bluuebunny/crossref_metadata_2025 huggingface dataset:
Multifractal Fluctuation Analysis of Correlations Between the Sector Stock Markets in China and the US
Authors: Feng You-Shuai , Wang Hong-Yong
Published: December 2020

With the rapid development of economic globalization, the stock markets in China and the US are increasingly linked. The fluctuation features and cross-correlations of the two countries’ markets have attracted extensive attention from market investors and researchers. In this paper, the fractal analysis methods including multifractal asymmetric detrended cross-correlation analysis (MF-ADCCA) and coupled detrended cross-correlation analysis (CDCCA) are applied to explore the volatilities of CSI300 and SP500 sector stock indexes as well as the cross-correlations and coupling cross-correlations between the two corresponding sector stock indexes. The results show that the auto-correlations, cross-correlations and coupling cross-correlations have multifractal fluctuation characteristics, and that the cross-correlations are asymmetric. Additionally, the coupling cross-correlation strengths are distinct due to the different influence of long-range correlations and fat-tailed distribution. Further, the co-movement between China and the US sector stock markets is susceptible to external market factors such as major economic events and national policies.
Single depth map super-resolution via a deep feedback network
Authors: Wu Guoliang , Wang Yanjie , Li Shi
Published: December 2020

Existing depth map-based super-resolution (SR) methods cannot achieve satisfactory results in depth map detail restoration. For example, boundaries of the depth map are always difficult to reconstruct effectively from the low-resolution (LR) guided depth map particularly at big magnification factors. In this paper, we present a novel super-resolution method for single depth map by introducing a deep feedback network (DFN), which can effectively enhance the feature representations at depth boundaries that utilize iterative up-sampling and down-sampling operations, building a deep feedback mechanism by projecting high-resolution (HR) representations to low-resolution spatial domain and then back-projecting to high-resolution spatial domain. The deep feedback (DF) block imitates the process of image degradation and reconstruction iteratively. The rich intermediate high-resolution features effectively tackle the problem of depth boundary ambiguity in depth map super-resolution. Extensive experimental results on the benchmark datasets show that our proposed DFN outperforms the state-of-the-art methods.
Separation of variables in Hamilton–Jacobi and Klein–Gordon–Fock equations for a charged test particle in the stackel spaces of type (1.1)
Authors: Obukhov Valeriy
Published: December 2020

All equivalence classes for electromagnetic potentials and space-time metrics of Stackel spaces provided that Hamilton–Jacobi equation and Klein–Gordon–Fock equation for a charged test particle can be integrated by the method of complete separation of variables are found. The separation is carried out using the complete sets of mutually commuting integrals of motion of type (1.1) whereby in a privileged coordinate system, the given equations turn into parabolic type equations. Hence, these metrics can be used as models for describing plane gravitational waves.
Direct N2O decomposition over Yb2O3-CuO catalysts with C-type cubic structure
Authors: Cho Chang-Min , Nunotani Naoyoshi , Imanaka Nobuhito
Published: December 2020

Novel Yb2O3-CuO catalysts with C-type cubic structure were synthesized for direct nitrous oxide (N2O) decomposition. By introducing Cu[Formula: see text] ions into Yb2O3 lattice, the enhancement in the catalytic activity was recognized owing to the improvement of redox properties and the generation of oxide ion vacancies. Among the catalysts prepared, the highest activity was obtained for the (Yb[Formula: see text]Cu[Formula: see text]O[Formula: see text] catalyst, and the complete N2O decomposition was achieved at the temperature as low as 400[Formula: see text]C. In addition, the catalyst showed high durability for co-existing of oxygen gas and water vapor.
Electrical conduction properties of the BZT–BST ceramics
Authors: Patel Satyanarayan , Yadav Harekrishna
Published: December 2020

0.5Ba([Formula: see text][Formula: see text]O3-0.5([Formula: see text][Formula: see text]TiO3 (BZT–BST) has been explored in recent times for potential applications in energy harvesting, electrocaloric and energy storage. To this end, energy harvesting/conversion and storage applications require an understanding of the conduction and loss mechanisms. The conduction mechanism in BZT–BST ceramics is studied using impedance spectroscopy (IS) at 0.1 Hz−3 MHz and 100−600[Formula: see text]C. Impedance study reveals the presence of two types of relaxation processes due to grain and grain boundary contributions. The relaxation time and dc conductivity activation energies are obtained as 1.12/1.3 eV and 1.05/1.2eV for bulk/grain boundary, respectively, and found that oxygen vacancies dominated electrical behavior. The relaxation mechanism follows non-Debye-type behavior. The high resistance of the grain (bulk) in the ferroelectric region does not contribute to the high losses; the losses probably result from the phase transition. Also, BZT–BST ceramics exhibit a negative temperature coefficient of resistance (NTCR) behaviour. From a practical application point of view in the temperature regime of 25–65[Formula: see text]C, the loss’s contribution is low. The significant contributions of loss result from the response of phase-transition in this temperature range (25–65[Formula: see text]C).
Engineering of dielectric composites on electromagnetic and microwave absorbing properties for operation in the X-band
Authors: Singh Bhoopendra , Pratap Vivek , Katiyar Mohit , Abbas S. M. , Sharma Y. K. , Siddiqui A. M. , Prasad N. Eswara
Published: December 2020

In this study, carbon black (CB) powder-loaded polyurethane (PU) composites (CB–PU composites) were prepared by melt mixing method with different volume percentages (45, 50, 55, 58 and 61 vol.%) of CB in the PU matrix. The prepared CB–PU composites had been further studied for surface morphology using the field-emission scanning electron microscopy (FESEM) technique. Dielectric properties in terms of real permittivity ([Formula: see text] and imaginary permittivity ([Formula: see text] of the fabricated composites were computed using an Agilent E8364B vector network analyzer in the frequency range of 8–12 GHz ([Formula: see text]-band). Dielectric loss factor of the prepared CB–PU composites was computed in terms of the dielectric loss tangent (tan [Formula: see text] = [Formula: see text]/[Formula: see text]. Microwave absorbing properties were appraised in terms of the reflection loss (RL) which in turn was calculated for varying thicknesses of the prepared composites from the measured real and imaginary permittivity data. The minimum RL was observed as −20.10 dB for the absorber with a thickness of 2.2 mm and the bandwidth achieved was 1.92 GHz for RL [Formula: see text]10 dB. Based on the above results these CB–PU composites have potential use as effective microwave absorbers in 8–12-GHz ([Formula: see text]-band) frequency range.
Eruption history, petrogeochemistry, and geodynamic background of Tengchong volcanoes in Yunnan Province, SW China
Authors: Yu Hongmei , Zhao Bo , Chen Zhengquan , Wei Haiquan , Yang Wenjian , Bai Xiang
Published: December 2020

The Tengchong Volcanic Field (TVF) is one of the youngest volcanic areas in China, and is located in the southwestern part of Yunnan Province, China, adjacent to the collision zone between the Indian and Eurasian plates. This paper summarizes the results of previous research on the eruption history, petrochemistry and geodynamic background of the TVF and presents a detailed analysis of the available data. Eruptions took place from the Pliocene to the Holocene and were divided into five stages. The composition of the magma went through two cycles: the

N

2

−

Q

P

1

−

Q

P

2

volcanic rocks went through the evolutionary process from basalt to dacite and the

Q

P

3

−

Qh

magma evolved from trachybasalt to trachyte. The evolution of magma is mainly related to the fractional crystallization of pyroxene and ilmenite. The mantle source area of the TVF volcanic rocks was caused by mixing between the mid-ocean ridge basalt-source mantle and the eastern Indian continental margin sediments to different degrees. Geophysical data also showed that the Indian plate has been subducted under the TVF area. There are also magma chambers in the crust within a depth of 25 km in the TVF that are replenished by mantle magma.
A geomagnetic polarity timescale for the Carboniferous
Authors: Hounslow Mark W.
Published: December 2020

The geomagnetic polarity pattern for the Carboniferous is incompletely known with the best-resolved parts in the Serpukhovian and Bashkirian. Hence, data from both igneous and sedimentary units are also used in an additional polarity bias evaluation. In the Tournaisian to mid Visean interval polarity is mainly derived from palaeopole-type palaeomagnetic studies, allowing identification of polarity bias chrons. Seven polarity bias chrons exist in the Mississippian (MI1n
B
to MI4n
B
) with an additional 33 conventional magnetochrons and submagnetochrons (MI4r to MI9r). The Moscovian and Gzhelian polarity is best resolved in magnetostratigraphic studies from the Donets Basin and the southern Urals. Dispute about the reliability of these data is ill-founded, since an assessment of supporting data from palaeopole-type studies suggests that these datasets currently provide the best magnetic polarity data through the Pennsylvanian. Polarity bias assessment indicates a normal polarity bias zone in the Kasimovian. In the Pennsylvanian there are 27 conventional magnetochrons and submagnetochrons (PE1n to CI1r) and one normal polarity bias chron (PE8n
B
). The Kiaman Superchron begins in the mid Bashkirian, with clear data indicating brief normal polarity submagnetochrons within the Superchron. The magnetochron timescale is calibrated using 31 U–Pb zircon dates and a quantitative Bayesian-based age-scaling procedure.
Generalized Weakly Hard Schedulability Analysis for Real-Time Periodic Tasks
Authors: Pazzaglia Paolo , Sun Youcheng , Natale Marco Di
Published: December 2020

The weakly hard real-time model is an abstraction for applications, including control systems, that can tolerate occasional deadline misses, but can also be compromised if a sufficiently high number of late terminations occur in a given time window. The weakly hard model allows us to constrain the maximum number of acceptable missed deadlines in any set of consecutive task executions. A big challenge for weakly hard systems is to provide a
schedulability analysis
that applies to a general task model, while avoiding excessive pessimism. In this work, we develop a general weakly hard analysis based on a Mixed Integer Linear Programming (MILP) formulation. The analysis applies to constrained-deadline periodic real-time systems scheduled with fixed priority and no knowledge of the task activation offsets, while allowing for activation jitter. Our analysis considers two common policies for handling missed deadlines, i.e., (i) letting the job continue until completion or (ii) killing its execution immediately. For this policy, ours is the first and only m-k analysis currently available. Experiments conducted on randomly generated task sets show the applicability and accuracy of the proposed technique as well as the improvements with respect to competing techniques.
Adaptive Task Allocation and Scheduling on NoC-based Multicore Platforms with Multitasking Processors
Authors: Paul Suraj , Chatterjee Navonil , Ghosal Prasun , Diguet Jean-Philippe
Published: December 2020

The application workloads in modern multicore platforms are becoming increasingly dynamic. It becomes challenging when multiple applications need to be executed in parallel in such systems. Mapping and scheduling of these applications are critical for system performance and energy consumption, especially in Network-on-Chip– (NoC) based multicore systems. These systems with multitasking processors offer a better opportunity for parallel application execution. Mapping solutions generated at design time may be inappropriate for dynamic workloads. To improve the utilization of the underlying multicore platform and cope with the dynamism of application workload, often task allocation is carried out dynamically. This article presents a hybrid task allocation and scheduling strategy that exploits the design-time results at runtime. By considering the multitasking capability of the processors, communication energy, and timing characteristics of the tasks, different allocation options are obtained at design time. During runtime, based on the availability of the platform resources and application requirements, the design-time allocations are adapted for mapping and scheduling of tasks, which result in improved runtime performance. Experimental results demonstrate that the proposed approach achieves an on average 11.5%, 22.3%, 28.6%, and 34.6% reduction in communication energy consumption as compared to CAM [18], DEAMS [4], TSMM [38], and CPNN [32], respectively, for NoC-based multicore platforms with multitasking processors. Also, the deadline satisfaction of the tasks of allocated applications improves on an average by 32.8% when compared with the state-of-the-art dynamic resource allocation approaches.
Improving the Performance of Hybrid Caches Using Partitioned Victim Caching
Authors: Agarwal Sukarn , Kapoor Hemangee K.
Published: December 2020

Non-Volatile Memory technologies are coming as a viable option on account of the high density and low-leakage power over the conventional SRAM counterpart. However, the increased write latency reduces their chances as a substitute for SRAM. To attenuate this problem, a hybrid STT-RAM-SRAM architecture is proposed where with large STT-RAM ways, the small SRAM ways are incorporated for handling the write operations. However, the performance gain obtained from such an architecture is not as much as expected on account of the larger miss rate caused by smaller SRAM partition. This, in turn, may limit the amount of cache capacity.

This article attempts to reduce the miss penalty and improve the average memory access time by retaining the victims evicted from the hybrid cache in a smaller, fully associative SRAM structure called the victim cache. The victim cache is accessed on a miss in the primary hybrid cache. Hits in the victim cache require an exchange of the block between the main hybrid cache and the victim cache. In such cases, to effectively place the required block in the appropriate region of the main hybrid cache, we propose an access-based block placement technique. Besides, to manage the runtime load and the uneven evictions of the SRAM partition, we also present a dynamic region-based victim cache partitioning method to hold the victims dedicated to each region. Experimental evaluation on a full system simulator shows significant improvement in the performance and execution time along with a reduction in the overall miss rate. The proposed policy also increases the endurance of Hybrid Cache Architectures (HCA) by reducing writes in the STT partition.
Dynamic Graph Mining for Multi-weight Multi-destination Route Planning with Deadlines Constraints
Authors: Huang Yu , Ying Josh Jia-Ching , Yu Philip S. , Tseng Vincent S.
Published: December 2020

Route planning satisfied multiple requests is an emerging branch in the route planning field and has attracted significant attention from the research community in recent years. The prevailing studies focus only on seeking a route by minimizing a single kind of Travel Cost, such as trip time or distance, among others. In reality, most users would like to choose an appropriate route, neither fastest nor shortest route. Usually, a user may have multiple requirements, and an appropriate route would satisfy all requirements requested by the user. In fact, planning an appropriate route could be formulated as a problem of
Multi-weight Multi-destination Route Planning with Deadlines Constraints
(MWMDRP-DC). In this article, we propose a framework, namely, MWMD-Router, which addresses the MWMDRP-DC problem comprehensively. To consider the travel costs with time-variation, we propose not only four novel dynamic graph miner to extract travel costs that reveal users’ requirements but also two new algorithms, namely,
Basic MWMD Route Planning
and
Advanced MWMD Route Planning
, to plan a route that satisfies deadline requirements and optimizes another criterion like travel cost with time-variation efficiently. To the best of our knowledge, this is the first work on route planning that considers handling multiple deadlines for multi-destination planning as well as optimizing multiple travel costs with time-variation simultaneously. Experimental results demonstrate that our proposed algorithms deliver excellent performance with respect to efficiency and effectiveness.
Interprocedural Context-Unbounded Program Analysis Using Observation Sequences
Authors: Liu Peizun , Wahl Thomas , Reps Thomas
Published: December 2020

A classical result by Ramalingam about synchronization-sensitive interprocedural program analysis implies that reachability for concurrent threads running recursive procedures is undecidable. A technique proposed by Qadeer and Rehof, to bound the number of context switches allowed between the threads, leads to an incomplete solution that is, however, believed to catch “most bugs” in practice, as errors tend to occur within few contexts. The question of whether the technique can also prove the absence of bugs at least in some cases has remained largely open.

Toward closing this gap, we introduce in this article the generic verification paradigm of
observation sequences
for resource-parameterized programs. Such a sequence observes how increasing the resource parameter affects the reachability of states satisfying a given property. The goal is to show that increases beyond some “cutoff” parameter value have no impact on the reachability—the sequence has
converged
. This allows us to conclude that the property holds for all parameter values.

We applied this paradigm to the context-
unbounded
program analysis problem, choosing the resource to be the number of permitted thread context switches. The result is a partially correct interprocedural reachability analysis technique for concurrent shared-memory programs. Our technique may not terminate but is able to both refute and prove context-unbounded safety for such programs. We demonstrate the effectiveness and efficiency of the technique using a variety of benchmark programs. The safe instances cannot be proved safe by earlier, context-bounded methods.
Accelerating Large-Scale Heterogeneous Interaction Graph Embedding Learning via Importance Sampling
Authors: Ji Yugang , Yin Mingyang , Yang Hongxia , Zhou Jingren , Zheng Vincent W. , Shi Chuan , Fang Yuan
Published: December 2020

In real-world problems, heterogeneous entities are often related to each other through multiple interactions, forming a Heterogeneous Interaction Graph (HIG). While modeling HIGs to deal with fundamental tasks, graph neural networks present an attractive opportunity that can make full use of the heterogeneity and rich semantic information by aggregating and propagating information from different types of neighborhoods. However, learning on such complex graphs, often with millions or billions of nodes, edges, and various attributes, could suffer from expensive time cost and high memory consumption. In this article, we attempt to accelerate representation learning on large-scale HIGs by adopting the importance sampling of heterogeneous neighborhoods in a batch-wise manner, which naturally fits with most batch-based optimizations. Distinct from traditional homogeneous strategies neglecting semantic types of nodes and edges, to handle the rich heterogeneous semantics within HIGs, we devise both type-dependent and type-fusion samplers where the former respectively samples neighborhoods of each type and the latter jointly samples from candidates of all types. Furthermore, to overcome the imbalance between the down-sampled and the original information, we respectively propose heterogeneous estimators including the self-normalized and the adaptive estimators to improve the robustness of our sampling strategies.

Finally, we evaluate the performance of our models for node classification and link prediction on five real-world datasets, respectively. The empirical results demonstrate that our approach performs significantly better than other state-of-the-art alternatives, and is able to reduce the number of edges in computation by up to 93%, the memory cost by up to 92% and the time cost by up to 86%.
Heterogeneous Graphlets
Authors: Rossi Ryan A. , Ahmed Nesreen K. , Carranza Aldo , Arbour David , Rao Anup , Kim Sungchul , Koh Eunyee
Published: December 2020

In this article, we introduce a generalization of graphlets to heterogeneous networks called
typed graphlets
. Informally, typed graphlets are small typed induced subgraphs. Typed graphlets generalize graphlets to rich heterogeneous networks as they explicitly capture the higher-order typed connectivity patterns in such networks. To address this problem, we describe a general framework for counting the occurrences of such typed graphlets. The proposed algorithms leverage a number of combinatorial relationships for different typed graphlets. For each edge, we count a few typed graphlets, and with these counts along with the combinatorial relationships, we obtain the exact counts of the other typed graphlets in
o
(1) constant time. Notably, the worst-case time complexity of the proposed approach matches the time complexity of the best known untyped algorithm. In addition, the approach lends itself to an efficient lock-free and asynchronous parallel implementation. While there are no existing methods for typed graphlets, there has been some work that focused on computing a different and much simpler notion called colored graphlet. The experiments confirm that our proposed approach is orders of magnitude faster
and
more space-efficient than methods for computing the simpler notion of colored graphlet. Unlike these methods that take hours on small networks, the proposed approach takes only seconds on large networks with millions of edges. Notably, since typed graphlet is more general than colored graphlet (and untyped graphlets), the counts of various typed graphlets can be combined to obtain the counts of the much simpler notion of colored graphlets. The proposed methods give rise to new opportunities and applications for typed graphlets.
Golden Chip-Free Trojan Detection Leveraging Trojan Trigger’s Side-Channel Fingerprinting
Authors: He Jiaji , Ma Haocheng , Liu Yanjiang , Zhao Yiqiang
Published: December 2020

Hardware Trojans (HTs) have become a major threat for the integrated circuit industry and supply chain and have motivated numerous developments of HT detection schemes. Although the side-channel HT detection approach is among the most promising solutions, most of the previous methods require a trusted golden chip reference. Furthermore, detection accuracy is often influenced by environmental noise and process variations. In this article, a novel electromagnetic (EM) side-channel fingerprinting-based HT detection method is proposed. Different from previous methods, the proposed solution eliminates the requirement of a trusted golden fabricated chip. Rather, only the genuine RTL code is required to generate the EM signatures as references. A factor analysis method is utilized to extract the spectral features of the HT trigger’s EM radiation, and then a
k
-means clustering method is applied for HT detection. Experimentation on two selected sets of Trust-Hub benchmarks has been performed on FPGA platforms, and the results show that the proposed framework can detect all dormant HTs with a high confidence level.
MeSHProbeNet-P
Authors: Xun Guangxu , Jha Kishlay , Zhang Aidong
Published: December 2020

Indexing biomedical research articles with Medical Subject Headings (MeSH) can greatly facilitate biomedical research and information retrieval. Currently MeSH indexing is performed by human experts. To alleviate the time consumption and monetary cost caused by manual indexing, many automatic MeSH indexing models have been developed, such as MeSHProbeNet, DeepMeSH, and NLM’s official model Medical Text Indexer. In this article, we propose an end-to-end framework, MeSHProbeNet-P, which extends MeSHProbeNet with personalizable MeSH probes. In MeSHProbeNet-P, each MeSH probe carries certain aspects of biomedical knowledge and extracts related information from input articles. MeSHProbeNet-P is able to automatically personalize its MeSH probes for different input articles to ensure that the current MeSH probes best fit the current input article and the most informative features can be extracted from the article. We demonstrate the effectiveness of MeSHProbeNet-P in a real-world large-scale MeSH indexing challenge. MeSHProbeNet-P won the first place in the first batch of Task A in the 2019 BioASQ challenge. The result on the first test set of the challenge is reported in this article. We also provide ablation studies to show the advantages of personalizable MeSH probes.
MAGNETO
Authors: Ibrahim Omar Adel , Sciancalepore Savio , Oligeri Gabriele , Pietro Roberto Di
Published: December 2020

Universal Serial Bus (USB) Flash Drives are nowadays one of the most convenient and diffused means to transfer files, especially when no Internet connection is available. However, USB flash drives are also one of the most common attack vectors used to gain unauthorized access to host devices. For instance, it is possible to replace a USB drive so that when the USB key is connected, it would install passwords stealing tools, root-kit software, and other disrupting malware. In such a way, an attacker can steal sensitive information via the USB-connected devices, as well as inject any kind of malicious software into the host.

To thwart the above-cited raising threats, we propose MAGNETO, an efficient, non-interactive, and privacy-preserving framework to verify the authenticity of a USB flash drive, rooted in the analysis of its unintentional magnetic emissions. We show that the magnetic emissions radiated during boot operations on a specific host are unique for each device, and sufficient to uniquely fingerprint both the brand and the model of the USB flash drive, or the specific USB device, depending on the used equipment. Our investigation on 59 different USB flash drives—belonging to 17 brands, including the top brands purchased on Amazon in mid-2019—reveals a minimum classification accuracy of 98.2% in the identification of both brand and model, accompanied by a negligible time and computational overhead. MAGNETO can also identify the specific USB Flash drive, with a minimum classification accuracy of 91.2%. Overall, MAGNETO proves that unintentional magnetic emissions can be considered as a viable and reliable means to fingerprint read-only USB flash drives. Finally, future research directions in this domain are also discussed.
DNMT1-mediated lncRNA MEG3 methylation accelerates endothelial-mesenchymal transition in diabetic retinopathy through the PI3K/Akt/mTOR signaling pathway
Authors: He Yue , Dan Yujiao , Gao Xiaorong , Huang Li , Lv Hongbin , Chen Jie
Published: December 2020

Diabetic retinopathy (DR) is one of the serious complications that occurs in diabetic patients that frequently causes blindness. Long noncoding RNAs (lncRNAs) have been associated with DR pathology. This study aimed to determine the underlying mechanism of lncRNA maternally expressed gene 3 (MEG3) in association with DNA methyltransferase 1 (DNMT1) in the endothelial-mesenchymal transition (endMT) that occurs in DR. A rat model of DR was induced by streptozotocin (STZ) injection, and a high-glucose (HG)-induced cell model was established by exposing microvascular endothelial cells obtained from retina of rats to HG. Subsequently, MEG3 was overexpressed in rat and cell models to characterize its impact on endMT in DR and the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Furthermore, the methylation level of MEG3 promoter region was determined with the application of methylation-specific polymerase chain reaction, followed by chromatin immunoprecipitation assay for methyltransferase enrichment. Finally, we examined the regulation of DNMT1 on MEG3 methylation and endMT in the HG-induced cell model. The results obtained revealed downregulated MEG3 expression in DR rat and cell models. Overexpressed MEG3 was shown to suppress endMT in DR rat and cell models through the inhibition of the PI3K/Akt/mTOR signaling pathway. Notably, DNMT1 could promote MEG3 promoter methylation to inhibit MEG3 expression by recruiting methyltransferase, which activated the PI3K/Akt/mTOR signaling pathway to accelerate endMT in DR. These findings further highlighted the inhibitory effect of MEG3 on endMT in DR, thus presenting a novel therapeutic target candidate for DR treatment.
Metabolic responses to intermittent hypoxia are regulated by sex and estradiol in mice
Authors: Marcouiller François , Jochmans-Lemoine Alexandra , Ganouna-Cohen Gauthier , Mouchiroud Mathilde , Laplante Mathieu , Marette André , Bairam Aida , Joseph Vincent
Published: December 2020

We assessed fasting glycemic control, and tolerance to insulin and glucose in male and female mice exposed to intermittent hypoxia. IH improves glucose tolerance in males but had opposite effects in females. This response was amplified following ovariectomy in females and prevented by estradiol supplementation. Metabolic consequences of IH differ between males and females and are regulated by estradiol in female mice.
Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition
Authors: Boulet Nathalie , Luijten Ineke H.N , Cannon Barbara , Nedergaard Jan
Published: December 2020

A regulatory or mediatory role—positive or negative—for macrophages in the recruitment of brown adipose tissue is presently discussed. As the recruited state in the tissue is a dynamic process, maintenance of the recruited state would need persistent alterations in macrophage complement. Contrary to this expectation, we demonstrate here an absence of alterations in macrophage complement in thermogenically recruited brown—or brite/beige—adipose tissues. Macrophage regulation of thermogenic capacity is thus less likely.
Gut-to-brain signals in feeding control
Authors: Moura-Assis Alexandre , Friedman Jeffrey M. , Velloso Licio A.
Published: December 2020

Interoceptive signals from gut and adipose tissue and sensory cues from the environment are integrated by hubs in the brain to regulate feeding behavior and maintain homeostatic control of body weight. In vivo neural recordings have revealed that these signals control the activity of multiple layers of hunger neurons and eating is not only the result of feedback correction to a set point, but can also be under the influence of anticipatory regulations. A series of recent technical developments have revealed how peripheral and sensory signals, in particular, from the gut are conveyed to the brain to integrate neural circuits. Here, we describe the mechanisms involved in gastrointestinal stimulation by nutrients and how these signals act on the hindbrain to generate motivated behaviors. We also consider the organization of multidirectional intra- and extrahypothalamic circuits and how this has created a framework for understanding neural control of feeding.
Increased vascular permeability and severe renal tubular damage after ischemia-reperfusion injury in mice lacking adiponectin or T-cadherin
Authors: Tsugawa-Shimizu Yuri , Fujishima Yuya , Kita Shunbun , Minami Satoshi , Sakaue Taka-aki , Nakamura Yuto , Okita Tomonori , Kawachi Yusuke , Fukada Shiro , Namba-Hamano Tomoko , Takabatake Yoshitsugu , Isaka Yoshitaka , Nishizawa Hitoshi , Ranscht Barbara , Maeda Norikazu , Shimomura Iichiro
Published: December 2020

In the kidney, T-cadherin-associated adiponectin protein existed on peritubular capillary pericytes. In an acute renal ischemia-reperfusion model, deficiency of adiponectin or T-cadherin exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability, accompanied by severe pericyte loss. In vitro, adiponectin promoted exosome secretion from mouse primary pericytes in a T-cadherin-dependent manner. Adiponectin plays an important role in maintaining the capillary network and amelioration of renal tubular injury by binding to T-cadherin.
Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats
Authors: King Andrew J. , Kohler Jill , Fung Cyra , Jiang Zhengfeng , Quach Allison , Kumaraswamy Padmapriya , Chertow Glenn M. , Rosenbaum David P.
Published: December 2020

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0–3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% ( P < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.
Novel Fanconi renotubular syndromes provide insights in proximal tubule pathophysiology
Authors: Lemaire Mathieu
Published: December 2020

The various forms of Fanconi renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal tubule physiology. This review will describe the clinical characteristics, genetic underpinnings, and underlying pathophysiology of the major forms of FRST. Although the classic forms of FRTS will be presented (e.g., Dent disease or Lowe syndrome), particular attention will be paid to five of the most recently discovered FRTS subtypes caused by mutations in the genes encoding for L-arginine:glycine amidinotransferase ( GATM), solute carrier family 34 (type Ii sodium/phosphate cotransporter), member 1 ( SLC34A1), enoyl-CoAhydratase/3-hydroxyacyl CoA dehydrogenase ( EHHADH), hepatocyte nuclear factor 4A ( HNF4A), or NADH dehydrogenase complex I, assembly factor 6 ( NDUFAF6). We will explore how mutations in these genes revealed unexpected mechanisms that led to compromised proximal tubule functions. We will also describe the inherent challenges associated with gene discovery studies based on findings derived from small, single-family studies by focusing the story of FRTS type 2 ( SLC34A1). Finally, we will explain how extensive alternative splicing of HNF4A has resulted in confusion with mutation nomenclature for FRTS type 4.
Effects of intravesical prostaglandin E2 on bladder function are preserved in capsaicin-desensitized rats
Authors: Hokanson James A. , Langdale Christopher L. , Milliken Philip H. , Sridhar Arun , Grill Warren M.
Published: December 2020

Prostaglandin E2 (PGE2) instilled into the bladder generates symptoms of urinary urgency in healthy women and reduces bladder capacity and urethral pressure in both humans and female rats. Systemic capsaicin desensitization, which causes degeneration of C-fibers, prevented PGE2-mediated reductions in bladder capacity, suggesting that PGE2 acts as an irritant (Maggi CA, Giuliani S, Conte B, Furio M, Santicioli P, Meli P, Gragnani L, Meli A. Eur J Pharmacol 145: 105–112, 1988). In the present study, we instilled PGE2 in female rats after capsaicin desensitization but without the hypogastric nerve transection that was conducted in the Maggi et al. study. One week after capsaicin injection (125 mg/kg sc), rats underwent cystometric and urethral perfusion testing under urethane anesthesia with saline and 100 µM PGE2. Similar to naïve rats, capsaicin-desensitized rats exhibited a reduction in bladder capacity from 1.23 ± 0.08 mL to 0.70 ± 0.10 mL ( P = 0.002, n = 9), a reduction in urethral perfusion pressure from 19.3 ± 2.1 cmH2O to 10.9 ± 1.2 cmH2O ( P = 0.004, n = 9), and a reduction in bladder compliance from 0.13 ± 0.020 mL/cmH2O to 0.090 ± 0.014 mL/cmH2O ( P = 0.011, n = 9). Thus, changes in bladder function following the instillation of PGE2 were not dependent on capsaicin-sensitive pathways. Further, these results suggest that urethral relaxation/weakness and/or increased detrusor pressure as a result of decreased compliance may contribute to urinary urgency and highlight potential targets for new therapies for overactive bladder.
Renoprotective effect of Stat1 deletion in murine aristolochic acid nephropathy
Authors: Feng Wenguang , Ying Wei-Zhong , Li Xingsheng , Curtis Lisa M. , Sanders Paul W.
Published: December 2020

Injured tubule epithelium stimulates a profibrotic milieu that accelerates loss of function in chronic kidney disease (CKD). This study tested the role of signal transducer and activator of transcription 1 (STAT1) in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD. Mean serum creatinine concentration increased in wild-type (WT) littermates treated with AA, whereas Stat1−/− mice were protected. Focal increases in the apical expression of kidney injury molecule (KIM)-1 were observed in the proximal tubules of WT mice with AA treatment but were absent in Stat1−/− mice in the treatment group as well as in both control groups. A composite injury score, an indicator of proximal tubule injury, was reduced in Stat1−/− mice treated with AA. Increased expression of integrin-β6 and phosphorylated Smad2/3 in proximal tubules as well as interstitial collagen and fibronectin were observed in WT mice following AA treatment but were all decreased in AA-treated Stat1−/− mice. The data indicated that STAT1 activation facilitated the development of progressive kidney injury and interstitial fibrosis in AA nephropathy.
Mapping nephron mass in vivo using positron emission tomography
Authors: Baldelomar Edwin J. , Reichert David E. , Shoghi Kooresh I. , Beeman Scott C. , Charlton Jennifer R. , Strong Lori , Fettig Nikki , Klaas Amanda , Bennett Kevin M.
Published: December 2020

Nephron number varies widely in humans. A low nephron endowment at birth or a loss of functioning nephrons is strongly linked to increased susceptibility to chronic kidney disease. In this work, we developed a contrast agent, radiolabeled cationic ferritin (RadioCF), to map functioning glomeruli in vivo in the kidney using positron emission tomography (PET). PET radiotracers can be detected in trace doses (<30 nmol), making them useful for rapid clinical translation. RadioCF is formed from cationic ferritin (CF) and with a radioisotope, Cu-64, incorporated into the ferritin core. We showed that RadioCF binds specifically to kidney glomeruli after intravenous injection in mice, whereas radiolabeled noncationic ferritin (RadioNF) and free Cu-64 do not. We then showed that RadioCF-PET can distinguish kidneys in healthy wild-type (WT) mice from kidneys in mice with oligosyndactylism (Os/+), a model of congenital hypoplasia and low nephron mass. The average standardized uptake value (SUV) measured by PET 90 min after injection was 21% higher in WT mice than in Os/+ mice, consistent with the higher glomerular density in WT mice. The difference in peak SUV from SUV at 90 min correlated with glomerular density in male mice from both WT and Os/+ cohorts ( R2 = 0.98). Finally, we used RadioCF-PET to map functioning glomeruli in a donated human kidney. SUV within the kidney correlated with glomerular number ( R2= 0.78) measured by CF-enhanced magnetic resonance imaging in the same locations. This work suggests that RadioCF-PET appears to accurately detect nephron mass and has the potential for clinical translation.
Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury
Authors: Hu Yi , Yang Chun , Amorim Tania , Maqbool Mohsin , Lin Jenny , Li Chen , Fang Chuanfeng , Xue Li , Kwart Ariel , Fang Hua , Yin Mei , Janocha Allison J. , Tsuchimoto Daisuke , Nakabeppu Yusaku , Jiang Xiaofeng , Mejia-Garcia Alex , Anwer Faiz , Khouri Jack , Qi Xin , Zheng Qing Y. , Yu Jennifer S. , Yan Shan , LaFramboise Thomas , Anderson Kenneth C. , Herlitz Leal C. , Munshi Nikhil C. , Lin Jianhong , Zhao Jianjun
Published: December 2020

Cisplatin chemotherapy is standard care for many cancers but is toxic to the kidneys. How this toxicity occurs is uncertain. In this study, we identified apurinic/apyrimidinic endonuclease 2 (APE2) as a critical molecule upregulated in the proximal tubule cells (PTC) following cisplatin-induced nuclear DNA and mitochondrial DNA damage in cisplatin-treated C57B6J mice. The APE2 transgenic mouse phenotype recapitulated the pathophysiological features of C-AKI (acute kidney injury, AKI) in the absence of cisplatin treatment. APE2 pulldown-MS analysis revealed that APE2 binds myosin heavy-Chain 9 (MYH9) protein in mitochondria after cisplatin treatment. Human MYH9-related disorder is caused by mutations in MYH9 that eventually lead to nephritis, macrothrombocytopenia, and deafness, a constellation of symptoms similar to the toxicity profile of cisplatin. Moreover, cisplatin-induced C-AKI was attenuated in APE2-knockout mice. Taken together, these findings suggest that cisplatin promotes AKI development by upregulating APE2, which leads to subsequent MYH9 dysfunction in PTC mitochondria due to an unrelated role of APE2 in DNA damage repair. This postulated mechanism and the availability of an engineered transgenic mouse model based on the mechanism of C-AKI provides an opportunity to identify novel targets for prophylactic treatment of this serious disease.

Significance:

These results reveal and highlight an unexpected role of APE2 via its interaction with MYH9 and suggest that APE2 has the potential to prevent acute kidney injury in patients with cisplatin-treated cancer.
ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma
Authors: Myojin Yuta , Kodama Takahiro , Maesaka Kazuki , Motooka Daisuke , Sato Yu , Tanaka Satoshi , Abe Yuichi , Ohkawa Kazuyoshi , Mita Eiji , Hayashi Yoshito , Hikita Hayato , Sakamori Ryotaro , Tatsumi Tomohide , Taguchi Ayumu , Eguchi Hidetoshi , Takehara Tetsuo
Published: December 2020

Purpose:

Hepatocellular carcinoma (HCC) is characterized by high intertumor heterogeneity of genetic drivers. Two multitarget tyrosine kinase inhibitors (TKI), lenvatinib and sorafenib, are used as standard-of-care chemotherapeutics in patients with advanced HCC, but a stratification strategy has not been established because of a lack of efficacious biomarkers. Therefore, we sought biomarkers that indicate lenvatinib-susceptible HCC.

Experimental Design:

We performed genetic screening of HCC driver genes involved in TKI susceptibility using a novel HCC mouse model in which tumor diversity of genetic drivers was recapitulated. A biomarker candidate was evaluated in human HCC cell lines. Secreted proteins from HCC cells were then screened using mass spectrometry. Serum and tumor levels of the biomarker candidates were analyzed for their association and prediction of overall survival in patients with HCC.

Results:

We found that lenvatinib selectively eliminated FGF19-expressing tumors, whereas sorafenib eliminated MET- and NRAS-expressing tumors. FGF19 levels and lenvatinib susceptibility were correlated in HCC cell lines, and FGF19 inhibition eliminated lenvatinib susceptibility. Lenvatinib-resistant HCC cell lines, generated by long-term exposure to lenvatinib, showed FGF19 downregulation but were resensitized to lenvatinib by FGF19 reexpression. Thus, FGF19 is a tumor biomarker of lenvatinib-susceptible HCC. Proteome and secretome analyses identified ST6GAL1 as a tumor-derived secreted protein positively regulated by FGF19 in HCC cells. Serum ST6GAL1 levels were positively correlated with tumor FGF19 expression in patients with surgically resected HCC. Among patients with serum ST6GAL1-high HCC who underwent TKI therapy, lenvatinib therapy showed significantly better survival than sorafenib.

Conclusions:

Serum ST6GAL may be a novel biomarker that identifies lenvatinib-susceptible FGF19-driven HCC.
FDA Approval Summary: Lurbinectedin for the Treatment of Metastatic Small Cell Lung Cancer
Authors: Singh Sonia , Jaigirdar Adnan A. , Mulkey Flora , Cheng Joyce , Hamed Salaheldin S. , Li Yangbing , Liu Jiang , Zhao Hong , Goheer Anwar , Helms Whitney S. , Wang Xing , Agarwal Rajiv , Pragani Rajan , Korsah Kwadwo , Tang Shenghui , Leighton John , Rahman Atiqur , Beaver Julia A. , Pazdur Richard , Theoret Marc R. , Singh Harpreet
Published: December 2020

On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The confirmed ORR determined by investigator assessment using RECIST 1.1 in the approved SCLC patient population was 35% [95% confidence interval (CI): 26–45], with a median DOR of 5.3 (95% CI: 4.1–6.4) months. The drug label includes warnings and precautions for myelosuppression, hepatotoxicity, and embryo-fetal toxicity. This is the first drug approved by the FDA in over 20 years in the second line for patients with metastatic SCLC. Importantly, this approval includes an indication for patients who have platinum-resistant disease, representing an area of particular unmet need.