bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combinatorial benefit without synergy in recent clinical trials of immune checkpoint inhibitors
Authors: Palmer Adam C. , Izar Benjamin , Hwangbo Haeun , Sorger Peter K. 
Published: July 2020

ABSTRACTHundreds of clinical trials are testing combinations of Immune Checkpoint Inhibitors (ICIs) with other cancer therapies in the hope that they will have additive or synergistic efficacy involving mechanisms such as immune priming. However we find that the clinically observed benefits of recently reported and approved combination therapies with ICIs are fully and accurately accounted for by increasing the chance of a single-agent response in individual patients (drug independence), with no requirement for additive or synergistic efficacy (correlation between observed and expected Progression Free Survival: Pearson r = 0.98, P = 5×10−9, n = 4173 patients in 14 trials). Thus, the likely anti-tumor efficacy of new ICI combinations can be predicted if monotherapy data are available; predicting adverse effects remain challenging. Realizing the promise of drug additivity or synergy is likely to require better response biomarkers that identify patients in whom multiple constituents of a combination therapy are active.
Muting, not fragmentation, of functional brain networks under general anesthesia
Authors: Areshenkoff Corson N. , Nashed Joseph Y. , Hutchison R. Matthew , Hutchison Melina , Levy Ron , Cook Douglas J. , Menon Ravi S. , Everling Stefan , Gallivan Jason P. 
Published: July 2020

AbstractChanges in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and disruption in the brains ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities considered hallmarks of fragmentation are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness.
Convergent Evolution of Pain-Inducing Defensive Venom Components in Spitting Cobras
Authors: Kazandjian T.D. , Petras D. , Robinson S.D. , van Thiel J. , Greene H.W. , Arbuckle K. , Barlow A. , Carter D.A. , Wouters R.M. , Whiteley G. , Wagstaff S.C. , Arias A.S. , Albulescu L-O. , von Plettenberg Laing A. , Hall C. , Heap A. , Penrhyn-Lowe S. , McCabe C.V. , Ainsworth S. , da Silva R.R. , Dorrestein P.C. , Richardson M.K. , Gutiérrez J.M. , Calvete J.J. , Harrison R.A. , Vetter I. , Undheim E.A.B. , Wüster W. , Casewell N.R. 
Published: July 2020

AbstractConvergent evolution provides unparalleled insights into the selective drivers underlying evolutionary change. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of spitting cobras have independently evolved the ability to use venom as a defensive projectile. Using gene, protein and functional analyses, we show that the three spitting lineages possess venom characterized by an upregulation of PLA2toxins, which potentiate the action of venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by exaptations. Notably, the timing of their origins suggests that defensive venom spitting may have evolved in response to the emergence of bipedal hominids in Africa and Asia.One Sentence SummaryVenom spitting by snakes coincides with the emergence of hominins and is underpinned by convergent increases in pain-enhancing toxins
PTM-Shepherd: analysis and summarization of post-translational and chemical modifications from open search results
Authors: Geiszler Daniel J. , Kong Andy T. , Avtonomov Dmitry M. , Yu Fengchao , Leprevost Felipe V. , Nesvizhski Alexey I. 
Published: July 2020

ABSTRACTOpen searching has proven to be an effective strategy for identifying both known and unknown modifications in shotgun proteomics experiments. Rather than being limited to a small set of user-specified modifications, open searches identify peptides with any mass shift that may correspond to a single modification or a combination of several modifications. Here we present PTM-Shepherd, a bioinformatics tool that automates characterization of PTM profiles detected in open searches based on attributes such as amino acid localization, fragmentation spectra similarity, retention time shifts, and relative modification rates. PTM-Shepherd can also perform multi-experiment comparisons for studying changes in modification profiles, e.g. in data generated in different laboratories or under different conditions. We demonstrate how PTM-Shepherd improves the analysis of data from formalin-fixed paraffin-embedded samples, detects extreme underalkylation of cysteine in some datasets, discovers an artefactual modification introduced during peptide synthesis, and uncovers site-specific biases in sample preparation artifacts in a multi-center proteomics profiling study.
CircTulp4 functions in Alzheimer’s disease pathogenesis by regulating its parental gene, Tulp4
Authors: Ma Nana , Pan Jie , Wu Qi , Yu Bo , Wan Jun , Zhang Wei 
Published: July 2020

AbstractAlzheimer’s disease (AD)—one of the most common neurodegenerative diseases worldwide—impairs cognition, memory, and language ability and causes dementia. However, AD pathogenesis remains poorly elucidated. Recently, a potential link between AD and circular RNAs (circRNAs) has been uncovered, but only a few circRNAs that might be involved in AD have been identified. Here, we systematically investigated circRNAs in the APP/PS1 model mouse brain through deep RNA-sequencing. We report that circRNAs are markedly enriched in the brain and that several circRNAs exhibit differential expression between wild-type and APP/PS1 mice. We characterized one abundant circRNA, circTulp4, derived from Intron1 of the geneTulp4. Our results indicate that circTulp4 predominantly localizes in the nucleus and interacts with U1 snRNP and RNA polymerase II to modulate the transcription of its parental gene,Tulp4, and thereby regulate the function of the nervous system and might participate in the development of AD.
Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition
Authors: Dearden Richard P. , Giles Sam 
Published: July 2020

AbstractThe teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching ‘acanthodian’-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckel’s cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth ofAcanthodopsisare borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly.
Reference data based insights expand understanding of human metabolomes
Authors: Gauglitz Julia M. , Bittremieux Wout , Williams Candace L. , Weldon Kelly C. , Panitchpakdi Morgan , Di Ottavio Francesca , Aceves Christine M. , Brown Elizabeth , Sikora Nicole C. , Jarmusch Alan K. , Martino Cameron , Tripathi Anupriya , Sayyari Erfan , Shaffer Justin P. , Coras Roxana , Vargas Fernando , Goldasich Lindsay DeRight , Schwartz Tara , Bryant MacKenzie , Humphrey Gregory , Johnson Abigail J. , Spengler Katharina , Belda-Ferre Pedro , Diaz Edgar , McDonald Daniel , Zhu Qiyun , Nguyen Dominic S. , Elijah Emmanuel O. , Wang Mingxun , Marotz Clarisse , Sprecher Kate E. , Robles Daniela Vargas , Withrow Dana , Ackermann Gail , Herrera Lourdes , Bradford Barry J. , Mauriz Marques Lucas Maciel , Amaral Juliano Geraldo , Silva Rodrigo Moreira , Veras Flávio Protaso , Cunha Thiago Mattar , Ribeiro Oliveira Rene Donizeti , Louzada-Junior Paulo , Mills Robert H. , Galasko Douglas , Dulai Parambir S. , Wittenberg Curt , Gonzalez David J. , Terkeltaub Robert , Doty Megan M. , Kim Jae H. , Rhee Kyung E. , Beauchamp-Walters Julia , Wright Kenneth P. , Dominguez-Bello Maria Gloria , Manary Mark , Oliveira Michelli F. , Boland Brigid S. , Lopes Norberto Peporine , Guma Monica , Swafford Austin D. , Dutton Rachel J. , Knight Rob , Dorrestein Pieter C. 
Published: July 2020

SummaryThe human metabolome has remained largely unknown, with most studies annotating ∼10% of features. In nucleic acid sequencing, annotating transcripts by source has proven essential for understanding gene function. Here we generalize this concept to stool, plasma, urine and other human metabolomes, discovering that food-based annotations increase the interpreted fraction of molecular features 7-fold, providing a general framework for expanding the interpretability of human metabolomic “dark matter.”
The Cuban Human Brain Mapping Project population based normative EEG, MRI, and Cognition dataset
Authors: Valdes-Sosa Pedro A. , Galan Lidice , Bosch-Bayard Jorge , Bringas Vega Maria L. , Vazquez Eduardo Aubert , Das Samir , Alba Trinidad Virues , Madjar Cecile , Mohades Zia , MacIntyre Leigh C. , Rogers Christine , Brown Shawn , Urrutia Lourdes Valdes , Gil Iris Rodriguez , Evans Alan C. , Valdes Sosa Mitchell J. 
Published: July 2020

AbstractThe Cuban Human Brain Mapping Project (CHBMP) repository is an open multimodal neuroimaging and cognitive dataset from 282 healthy participants (31.9 ± 9.3 years, age range 18–68 years). This dataset was acquired from 2004 to 2008 as a subset of a larger stratified random sample of 2,019 participants from La Lisa municipality in La Habana, Cuba. The exclusion included presence of disease or brain dysfunctions. The information made available for all participants comprises: high-density (64-120 channels) resting state electroencephalograms (EEG), magnetic resonance images (MRI), psychological tests (MMSE, Wechsler Adult Intelligence Scale -WAIS III, computerized reaction time tests using a go no-go paradigm), as well as general information (age, gender, education, ethnicity, handedness and weight). The EEG data contains recordings with at least 30 minutes duration including the following conditions: eyes closed, eyes open, hyperventilation and subsequent recovery. The MRI consisted in anatomical T1 and T2 as well as diffusion weighted (DWI) images acquired on a 1.5 Tesla system. The data is available for registered users on the LORIS database which is part of the MNI neuroinformatics ecosystem.
Temperature impacts the transmission of malaria parasites byAnopheles gambiaeandAnopheles stephensimosquitoes
Authors: Villena Oswaldo C. , Ryan Sadie J. , Murdock Courtney C. , Johnson Leah R. 
Published: July 2020

AbstractExtrinsic environmental factors influence the spatio-temporal dynamics of many organisms, including insects that transmit the pathogens responsible for vector-borne diseases (VBDs). Temperature is an especially important constraint on the fitness of a wide variety of insects, as they are primarily ectotherms. Temperature constrains the distribution of ectotherms and therefore of the infections that they spread in both space and time. More concretely, a mechanistic understanding of how temperature impacts traits of ectotherms to predict the distribution of ectotherms and vector-borne infections is key to predicting the consequences of climate change on transmission of VBDs like malaria. However, the response of transmission to temperature and other drivers is complex, as thermal traits of ectotherms are typically non-linear, and they interact to determine transmission constraints. In this study, we assess and compare the effect of temperature on the transmission of two malaria parasites,Plasmodium falciparumandPlasmodium vivax, by two malaria vector species,Anopheles gambiaeandAnopheles stephensi. We model the non-linear responses of temperature dependent mosquito and parasite traits (mosquito development rate, bite rate, fecundity, egg to adult survival, vector competence, mortality rate, and parasite development rate) and incorporate these traits into a suitability metric based on a model for the basic reproductive number across temperatures. Our model predicts that the optimum temperature for transmission suitability is similar for the four mosquito-parasite combinations assessed in this study. The main differences are found at the thermal limits. More specifically, we found significant differences in the upper thermal limit between parasites spread by the same mosquito (An. stephensi) and between mosquitoes carryingP. falciparum. In contrast, at the lower thermal limit the significant differences were primarily between the mosquito species that both carried the same pathogen (e.g.,An. stephensiandAn. gambiaeboth withP. falciparum). Using prevalence data from Africa and Asia, we show that the transmission suitability metricS(T) calculated from our mechanistic model is an important predictor of malaria prevalence. We mapped risk to illustrate the areas in Africa and Asia that are suitable for malaria transmission year-round based temperature.
Inactivation analysis of SARS-CoV-2 by specimen transport media, nucleic acid extraction reagents, detergents and fixatives
Authors: Welch Stephen R. , Davies Katherine A. , Buczkowski Hubert , Hettiarachchi Nipunadi , Green Nicole , Arnold Ulrike , Jones Matthew , Hannah Matthew J. , Evans Reah , Burton Christopher , Burton Jane E. , Guiver Malcolm , Cane Patricia A. , Woodford Neil , Bruce Christine B. , Roberts Allen D. G. , Killip Marian J. 
Published: July 2020

AbstractThe COVID-19 pandemic has necessitated a rapid multi-faceted response by the scientific community, bringing researchers, health officials and industry together to address the ongoing public health emergency. To meet this challenge, participants need an informed approach for working safely with the etiological agent, the novel human coronavirus SARS-CoV-2. Work with infectious SARS-CoV-2 is currently restricted to high-containment laboratories, but material can be handled at a lower containment level after inactivation. Given the wide array of inactivation reagents that are being used in laboratories during this pandemic, it is vital that their effectiveness is thoroughly investigated. Here, we evaluated a total of 23 commercial reagents designed for clinical sample transportation, nucleic acid extraction and virus inactivation for their ability to inactivate SARS-CoV-2, as well as seven other common chemicals including detergents and fixatives. As part of this study, we have also tested five filtration matrices for their effectiveness at removing the cytotoxic elements of each reagent, permitting accurate determination of levels of infectious virus remaining following treatment. In addition to providing critical data informing inactivation methods and risk assessments for diagnostic and research laboratories working with SARS-CoV-2, these data provide a framework for other laboratories to validate their inactivation processes and to guide similar studies for other pathogens.
The Rice Plastidial Phosphorylase Participates Directly In Both Sink And Source Processes
Authors: Koper Kaan , Hwang Seon-Kap , Wood Magnus , Singh Salvinder , Cousins Asaph , Kirchhoff Helmut , Okita Thomas W. 
Published: July 2020

AbstractA distinctive structural feature of the higher plant plastidial starch phosphorylase (Pho1) is a 50 to 82 amino acid long peptide (L50 - L82), which is absent in phosphorylases from non-plant organisms. To study the function of the rice Pho1 L80 peptide, we complemented apho1−rice mutant (BMF136) with the wildtype Pho1 gene or with a Pho1 gene lacking the L80 region (Pho1ΔL80). While expression of Pho1 in BMF136 restored normal wildtype phenotype, the introduction of Pho1ΔL80 enhanced growth rate and plant productivity above wildtype levels. Mass spectrometry analysis of proteins captured by anti-Pho1 showed the surprising presence of PsaC, the terminal electron acceptor/donor subunit of photosystem I (PSI). This unexpected interaction was substantiated by reciprocal immobilized protein pulldown assays of seedling extracts and supported by the presence of Pho1 on isolated PSI complexes resolved by blue native gels. Spectrophotometric studies showed that Pho1ΔL80 plants exhibited modified PSI and enhanced CO2assimilation properties. Collectively, these findings indicate that the higher plant Pho1 has dual roles as a potential modulator of source and sink processes.
Intraspecific genetic variation for anesthesia success in a New Zealand freshwater snail
Authors: Song Qiudong , Magnuson Richard , Jalinsky Joseph , Roseman Marissa , Neiman Maurine 
Published: July 2020

ABSTRACTIntraspecific genetic variation can drive phenotypic variation even across very closely related individuals. Here, we demonstrate that genetic differences between snails are a major contributor to wide variation in menthol anesthesia success in an important freshwater snail model system,Potamopyrgus antipodarum. Anesthesia is used to immobilize organisms for experiments and surgical procedures and to humanely mitigate pain. This is the first example of which we are aware of a role for genetic variation in anesthesia success in a mollusk. These findings highlight the fact that using only one strain or lineage for many experiments will not provide a full picture of phenotypic variation, demonstrate the importance of optimizing biomedically relevant techniques and protocols across a variety of genetic backgrounds, illuminate a potential mechanism underlying previously documented challenges in molluscan anesthesia, and set the stage for powerful and humane manipulative experiments inP. antipodarum.
Plasma lipid and liporotein biomarkers in LBC1936: Do they predict general cognitive ability and brain structure?
Authors: Harris Sarah E. , Ritchie Stuart J , Correia Gonçalo D S , Jiménez Beatriz , Fawns-Ritchie Chloe , Pattie Alison , Corley Janie , Maniega Susana Muñoz , Hernández Maria Valdés , Starr John M. , Hill Derek , Wren Paul , Bastin Mark E. , Lewis Matthew R , Wardlaw Joanna M. , Deary Ian J. 
Published: July 2020

AbstractIdentifying predictors of cognitive ability and brain structure in later life is an important step towards understanding the mechanisms leading to cognitive decline and dementia. This study used ultra-performance liquid chromatography mass spectrometry (UPLC-MS) and nuclear magnetic resonance (NMR) to measure targeted and untargeted metabolites, mainly lipids and lipoproteins, in ∼600 members of the Lothian Birth Cohort 1936 (LBC1936) at aged ∼73 years. Penalized regression models (LASSO) were then used to identify sets of metabolites that predict variation in general cognitive ability and structural brain variables. UPLC-MS-POS measured lipids, together predicted 19% of the variance in total brain volume and 17% of the variance in both grey matter and normal appearing white matter volumes. Multiple subclasses of lipids were included in the predictor, but the best performing lipid was the sphingomyelin SM(d18:2/14:0) which occurred in 100% of iterations of all three significant models. No metabolite set predicted cognitive ability, or white matter hyperintensities or connectivity. Future studies should concentrate on identifying specific lipids as potential cognitive and brain-structural biomarkers in older individuals.
DNA methylation site loss for plasticity-led novel trait genetic fixation
Authors: Katsumura Takafumi , Sato Suguru , Yamashita Kana , Oda Shoji , Gakuhari Takashi , Tanaka Shodai , Fujitani Kazuko , Nishimaki Toshiyuki , Imai Tadashi , Yoshiura Yasutoshi , Takeshima Hirohiko , Hashiguchi Yasuyuki , Sekita Yoichi , Mitani Hiroshi , Ogawa Motoyuki , Takeuchi Hideaki , Oota Hiroki 
Published: July 2020

AbstractMany organisms exhibit phenotypic plasticity that changes their traits in response to their environment. Whether or not this plasticity contributes to adaptive evolution is a fundamental question in evolutionary biology because various studies report that natural populations adapt to rapid environmental changes via plasticity, which often “triggers” novel adaptive traits. While such alternative phenotypes could be induced by nongenetic perturbations that include gene expression noise or epigenetic modification caused by environmental change, it remains unknown what molecular mechanism genetically fix the alternative phenotypes as adaptive traits passed into the next generation. Here we show that a decrease in methylated CpG sites leads to loss of plasticity, which triggers genetic fixation of novel traits, in medaka fish (Oryzias latipes). We found that the gut length was correlated with the number of methylated CpG sites upstream of thePlxnb3gene. The medaka, in which the methylated DNA region is deleted by CRISPR/Cas9, showed a loss of plasticity in gut length.Moreover, standing variation in the promoter region of another gene,Ppp3r1, made a longer gut stably in wild medaka groups that lost the gut-length plasticity. Furthermore, our phylogenetic analysis revealed the timing of these evolutionary events, indicating that the loss of phenotypic plasticity by nucleotide substitutions initiates the process of genetic fixation of the novel trait. That is, while phenotypic plasticity plays a role as a buffer of evolution and contributes to environmental adaptation, as previously thought, our molecular data suggest that mutation on CpG site causing the loss of phenotypic plasticity, is the trigger for a generation of novel traits.