bluuebunny/crossref_metadata_2025 huggingface dataset:
Day‐ahead scheduling of integrated electricity and district heating system with an aggregated model of buildings for wind power accommodation
Authors: Zhang Rufeng , Jiang Tao , Li Wenming , Li Guoqing , Chen Houhe , Li Xue
Published: January 2019

In traditional integrated electricity and district heating systems, the inflexible operation of combined heat and power units leads to a large amount of wind power curtailments during winter. The thermal inertia of aggregated buildings can provide additional operational flexibility to promote wind power accommodation. In this study, a day‐ahead scheduling model for integrated electricity and district heating system considering the thermal inertia of buildings is proposed. In this work, the operation model of the district heating network under constant mass flow and variable temperature operation strategy is presented, and the aggregated model of buildings based on the detailed thermal model of buildings is established. Then, the scheduling framework is analysed and the day‐ahead scheduling model is formulated as quadratic programming problem to minimise the operation cost of integrated electricity and district heating system. The validity of the proposed model is verified by the case studies performed on a 6‐bus power system with a 6‐node heating system and IEEE 39‐bus electricity system with a 16‐node heating system. The results demonstrate that the thermal inertia of buildings can provide additional operational flexibility and effectively help reduce wind power curtailment and operation costs.
Researches on grounding modes of the AC/DC hybrid system with various distributed renewable energy
Authors: Xu Qi , He Jianzong , Huang Songbo , Zeng Jie , Fan Chunju , Wang Wei
Published: January 2019

With the considerable demand for distributed renewable energy and the significant increase of generalised DC loads, such as IT equipment, DC air‐conditioner, electric vehicle, the traditional AC distribution network is no longer efficient. Driven by the rapid development of power electronics technology, the AC/ DC hybrid system is an effective way for large capacity AC/DC sources and loads efficient integrated. To ensure the stable operation of AC/DC hybrid system, the grounding mode analysis is necessary, which is the precondition for overvoltage analysis, lightning arrester configuration, and protection design. To select grounding mode of AC/DC hybrid system, the detailed system structure scheme is first determined considering the factors such as integrated object, reliability requirement, capacity of sources and loads, and converter type. Then the main connection scheme is selected considering the principle of line insulation, economy, and reliability. Based on the system structure and main connection scheme, a suitable grounding mode is selected for the AC/DC hybrid system with various distributed renewable energy, by weighing various factors such as power supply reliability, protection sensitivity, insulation level, and personal safety.
Coordinated operation control on low DC voltage of HVDC integrating wind farms
Authors: Zhang Qingzhi , Zhao Chenggong , Du Chuan
Published: January 2019

In recent years, with the development of high voltage direct current (HVDC) transmission technology, wind power integration with modular multiple converter‐HVDC (MMC‐HVDC) has been widely researched and applied. However, the conventional control methods on wind power integration cannot match the flexibility needing of loads. In this paper, a wind power integration system with permanent magnet direct‐drive wind farm and full‐bridge MMC is proposed. It has the characteristics of independent control of AC and DC current, which can realise the stable operation of the system under low DC voltage, so that to effectively avoid the accident of the wind turbine cut‐off caused by the load reduce. When the DC voltage drops, the system can maintain a constant AC voltage at the wind power integration point, so that the wind farm can operate normally. Finally, the simulation results in PSCAD/EMTDC show that the proposed system and its control strategy are correct.
Multi‐scale AC−DC system voltage security regions
Authors: Ge Huiyang , Sun Hongbin , Wang Bin
Published: January 2019

Recently, China Power Grid has built a number of multi‐infeed AC−DC systems, as the safety issues caused by voltage fluctuations have drawn much attention. The security device of a DC system is applied to correct voltage. First, it brings a new voltage control mode, classifies the DC system control device and disturbance mode, and puts forward an online evaluation skeleton drawing in AC−DC voltage security regions. Second, the optimisation model of voltage safety regions in different scales has been built based on this skeleton drawing. Finally, the feasibility and effectiveness of this method was proved through simulation of the Institute of Electrical and Electronics Engineers system.
Capacitor voltage balancing control with reducing the average switching frequency in MMC
Authors: Wang Shunliang , Liu Tianqi , Huang XingChuan , Yu Yuexiao
Published: January 2019

Modular multilevel converter (MMC) has a very good application prospect in the flexible high‐voltage direct current (HVDC) transmission, but higher self‐loss will affect the efficiency and restrict the development. Here, the MMC in voltage source converter‐based HVDC as the research object, the control and modulation algorithms are designed on the basis of analysing its working principle. The capacitor voltage imbalance problem is existed in the converter because that the capacitor of each module is independent. The factors of switching actions in balancing control technology based on the sorting method of sub‐module capacitor voltages are analysed in detail. Then, an optimised balancing control algorithm by setting two balancing control thresholds is proposed to reduce the average switching frequency. Finally, a two ends HVDC transmission system was built in MATLAB/SIMULINK to verify the optimisation. The simulation research results show that the optimised balancing control can ensure sub‐module capacitor voltage is in balanced and does not increase the AC output voltage harmonic content, and obviously reduce the average switching frequency of switching devices, and with the increase of number of level, the more obvious optimisation effect.
Preliminary design of a robotic system for kinaesthetic training of surgical tasks
Authors: Hong Kaiwen , Sun Yue , He Jiale , Lei Yong , Yang Liangjing
Published: January 2019

This study aims to develop a robotic system human–machine interaction (HMI) to facilitate surgical training through visual and kinaesthetic feedbacks. This is motivated by the pressing need for effective surgical training and the unaddressed gaps in existing surgical training simulator for minimally invasive procedures. This study establishes the design concept and scope for development to facilitate the required HMI training model. Subsequently, implementation and demonstration of the model is carried out with analytical experiments to assess the feasibility of the proposed concept. The design concept of the robotic system for training is demonstrated through an user experiment. Results suggest viability and observable benefits in the authors’ proposed kinaesthetic HMI guidance for the trainee. Potential impact of this study includes the development of a novel training paradigm that engages trainees through collaborative training facilitated by human trainers and active kinaesthetic simulation. Although motivated by surgical training applications, the concept developed in this study can potentially be extended for general motor skill learning.
Modelling and delay analysis of on‐chip differential carbon nanotube interconnects
Authors: Cheng Zi‐Han , Zhao Wen‐Sheng , Wang Da‐Wei , Wang Jing , Dong Linxi , Wang Gaofeng
Published: January 2019

Differential signalling is widely used in modern integrated circuits to guarantee signal integrity. In this work, differential carbon nanotube (CNT) interconnects are studied, with both voltage‐ and current‐mode signalling schemes considered. An odd‐mode half‐circuit model of the differential CNT interconnects is developed, with transient response and time delay captured accurately. Finally, based on interval analysis, the effects of parameter variations on the differential CNT interconnects are investigated.
Cardiomyocyte contractile force changes in response to AGRWE detected by AFM
Authors: Qu YingMin , Zhao Feihu , Wang Xinyue , Liu Jinyun , Li Jingmei , Song Zhengxun , Wang Zuobin
Published: January 2019

The cardiac contractile force is an important predictor of healthy and cardiovascular diseases. The changes of cardiomyocyte contractile force in response to American ginseng root water extract (AGRWE) detected by atomic force microscope have not been investigated yet. This study examined the effects of AGRWE on single beating cardiomyocytes extracted from a newborn rat. The same cardiomyocytes were incubated with AGRWE at a concentration of 50 μg/ml for about 30 min, and the cardiomyocytes’ contractile force increased from 1.74 ± 1.01 to 3.49 ± 1.53 nN. The mean value of the contractile strain calculated was 3.32 ± 1.55% for the cardiomyocyte before the treatment with AGRWE, while for the cardiomyocyte treated with AGRWE it increased to 4.60 ± 1.35%. The results also showed that the beating rate of the same single beating cardiomyocytes was decreased from 34 ± 11 beats/min (control, n = 10) to 20 ± 9 beats/min. In conclusion, the experimental results have shown clearly that the contractile forces and strain of single beating cardiomyocytes treated with AGRWE are significantly higher than the control group, while the heart rate was decreased. It suggests that ginseng agents are promising candidates in improving cardiac functions for treating heart failure.
Teaching a robot to use electric tools with regrasp planning
Authors: Raessa Mohamed , Sánchez Daniel , Wan Weiwei , Petit Damien , Harada Kensuke
Published: January 2019

This study presents a straightforward method to teach robots to use tools. Teaching robots is crucial in quickly deploying and reconfiguring robots in next‐generation factories. Conventional methods require third‐party systems like wearable devices or complicated vision system to capture, analyse, and map human grasps, motion, and tool poses to robots. These systems assume lots of experience from their users. Unlike the conventional methods, this study does not involve learning human motion and skills. Instead, it only learns the object goal poses from the human user whilst employs regrasp planning to generate robot motion. The method is most suitable for a robot to learn the usage of electric tools that can be operated by simply switching on and off. The proposed method is validated using a dual‐arm robot with hand‐mounted cameras and several tools. Experimental results show that the proposed method is robust, feasible, and simple to teach robots. It can find a collision‐free and kino‐dynamic feasible grasp sequences and motion trajectories when the goal pose is reachable. The method allows the robot to automatically choose placements or handover considering the surrounding environment as intermediate states to change the pose of the tool and use tools following human demonstrations.
Dark matter response to galaxy assembly history
Authors: Artale María Celeste , Pedrosa Susana E. , Tissera Patricia B. , Cataldi Pedro , Di Cintio Arianna
Published: January 2019

Aims. It is well known that the presence of baryons affects the dark matter host haloes. Exploring the galaxy assembly history together with the dark matter haloes properties through time can provide a way to measure these effects.

Methods. We have studied the properties of four Milky Way mass dark matter haloes from the Aquarius project during their assembly history, between z = 0 − 4. In this work, we used a published SPH run and the dark matter only counterpart as case studies. To asses the robustness of our findings, we compared them with one of the haloes run using a moving-mesh technique and different sub-grid scheme.

Results. Our results show that the cosmic evolution of the dark matter halo profiles depends on the assembly history of the baryons. We find that the dark matter profiles do not significantly change with time, hence they become stable, when the fraction of baryons accumulated in the central regions reaches 80 per cent of its present mass within the virial radius. Furthermore, the mass accretion history shows that the haloes that assembled earlier are those that contain a larger amount of baryonic mass aforetime, which in turn allows the dark matter halo profiles to reach a stable configuration earlier. For the SPH haloes, we find that the specific angular momentum of the dark matter particles within the five per cent of the virial radius at z = 0, remains approximately constant from the time at which 60 per cent of the stellar mass is gathered. We have explored different theoretical and empirical models for the contraction of the haloes through redshift. A model to better describe the contraction of the haloes through redshift evolution must depend on the stellar mass content in the inner regions.
Analysis of building and its components condition assessment case study of dormitory buildings
Authors: Linggar Sahaduta , Aminullah Akhmad , Triwiyono Andreas
Published: January 2019

Condition Assessment of assets is one of stages in assets management system that supports effective and efficient improvement and maintenance strategy. The objective of this paper is to develop a condition assessment model based on important components that build an asset. A building asset hierarchy is proposed in which four main categories that build spaces inside building is the principle element of evaluation. The Physical component in which selected as the variable of this research, based on Regulation of the Minister of Public Works of Indonesia no.24 in 2008 about building maintenance guidelines. Data are collected via questionnaires from experts to ranking and assign relative weights as model’s attribute using Confirmatory Factor Analysis (CFA) in Structural Equation Modeling (SEM) techniques. Multi attribute utility theory (MAUT) is used to calculate entire building condition based on rank and relative weight of selected components. This research model is applied to a case study dormitory of Universitas Gadjah Mada, located in Yogyakarta. Result of the research is condition of the entire building based on components that build spaces inside that building. This result of this research will assist owners and facility managers in select effective and efficient improvement and maintenance strategy for the building.
Comparison of Outcomes in Oncoplastic Pelvic Reconstruction with VRAM versus Omental Flaps: A Large Cohort Analysis
Authors: Chaudhry Arif , Oliver Jeremie D. , Vyas Krishna S. , Tran Nho V. , Martinez-Jorge Jorys , Larson David , Dozois Eric , Nelson Heidi , Manrique Oscar J.
Published: January 2019

Background The purpose of this study is to describe our experience and outcomes in oncoplastic pelvic reconstruction for patients who underwent either vertical rectus abdominis musculocutaneous (VRAM) or omental flap following abdominoperineal resection (APR) at a single tertiary care institution.

Methods All patients who underwent pelvic reconstruction following APR with either VRAM or omental flaps from January 1992 to January 2017 were retrospectively reviewed. Patient demographics and relevant comorbidities including chemotherapy and radiation therapy data were collected and analyzed. In addition, margin status at the time of oncologic resection was analyzed. Flap-specific data were collected for each approach. Oncologic data collected included cancer type, stage at time of APR, and rate of tumor recurrence within the flap.

Results A total of 562 patients were identified who underwent pelvic reconstruction with either VRAM or omental pedicle flaps. Of these, 274 (48.8%) underwent VRAM reconstruction and 288 (51.2%) underwent omental flap reconstruction. All margins were negative at time of cancer ablation surgery. Complications data included: seroma (VRAM = 2 [0.36%]; omentum = 32 [5.69%], p < 0.0001), wound dehiscence (VRAM = 31 [5.52%]; omentum = 17 [3.02%], p = 0.022), abscess (VRAM = 4 [0.71%]; omentum = 27 [4.8%], p < 0.0001), cellulitis (VRAM = 2 [0.36%]; omentum = 10 [1.78%], p = 0.025). Statistical comparison of tumor recurrence between these two reconstructive approaches showed a significantly higher recurrence rate in omental flaps compared with VRAM flaps (p = 0.000127).

Conclusion The results of this study suggest a significantly higher tumor recurrence rate in omental flap pelvic reconstruction compared with VRAM flaps. This knowledge has the potential to influence surgical planning and flap selection in pelvic reconstruction.
Concentration of quantum states from quantum functional and transportation cost inequalities
Authors: Rouzé Cambyse , Datta Nilanjana
Published: January 2019

Quantum functional inequalities (e.g., the logarithmic Sobolev and Poincaré inequalities) have found widespread application in the study of the behavior of primitive quantum Markov semigroups. The classical counterparts of these inequalities are related to each other via a so-called transportation cost inequality of order 2 (TC2). The latter inequality relies on the notion of a metric on the set of probability distributions called the Wasserstein distance of order 2. (TC2) in turn implies a transportation cost inequality of order 1 (TC1). In this paper, we introduce quantum generalizations of the inequalities (TC1) and (TC2), making use of appropriate quantum versions of the Wasserstein distances, one recently defined by Carlen and Maas and the other defined by us. We establish that these inequalities are related to each other, and to the quantum modified logarithmic Sobolev- and Poincaré inequalities, as in the classical case. We also show that these inequalities imply certain concentration-type results for the invariant state of the underlying semigroup. We consider the example of the depolarizing semigroup to derive concentration inequalities for any finite dimensional full-rank quantum state. These inequalities are then applied to derive upper bounds on the error probabilities occurring in the setting of finite blocklength quantum parameter estimation.
Bandgap engineering in aperiodic Thue-Morse graphene superlattices
Authors: Carrillo-Delgado E. A. , Gaggero-Sager L. M. , Rodríguez-Vargas I.
Published: January 2019

The lack of bandgap in graphene is the main factor that prevents that this outstanding material be implemented in optoelectronics. In this work, we show that by nanostructuring graphene aperiodically it is possible to have an efficient transmission bandgap engineering. In particular, we are considering aperiodic graphene superlattices in which electrostatic barriers are arranged following the basic construction rules of the Thue-Morse sequence. We find that the transmission bandgap can be modulated readily by changing the angle of incidence as well as by appropriately choosing the generation of the Thue-Morse superlattice. Even, this angle-dependent bandgap engineering is more effective than the corresponding one for periodic graphene superlattices.
CSIRO and land research in Papua New Guinea 1950–2000: part 2: post-Independence
Authors: Keig Gael , Hide Robin L. , Cuddy Susan M. , Buettikofer Heinz , Bellamy Jennifer A. , Bleeker Pieter , Freyne David , McAlpine John
Published: January 2019

Following Papua New Guinea (PNG) Independence in 1975, the new administration approached Australia’s Commonwealth Scientific and Industrial Research Organisation (CSIRO) directly concerning the need to address issues related to food security and village-based agriculture. A subsequent series of collaborative research projects between CSIRO and PNG government departments built upon the existing survey information to provide PNG with one of the earliest national-level, computer-based resource information systems, with widespread applications, particularly in agriculture, forestry, environmental management and planning. Part 1 of this historical review discussed the evolution, conduct and outcomes of the CSIRO integrated surveys over the period 1950–75, while Part 2 describes the subsequent research projects that arose from the surveys and concluded in 2000. In addition, the legacy of CSIRO involvement in land research in PNG is examined in relation to advances made both within individual scientific disciplines and in other relevant technological fields, and to operational challenges and structural change within the organisation.
Responses of soil organic carbon, aggregate stability, carbon and nitrogen fractions to 15 and 24 years of no-till diversified crop rotations
Authors: Maiga Amadou , Alhameid Abdullah , Singh Shikha , Polat Atilla , Singh Jasdeep , Kumar Sandeep , Osborne Shannon
Published: January 2019

Diversification within a cropping system together with no-till (NT) soil management can help to improve soil organic carbon (SOC). The present study was conducted to assess the impacts of crop diversity through crop rotations on SOC and other selected soil properties. The long-term experimental sites were located in Beresford and Brookings, South Dakota, USA. The Beresford site was initiated in 1991 (24 years) on Egan soil series (fine-silty, mixed, superactive, mesic Udic Haplustolls), whereas, the Brookings site was established in 2000 (14 years) on a Barnes clay loam soil (fine-loamy, mixed, superactive, frigid Calcic Hapludolls) under a randomised complete block design with four replications. Treatments at both sites consisted of a 2-year (corn (Zea mays L.)–soybean (Glycine max L.)), and a 4-year (corn–soybean–winter wheat (Triticum aestivum L.)–oat (Avena sativa L.)) rotation, all managed under NT soil management. Soil samples were collected in the fall of 2015 after crop harvest under the corn phase. Data showed that 4-year rotation increased SOC stock (8.3% in Brookings and 22% in Beresford) compared with that under 2-year rotation (not always significant) in the soil profile 0–60cm. Soil particulate organic matter and organic matter were always higher under 4-year rotation than under 2-year rotation at 0–5 and 5–15cm depths at both sites. Surface soil aggregate stability was improved in both locations under 4-year rotation (12% in Brookings, 4% in Beresford). Additionally, at 0–5cm depth, the 4-year rotation increased light fractions of carbon (18% in Brookings, and 32% in Beresford) compared with 2-year. Results from this study showed that the use of diverse crop rotations (4-year) for longer (>24 years) duration enhanced SOC, carbon and nitrogen fractions, and soil aggregation compared with those under corn–soybean (2-year) rotation.
Structural basis for substrate binding and specificity of a sodium–alanine symporter AgcS
Authors: Ma Jinming , Lei Hsiang-Ting , Reyes Francis E. , Sanchez-Martinez Silvia , Sarhan Maen F. , Hattne Johan , Gonen Tamir
Published: January 2019

The amino acid, polyamine, and organocation (APC) superfamily is the second largest superfamily of membrane proteins forming secondary transporters that move a range of organic molecules across the cell membrane. Each transporter in the APC superfamily is specific for a unique subset of substrates, even if they possess a similar structural fold. The mechanism of substrate selectivity remains, by and large, elusive. Here, we report two crystal structures of an APC member from
Methanococcus maripaludis
, the alanine or glycine:cation symporter (AgcS), with
l
- or
d
-alanine bound. Structural analysis combined with site-directed mutagenesis and functional studies inform on substrate binding, specificity, and modulation of the AgcS family and reveal key structural features that allow this transporter to accommodate glycine and alanine while excluding all other amino acids. Mutation of key residues in the substrate binding site expand the selectivity to include valine and leucine. These studies provide initial insights into substrate selectivity in AgcS symporters.
More than 18,000 effectors in the
Legionella
genus genome provide multiple, independent combinations for replication in human cells
Authors: Gomez-Valero Laura , Rusniok Christophe , Carson Danielle , Mondino Sonia , Pérez-Cobas Ana Elena , Rolando Monica , Pasricha Shivani , Reuter Sandra , Demirtas Jasmin , Crumbach Johannes , Descorps-Declere Stephane , Hartland Elizabeth L. , Jarraud Sophie , Dougan Gordon , Schroeder Gunnar N. , Frankel Gad , Buchrieser Carmen
Published: January 2019

The genus
Legionella
comprises 65 species, among which
Legionella pneumophila
is a human pathogen causing severe pneumonia. To understand the evolution of an environmental to an accidental human pathogen, we have functionally analyzed 80
Legionella
genomes spanning 58 species. Uniquely, an immense repository of 18,000 secreted proteins encoding 137 different eukaryotic-like domains and over 200 eukaryotic-like proteins is paired with a highly conserved type IV secretion system (T4SS). Specifically, we show that eukaryotic Rho- and Rab-GTPase domains are found nearly exclusively in eukaryotes and
Legionella
. Translocation assays for selected Rab-GTPase proteins revealed that they are indeed T4SS secreted substrates. Furthermore, F-box, U-box, and SET domains were present in >70% of all species, suggesting that manipulation of host signal transduction, protein turnover, and chromatin modification pathways are fundamental intracellular replication strategies for legionellae. In contrast, the Sec-7 domain was restricted to
L. pneumophila
and seven other species, indicating effector repertoire tailoring within different amoebae. Functional screening of 47 species revealed 60% were competent for intracellular replication in THP-1 cells, but interestingly, this phenotype was associated with diverse effector assemblages. These data, combined with evolutionary analysis, indicate that the capacity to infect eukaryotic cells has been acquired independently many times within the genus and that a highly conserved yet versatile T4SS secretes an exceptional number of different proteins shaped by interdomain gene transfer. Furthermore, we revealed the surprising extent to which legionellae have coopted genes and thus cellular functions from their eukaryotic hosts, providing an understanding of how dynamic reshuffling and gene acquisition have led to the emergence of major human pathogens.
Chromatin features constrain structural variation across evolutionary timescales
Authors: Fudenberg Geoff , Pollard Katherine S.
Published: January 2019

Significance

Noncoding DNA sequences play crucial roles in gene regulation, including via three-dimensional genome organization where they define chromatin boundaries and segment the genome into a sequence of insulated neighborhoods. However, the relative importance of noncoding DNA elements, particularly in comparison with protein-coding DNA sequences, remains more poorly characterized. Here, we systematically test if chromatin boundary disruptions are under purifying selection. Our analyses uncover a genomewide depletion of structural variants that would have the potential to alter chromatin structure. This in turn has implications for predicting not only which variants are likely pathogenic in clinical genetics settings, but also which are likely key innovations in primate evolution, and argues for expanding the current gene-centric paradigm for interpreting structural variants.
Nonequilibrium correlations in minimal dynamical models of polymer copying
Authors: Poulton Jenny M. , ten Wolde Pieter Rein , Ouldridge Thomas E.
Published: January 2019

Significance

The ordering of chemical units within DNA, RNA, and proteins carries information about how living cells operate, and copying these sequences accurately is vital. We have a limited understanding of the fundamental physical underpinnings of these processes, since important mechanistic constraints due to the need to separate daughter sequences from their templates have never been investigated in detail. By considering the simplest models that incorporate these constraints, we highlight their profound consequences in terms of the effort that must be expended to make accurate copies. These insights will help us to understand not only life today but also how early replicators may have functioned in the past, and how we might develop synthetic copiers in the future.
Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells
Authors: Nelson Christine E. , Mills Lauren J. , McCurtain Jennifer L. , Thompson Emily A. , Seelig Davis M. , Bhela Siddheshvar , Quarnstrom Clare F. , Fife Brian T. , Vezys Vaiva
Published: January 2019

Significance

Cancer immunotherapies, such as immune checkpoint blockade, work by stimulating immune cells to kill tumors. Unfortunately, not all patients respond to checkpoint treatment, which also causes autoimmune side effects due to self-reactive immune cell activation. This study uncovers immune subtypes that respond best to this immunotherapy and reveals methods to reinvigorate dysfunctional antitumor immune responses. We show that self-reactive CD8 T cells can be pathogenic or nonresponsive to checkpoint blockade therapy depending on their activation status. In addition, tolerant self-reactive CD8 T cells bear striking similarity to dysfunctional tumor-specific CD8 T cells. Finally, we demonstrate that previously tolerant self-specific CD8 T cells can eliminate aggressive tumors bearing self-antigens without concomitant autoimmunity after robust antigenic vaccination in concert with PD-L1 blockade.
Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy
Authors: Bernard-Marissal Nathalie , van Hameren Gerben , Juneja Manisha , Pellegrino Christophe , Louhivuori Lauri , Bartesaghi Luca , Rochat Cylia , El Mansour Omar , Médard Jean-Jacques , Croisier Marie , Maclachlan Catherine , Poirot Olivier , Uhlén Per , Timmerman Vincent , Tricaud Nicolas , Schneider Bernard L. , Chrast Roman
Published: January 2019

Significance

Interactions between mitochondria and the endoplasmic reticulum (ER) at the level of mitochondria-associated membranes (MAM) constitute a key signaling hub, emerging as a shared target altered in multiple neurodegenerative diseases. We use both in vivo and in vitro models of Charcot–Marie–Tooth type 2A, an axonal form of neuropathy, to demonstrate that the presence of mutated Mitofusin 2 leads to altered MAM. In neurons, these modifications occur concomitantly with activation of ER stress response, dysregulated calcium handling, and alterations in mitochondrial morphology and transport, collectively contributing to axonopathy. Importantly, the reported results indicate that the pathological consequences of mutated Mitofusin 2 may be targeted with drugs reinforcing the ER–mitochondria cross-talk and/or reducing ER stress.
Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds
Authors: Cruz-Migoni Abimael , Canning Peter , Quevedo Camilo E. , Bataille Carole J. R. , Bery Nicolas , Miller Ami , Russell Angela J. , Phillips Simon E. V. , Carr Stephen B. , Rabbitts Terence H.
Published: January 2019

TheRASgene family is frequently mutated in human cancers, and the quest for compounds that bind to mutant RAS remains a major goal, as it also does for inhibitors of protein–protein interactions. We have refined crystallization conditions for KRAS169Q61H-yielding crystals suitable for soaking with compounds and exploited this to assess new RAS-binding compounds selected by screening a protein–protein interaction-focused compound library using surface plasmon resonance. Two compounds, referred to as PPIN-1 and PPIN-2, with related structures from 30 initial RAS binders showed binding to a pocket where compounds had been previously developed, including RAS effector protein–protein interaction inhibitors selected using an intracellular antibody fragment (called Abd compounds). Unlike the Abd series of RAS binders, PPIN-1 and PPIN-2 compounds were not competed by the inhibitory anti-RAS intracellular antibody fragment and did not show any RAS-effector inhibition properties. By fusing the common, anchoring part from the two new compounds with the inhibitory substituents of the Abd series, we have created a set of compounds that inhibit RAS-effector interactions with increased potency. These fused compounds add to the growing catalog of RAS protein–protein inhibitors and show that building a chemical series by crossing over two chemical series is a strategy to create RAS-binding small molecules.
Illuminating spatial A-to-I RNA editing signatures within the
Drosophila
brain
Authors: Sapiro Anne L. , Shmueli Anat , Henry Gilbert Lee , Li Qin , Shalit Tali , Yaron Orly , Paas Yoav , Billy Li Jin , Shohat-Ophir Galit
Published: January 2019

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is a ubiquitous mechanism that generates transcriptomic diversity. This process is particularly important for proper neuronal function; however, little is known about how RNA editing is dynamically regulated between the many functionally distinct neuronal populations of the brain. Here, we present a spatial RNA editing map in the
Drosophila
brain and show that different neuronal populations possess distinct RNA editing signatures. After purifying and sequencing RNA from genetically marked groups of neuronal nuclei, we identified a large number of editing sites and compared editing levels in hundreds of transcripts across nine functionally different neuronal populations. We found distinct editing repertoires for each population, including sites in repeat regions of the transcriptome and differential editing in highly conserved and likely functional regions of transcripts that encode essential neuronal genes. These changes are site-specific and not driven by changes in
Adar
expression, suggesting a complex, targeted regulation of editing levels in key transcripts. This fine-tuning of the transcriptome between different neurons by RNA editing may account for functional differences between distinct populations in the brain.
Standing genetic variation as the predominant source for adaptation of a songbird
Authors: Lai Yu-Ting , Yeung Carol K. L. , Omland Kevin E. , Pang Er-Li , Hao Yu , Liao Ben-Yang , Cao Hui-Fen , Zhang Bo-Wen , Yeh Chia-Fen , Hung Chih-Ming , Hung Hsin-Yi , Yang Ming-Yu , Liang Wei , Hsu Yu-Cheng , Yao Cheng-Te , Dong Lu , Lin Kui , Li Shou-Hsien
Published: January 2019

What kind of genetic variation contributes the most to adaptation is a fundamental question in evolutionary biology. By resequencing genomes of 80 individuals, we inferred the origin of genomic variants associated with a complex adaptive syndrome involving multiple quantitative traits, namely, adaptation between high and low altitudes, in the vinous-throated parrotbill (
Sinosuthora webbiana
) in Taiwan. By comparing these variants with those in the Asian mainland population, we revealed standing variation in 24 noncoding genomic regions to be the predominant genetic source of adaptation. Parrotbills at both high and low altitudes exhibited signatures of recent selection, suggesting that not only the front but also the trailing edges of postglacial expanding populations could be subjected to environmental stresses. This study verifies and quantifies the importance of standing variation in adaptation in a cohort of genes, illustrating that the evolutionary potential of a population depends significantly on its preexisting genetic diversity. These findings provide important context for understanding adaptation and conservation of species in the Anthropocene.
Microbial mechanisms and ecosystem flux estimation for aerobic NO
y
emissions from deciduous forest soils
Authors: Mushinski Ryan M. , Phillips Richard P. , Payne Zachary C. , Abney Rebecca B. , Jo Insu , Fei Songlin , Pusede Sally E. , White Jeffrey R. , Rusch Douglas B. , Raff Jonathan D.
Published: January 2019

Significance

Reactive nitrogen oxides (NO
y
) can negatively impact air quality, visibility, and human health. Biogenic sources of NO
y
are poorly understood despite their growing importance in future scenarios of decreasing anthropogenic emissions. Using soil from two forest stands that differ in plant and soil characteristics, we show that ammonia-oxidizing bacteria and to a lesser extent, heterotrophic microbes are the primary producers of NO
y
. Moreover, we show that ammonia-oxidizing archaea contribute little to NO
y
yet play a central role in determining nitrogen-cycle rates in forests. Given known relationships between tree species and soil characteristics, we conclude that NO
y
emissions are spatially variable, occurring in hotspots throughout the eastern United States.
Multiomics resolution of molecular events during a day in the life of Chlamydomonas
Authors: Strenkert Daniela , Schmollinger Stefan , Gallaher Sean D. , Salomé Patrice A. , Purvine Samuel O. , Nicora Carrie D. , Mettler-Altmann Tabea , Soubeyrand Eric , Weber Andreas P. M. , Lipton Mary S. , Basset Gilles J. , Merchant Sabeeha S.
Published: January 2019

The unicellular green alga
Chlamydomonas reinhardtii
displays metabolic flexibility in response to a changing environment. We analyzed expression patterns of its three genomes in cells grown under light–dark cycles. Nearly 85% of transcribed genes show differential expression, with different sets of transcripts being up-regulated over the course of the day to coordinate cellular growth before undergoing cell division. Parallel measurements of select metabolites and pigments, physiological parameters, and a subset of proteins allow us to infer metabolic events and to evaluate the impact of the transcriptome on the proteome. Among the findings are the observations that
Chlamydomonas
exhibits lower respiratory activity at night compared with the day; multiple fermentation pathways, some oxygen-sensitive, are expressed at night in aerated cultures; we propose that the ferredoxin, FDX9, is potentially the electron donor to hydrogenases. The light stress-responsive genes
PSBS
,
LHCSR1
, and
LHCSR3
show an acute response to lights-on at dawn under abrupt dark-to-light transitions, while
LHCSR3
genes also exhibit a later, second burst in expression in the middle of the day dependent on light intensity. Each response to light (acute and sustained) can be selectively activated under specific conditions. Our expression dataset, complemented with coexpression networks and metabolite profiling, should constitute an excellent resource for the algal and plant communities.
REM sleep’s unique associations with corticosterone regulation, apoptotic pathways, and behavior in chronic stress in mice
Authors: Nollet Mathieu , Hicks Harriet , McCarthy Andrew P. , Wu Huihai , Möller-Levet Carla S. , Laing Emma E. , Malki Karim , Lawless Nathan , Wafford Keith A. , Dijk Derk-Jan , Winsky-Sommerer Raphaelle
Published: January 2019

One of sleep’s putative functions is mediation of adaptation to waking experiences. Chronic stress is a common waking experience; however, which specific aspect of sleep is most responsive, and how sleep changes relate to behavioral disturbances and molecular correlates remain unknown. We quantified sleep, physical, endocrine, and behavioral variables, as well as the brain and blood transcriptome in mice exposed to 9 weeks of unpredictable chronic mild stress (UCMS). Comparing 46 phenotypic variables revealed that rapid–eye-movement sleep (REMS), corticosterone regulation, and coat state were most responsive to UCMS. REMS theta oscillations were enhanced, whereas delta oscillations in non-REMS were unaffected. Transcripts affected by UCMS in the prefrontal cortex, hippocampus, hypothalamus, and blood were associated with inflammatory and immune responses. A machine-learning approach controlling for unspecific UCMS effects identified transcriptomic predictor sets for REMS parameters that were enriched in 193 pathways, including some involved in stem cells, immune response, and apoptosis and survival. Only three pathways were enriched in predictor sets for non-REMS. Transcriptomic predictor sets for variation in REMS continuity and theta activity shared many pathways with corticosterone regulation, in particular pathways implicated in apoptosis and survival, including mitochondrial apoptotic machinery. Predictor sets for REMS and anhedonia shared pathways involved in oxidative stress, cell proliferation, and apoptosis. These data identify REMS as a core and early element of the response to chronic stress, and identify apoptosis and survival pathways as a putative mechanism by which REMS may mediate the response to stressful waking experiences.
Motile cilia of the male reproductive system require miR-34/miR-449 for development and function to generate luminal turbulence
Authors: Yuan Shuiqiao , Liu Yue , Peng Hongying , Tang Chong , Hennig Grant W. , Wang Zhuqing , Wang Li , Yu Tian , Klukovich Rachel , Zhang Ying , Zheng Huili , Xu Chen , Wu Jingwen , Hess Rex A. , Yan Wei
Published: January 2019

Cilia are cell-surface, microtubule-based organelles that project into extracellular space. Motile cilia are conserved throughout eukaryotes, and their beat induces the flow of fluid, relative to cell surfaces. In mammals, the coordinated beat of motile cilia provides highly specialized functions associated with the movement of luminal contents, as seen with metachronal waves transporting mucus in the respiratory tract. Motile cilia are also present in the male and female reproductive tracts. In the female, wave-like motions of oviductal cilia transport oocytes and embryos toward the uterus. A similar function has been assumed for motile cilia in efferent ductules of the male—i.e., to transport immotile sperm from rete testis into the epididymis. However, we report here that efferent ductal cilia in the male do not display a uniform wave-like beat to transport sperm solely in one direction, but rather exert a centripetal force on luminal fluids through whip-like beating with continual changes in direction, generating turbulence, which maintains immotile spermatozoa in suspension within the lumen. Genetic ablation of two miRNA clusters (
miR-34b/c
and
-449a/b/c
) led to failure in multiciliogenesis in murine efferent ductules due to dysregulation of numerous genes, and this mouse model allowed us to demonstrate that loss of efferent duct motile cilia causes sperm aggregation and agglutination, luminal obstruction, and sperm granulomas, which, in turn, induce back-pressure atrophy of the testis and ultimately male infertility.
Liquid water is a dynamic polydisperse branched polymer
Authors: Naserifar Saber , Goddard William A.
Published: January 2019

Significance

In contrast to ice, in which each water makes strong hydrogen bonds (SHBs) to four neighbors, we show that upon melting the number of SHBs drops quickly to two in liquid water. These two SHBs couple into chains containing ∼150 waters resembling a branched polymer. The lifetime of each SHB at 298 K is 90.3 fs (11 OH vibrational periods), so the polymer branches evolve dynamically. This dynamics-branched polymer paradigm may explain long-standing puzzles of water, such as the critical point at 227 K in supercooled water (which may correspond to a glass transition caused by an increase in the SHB lifetime). It may explain the observed angular correlations in water that persist for 20 nm.
Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma
Authors: Zhao Yanxia , Cao Jinghong , Melamed Alexander , Worley Michael , Gockley Allison , Jones Dennis , Nia Hadi T. , Zhang Yanling , Stylianopoulos Triantafyllos , Kumar Ashwin S. , Mpekris Fotios , Datta Meenal , Sun Yao , Wu Limeng , Gao Xing , Yeku Oladapo , del Carmen Marcela G. , Spriggs David R. , Jain Rakesh K. , Xu Lei
Published: January 2019

Significance

Despite initial responsiveness to chemotherapy, the overwhelming majority of advanced ovarian cancer patients relapse with resistant disease. Thus, developing more effective strategies for ovarian cancer treatment is a high clinical priority. Here, we report that targeting angiotensin signaling with losartan, an angiotensin receptor blocker, can reduce extracellular matrix in ovarian tumors and the associated physical barriers that normally hinder drug delivery and efficacy. These changes in the tumor microenvironment lead to improved response to chemotherapy, and, importantly, decrease ascites—a major burden for ovarian cancer patients. These preclinical findings are in concert with our retrospective analysis showing improved survival in patients receiving angiotensin system inhibitors concurrently with standard treatment for ovarian cancer and should be tested in a clinical trial.
Homoharringtonine deregulates
MYC
transcriptional expression by directly binding NF-κB repressing factor
Authors: Chen Xin-Jie , Zhang Wei-Na , Chen Bing , Xi Wen-Da , Lu Ying , Huang Jin-Yan , Wang Yue-Ying , Long Jun , Wu Song-Fang , Zhang Yun-Xiang , Wang Shu , Li Si-Xing , Yin Tong , Lu Min , Xi Xiao-Dong , Li Jun-Min , Wang Kan-Kan , Chen Zhu , Chen Sai-Juan
Published: January 2019

Homoharringtonine (HHT), a known protein synthesis inhibitor, has an anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myelogenous leukemia (AML) with favorable and intermediate prognoses, especially in the t(8;21) subtype. Here we provide evidence showing that HHT inhibits the activity of leukemia-initiating cells (Lin
−
/Sca-1
−
/c-kit
+
; LICs) in a t(8;21) murine leukemia model and exerts a down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). We discovered that NF-κB repressing factor (NKRF) is bound directly by HHT via the second double-strand RNA-binding motif (DSRM2) domain, which is the nuclear localization signal of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding sites to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from the nucleus (including nucleoli) to the cytoplasm by occupying the DSRM2 domain, strengthens the p65–NKRF interaction, and interferes with p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on the
MYC
gene. Moreover, HHT significantly decreases the expression of
KIT
, a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation. Our work thus identifies a mechanism of action of HHT that is different from, but acts in concert with, the known mode of action of this compound. These results justify further clinical testing of HHT in AML.
Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma
Authors: Villanova Tania , Gesmundo Iacopo , Audrito Valentina , Vitale Nicoletta , Silvagno Francesca , Musuraca Chiara , Righi Luisella , Libener Roberta , Riganti Chiara , Bironzo Paolo , Deaglio Silvia , Papotti Mauro , Cai Renzhi , Sha Wei , Ghigo Ezio , Schally Andrew V. , Granata Riccarda
Published: January 2019

Significance

Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis and limited treatment options. MPM remains a serious public health problem, and novel therapeutic strategies are urgently needed. The antitumor properties of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different cancers; however, their influence in MPM remains unexplored. Our work shows that GHRH antagonists MIA-602 and MIA-690 reduce survival, proliferation, and migration of human MPM cell lines and primary MPM cells in vitro by modulating apoptotic and oncogenic pathways. In vivo, GHRH antagonists inhibited the growth of MPM xenografts and blunted the production of growth factors in tumors. Overall, the inhibitory activities described in this study suggest that GHRH antagonists may be considered for development of therapies for MPM.