bluuebunny/crossref_metadata_2025_split huggingface dataset:
Response-Time Analysis for Task Chains with Complex Precedence and Blocking Relations
Authors: Schlatow Johannes , Ernst Rolf 
Published: September 2017

For the development of complex software systems, we often resort to component-based approaches that separate the different concerns, enhance verifiability and reusability, and for which microkernel-based implementations are a good fit to enforce these concepts. Composing such a system of several interacting software components will, however, lead to complex precedence and blocking relations, which must be taken into account when performing latency analysis. When modelling these systems by classical task graphs, some of these effects are obfuscated and tend to render such an analysis either overly pessimistic or even optimistic.
We therefore firstly present a novel task (meta-)model that is more expressive and accurate w.r.t. these (functional) precedence and mutual blocking relations. Secondly, we apply the busy-window approach and formulate a modular response-time analysis on task-chain level suitable but not restricted to static-priority scheduled systems. We show that the conjunction of both concepts allows the calculation of reasonably tight latency bounds for scenarios not adequately covered by related work.
FlashKV
Authors: Zhang Jiacheng , Lu Youyou , Shu Jiwu , Qin Xiongjun 
Published: September 2017

As the cost-per-bit of solid state disks is decreasing quickly, SSDs are supplanting HDDs in many cases, including the primary storage of key-value stores. However, simply deploying LSM-tree-based key-value stores on commercial SSDs is inefficient and induces heavy write amplification and severe garbage collection overhead under write-intensive conditions. The main cause of these critical issues comes from the triple redundant management functionalities lying in the LSM-tree, file system and flash translation layer, which block the awareness between key-value stores and flash devices. Furthermore, we observe that the performance of LSM-tree-based key-value stores is improved little by only eliminating these redundant layers, as the I/O stacks, including the cache and scheduler, are not optimized for LSM-tree’s unique I/O patterns.
To address the issues above, we propose FlashKV, an LSM-tree based key-value store running on open-channel SSDs. FlashKV eliminates the redundant management and semantic isolation by directly managing the raw flash devices in the application layer. With the domain knowledge of LSM-tree and the open-channel information, FlashKV employs a parallel data layout to exploit the internal parallelism of the flash device, and optimizes the compaction, caching and I/O scheduling mechanisms specifically. Evaluations show that FlashKV effectively improves system performance by 1.5× to 4.5× and decreases up to 50% write traffic under heavy write conditions, compared to LevelDB.
Breathing above the brain stem: volitional control and attentional modulation in humans
Authors: Herrero Jose L. , Khuvis Simon , Yeagle Erin , Cerf Moran , Mehta Ashesh D. 
Published: September 2017

Whereas the neurophysiology of respiration has traditionally focused on automatic brain stem processes, higher brain mechanisms underlying the cognitive aspects of breathing are gaining increasing interest. Therapeutic techniques have used conscious control and awareness of breathing for millennia with little understanding of the mechanisms underlying their efficacy. Using direct intracranial recordings in humans, we correlated cortical and limbic neuronal activity as measured by the intracranial electroencephalogram (iEEG) with the breathing cycle. We show this to be the direct result of neuronal activity, as demonstrated by both the specificity of the finding to the cortical gray matter and the tracking of breath by the gamma-band (40–150 Hz) envelope in these structures. We extend prior observations by showing the iEEG signal to track the breathing cycle across a widespread network of cortical and limbic structures. We further demonstrate a sensitivity of this tracking to cognitive factors by using tasks adapted from cognitive behavioral therapy and meditative practice. Specifically, volitional control and awareness of breathing engage distinct but overlapping brain circuits. During volitionally paced breathing, iEEG-breath coherence increases in a frontotemporal-insular network, and during attention to breathing, we demonstrate increased coherence in the anterior cingulate, premotor, insular, and hippocampal cortices. Our findings suggest that breathing can act as an organizing hierarchical principle for neuronal oscillations throughout the brain and detail mechanisms of how cognitive factors impact otherwise automatic neuronal processes during interoceptive attention. NEW & NOTEWORTHY Whereas the link between breathing and brain activity has a long history of application to therapy, its neurophysiology remains unexplored. Using intracranial recordings in humans, we show neuronal activity to track the breathing cycle throughout widespread cortical/limbic sites. Volitional pacing of the breath engages frontotemporal-insular cortices, whereas attention to automatic breathing modulates the cingulate cortex. Our findings imply a fundamental role of breathing-related oscillations in driving neuronal activity and provide insight into the neuronal mechanisms of interoceptive attention.
SMYD5 Controls Heterochromatin and Chromosome Integrity during Embryonic Stem Cell Differentiation
Authors: Kidder Benjamin L. , He Runsheng , Wangsa Darawalee , Padilla-Nash Hesed M. , Bernardo M. Margarida , Sheng Shijie , Ried Thomas , Zhao Keji 
Published: September 2017

Abstract
Epigenetic regulation of chromatin states is thought to control gene expression programs during lineage specification. However, the roles of repressive histone modifications, such as trimethylated histone lysine 20 (H4K20me3), in development and genome stability are largely unknown. Here, we show that depletion of SET and MYND domain–containing protein 5 (SMYD5), which mediates H4K20me3, leads to genome-wide decreases in H4K20me3 and H3K9me3 levels and derepression of endogenous LTR- and LINE-repetitive DNA elements during differentiation of mouse embryonic stem cells. SMYD5 depletion resulted in chromosomal aberrations and the formation of transformed cells that exhibited decreased H4K20me3 and H3K9me3 levels and an expression signature consistent with multiple human cancers. Moreover, dysregulated gene expression in SMYD5 cancer cells was associated with LTR and endogenous retrovirus elements and decreased H4K20me3. In addition, depletion of SMYD5 in human colon and lung cancer cells results in increased tumor growth and upregulation of genes overexpressed in colon and lung cancers, respectively. These findings implicate an important role for SMYD5 in maintaining chromosome integrity by regulating heterochromatin and repressing endogenous repetitive DNA elements during differentiation. Cancer Res; 77(23); 6729–45. ©2017 AACR.
Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma
Authors: Yuan Jiang , Jiang Yan-Yi , Mayakonda Anand , Huang Moli , Ding Ling-Wen , Lin Han , Yu Fenggang , Lu Yanan , Loh Thomas Kwok Seng , Chow Marilynn , Savage Samantha , Tyner Jeffrey W. , Lin De-Chen , Koeffler H. Phillip 
Published: September 2017

Abstract
Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced antineoplastic activities both in vitro and in vivo. An integrative analysis using both whole-transcriptome sequencing and chromatin immunoprecipitation sequencing pinpointed oncogenic transcriptional amplification mediated by super-enhancers (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated networks identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2, and the long noncoding RNA TP53TG1. These transcripts were highly and specifically expressed in NPC and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK, and TEAD1) may help establish and maintain SE activity across the genome. Taken together, our data establish the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimens for this disease. Cancer Res; 77(23); 6614–26. ©2017 AACR.
Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma
Authors: Matsumoto Tomonori , Takai Atsushi , Eso Yuji , Kinoshita Kazuo , Manabe Toshiaki , Seno Hiroshi , Chiba Tsutomu , Marusawa Hiroyuki 
Published: September 2017

Abstract
Hepatocellular carcinoma (HCC) originates from regenerating liver cells with genetic alterations in chronically inflamed liver. Ductal cells and hepatocytes proliferate for liver regeneration, and proliferating ductal cells (PDC) derived from bile ductules have long been considered putative liver stem/progenitor cells and candidate cellular origins of HCC. The potential of PDC as tumor-originating cells, however, remains controversial in contrast to accumulating evidence that HCC originates from hepatocytes. Here, we demonstrate that PDCs expressing the established surface and cancer stem cell marker EpCAM give rise to HCC in inflamed liver. EpCAM-expressing PDCs were specifically labeled in newly developed EpcamCreERT2 mice and traced in a chemically induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. Lineage-tracing experiments revealed that labeled PDC differentiated into cholangiocytes, but not into hepatocytes, in the chemically damaged liver. Nevertheless, EpCAM-positive PDC with genetic alterations gave rise to HCC after 8 months of chemical administration. PDC-derived HCC showed histologic characteristics of concomitant ductule-like structures resembling human cholangiolocellular carcinoma (CLC) and exhibited serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. The Wnt signaling pathway was specifically upregulated in the CLC components of PDC-derived HCC. Our findings provide direct experimental evidence that EpCAM-expressing PDC could be a cellular origin of HCC, suggesting the existence of stem/progenitor-derived hepatocarcinogenesis. Cancer Res; 77(22); 6131–43. ©2017 AACR.
Head and Neck Squamous Cell Carcinomas Are Characterized by a Stable Immune Signature Within the Primary Tumor Over Time and Space
Authors: Wood Oliver , Clarke James , Woo Jeongmin , Mirza Adal H. , Woelk Christopher H. , Thomas Gareth J. , Vijayanand Pandurangan , King Emma , Ottensmeier Christian H. 
Published: September 2017

Abstract
Purpose: Genetic and morphologic heterogeneity is well-documented in solid cancers. Immune cells are also variably distributed within the tumor; this heterogeneity is difficult to assess in small biopsies, and may confound our understanding of the determinants of successful immunotherapy. We examined the transcriptomic variability of the immunologic signature in head and neck squamous cell carcinoma (HNSCC) within individual tumors using transcriptomic and IHC assessments.
Experimental Design: Forty-four tumor biopsies from 16 HNSCC patients, taken at diagnosis and later at resection, were analyzed using RNA-sequencing. Variance filtering was used to identify the top 4,000 most variable genes. Principal component analysis, hierarchical clustering, and correlation analysis were performed. Gene expression of CD8A was correlated to IHC analysis.
Results: Analysis of immunologic gene expression was highly consistent in replicates from the same cancer. Across the cohort, samples from the same patient were most similar to each other, both spatially (at diagnosis) and, notably, over time (diagnostic biopsy compared with resection); comparison of global gene expression by hierarchical clustering (P ≤ 0.0001) and correlation analysis [median intrapatient r = 0.82; median interpatient r = 0.63]. CD8A gene transcript counts were highly correlated with CD8 T-cell counts by IHC (r = 0.82).
Conclusions: Our data demonstrate that in HNSCC the global tumor and adaptive immune signatures are stable between discrete parts of the same tumor and also at different timepoints. This suggests that immunologic heterogeneity may not be a key reason for failure of immunotherapy and underpins the use of transcriptomics for immunologic evaluation of novel agents in HNSCC patients. Clin Cancer Res; 23(24); 7641–9. ©2017 AACR.
Immune Activation in Early-Stage Non–Small Cell Lung Cancer Patients Receiving Neoadjuvant Chemotherapy Plus Ipilimumab
Authors: Yi John S. , Ready Neal , Healy Patrick , Dumbauld Chelsae , Osborne Robyn , Berry Mark , Shoemaker Debra , Clarke Jeffrey , Crawford Jeffrey , Tong Betty , Harpole David , D'Amico Thomas A. , McSherry Frances , Dunphy Frank , McCall Shannon J. , Christensen Jared D. , Wang Xiaofei , Weinhold Kent J. 
Published: September 2017

Abstract
Purpose: To determine the immunologic effects of neoadjuvant chemotherapy plus ipilimumab in early-stage non–small cell lung cancer (NSCLC) patients.
Experimental Design: This is a single-arm chemotherapy plus phased ipilimumab phase II study of 24 treatment-naïve patients with stage IB–IIIA NSCLC. Patients received neoadjuvant therapy consisting of 3 cycles of paclitaxel with either cisplatin or carboplatin and ipilimumab included in the last 2 cycles.
Results: Chemotherapy alone had little effect on immune parameters in PBMCs. Profound CD28-dependent activation of both CD4 and CD8 cells was observed following ipilimumab. Significant increases in the frequencies of CD4+ cells expressing activation markers ICOS, HLA-DR, CTLA-4, and PD-1 were apparent. Likewise, increased frequencies of CD8+ cells expressing the same activation markers, with the exception of PD-1, were observed. We also examined 7 resected tumors and found higher frequencies of activated tumor-infiltrating lymphocytes than those observed in PBMCs. Surprisingly, we found 4 cases of preexisting tumor-associated antigens (TAA) responses against survivin, PRAME, or MAGE-A3 present in PBMC at baseline, but neither increased frequencies nor the appearance of newly detectable responses following ipilimumab therapy. Ipilimumab had little effect on the frequencies of circulating regulatory T cells and MDSCs.
Conclusions: This study did not meet the primary endpoint of detecting an increase in blood-based TAA T-cell responses after ipilimumab. Collectively, these results highlight the immune activating properties of ipilimumab in early-stage NSCLC. The immune profiling data for ipilimumab alone can contribute to the interpretation of immunologic data from combined immune checkpoint blockade immunotherapies. Clin Cancer Res; 23(24); 7474–82. ©2017 AACR.
A First-in-Human Phase I Study of the Anticancer Stem Cell Agent Ipafricept (OMP-54F28), a Decoy Receptor for Wnt Ligands, in Patients with Advanced Solid Tumors
Authors: Jimeno Antonio , Gordon Michael , Chugh Rashmi , Messersmith Wells , Mendelson David , Dupont Jakob , Stagg Robert , Kapoun Ann M. , Xu Lu , Uttamsingh Shailaja , Brachmann Rainer K. , Smith David C. 
Published: September 2017

Abstract
Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem cell function. Ipafricept (OMP-54F28) is a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This trial evaluated ipafricept in patients with solid tumors.
Experimental design: A 3+3 design was used; ipafricept was given intravenously every 3 weeks. The objectives were determination of dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and preliminary efficacy.
Results: 26 patients were treated in seven dose-escalation cohorts (0.5, 1, 2.5, 5, 10, 15, and 20 mg/kg). No further dose escalation was pursued as PK modeling indicated that the target efficacious dose was reached at 10 mg/kg, and fragility fractures occurred at 20 mg/kg. Most common related grade 1 and 2 adverse events (AEs; ≥20% of patients) were dysgeusia, decreased appetite, fatigue, and muscle spasms. Ipafricept-related grade 3 TEAEs included hypophosphatemia and weight decrease (1 subject each, 3.8%). Ipafricept half-life was ∼4 days and had low incidence of antidrug antibody formation (7.69%) with no impact on drug exposure. Six patients had β-C-terminal telopeptide (β-CTX) doubling from baseline, which was reversible. PD modulation of Wnt pathway genes in hair follicles occurred ≥2.5 mg/kg. Two desmoid tumor and a germ cell cancer patient experienced stable disease for &gt;6 months.
Conclusions: Ipafricept was well tolerated, with RP2D of 15 mg/kg Q3W. Prolonged SD was noted in desmoid tumor and germ cell cancer patients. Clin Cancer Res; 23(24); 7490–7. ©2017 AACR.
Estado, arquitetura e desenvolvimento. A ação habitacional do Iapi (Editora UNIFESP, Sao Paulo, 2016)
Authors: Ballent Anahi 
Published: September 2017

Reseña del libro Estado, Arquitetura e Desenvolvimento. A Ação Habitacional do Iapi (Editora UNIFESP, Sao Paulo, 2016), de Nilce Aravecchia-Botas.
Coronary Artery Calcium Distribution Is an Independent Predictor of Incident Major Coronary Heart Disease Events
Authors: Ferencik Maros , Pencina Karol M. , Liu Ting , Ghemigian Khristine , Baltrusaitis Kristin , Massaro Joseph M. , D’Agostino Ralph B. , O’Donnell Christopher J. , Hoffmann Udo 
Published: September 2017

Background—
The presence and extent of coronary artery calcium (CAC) are associated with increased risk for cardiovascular events. We determined whether information on the distribution of CAC and coronary dominance as detected by cardiac computed tomography were incremental to traditional Agatston score (AS) in predicting incident major coronary heart disease (CHD).

Methods and Results—

We assessed total AS and the presence of CAC per coronary artery, per segment, and coronary dominance by computed tomography in participants from the offspring and third-generation cohorts of the Framingham Heart Study. The primary outcome was major CHD (myocardial infarction or CHD death). We performed multivariable Cox proportional hazards analysis and calculated relative integrated discrimination improvement. In 1268 subjects (mean age, 56.2±10.3 years, 63.2% men) with AS >0 and no history of major CHD, a total of 42 major CHD events occurred during median follow-up of 7.4 years. The number of coronary arteries with CAC (hazard ratio, 1.68 per artery; 95% confidence interval, 1.10–2.57;
P
=0.02) and the presence of CAC in the proximal dominant coronary artery (hazard ratio, 2.59; 95% confidence interval, 1.15–5.83;
P
=0.02) were associated with major CHD events after multivariable adjustment for Framingham risk score and categories of AS. In addition, measures of CAC distribution improved discriminatory capacity for major CHD events (relative integrated discrimination improvement, 0.14).

Conclusions—
Distribution of coronary atherosclerosis, especially CAC in the proximal dominant coronary artery and an increased number of coronary arteries with CAC, predict major CHD events independently of the traditional AS in community-dwelling men and women.
Synergism of Short-Term Air Pollution Exposures and Neighborhood Disadvantage on Initial Stroke Severity
Authors: Wing Jeffrey J. , Sánchez Brisa N. , Adar Sara D. , Meurer William J. , Morgenstern Lewis B. , Smith Melinda A. , Lisabeth Lynda D. 
Published: September 2017

Background and Purpose—
Little is known about the relation between environment and stroke severity. We investigated associations between environmental exposures, including neighborhood socioeconomic disadvantage and short-term exposure to airborne particulate matter <2.5 μm and ozone, and their interactions with initial stroke severity.

Methods—
First-ever ischemic stroke cases were identified from the Brain Attack Surveillance in Corpus Christi project (2000–2012). Associations between pollutants, disadvantage, and National Institutes of Health Stroke Scale were modeled using linear and logistic regression with adjustment for demographics and risk factors. Pollutants and disadvantage were modeled individually, jointly, and with interactions.

Results—

Higher disadvantage scores and previous-day ozone concentrations were associated with higher odds of severe stroke. Higher levels of particulate matter <2.5 μm were associated with higher odds of severe stroke among those in higher disadvantage areas (odds ratio, 1.24; 95% confidence interval, 1.00–1.55) but not in lower disadvantage areas (odds ratio, 0.82; 95% confidence interval, 0.56–1.22;
P
interaction =0.097).

Conclusions—
Air pollution exposures and neighborhood socioeconomic status may be important in understanding stroke severity. Future work should consider the multiple levels of influence on this important stroke outcome.
Discrete Sparse Coding
Authors: Exarchakis Georgios , Lücke Jörg 
Published: September 2017

Sparse coding algorithms with continuous latent variables have been the subject of a large number of studies. However, discrete latent spaces for sparse coding have been largely ignored. In this work, we study sparse coding with latents described by discrete instead of continuous prior distributions. We consider the general case in which the latents (while being sparse) can take on any value of a finite set of possible values and in which we learn the prior probability of any value from data. This approach can be applied to any data generated by discrete causes, and it can be applied as an approximation of continuous causes. As the prior probabilities are learned, the approach then allows for estimating the prior shape without assuming specific functional forms. To efficiently train the parameters of our probabilistic generative model, we apply a truncated expectation-maximization approach (expectation truncation) that we modify to work with a general discrete prior. We evaluate the performance of the algorithm by applying it to a variety of tasks: (1) we use artificial data to verify that the algorithm can recover the generating parameters from a random initialization, (2) use image patches of natural images and discuss the role of the prior for the extraction of image components, (3) use extracellular recordings of neurons to present a novel method of analysis for spiking neurons that includes an intuitive discretization strategy, and (4) apply the algorithm on the task of encoding audio waveforms of human speech. The diverse set of numerical experiments presented in this letter suggests that discrete sparse coding algorithms can scale efficiently to work with realistic data sets and provide novel statistical quantities to describe the structure of the data.