 2021

AbstractOur study aimed to assess the contribution of natural parasitism due toNecremnus tutaeRibes & Bernardo (Hymenoptera: Eulophidae) to the biological control ofTuta absoluta(Meyrick) (Lepidopera:Gelechiidae) in commercial plots where an IPM program based on the use of predatory mirid bugs was implemented. During the samplings, the presence of another parasitoid was detected and, therefore, a second part of our study intended to identify this species and to evaluate the importance of its natural populations in the biological control of the pest. Leaflets withT. absolutagalleries were collected during 2017–2020 from commercial tomato plots in the horticultural production area of Catalonia (Northeast Spain), including greenhouses, open fields, and roof covered tunnels that lack side walls. In the laboratory,T. absolutalarvae were classified as ectoparasitized, alive, or dead. Reared parasitoids from ectoparasitized larvae were mostly morphologically identified asNecremnussp. with parasitism rates that peaked in summer months with values between 9 and 15%. Some of these ectoparasitized larvae also yielded another parasitoid identified asDolichogenidea gelechiidivorisMarsh (Hymenoptera: Braconidae) by both morphological and molecular-DNA barcoding methods. In 2020, parasitism rates due toD. gelechiidivoristhat increased with season up to 22%. Our work reports for the first time in Europe the presence of the neotropical speciesD. gelechiidivorisadding this biocontrol agent to the resident parasitoid complex ofT. absolutain Spain.
IN VIVO ANALYSIS OF THE ROLE OF GASDERMIN-B (GSDMB) IN CANCER USING NOVEL KNOCK-IN MOUSE MODELS
Authors: Sarrio David , Rojo-Sebastián Alejandro , Teijo Ana , Pérez-López María , Díaz-Martín Eva , Martínez Lidia , Morales Saleta , García-Sanz Pablo , Palacios José , Moreno-Bueno Gema 
Published: May 2021

ABSTRACTBackgroundGasdermin-B gene (GSDMB) is frequently over-expressed in tumors, and its shortest translated variant (isoform 2; GSDMB2) increases aggressive behavior in breast cancer cells. Paradoxically, GSDMB could have either pro-tumor or tumor suppressor properties depending on the biological context. Since GSDMB gene is not present in the mouse genome, deciphering fully the functional roles of GSDMB in cancer requires novel in vivo models.MethodsWe first generated by gene targeting a conditional knock-in mouse model (R26-STOP-GB2) harboring human GSDMB2 transcript within the ROSA26 locus. We next derived the R26-GB2 model ubiquitously expressing GSDMB2 in multiple tissues (confirmed by western blot and immunohistochemistry) and performed a comprehensive histopathological analysis in multiple tissues from 75 male and female mice up to 18 months of age. Additionally, we produced the double transgenic model R26-GB2/MMTV-PyMT, co-expressing GSDMB2 and the Polyoma-Middle-T oncogene, and assessed breast cancer generation and progression in GSDMB2-homozygous (n=10) and control (n=17) female mice up to 15 weeks of age.ResultsIn the R26-GB2 model, which showed different GSDMB2 cytoplasmic and/or nuclear localization among tissues, we investigated if GSDMB2 expression had intrinsic tumorigenic activity. 41% of mice developed spontaneous lung tumors, but neither the frequency nor the histology of these neoplasias was significantly different from wildtype animals. Strikingly, while 17% control mice developed gastric carcinomas, no GSDMB2-positive mice did. No other tumor types or additional histological alterations were frequently seen in these mice. In the R26-GB2/MMTV-PyMT model, the strong nucleus-cytoplasmic GSDMB2 expression in breast cancer cells did not significantly affect cancer formation (number of tumors, latency, tumor weight, histology or proliferation) or lung metastasis potential compared to controls.ConclusionsGSDMB2 expression alone does not have an overall tumorigenic potential in mice, but it might reduce gastric carcinogenesis. Contrary to human cancers, GSDMB2 upregulation does not significantly affect breast cancer generation and progression in mouse models. However, to evidence the GSDMB functions in cancer and other pathologies in vivo may require the presence of specific stimulus or cellular contexts. Our novel mouse strains will serve as the basis for the future development of more precise tissue-specific and context-dependent cancer models.
Effect of Suppression of Rotational Joint Instability on Cartilage and Meniscus Degeneration in Mouse Osteoarthritis Model
Authors: Arakawa Kohei , Takahata Kei , Oka Yuichiro , Ozone Kaichi , Morosawa Kzuma , Enomoto Saaya , Murata Kenji , Kanemura Naohiko , Kokubun Takanori 
Published: May 2021

ABSTRACTObjectiveJoint instability and meniscal dysfunction contribute to the onset and progression of knee osteoarthritis (OA). In the destabilization of the medial meniscus (DMM) model, secondary OA occurs due to the rotational instability and increases compressive stress resulting from the meniscal dysfunction. We created a new controlled abnormal tibial rotation (CATR) model that reduces the rotational instability that occurs in the DMM model. So, we aimed to investigate whether rotational instability affects articular cartilage degeneration using the DMM and CATR models, as confirmed using histology and immunohistochemistry.DesignTwelve-week-old male mice were randomized into 3 groups: DMM group, CATR group, and INTACT group (right knee of the DMM group). After 8 and 12 weeks, we performed the tibial rotational test, safranin-O/fast green staining, and immunohistochemical staining for TNF-α and MMP-13.ResultsThe rotational instability in the DMM group was significantly higher than that of the other groups. And articular cartilage degeneration was higher in the DMM group than in the other groups. However, meniscal degeneration was observed in both DMM and CATR groups. The TNF-α and MMP-13 positive cell rates in the articular cartilage of the CATR group were lower than those in the DMM group.ConclusionsWe found that the articular cartilage degeneration was effectively suppressed by controlling the rotational instability caused by meniscal dysfunction. These findings suggest that suppression of rotational instability in the knee joint is an effective therapeutic measure for preventing OA progression.
Investigation of extramammary sources of Group BStreptococcusreveals its unusual ecology and epidemiology in camels
Authors: Seligsohn Dinah , Crestani Chiara , Gitahi Nduhiu , Flodin Emelie Lejon , Chenais Erika , Zadoks Ruth N. 
Published: May 2021

AbstractCamels are vital to food production in the drylands of the Horn of Africa, with milk as their main contribution to food security. A major constraint to camel milk production is mastitis, inflammation of the mammary gland. The condition negatively impacts milk yield and quality as well as household income. The leading cause of mastitis in dairy camels isStreptococcus agalactiae,group BStreptococcus(GBS), which is also a commensal and pathogen of humans. It has been suggested that extramammary reservoirs for this pathogen may contribute to the occurrence of mastitis in camels. We explored the molecular epidemiology of GBS in camels using a cross-sectional study design for sample collection and phenotypic, genomic and phylogenetic analysis of isolates. Among 88 adult camels and 93 calves from six herds in Laikipia County, Kenya, GBS was detected in 20% of 50 milk samples, 25% of 152 nasal swabs, 8% of 90 oral swabs and 3% of 90 rectal swabs, but not in vaginal swabs. Per camel herd, two to four sequence types (ST) were present. More than half of the isolates belonged to ST617 or its single-locus variant, ST1652, with these STs found across all sample types. Serotype VI was detected in 30 of 58 isolates. In three herds, identical STs were detected in milk and swab samples, suggesting that extramammary sources of GBS may contribute to the maintenance and spread of GBS within camel herds. This needs to be considered when developing prevention and control strategies. In addition, the high nasal carriage rate, low recto-vaginal carriage rate, and high prevalence of serotype VI for GBS in camels are in stark contrast to the distribution of GBS in humans and reveal hitherto unknown ecological and molecular features of this bacterial species.
Pathways of savannization in a mesic African savanna-forest mosaic following an extreme fire
Authors: Beckett Heath , Staver A. Carla , Charles-Dominique Tristan , Bond William J. 
Published: May 2021

AbstractFires in savannas limit tree cover, thereby promoting flammable grass accumulation and fuelling further frequent fires. Meanwhile, forests and thickets form dense canopies that reduce C4-grass fuel loads and creating a humid microclimate, thereby excluding fires under typical climatic conditions.However, extreme fires occasionally burn into these closed-canopy systems. Although these rare fires cause substantial tree mortality and can make repeat fires more likely, the long-term consequences of an extreme fire for closed canopy vegetation structure and potential to convert to savanna (hereafter “savannization”) remain largely unknown.Here, we analysed whether an extreme fire could, alone, alter species composition, vegetation structure, and fire regimes of closed-canopy ecosystems in an intact savanna-forest-thicket mosaic, or whether successive fires after an initial extreme fire were necessary to trigger a biome transition between from forest to savanna.We found that forests that only burned once recovered, whereas those that burned again following an initial extreme fire transitioned from closed-canopy forests towards open, grassy savannas.While thickets had less tree mortality in fires than forests, repeat fires nonetheless precipitated a transition towards savannas.Colonization of the savanna tree community lagged behind the grass community, but also began to transition.SynthesisOur results suggest that rare extreme fires, followed by repeated burning can indeed result in savannization in places where savanna and forest represent alternative stable states.
de novo variant calling identifies cancer mutation profiles in the 1000 Genomes Project
Authors: Ng Jeffrey K. , Vats Pankaj , Fritz-Waters Elyn , Sarkar Stephanie , Sams Eleanor I. , Padhi Evin M. , Payne Zachary L. , Leonard Shawn , West Marc A. , Prince Chandler , Trani Lee , Jansen Marshall , Vacek George , Samadi Mehrzad , Harkins Timothy T. , Pohl Craig , Turner Tychele N. 
Published: May 2021

ABSTRACTDetection of de novo variants (DNVs) is critical for studies of disease-related variation and mutation rates. We developed a GPU-based workflow to rapidly call DNVs (HAT) and demonstrated its effectiveness by applying it to 4,216 Simons Simplex Collection (SSC) whole-genome sequenced parent-child trios from DNA derived from blood. In our SSC DNV data, we identified 78 ± 15 DNVs per individual, 18% ± 5% at CpG sites, 75% ± 9% phased to the paternal chromosome of origin, and an average allele balance of 0.49. These calculations are all in line with DNV expectations. We sought to build a control DNV dataset by running HAT on 602 whole-genome sequenced parent-child trios from DNA derived from lymphoblastoid cell lines (LCLs) from the publicly available 1000 Genomes Project (1000G). In our 1000G DNV data, we identified 740 ± 967 DNVs per individual, 14% ± 4% at CpG sites, 61% ± 11% phased to the paternal chromosome of origin, and an average allele balance of 0.41. Of the 602 trios, 80% had > 100 DNVs and we hypothesized the excess DNVs were cell line artifacts. Several lines of evidence in our data suggest that this is true and that 1000G does not appear to be a static reference. By mutation profile analysis, we tested whether these cell line artifacts were random and found that 40% of individuals in 1000G did not have random DNV profiles; rather they had DNV profiles matching B-cell lymphoma. Furthermore, we saw significant excess of protein-coding DNVs in 1000G in the gene IGLL5 that has already been implicated in this cancer. As a result of cell line artifacts, 1000G has variants present in DNA repair genes and at Clinvar pathogenic or likely-pathogenic sites. Our study elucidates important implications of the use of sequencing data from LCLs for both reference building projects as well as disease-related projects whereby these data are used in variant filtering steps.
Deciphering microbiome impacts on fungal-microalgal interaction in a marine environment using metabolomics
Authors: Berry Olivier , Briand Enora , Bagot Alizé , Chaigne Maud , Meslet-Cladière Laurence , Wang Julien , Grovel Olivier , Jansen Jeroen J. , Ruiz Nicolas , du Pont Thibaut Robiou , François Pouchus Yves , Hess Philipp , Bertrand Samuel 
Published: May 2021

AbstractThe comprehension of microbial interactions is one of the key challenges in microbial ecology. The present study focuses on studying the chemical interaction between the toxic dinoflagellate Prorocentrum lima PL4V strain and associated fungal strains (two Penicillium sp. strains and three Aspergillus sp) among which the Aspergillus pseudoglaucus strain MMS1589 was selected for further co-culture experiment. Such rarely studied interaction (fungal-microalgal) was explored in axenic and non-axenic conditions, in a dedicated microscale marine environment (hybrid solid/liquid conditions), to delineate specialized metabolome alteration in relation to the P. lima and A. pseudoglaucus co-culture in regard to the presence of their associated bacteria. Such alteration was monitored by high-performance liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). In-depth analysis of the resulting data highlighted (1) the chemical modification associated to fungal-microalgal co-culture, and (2) the impact of associated bacteria in microalgal resilience to fungal interaction. Even if only a very low number of highlighted metabolites were fully characterised due to the poor chemical investigation of the studied species, a clear co-culture induction of the dinoflagellate toxins okadaic acid and dinophysistoxin 1 was observed. Such results highlight the importance to consider microalgal microbiome to study parameters regulating toxin production. Finally, a microscopic observation showed an unusual physical interaction between the fungal mycelium and the dinoflagellates.
Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls
Authors: Laufer Benjamin I. , Neier Kari E. , Valenzuela Anthony E. , Yasui Dag H. , Schmidt Rebecca J. , Lein Pamela J. , LaSalle Janine M. 
Published: May 2021

AbstractBackgroundPolychlorinated biphenyls (PCBs) are developmental neurotoxicants implicated as environmental risk factors for neurodevelopmental disorders (NDD), including autism spectrum disorders (ASD).ObjectiveWe examined the effects of prenatal exposure to a human-relevant mixture of PCBs on the DNA methylome of fetal mouse brain and placenta to determine if there was a shared subset of differentially methylated regions (DMRs).MethodsA PCB mixture formulated to model the 12 most abundant congeners detected in the serum of pregnant women from a prospective high-risk ASD cohort was administered to female mice prior to and during pregnancy. Whole-genome bisulfite sequencing (WGBS) was performed to assess genome-wide DNA methylation profiles of placenta and brain on gestational day 18.ResultsWe found thousands of significant (empiricalp< 0.05) DMRs distinguishing placentas and brains from PCB-exposed embryos from sex-matched vehicle controls. In both placenta and brain, PCB-associated DMRs were significantly (p< 0.005) enriched for functions related to neurodevelopment, cellular adhesion, and cellular signaling, and significantly (Odds Ratio > 2.4,q< 0.003) enriched for bivalent chromatin marks. The placenta and brain PCB DMRs overlapped significantly (Z-score = 4.5,p= 0.0001) by genomic coordinate and mapped to a shared subset of genes significantly (q< 0.05) enriched for Wnt signaling, Slit/Robo signaling, and genes differentially expressed in multiple NDD/ASD models. The placenta and brain DMRs also significantly (q< 0.05) overlapped by genomic coordinate with brain samples from humans with Rett syndrome and Dup15q syndrome.DiscussionThese results demonstrate that placenta can be used as a surrogate for embryonic brain DNA methylation changes over genes relevant to NDD/ASD in a mouse model of prenatal PCB exposure.
The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases
Authors: Schneider Samuel H. , Kozuch Jacek , Boxer Steven G. 
Published: May 2021

AbstractThe interplay of enzyme active site electrostatics and chemical positioning are important for understanding the origin(s) of enzyme catalysis and the design of novel catalysts. We reconstruct the evolutionary trajectory of TEM-1 β-lactamase to TEM-52 towards extended-spectrum activity to better understand the emergence of antibiotic resistance and to provide insights into the structure-function paradigm and non-covalent interactions involved in catalysis. Utilizing a detailed kinetic analysis and the vibrational Stark effect, we quantify the changes in rates and electric fields in the Michaelis and acyl-enzyme complexes for penicillin G and cefotaxime to ascertain the evolutionary role of electric fields to modulate function. These data are combined with MD simulations to interpret and quantify the substrate-dependent structural changes during evolution. We observe that this evolutionary trajectory utilizes a large preorganized electric field and substrate-dependent chemical positioning to facilitate catalysis. This governs the evolvability, substrate promiscuity, and protein fitness landscape in TEM β-lactamase antibiotic resistance.
Protein sensors of bacterial kinase activity reveal antibiotic-dependent kinase activation in single cells
Authors: Zheng Christine R. , Singh Abhyudai , Libby Alexandra , Silver Pamela A. , Libby Elizabeth A. 
Published: May 2021

AbstractA lack of direct single-cell readouts for bacterial kinase activity remains a major barrier to our understanding of most signaling systems. At the single-cell-level, protein kinase activity is typically inferred by the activity of downstream transcriptional reporters. Complicating this approach in vivo, promoters are often co-regulated by several pathways, making the activity of a specific kinase difficult to deconvolve. Here, we have designed and constructed new, direct and specific sensors of bacterial kinase activity, including FRET-based sensors, as well as a synthetic transcription factor that responds to phosphorylation. We demonstrate the utility of these reporters in measuring kinase activity in population-based and single-cell assays during various growth phases and antibiotic treatments. These sensors respond to a highly conserved bacterial Ser/Thr kinase, PrkC that has no known dedicated transcription factor and whose regulon is known to be convolved with an essential signaling system. We used these new sensors to measure PrkC activity in colonies, bulk culture, and single cells. Together these new sensors provide evidence for considerable heterogeneity in PrkC activity in actively growing populations. We further demonstrate that PrkC activity increases in response to a cell-wall active antibiotic that blocks the late steps in peptidoglycan synthesis (cefotaxime), but not the early steps (fosfomycin). This is consistent with a model where PrkC senses and responds to blocks in the extracellular steps in cell wall synthesis. As the design of these phosphorylation sensors is modular, we anticipate that this work may have broad applications to other bacterial signaling systems in the future.
Personalized chordoma organoids for drug discovery studies
Authors: Shihabi Ahmad Al , Davarifar Ardalan , Lam Nguyen Huyen Thi , Tavanaie Nasrin , Nelson Scott D. , Yanagawa Jane , Federman Noah , Bernthal Nicholas , Hornicek Francis , Soragni Alice 
Published: May 2021

AbstractChordomas are rare tumors of notochordal origin, most commonly arising in the sacrum or skull base. Primary treatment of chordoma is surgery, however complete resection is not always feasible due to their anatomic location, and recurrence rates remain high. Chordomas are considered insensitive to conventional chemotherapy, and their rarity complicates running timely and adequately powered trials to identify effective regimens. Therefore, there is a need for discovery of novel therapeutic approaches. Drug discovery efforts in chordoma have been mostly limited to cell line models. Patient-derived organoids can accelerate drug discovery studies and predict patient responses to therapy. In this proof-of-concept study, we successfully established organoids from seven chordoma tumor samples obtained from five patients presenting with tumors in different sites and stages of disease. The organoids recapitulated features of the original parent tumors and inter-as well as intra-patient heterogeneity. High-throughput screenings performed on the organoids highlighted targeted agents such as PI3K/mTOR, EGFR, and JAK2/STAT3 inhibitors among the most effective molecules. Pathway analysis underscored how the NF-kB and IGF-1R pathways are sensitive to perturbations and potential targets to pursue for combination therapy of chordoma.