bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab plus radiotherapy with or without temozolomide in newly diagnosed glioblastoma: Results from exploratory phase I cohorts of CheckMate 143
Authors: Omuro Antonio , Reardon David A , Sampson John H , Baehring Joachim , Sahebjam Solmaz , Cloughesy Timothy F , Chalamandaris Alexandros-Georgios , Potter Von , Butowski Nicholas , Lim Michael 
Published: February 2022

AbstractBackgroundThe phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma.MethodsIn total, 136 patients were enrolled. In part A (safety lead-in), 31 patients (n = 15, methylated/unknown MGMT promoter; n = 16, unmethylated MGMT promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated MGMT promoter received NIVO+RT. In part B (expansion), patients with unmethylated MGMT promoter were randomized to NIVO+RT+TMZ (n = 29) or NIVO+RT (n = 30). Primary endpoint was safety/tolerability; secondary endpoint was overall survival (OS).ResultsNIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+RT+TMZ) and 28.6% (NIVO+RT) in part B. No new safety signals were detected. In part A, median OS (mOS) with NIVO+RT+TMZ was 33.38 months (95% CI, 16.2 to not estimable) in patients with methylated MGMT promoter. In patients with unmethylated MGMT promoter, mOS was 16.49 months (12.94–22.08) with NIVO+RT+TMZ and 14.41 months (12.55–17.31) with NIVO+RT. In part B, mOS was 14.75 months (10.01–18.6) with NIVO+RT+TMZ and 13.96 months (10.81–18.14) with NIVO+RT in patients with unmethylated MGMT promoter.ConclusionsCheckMate 143 was the first trial evaluating immune checkpoint inhibition with first-line treatment of glioblastoma. Results showed that NIVO can be safely combined with RT±TMZ, with no new safety signals. Toxicities, including lymphopenia, were more frequent with NIVO+RT+TMZ. OS was similar with or without TMZ in patients with unmethylated MGMT promoter, and differences by MGMT methylation status were observed.
The Emergence of Market Structure
Authors: Farboodi Maryam , Jarosch Gregor , Shimer Robert 
Published: February 2022

Abstract
We study a model of over-the-counter trading in which ex ante identical traders invest in a contact technology and participate in bilateral trade. We show that a rich market structure emerges both in equilibrium and in an optimal allocation. There is continuous heterogeneity in market access under weak regularity conditions. If the cost per contact is constant, heterogeneity is governed by a power law and there are middlemen, market participants with unboundedly high contact rates who account for a positive fraction of meetings. Externalities lead to overinvestment in equilibrium, and policies that reduce investment in the contact technology can improve welfare. We relate our findings to important features of real-world trading networks.
The performance of different classification criteria for systemic lupus erythematosus in a real-world rheumatology department
Authors: Tan Brandon C H , Tang Isaac , Bonin Julie , Koelmeyer Rachel , Hoi Alberta 
Published: February 2022

Abstract

Objective
New classification criteria have been proposed to improve classification of systemic lupus erythematosus (SLE). We aimed to evaluate their performance by determining their sensitivity, specificity and accuracy in a real-world rheumatology department.

Methods
SLE patients who were enrolled in the Australian Lupus Registry and Biobank were included and compared with controls recruited from other rheumatology clinics. Clinical and immunological features were reviewed, according to ACR 1997, SLICC 2012, EULAR/ACR 2019, or Systemic Lupus Erythematosus Risk Probability Index (SLERPI). Performance of each set of criteria was evaluated for the overall cohort and in a subgroup of patients with early SLE.

Results
The study included 394 SLE and 123 control patients with other rheumatological conditions. Sensitivity was highest using SLICC 2012 or SLERPI 2020 criteria. Specificity was highest using ACR 1997 criteria. The SLICC 2012 criteria had the highest overall accuracy at 94.4% (95% CI: 91.7, 97.1%). In the subgroup analysis of SLE patients with early disease, SLICC 2012 performed similarly well.

Conclusions
The sensitivity and specificity of each set of classification criteria vary slightly, with SLICC 2012 and SLERPI 2020 having the highest sensitivities and the ACR 1997 criteria having the highest specificity in our patient cohort. All classification criteria serve as good instructional aids for clinicians to understand SLE manifestations. For the Australian Lupus Registry and Biobank, we will continue to use the ACR 1997 and/or SLICC 2012 as entry to the observational cohort.
DISTRIBUTION OF GAMMA RADIATION DOSE RATE AND ACTIVITY CONCENTRATION IN SOIL RELATED WITH NATURAL RADIONUCLIDES ON TAIWAN MAIN ISLAND
Authors: Saito Kyoko , Inoue Kazumasa , Ishita Yuya , Shimizu Hideo , Fukushi Masahiro 
Published: February 2022

Abstract
To enable precise assessment of health impacts following a nuclear power plant accident, extensive and detailed data on environmental radiation levels are needed. This study was undertaken to investigate the air and the soil radiation levels using a car-borne survey on the main island of Taiwan where no extensive environmental radiation distribution survey had been conducted before. The mean air absorbed dose rate on this island was 57 ± 10 nGy h−1. The measured dose rate distribution varied depending on the geology of the soils, and ranged from 22 to 113 nGy h−1. The mean radiation level in soil was 539 ± 124 Bq kg−1 for 40K, 23 ± 8 Bq kg−1 for 238U and 41 ± 22 Bq kg−1 for 232Th. The air absorbed dose rate (58 nGy h−1) calculated from these data of mean radiation level in soil was comparable to that determined by the car-borne survey method. Thus, this study yielded detailed data on air absorbed dose rate depending primarily on the geology of the soils on the main island of Taiwan.
Perspective – ultrastructural analyses reflect the effects of sleep and sleep loss on neuronal cell biology
Authors: Wang Lijing , Aton Sara J 
Published: February 2022

Abstract
Recent electron microscopic analyses of neurons in the Drosophila and rodent brain demonstrate that acute or chronic sleep loss can alter the structures of various organelles, including mitochondria, nucleus, and Golgi apparatus. Here, we discuss these findings in the context of biochemical findings from the sleep deprived brain, to clarify how these morphological changes may related to altered organelle function. We discuss how, taken together, the available data suggest that sleep loss (particularly chronic sleep loss) disrupts such fundamental cellular processes as transcription, translation, intracellular transport, and metabolism. A better understanding of these effects will have broad implications for understanding the biological importance of sleep, and the relationship of sleep loss to neuropathology.
Jobs and Productivity Growth in Global Value Chains: New Evidence for Twenty-five Low- and Middle-Income Countries
Authors: Pahl Stefan , Timmer Marcel P , Gouma Reitze , Woltjer Pieter J 
Published: February 2022

Abstract
Using newly developed data, the evolution of job and productivity growth in global value chains (GVCs) is analyzed for 25 low- and middle-income countries. GVC jobs are found to be more productive than non-GVC jobs. Their share in the total labor force is small, in particular for low-income countries. Growth in GVC jobs varies widely across countries in the period 2000–2014. Part of this can be accounted for by differences in the type of consumer market served. A bigger part is accounted for by the speed with which countries expand activities within supply chains, measured by their shares in GVC value added. Expansion in GVCs is positively correlated with labor productivity across countries as well as over time within GVCs.
Clinical Management of Sleep and Sleep Disorders With Cannabis and Cannabinoids
Authors: Monti Jaime M. , Pandi-Perumal Seithikurippu R. 
Published: February 2022

Abstract
Phytocannabinoid derivatives are among the several compounds found in the cannabis plant. The phytocannabinoid chemicals Δ9-tetrahydrocannabinol (THC) and cannabidiol are mostly responsible for the drug's behavioral effects. Chronic cannabis administration has been shown to disrupt circadian rhythms and reduce the duration of the deepest phase (stage N3) of nonrapid eye movement sleep. Cannabidiol is thought to be responsible for the disruption of the circadian rhythm, whereas THC is thought to be accountable for the changes in sleep architecture. The quality of one's sleep has a significant impact on cannabis abstinence or relapse. As a result, the diminished sleep-promoting efficiency of cannabis in chronic users, as well as the resulting sleep difficulties once cannabis use is stopped, may sabotage attempts to quit and raise the risk of relapse. In individuals with obstructive sleep apnea who do not complain about the treatment process known as continuous positive airway pressure, cannabinoids are one of the treatments being considered. In this regard, preclinical investigations have demonstrated that combining the agent oleamide and THC aids in the stabilization of respiration in all stages of sleep as well as the maintenance of autonomic stability during sleep. The synthetic THC dronabinol was found to lower the apnea-hypopnea index in a clinical investigation and is regarded safe for the short-term treatment of obstructive sleep apnea. Patients experiencing nightmares who had been diagnosed with posttraumatic stress disorder were given the synthetic endocannabinoid receptor agonist nabilone. When compared with a placebo, the chemical proved helpful in reducing the frequency of nightmares. It is worth noting that a single study that looked at the effects of cannabidiol on REM behavior disorder found that symptoms improved. Based on the available findings, cannabinoids can be used as an alternate treatment for various sleep disorders. However, additional research is needed to corroborate the conclusions of these investigations.
Assessment of private variants in PRKN, PARK7 and PINK1 in Parkinson’s disease
Authors: Hu Jing , Waters Cheryl H. , Spiegelman Dan , Fon Edward A. , Yu Eric , Asayesh Farnaz , Krohn Lynne , Saini Prabhjyot , Alcalay Roy N. , Hassin-Baer Sharon , Gan-Or Ziv , Krainc Dimitri , Zhang BaoRong , Bustos Bernabe I. , Lubbe Steven J. ,   the International Parkinson’s Disease Genomics Consortium (IPDGC)
Published: February 2022

AbstractRecessive mutations in PRKN, PARK7 and PINK1 are established causes of early-onset Parkinson’s disease (EOPD). Previous studies have interrogated the role of heterozygous variants in these genes but mainly focused on rare (minor allele frequency [MAF] <1%) damaging variants or established mutations. Here, we assessed heterozygous private PRKN, PARK7 and PINK1 variants in PD risk in four large-scale PD case-control datasets by performing gene-wise burden analyses using sequencing data totaling 5,829 PD cases and 7,221 controls, and summary allele counts from 9,501 PD cases and 48,207 controls. Results showed no significant burden in all three genes after meta-analyses. Burden in EOPD (age at onset <50 years) and late-onset PD (≥50 years) remained nonsignificant. In summary, we found no evidence to support the association of the excess burden of heterozygous private variants in PRKN, PARK7, and PINK1 with PD risk in the European population. Larger, more diverse cohorts are needed to accurately determine their role in PD.
Rich Experience Boosts Functional Connectome and High-Dimensional Coding in Hippocampal Network
Authors: Emery Brett Addison , Hu Xin , Khanzada Shahrukh , Kempermann Gerd , Amin Hayder 
Published: February 2022

ABSTRACTChallenging the brain with experiential richness creates tissue-level changes and synaptic plasticity, but the interjacent network level has not been accessible. We here show that environmental enrichment has unexpectedly far-reaching effects on network connectivity and multi-dimensional coding in the hippocampus. We present direct evidence that experience impacts local and global network connectivity, synchrony, and rhythmic dynamics. For this, we investigated the hippocampi from standard-housed mice (SD) and mice living in an enriched environment (ENR) using large-scaleex vivorecordings with a high-density microelectrode sensing array that – with the unprecedented spatiotemporal resolution–allowed simultaneous electrophysiological assessment across the entire circuit. In the absence of extrinsic electrical network stimulation, we found enhanced functional connectivity and high-dimensional coding in hippocampal-cortical networks of ENR mice. The mapped connectome illustrated a scale-free smallworld topology and an ENR-induced resilience to random failures. ENR enhanced large-scale spatiotemporal firing patterns, which facilitated efficient pattern separation and boosted the information encoded in the firing phases of slow oscillatory rhythms. Given that essentially all electrophysiological studies on network behaviors have been done on animals housed in stimulus-poor conditions, our SD mice showed the expected normal functionality. The literature consequently underestimates the extent of spontaneous network activity and connectivity under truly physiological conditions. Our results pave the way to unveil fundamental mechanisms of experience-dependent enhancement in the hippocampal network underlying high brain functions and provide markers for large-scale network remodeling and metaplasticity.
xcore: an R package for inference of gene expression regulators
Authors: Migdał Maciej , Winata Cecilia Lanny , Arakawa Takahiro , Takizawa Satoshi , Furuno Masaaki , Suzuki Harukazu , Arner Erik , Kaczkowski Bogumił 
Published: February 2022

AbstractElucidating the Transcription Factors (TFs) that drive the gene expression changes in a given experiment is one of the most common questions asked by researchers. The existing methods rely on the predicted Transcription Factor Binding Site (TFBS) to model the changes in the motif activity. Such methods only work for TFs that have a motif and assume the TF binding profile is the same in all cell types. Given the wealth of the ChIP-seq data available for a wide range of the TFs in various cell types, we propose that the modeling can be done using ChiP-seq “signatures” directly, effectively skipping the motif finding and TFBS prediction steps. We present xcore, an R package that allows Transcription Factor activity modeling based on their ChiP-seq signatures and user’s gene expression data. We also provide xcoredata a companion data package that provides a collection of preprocessed ChiP-seq signatures. We demonstrate that xcore leads to biologically relevant predictions using TGF-beta induced epithelial-mesenchymal transition and rinderpest infection time-course CAGE data as examples.Availability and Implementationxcore and xcoredata R packages are freely available at www.github.com/bkaczkowski/xcore and www.github.com/mcjmigdal/xcoredata.xcore user guide is available www.bkaczkowski.github.io/xcore/articles/xcore_vignette.html.Contactb.kaczkowski@gmail.com
Categorical bias as a crucial parameter in visual working memory: the effect of memory load and retention interval
Authors: Zhou Cherie , Lorist Monicque M. , Mathôt Sebastiaan 
Published: February 2022

AbstractVisual information can be stored as continuous as well as categorical representations in visual working memory (VWM) to guide subsequent behavior. Yet it is still unclear what determines whether VWM is represented as continuous or categorical information, or as a mix of both. Recent studies have shown that color VWM representations adjust flexibly depending on the number of memory items as well as the duration that these items need to be maintained for. The current study aims to extend and replicate these crucial effects. In a delayed estimation task, participants memorized one to four colored objects presented at different spatial locations, followed by a delay of 100, 500, 1,000, or 2,000 ms. Next, a probe indicated the location of the color that participants needed to report. We measured the extent to which responses were biased in the direction of prototypical colors. Crucially, we implemented this categorical bias in an extension to the classic mixture model (Zhang & Luck 2008) in which the center of the error distribution is a crucial parameter that characterizes the extent to which VWM is biased by color categories. We found that VWM shows a strong categorical bias in all cases, and that this bias increases with increasing memory load; strikingly, this effect of memory load on categorical bias is stronger at longer intervals (1,000 ms or longer), as compared to shorter intervals, yet it peaks for intermediate memory loads as opposed to the highest memory load. Overall, our results suggest that when visual information needs to be maintained for one second or longer, VWM becomes more reliant on categorical representations as memory load increases.
Caecilian genomes reveal the molecular basis of adaptation, and convergent evolution of limblessness in snakes and caecilians
Authors: Ovchinnikov Vladimir , Uliano-Silva Marcela , Wilkinson Mark , Wood Jonathan , Smith Michelle , Oliver Karen , Sims Ying , Torrance James , Suh Alexander , McCarthy Shane A. , Durbin Richard , O’Connell Mary J. 
Published: February 2022

AbstractWe present genome sequences for the caeciliansGeotrypetes seraphini(3.8Gb) andMicrocaecilia unicolor(4.7Gb), representatives of a limbless, mostly soil-dwelling amphibian clade with reduced eyes, and unique putatively chemosensory tentacles. More than 69% of both genomes are composed of repeats, with retrotransposons the most abundant. We identify 1,150 orthogroups which are unique to caecilians and enriched for functions in olfaction and detection of chemical signals. There are 379 orthogroups with signatures of positive selection on caecilian lineages with roles in organ development and morphogenesis, sensory perception and immunity amongst others. We discover that caecilian genomes are missing the ZRS enhancer of Sonic Hedgehog which is also mutated in snakes.In vivodeletions have shown ZRS is required for limb development in mice, thus revealing a shared molecular target implicated in the independent evolution of limblessness in snakes and caecilians.
Genetic immune escape landscape in primary and metastatic cancer
Authors: Martínez-Jiménez Francisco , Priestley Peter , Shale Charles , Baber Jonathan , Rozemuller Erik , Cuppen Edwin 
Published: February 2022

AbstractImmune surveillance escape is a hallmark of tumorigenesis1. Multiple studies have characterized the immune escape landscape across several untreated early-stage primary cancer types2–4. However, whether late-stage treated metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. Here, we performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,457 uniformly processed Whole Genome Sequencing (WGS) tumor samples including 58 cancer types from 1,943 primary untreated patients and 4,514 metastatic patients. To effectively address the complexity of the Human Leukocyte Antigen (HLA-I) locus and to characterize its tumor status, we developed LILAC, an open-source integrative framework. We demonstrate that one in four tumors harbor GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is highly consistent between primary and metastatic tumors for most cancer types with few exceptions such as prostate and thyroid carcinomas that have increased immune evasion frequencies in metastatic tumors. Positive selection analysis revealed that GIE alterations are frequently selected for in tumor evolution and that focal LOH of HLA-I, unlike non-focal LOH of HLA-I, tends to lose the HLA allele that presents the largest neoepitope repertoire. We also unraveled tumor genomic features contributing to immune escape incidence, including DNA repair deficiency, APOBEC activity, tobacco associated mutation load and viral DNA integration. Finally, there is a strong tendency for mid and high tumor mutation burden (TMB) tumors to preferentially select LOH of HLA-I for GIE whereas hypermutated samples favor global immune evasion strategies. Our results indicate that genetic immune escape is generally a pre-metastatic event during tumor evolution and that tumors adapt different strategies depending on their neoepitope burden.
T cells use distinct topological and membrane receptor scanning strategies that individually coalesce during receptor recognition
Authors: Cai En , Beppler Casey , Eichorst John , Marchuk Kyle , Krummel Matthew F. 
Published: February 2022

AbstractDuring immune surveillance, CD8 T cells scan the surface of antigen presenting cells using dynamic microvillar palpation and movements as well as by having their receptors pre-concentrated into patches. Here, we use real-time lattice light sheet microscopy to demonstrate the independence of microvillar and membrane receptor patch scanning. While T cell receptor (TCR) patches can distribute to microvilli, they do so stochastically and not preferentially as for other receptors such as CD62L. The distinctness of TCR patch movement from microvillar movement extends to many other receptors that form patches that also scan independently of the TCR. An exception to this is the CD8 co-receptor which largely co-migrates in patches that overlap with or are closely adjacent to those containing TCRs. Microvilli that assemble into a synapse contain various arrays of the engaged patches, notably of TCRs and the inhibitory receptor PD-1, creating a pastiche of occupancies that vary from microvillar contact to contact. In summary, this work demonstrates that localization of receptor patches within the membrane and on microvillar projections is stochastic prior to antigen detection and that such stochastic variation may play into the generation of many individually-composed receptor patch compositions at a single synapse.Significance statementMotile T cell microvilli palpate surfaces to facilitate surface scanning in a pattern that is independent of the movement of pre-formed patches of transmembrane antigen-receptors across those microvilli; once T cell receptors engage, the microvilli act to scaffold multiple receptors within a microvillar close-contact.