bluuebunny/crossref_metadata_2025 huggingface dataset:
Fault detection and estimation for a class of PIDE systems based on boundary observers
Authors: Xu Xiaodong , Yuan Yuan , Wang Meiling , Fu Mengyin , Dubljevic Stevan
Published: August 2019

In this paper, we propose a simultaneous state estimation and fault estimation approach for a class of first‐order hyperbolic partial integral differential equation systems. Specifically, we consider the multiplicative boundary actuator and sensor faults, ie, unknown fault parameters multiplying by the boundary input or boundary state (ie, output). As a consequence, two difficulties arise immediately: (1) simultaneous estimation of both plant state and faults is a nonlinear problem due to the multiplication between fault parameters and plant signals; (2) no prior information is available to determine the type (actuator or sensor) of faults. To overcome these difficulties, this paper develops adaptive fault parameter update laws and embeds the resulting laws into the plant state observer design. First, we propose new approaches to estimate actuator fault and sensor fault, respectively. Next, we develop a novel method to simultaneously estimate actuator and sensor faults. The proposed observer and update laws, designed using only one boundary measurement, ensure both state estimation and fault parameter estimation. By choosing appropriate Lyapunov functions, we prove that the estimates of state and fault parameters converge to an arbitrarily small neighborhood of their true values. Numerical simulations are used to demonstrate the effectiveness of the proposed estimation approaches.
Automatic targetless camera–LIDAR calibration by aligning edge with Gaussian mixture model
Authors: Kang Jaehyeon , Doh Nakju L.
Published: August 2019

This paper presents a calibration algorithm that does not require an artificial target object to precisely estimate a rigid‐body transformation between a camera and a light detection and ranging (LIDAR) sensor. The proposed algorithm estimates calibration parameters by minimizing a cost function that evaluates the edge alignment between two sensor measurements. In particular, the proposed cost function is constructed using a projection model‐based many‐to‐many correspondence of the edges to fully exploit measurements with different densities (dense photometry and sparse geometry). The alignment of the many‐to‐many correspondence is represented using the Gaussian mixture model (GMM) framework. Here, each component of the GMM, including weight, displacement, and standard deviation, is derived to suitably capture the intensity, location, and influential range of the edge measurements, respectively. The derived cost function is optimized by the gradient descent method with an analytical derivative. A coarse‐to‐fine scheme is also applied by gradually decreasing the standard deviation of the GMM to enhance the robustness of the algorithm. Extensive indoor and outdoor experiments validate the claim that the proposed GMM strategy improves the performance of the proposed algorithm. The experimental results also show that the proposed algorithm outperforms previous methods in terms of precision and accuracy by providing calibration parameters of standard deviations less than 0.6° and 2.1 cm with a reprojection error of 1.78 for a 2.1‐megapixel image (2,048 × 1,024) in the best case.
Tumour growth activation by the central nervous system—An integrative theory of cancer
Authors: Recio Alberto
Published: August 2019

The currently recognized mechanisms of the biology of cancer are not yet enough to explain the high incidence of the disease in industrialized countries. Survival and proliferation of cancer cells demand a well‐orchestrated combination of functional capabilities, or hallmarks, which requires complex signalling networks that often exceed the tumour boundaries. Based on latest research on environmental health and aiming to provide cancer with a coherent set of organizing principles, we propose an integrative model of carcinogenesis founded on tumour growth activation by the central nervous system as an adaptive, allostatic response to both environmental and emotional challenges. In this way, chronicity of physical as well as psychological stressors may be directly involved in cancer genesis and progression, after an early inflammatory stage. The model also contemplates accidental activation of the tumour growth programme following direct DNA damage, but as a rare event that does not account for most cancers in humans. Bodily and cellular mechanisms designed to facilitate tumorigenesis may include exacerbation of the sympathetic activity, overexpression of membrane ion channels, promotion of selected mutations and methylations, degradation of the mitochondria and reprogramming of adult stem cells.
A process partitioning technique for constructing decentralized web service compositions
Authors: Xue Gang , Liu Di , Liu Junsong , Yao Shaowen
Published: August 2019

Web service compositions have been widely applied in different applications. A service composition is usually implemented in either a centralized or decentralized manner. Compared with the centralized service composition, the decentralized composition has no central control component, and components interact with each other directly, thereby achieving better performance. Process partitioning is a technique to divide a process into multiple parts and has been shown that it can be successfully applied to decentralizing process‐driven service compositions. This paper proposes a new process partitioning technique for constructing decentralized service compositions. The proposed technique, which is based on typed digraphs and a graph transformation technique, is used for exploring available process partitioning solutions. For applications, this paper discusses the topology and interaction features about the partitioning solutions and summarizes a ranking method for them. Three experiments are conducted to evaluate the proposed methods in this paper. Experimental results show that the proposed methods can be applied in constructing decentralized service compositions effectively. In addition, the results also show that the decentralized compositions can have lower average response times and higher throughputs than the corresponding centralized compositions in the experiments.
When zoo visitors “connect” with a zoo animal, what does that mean?
Authors: Howell Tiffani J. , McLeod Emily M. , Coleman Grahame J.
Published: August 2019

Connection with a zoo animal may increase conservation‐mindedness in zoo visitors, potentially resulting in conservation‐oriented behavior change. No research has attempted to establish what this “connection” actually means. Visitors (N = 85) to Melbourne Zoo were asked to name the animal with which they most connected, the extent to which they connected with it, and to qualitatively describe what it meant to connect with that animal. Many (but not all) participants connected with charismatic megafauna: primate, great ape, large carnivore, or large herbivore. Qualitative analysis revealed five common themes in the meaning of connection: Appreciation, Attribution, Inspires Emotions, Interaction, and Proximity. Overall connection level was significantly correlated with perceptions of conservation caring for the chosen species. Future research should aim to determine what factors affect a zoo visitor's connection level, which could impact attitudes and behaviors toward conservation.
Prognostic Characteristics of Primary Squamous Cell Carcinoma of the Thyroid: A National Cancer Database Analysis
Authors: Limberg Jessica , Ullmann Timothy M. , Stefanova Dessislava , Finnerty Brendan M. , Beninato Toni , Fahey Thomas J. , Zarnegar Rasa
Published: August 2019

Background

Primary squamous cell carcinoma of the thyroid (ThySCC) is a rare cancer, primarily described only in case reports. We aimed to characterize the prognosis of ThySCC and compare its oncologic behavior to other thyroid malignancies.

Methods

The National Cancer Database was queried to identify patients with ThySCC, papillary, tall cell variant, poorly differentiated (PDTC), and anaplastic (ATC) subtypes of thyroid cancer treated from 2004 to 2015. Demographics, tumor characteristics, and treatments were compared by tumor type and assessed to identify independent predictors of overall survival (OS).

Results

Of 123,684 patients included, 314 had ThySCC. ThySCC patients had a 5‐year OS of 17.7%, more closely resembling ATC (8.3%) than PDTC or PTC. ThySCC and ATC patients had similar demographics, except ThySCC patients who were younger (68.0 vs. 70.2 years, p < 0.01). ThySCC tumors were smaller (mean 53.5 ± 45.7 vs. 69.5 ± 75.2 mm) with less frequent extrathyroidal extension (ETE) (64.0% vs. 73.8%), lymphovascular invasion (8.3% vs. 12.3%), and positive margins (22.0% vs. 28.3%) compared to ATCs (p < 0.05). ETE [HR 3.1 (95% CI 1.5–6.4), p < 0.05] and lymph node metastases [HR 2.2 (95% CI 1.2–4.0) p < 0.05] were independently associated with worse OS for ThySCC patients. Both ThySCC and ATC patients had similar surgical success rates, with R1 resection possible in 37.3% versus 35.0% of patients, respectively (p < 0.05). However, in contrast to ATC patients, adjuvant therapy was not associated with improved OS for ThySCC patients after complete resection.

Conclusions

ThySCC has a poor prognosis, similar to ATC, but with fewer aggressive features and no apparent survival benefit with adjuvant therapy after complete macroscopic surgical resection.
Utility of Activated Carbon Nanoparticle (CNP) During total Thyroidectomy for Clinically Nodal Positive Papillary Thyroid Carcinoma (PTC)
Authors: Min Lei , Lang Brian H. H. , Chen Weichun , Ai Qing , Jiang Jiang , Huang Zhi Heng
Published: August 2019

Background

Activated carbon nanoparticle (CNP) is a novel tracer that may facilitate nodal dissection in clinically nodal positive (cN1) papillary thyroid carcinoma (PTC). The present study compared the nodal yield and surgical outcomes between surgery with CNP and without CNP.

Methods

Patients who underwent total thyroidectomy with therapeutic nodal dissection for cN1 PTC were given the option of intraoperative CNP injection. Among those who received CNP, 0.2 mL CNP suspension was injected in both thyroid lobes before dissection. Study endpoints included number of total and metastatic lymph nodes, inadvertently removed parathyroid glands (PGs), postoperative parathyroid hormone, calcium, and post‐6‐month thyroglobulin (Tg). Biochemical complete response (BCR) was defined as Tg ≤ 1 ng/mL and/or stimulated Tg ≤ 2 ng/mL.

Results

One‐hundred and twenty patients (58.3%) received CNP, while 86 (41.7%) had surgery without CNP. Demographics, tumor characteristics, and operative time were comparable between the two groups. However, total mean number of normal and metastatic lymph nodes retrieved were significantly greater in CNP group (10.0 vs. 8.1, p = 0.032 and 4.5 vs. 2.7, p = 0.002, respectively). Rate of inadvertently removed PG was significantly less in CNP group (13.3% vs. 23.3%, p = 0.042). Postoperative Tg level and BCR were significantly lower in CNP group (9.9 ng/mL vs. 14.7 ng/mL, p = 0.297 and 82.4% vs. 72.9%, p = 0.002, respectively). However, large‐sized ( ≥ 3 cm) PTCs had a significantly lower nodal staining rate than smaller‐sized PTCs (10.3% vs. 69.4%, p < 0.001).

Conclusions

CNP injection can facilitate therapeutic central nodal dissection by increasing the nodal yield rates and reducing inadvertent PG removal. To enhance its utility, a greater volume of CNP might be necessary in larger‐sized (> 3 cm) PTCs.
Intra-articular Tranexamic Acid in Primary Total Knee Arthroplasty Decreases the Rate of Post-operative Blood Transfusions in People with Hemophilia: A Retrospective Case-Control Study
Authors: Rodriguez-Merchan E. Carlos , Encinas-Ullan Carlos A. , Gomez-Cardero Primitivo
Published: August 2019

Background

Blood transfusion rates after total knee arthroplasty (TKA) in patients without hemophilia have diminished with the use of a standardized multimodal blood loss prevention method (MBLPM) that includes intra-articular tranexamic acid (TXA) (MBLPM-TXA). However, the topic has not been addressed in people with hemophilia.

Questions/Purposes

Our aim was to investigate whether the MBLPM-TXA prevents blood loss in patients with hemophilia A who undergo TKA, thereby decreasing the need for post-operative blood transfusion.

Methods

This retrospective case–control comparative study involved 30 TKA patients who had a severe degree of hemophilia A without inhibitions: one group treated with the MBLPM-TXA ( n = 15) and a second group treated without it ( n = 15). In all cases, the pre-operative hemoglobin level was greater than 13 g/dL.

Results

The MBLPM-TXA group had a transfusion rate of zero, whereas 46.6% of the patients (seven of 15) in the non–MBLPM-TXA group needed transfusion.

Conclusion

This retrospective case–control study showed that the use of an MBLPM-TXA in patients with hemophilia A who underwent TKA was effective in reducing rates of transfusion. We recommend its use.
Laboratory evaluation to assess the effectiveness of inhibitive nano-water-based drilling fluids for Zubair shale formation
Authors: Alsaba Mortadha , Al Marshad Abdullah , Abbas Ahmed , Abdulkareem Talal , Al-Shammary Abdullah , Al-Ajmi Meshal , Kebeish Emad
Published: August 2019

While drilling through shale formations, shale hydration, including shale swelling and dispersion, is frequently reported as the main wellbore instability problems, particularly when conventional drilling fluids (water-based) are used. These problems have many adverse effects on the drilling operations resulting in non-productive time. Nanoparticles have been recently introduced as a unique alternative to improve the performance of water-based drilling fluids for shale applications. This paper presents an experimental evaluation to investigate the effectiveness of an inhibitive nano-water-based drilling fluid in reducing the swelling of Zubair shale formation. Well-preserved core samples, which were retrieved from Zubair formation, were characterized using X-ray diffraction, and X-ray fluoresces to quantify the amount of the swelling minerals. Scanning electron microscopy was used to identify the existence of microfractures within the samples. Three different nano-based drilling fluids containing titanium dioxide (TiO2), copper oxide (CuO), and magnesium oxide (MgO) at two different concentrations (0.5% and 1.5% by vol) were evaluated through a set of tests to assess the shale reactivity in the presence of these nano-based fluids. In addition, the effect of these nanoparticles on the rheological and filtration properties was studied. The results showed that the shale samples contain 41.26% silicon dioxide (SiO2) and 22.73% aluminum oxide (Al2O3), indicating the presence of smectite and illite. Based on the reactivity tests, fluids containing CuO at 1.5% by vol outperformed the other fluids in terms of reducing the reactivity, where the expansion rate was reduced by 82.7% compared to the reference sample submerged in fresh water. In addition, the addition of nanoparticles resulted in reducing the plastic viscosity, increasing both the yield point and gel strength, and reducing the fluid loss under low-pressure low-temperature conditions.
Impact of Index Surgical Care Setting on Perioperative Outcomes and Cost Following Penile Prosthesis Surgery
Authors: Berger Alexandra , Friedlander David F. , Herzog Peter , Ortega Gezzer , O’Leary Michael , Kathrins Martin , Trinh Quoc-Dien
Published: August 2019

Background

Penile prosthesis surgery has witnessed a migration from the inpatient to ambulatory surgical care setting. However, little is known about the cost savings afforded by this change in care setting and whether or not these savings come at the expense of worse perioperative outcomes.

Aim

The aim of this study was to identify predictors of index penile prosthesis (PP) surgery care setting, and whether ambulatory vs inpatient surgery is associated with comparable perioperative outcomes and costs.

Methods

This was a retrospective cohort study using all-payer claims data from the 2014 Healthcare Cost and Utilization Project State Databases from Florida and New York. Patient demographics, regional data, total charges (converted to costs), and 30-day revisit rates were abstracted for all patients undergoing index placement of an inflatable or malleable PP. Multivariable logistic and linear regression adjusted for facility clustering was utilized.

Outcomes

The outcomes were index surgical and 30-day postoperative costs, as well as 30-day revisit rates.

Results

Of the 1,790 patients undergoing an index surgery, 394 (22.0%) received care in the inpatient setting compared to 1,396 (78.0%) in the ambulatory setting. Adjusted index procedural ($9,319.66 vs $ 10,191.35; P < .001) and 30-day acute care costs ($9,461.74 vs $10,159.42; P < .001) were lower in the ambulatory setting. The underinsured experienced lower odds of receiving surgery in the ambulatory setting (Medicaid vs private: odds ratio [OR] 0.19; 95% CI 0.06−0.55; P < .001). There was no difference in risk-adjusted odds of experiencing a 30-day revisit between patients undergoing surgery in the ambulatory vs inpatient settings (OR 1.31; 95% CI 0.78−2.21; P = .3).

Clinical Translation

Ambulatory PP surgery confers significant cost savings and is associated with comparable perioperative outcomes relative to inpatient-based surgery.

Conclusions

Both clinical and nonclinical factors predict the care setting of index PP surgery. Notably, underinsured patients experienced lower odds of undergoing ambulatory surgery. Ambulatory surgery was less costly with similar 30-day revisit rates relative to inpatient-based care.
Exact pitch and heave flutter for the complex Theodorsen function
Authors: Farthing S.P.
Published: August 2019

Concepts of new fluttering wind and water mills led to general solution of flutter by a foil section free to pitch about an axis ahead of${1}/{4}$chord. The pitch damping of the vorticity being shed by lift change is negative singular via the imaginary part of the Theodorsen function. So a 2D airfoil can slowly flutter in pure pitch at a very high inertia with radian frequency and growth rate, reduced by windspeed/chord, resp. less than .087 and .01. At the frequency of nil net pitch damping, the binary inertia/damping cross determinant vanishes on a line in the imbalance vs inertia plane. The perturbed frequency contours just a bit above and below this ‘beab’ line spectacularly split to asymptote to the pure pitch inertia vertical of implied infinite heave stiffness. Higher frequency contours turn back towards the positive imbalance axis and then the origin, changing from hyperbolic to elliptical at exactly the same .087 and asymptoting to a line between the nexus and four times the nexus and a mode of effective pitch about${3}/{4}$chord. At .6 the pure pitch frequency the imaginary part dominates in the quadratic inertia and imbalance coefficients to bend the neutral contours down and across the quasi-steady line to even turn back to very large negative imbalance at small inertia, where kinematics then imply high mass. Diagonally mirror hyperbolae exist for greater than the pure pitch inertia with a different dynamic implication of very high foil mass.
Pure point spectrum for the Maryland model: a constructive proof
Authors: JITOMIRSKAYA SVETLANA , YANG FAN
Published: August 2019

We develop a constructive method to prove and study pure point spectrum for the Maryland model with Diophantine frequencies.
Uniqueness and time oscillating behaviour of finite points blow-up solutions of the fast diffusion equation
Authors: Hui Kin Ming
Published: August 2019

Let n ⩾ 3 and 0 < m < (n − 2)/n. We extend the results of Vazquez and Winkler (2011, J. Evol. Equ. 11, no. 3, 725–742) and prove the uniqueness of finite points blow-up solutions of the fast diffusion equation ut = Δum in both bounded domains and ℝn × (0, ∞). We also construct initial data such that the corresponding solution of the fast diffusion equation in bounded domain oscillates between infinity and some positive constant as t → ∞.
Who Has School Spirit? Explaining Voter Participation in School Board Elections
Authors: McGregor R. Michael , Lucas Jack
Published: August 2019

This research note examines the correlates of turnout in Canadian school board elections. Using individual-level data from the Canadian Municipal Election Study, we find that gender, education, left-wing ideology, Conservative partisanship and parental status were associated with participation in Calgary's 2017 public school board elections. Some of these patterns relate to the specific details of Calgary's 2017 election; others, we suggest, may be characteristic of school board elections more generally. We relate our findings to the literature on ballot roll-off and low-turnout elections.
Kant on Race and Barbarism: Towards a More Complex View on Racism and Anti-Colonialism in Kant
Authors: Eberl Oliver
Published: August 2019

Whether Kant’s late legal theory and his theory of race are contradictory in their account of colonialism has been a much-debated question that is also of highest importance for the evaluation of the Enlightenment’s contribution to Europe’s colonial expansion and the dispossession and enslavement of native and black peoples. This article discusses the problem by introducing the discourse on barbarism. This neglected discourse is the original and traditional European colonial vocabulary and served the justification of colonialism from ancient Greece throughout the Renaissance to the eighteenth century. Kant’s explicit rejection of this discourse and its prejudices reveals his early critical stance toward colonial judgements of native peoples even before he developed his legal theory. This development of his critical position can be traced in his writings on race: although he makes racist statements in these texts, his theory of race is not meant to ground moral judgements on ‘races’ or a racial hierarchy but to defend the unity of mankind under the given empirical reality of colonial hierarchies.
The WTO Panel Report inEU–Energy Packageand Its Implications for the EU's Gas Market and Energy Security
Authors: Pogoretskyy Vitaliy , Talus Kim
Published: August 2019

This article discusses the decision of the Panel of the World Trade Organization (WTO) in theEU–Energy Packagedispute between the Russian Federation and the European Union (EU) and certain of its Members. This decision is an important milestone in the history of the WTO. First, it presents a good example of how international economic disputes concerning politically sensitive matters, such as energy security, may be resolved in a pragmatic way, by adhering to multilateral trade rules of the WTO. Second, as the first WTO decision to address a Member's regulatory regime for natural gas, it reminds the WTO community that energy trade is not an alien subject for the WTO. In this article, we discuss some of the Panel's findings that may have significance for other similar cases, and examine the implications of these findings for the EU's internal gas market and energy security. The Panel's decision is currently under appeal with a ruling by the WTO Appellate Body not expected before the end of 2019. Hence, the outcome of this dispute remains uncertain.
Measurement and Modeling of High‐Frequency Acoustic Properties in Fine Sandy Sediments
Authors: Li G. , Wang J. , Liu B. , Meng X. , Kan G. , Pei Y.
Published: August 2019

The object of this study was to obtain the acoustic properties of fine sandy sediments with approximately 22% clay content from the East China Sea Shelf. This study conducted the in situ acoustic measurement to measure the sound speed and attenuation, and eight sediment cores were collected and measured the wet bulk density, porosity, and mean grain size in laboratory environment. The correlations between in situ sound speed ratio and physical properties show good accordance with two empirical equations, while the in situ attenuation factor deviated the regression curves. Both the sound speed ratio and the attenuation data show the obvious change against the measurement frequency. The comparisons of the measured sound speed ratio and attenuation to the Biot‐Stoll model predictions were performed. The sound speed ratio dispersion agrees well with the model prediction, when the permeability and pore size were calculated using the extended Kozeny‐Carman's equation and the extended Hovem's equation. The attenuation data in this study accords better with the prediction curves reported for fine sediments than that for coarse sediments from the 1999 Sediment Acoustics Experiment.
How Star Wars Won the Space Race and Other Things We’re Reading
Authors:   AGU
Published: August 2019

What Earth and space science stories are we recommending this week?
Exosomal PD-L1 promotes tumor growth through immune escape in non-small cell lung cancer
Authors: Kim Dong Ha , Kim HyeongRyul , Choi Yun Jung , Kim Seon Ye , Lee Jung-Eun , Sung Ki Jung , Sung Young Hoon , Pack Chan-Gi , Jung Min-kyo , Han Buhm , Kim Kunhee , Kim Woo Sung , Nam Soo Jeong , Choi Chang-Min , Yun Miyong , Lee Jae Cheol , Rho Jin Kyung
Published: August 2019

Programmed cell death protein-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway blockade is a promising new cancer therapy. Although PD-1/PD-L1 treatment has yielded clinical benefits in several types of cancer, further studies are required to clarify predictive biomarkers for drug efficacy and to understand the fundamental mechanism of PD-1/PD-L1 interaction between host and tumor cells. Here, we show that exosomes derived from lung cancer cells express PD-L1 and play a role in immune escape by reducing T-cell activity and promoting tumor growth. The abundance of PD-L1 on exosomes represented the quantity of PD-L1 expression on cell surfaces. Exosomes containing PD-L1 inhibited interferon-gamma (IFN-γ) secretion by Jurkat T cells. IFN-γ secretion was restored by PD-L1 knockout or masking on the exosomes. Both forced expression of PD-L1 on cells without PD-L1 and treatment with exosomes containing PD-L1 enhanced tumor growth in vivo. PD-L1 was present on exosomes isolated from the plasma of patients with non-small cell lung cancer, and its abundance in exosomes was correlated with PD-L1 positivity in tumor tissues. Exosomes can impair immune functions by reducing cytokine production and inducing apoptosis in CD8+T cells. Our findings indicate that tumor-derived exosomes expressing PD-L1 may be an important mediator of tumor immune escape.
Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains
Authors: Underhill Suzanne M. , Hullihen Patrick D. , Chen Jingshan , Fenollar-Ferrer Cristina , Rizzo M. A. , Ingram Susan L. , Amara Susan G.
Published: August 2019

The extensive use of amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of amphetamines and amphetamine-related drugs. We have previously shown that acute amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.
The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma
Authors: Li Jin , Li Zhongwu , Wu Yaping , Wang Yanling , Wang Dongmiao , Zhang Wei , Yuan Hua , Ye Jinhai , Song Xiaomeng , Yang Jianrong , Jiang Hongbing , Cheng Jie
Published: August 2019

The Hippo-TAZ signaling has emerged as a fundamental regulator underlying cancer stem cells (CSCs) stemness which intricately associates with local recurrence and metastatic spreading in head neck squamous cell carcinoma (HNSCC). However, the precise downstream targets of TAZ responsible for HNSCC CSCs maintenance remain largely underexplored. Here, we identified Sex determining region Y box 2 (SOX2) as a putative downstream target of TAZ to promote CSCs maintenance and tumorigenicity in HNSCC. Both TAZ and SOX2 were significantly enriched in CSCs subpopulation (CD44+CD133+) isolated from Cal27 and Fadu cells via fluorescence-activated cell sorting. TAZ knockdown significantly reduced expression of SOX2 at both mRNA and protein levels, whereas its ectopic overexpression markedly increased its abundance in HNSCC cells. Moreover, reintroduction of ectopic SOX2 abolished, at least in part, the reduced tumorsphere formation and tumorigenicity in vivo induced by TAZ knockdown. Mechanistically, transcriptional complex formed by TAZ and TEAD4 was recruited to two binding sites in SOX2 promoter, which in turn facilitated transcription of SOX2 in HNSCC cells. In addition, the abundance of TAZ and SOX2 was positively correlated in HNSCC clinical samples, and both upregulations of TAZ and SOX2 associated with the worst survival. Taken together, our data reveal a previously unknown mechanistic linkage between TAZ and SOX2 and identify SOX2 as a direct downstream target of TAZ in modulating CSCs self-renewal and maintenance in HNSCC. These findings suggest that targeting TAZ-SOX2 axis might be a promising therapeutic strategy for HNSCC.
Optineurin downregulation induces endoplasmic reticulum stress, chaperone-mediated autophagy, and apoptosis in pancreatic cancer cells
Authors: Ali Doaa M. , Ansari Shariq S. , Zepp Michael , Knapp-Mohammady Michaela , Berger Martin R.
Published: August 2019

Pancreatic ductal adenocarcinoma (PDAC) shows a high level of basal autophagy. Here we investigated the role of optineurin (OPTN) in PDAC cell lines, which is a prominent member of the autophagy system. To that purpose, mining of publically available databases showed that OPTN is highly expressed in PDAC and that high levels of expression are related to reduced survival. Therefore, the role of OPTN on proliferation, migration, and colony formation was investigated by transient knockdown in Miapaca, BXPC3, and Suit2-007 human PDAC cells. Furthermore, gene expression modulation in response to OPTN knockdown was assessed by microarray. The influence on cell cycle distribution and cell death signaling cascades was followed by FACS, assays for apoptosis, RT-PCR, and western blot. Finally, autophagy and ROS induction were screened by acridine orange and DCFH-DA fluorescent staining respectively. OPTN knockdown caused significant inhibition of colony formation, increased migration and no significant effect on proliferation in Miapaca, BXPC3 and Suit2-007 cells. The microarray showed modulation of 293 genes in Miapaca versus 302 in Suit2-007 cells, of which 52 genes overlapped. Activated common pathways included the ER stress response and chaperone-mediated autophagy, which was confirmed at mRNA and protein levels. Apoptosis was activated as shown by increased levels of cleaved PARP, Annexin V binding and nuclear fragmentation. OPTN knockdown caused no increased vacuole formation as assessed by acridine orange. Also, there was only marginally increased ROS production. Combination of OPTN knockdown with the autophagy inducer erufosine or LY294002, an inhibitor of autophagy, showed additive effects, which led us to hypothesize that they address different pathways. In conclusion, OPTN knockdown was related to activation of ER stress response and chaperone-mediated autophagy, which tend to confine the damage caused by OPTN knockdown and thus question its value for PDAC therapy.
A switch element in the autophagy E2 Atg3 mediates allosteric regulation across the lipidation cascade
Authors: Zheng Yumei , Qiu Yu , Grace Christy R. R. , Liu Xu , Klionsky Daniel J. , Schulman Brenda A.
Published: August 2019

Autophagy depends on the E2 enzyme, Atg3, functioning in a conserved E1-E2-E3 trienzyme cascade that catalyzes lipidation of Atg8-family ubiquitin-like proteins (UBLs). Molecular mechanisms underlying Atg8 lipidation remain poorly understood despite association of Atg3, the E1 Atg7, and the composite E3 Atg12–Atg5-Atg16 with pathologies including cancers, infections and neurodegeneration. Here, studying yeast enzymes, we report that an Atg3 element we term E123IR (E1, E2, and E3-interacting region) is an allosteric switch. NMR, biochemical, crystallographic and genetic data collectively indicate that in the absence of the enzymatic cascade, the Atg3E123IR makes intramolecular interactions restraining Atg3′s catalytic loop, while E1 and E3 enzymes directly remove this brace to conformationally activate Atg3 and elicit Atg8 lipidation in vitro and in vivo. We propose that Atg3′s E123IR protects the E2~UBL thioester bond from wayward reactivity toward errant nucleophiles, while Atg8 lipidation cascade enzymes induce E2 active site remodeling through an unprecedented mechanism to drive autophagy.
Tracking multiple components of a nuclear wavepacket in photoexcited Cu(I)-phenanthroline complex using ultrafast X-ray spectroscopy
Authors: Katayama Tetsuo , Northey Thomas , Gawelda Wojciech , Milne Christopher J. , Vankó György , Lima Frederico A. , Bohinc Rok , Németh Zoltán , Nozawa Shunsuke , Sato Tokushi , Khakhulin Dmitry , Szlachetko Jakub , Togashi Tadashi , Owada Shigeki , Adachi Shin-ichi , Bressler Christian , Yabashi Makina , Penfold Thomas J.
Published: August 2019

Disentangling the strong interplay between electronic and nuclear degrees of freedom is essential to achieve a full understanding of excited state processes during ultrafast nonadiabatic chemical reactions. However, the complexity of multi-dimensional potential energy surfaces means that this remains challenging. The energy flow during vibrational and electronic relaxation processes can be explored with structural sensitivity by probing a nuclear wavepacket using femtosecond time-resolved X-ray Absorption Near Edge Structure (TR-XANES). However, it remains unknown to what level of detail vibrational motions are observable in this X-ray technique. Herein we track the wavepacket dynamics of a prototypical [Cu(2,9-dimethyl-1,10-phenanthroline)2]+ complex using TR-XANES. We demonstrate that sensitivity to individual wavepacket components can be modulated by the probe energy and that the bond length change associated with molecular breathing mode can be tracked with a sub-Angstrom resolution beyond optical-domain observables. Importantly, our results reveal how state-of-the-art TR-XANES provides deeper insights of ultrafast nonadiabatic chemical reactions.
PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer
Authors: Costa Tânia D. F. , Zhuang Ting , Lorent Julie , Turco Emilia , Olofsson Helene , Masia-Balague Miriam , Zhao Miao , Rabieifar Parisa , Robertson Neil , Kuiper Raoul , Sjölund Jonas , Spiess Matthias , Hernández-Varas Pablo , Rabenhorst Uta , Roswall Pernilla , Ma Ran , Gong Xiaowei , Hartman Johan , Pietras Kristian , Adams Peter D. , Defilippi Paola , Strömblad Staffan
Published: August 2019

Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 – RELB - C/EBPβ axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPβ. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.
A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis
Authors: Qin Zhiwei , Devine Rebecca , Hutchings Matthew I. , Wilkinson Barrie
Published: August 2019

The formicamycin biosynthetic gene cluster encodes two groups of type 2 polyketide antibiotics: the formicamycins and their biosynthetic precursors the fasamycins, both of which have activity against methicillin-resistant Staphylococcus aureus. Here, we report the formicapyridines which are encoded by the same gene cluster and are structurally and biosynthetically related to the fasamycins and formicamycins but comprise a rare pyridine moiety. These compounds are trace-level metabolites formed by derailment of the major biosynthetic pathway. Inspired by evolutionary logic we show that rational mutation of a single gene in the biosynthetic gene cluster encoding an antibiotic biosynthesis monooxygenase (ABM) superfamily protein leads to a significant increase both in total formicapyridine production and their enrichment relative to the fasamycins/formicamycins. Our observations broaden the polyketide biosynthetic landscape and identify a non-catalytic role for ABM superfamily proteins in type II polyketide synthase assemblages for maintaining biosynthetic pathway fidelity.
CO2 electrochemical catalytic reduction with a highly active cobalt phthalocyanine
Authors: Wang Min , Torbensen Kristian , Salvatore Danielle , Ren Shaoxuan , Joulié Dorian , Dumoulin Fabienne , Mendoza Daniela , Lassalle-Kaiser Benedikt , Işci Umit , Berlinguette Curtis P. , Robert Marc
Published: August 2019

Molecular catalysts that combine high product selectivity and high current density for CO2 electrochemical reduction to CO or other chemical feedstocks are urgently needed. While earth-abundant metal-based molecular electrocatalysts with high selectivity for CO2 to CO conversion are known, they are characterized by current densities that are significantly lower than those obtained with solid-state metal materials. Here, we report that a cobalt phthalocyanine bearing a trimethyl ammonium group appended to the phthalocyanine macrocycle is capable of reducing CO2 to CO in water with high activity over a broad pH range from 4 to 14. In a flow cell configuration operating in basic conditions, CO production occurs with excellent selectivity (ca. 95%), and good stability with a maximum partial current density of 165 mA cm−2 (at −0.92 V vs. RHE), matching the most active noble metal-based nanocatalysts. These results represent state-of-the-art performance for electrolytic carbon dioxide reduction by a molecular catalyst.
WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
Authors: Chen Huimei , Moreno-Moral Aida , Pesce Francesco , Devapragash Nithya , Mancini Massimiliano , Heng Ee Ling , Rotival Maxime , Srivastava Prashant K. , Harmston Nathan , Shkura Kirill , Rackham Owen J. L. , Yu Wei-Ping , Sun Xi-Ming , Tee Nicole Gui Zhen , Tan Elisabeth Li Sa , Barton Paul J. R. , Felkin Leanne E. , Lara-Pezzi Enrique , Angelini Gianni , Beltrami Cristina , Pravenec Michal , Schafer Sebastian , Bottolo Leonardo , Hubner Norbert , Emanueli Costanza , Cook Stuart A. , Petretto Enrico
Published: August 2019

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
Expanding C–T base editing toolkit with diversified cytidine deaminases
Authors: Cheng Tian-Lin , Li Shuo , Yuan Bo , Wang Xiaolin , Zhou Wenhao , Qiu Zilong
Published: August 2019

Base editing tools for cytosine to thymine (C–T) conversion enable genome manipulation at single base-pair resolution with high efficiency. Available base editors (BEs) for C–T conversion (CBEs) have restricted editing scopes and nonnegligible off-target effects, which limit their applications. Here, by screening diversified lamprey cytidine deaminases, we establish various CBEs with expanded and diversified editing scopes, which could be further refined by various fusing strategies, fusing at either N-terminus or C–terminus of nCas9. Furthermore, off-target analysis reveals that several CBEs display improved fidelity. Our study expands the toolkits for C–T conversion, serves as guidance for appropriate choice and offers a framework for benchmarking future improvement of base editing tools.
Synthetic molecular recognition nanosensor paint for microalbuminuria
Authors: Budhathoki-Uprety Januka , Shah Janki , Korsen Joshua A. , Wayne Alysandria E. , Galassi Thomas V. , Cohen Joseph R. , Harvey Jackson D. , Jena Prakrit V. , Ramanathan Lakshmi V. , Jaimes Edgar A. , Heller Daniel A.
Published: August 2019

Microalbuminuria is an important clinical marker of several cardiovascular, metabolic, and other diseases such as diabetes, hypertension, atherosclerosis, and cancer. The accurate detection of microalbuminuria relies on albumin quantification in the urine, usually via an immunoturbidity assay; however, like many antibody-based assessments, this method may not be robust enough to function in global health applications, point-of-care assays, or wearable devices. Here, we develop an antibody-free approach using synthetic molecular recognition by constructing a polymer to mimic fatty acid binding to the albumin, informed by the albumin crystal structure. A single-walled carbon nanotube, encapsulated by the polymer, as the transduction element produces a hypsochromic (blue) shift in photoluminescence upon the binding of albumin in clinical urine samples. This complex, incorporated into an acrylic material, results in a nanosensor paint that enables the detection of microalbuminuria in patient samples and comprises a rapid point-of-care sensor robust enough to be deployed in resource-limited settings.
Tunable giant magnetoresistance in a single-molecule junction
Authors: Yang Kai , Chen Hui , Pope Thomas , Hu Yibin , Liu Liwei , Wang Dongfei , Tao Lei , Xiao Wende , Fei Xiangmin , Zhang Yu-Yang , Luo Hong-Gang , Du Shixuan , Xiang Tao , Hofer Werner A. , Gao Hong-Jun
Published: August 2019

Controlling electronic transport through a single-molecule junction is crucial for molecular electronics or spintronics. In magnetic molecular devices, the spin degree-of-freedom can be used to this end since the magnetic properties of the magnetic ion centers fundamentally impact the transport through the molecules. Here we demonstrate that the electron pathway in a single-molecule device can be selected between two molecular orbitals by varying a magnetic field, giving rise to a tunable anisotropic magnetoresistance up to 93%. The unique tunability of the electron pathways is due to the magnetic reorientation of the transition metal center, resulting in a re-hybridization of molecular orbitals. We obtain the tunneling electron pathways by Kondo effect, which manifests either as a peak or a dip line shape. The energy changes of these spin-reorientations are remarkably low and less than one millielectronvolt. The large tunable anisotropic magnetoresistance could be used to control electronic transport in molecular spintronics.
A STAT3-based gene signature stratifies glioma patients for targeted therapy
Authors: Tan Melanie Si Yan , Sandanaraj Edwin , Chong Yuk Kien , Lim See Wee , Koh Lynnette Wei Hsien , Ng Wai Hoe , Tan Nguan Soon , Tan Patrick , Ang Beng Ti , Tang Carol
Published: August 2019

Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition. We first establish a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigates STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. We show the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitizes STAT3-low cells and improves survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching.
Antimicrobial properties of the novel bacterial isolate Paenibacilllus sp. SMB1 from a halo-alkaline lake in India
Authors: Singh Harjodh , Kaur Manpreet , Jangra Manoj , Mishra Sunita , Nandanwar Hemraj , Pinnaka Anil Kumar
Published: August 2019

Antibiotic-resistance is ever growing burden on our society for the past many years. Many synthetic chemistry approaches and rational drug-design have been unable to pace up and tackle this problem. Natural resources, more specifically, the microbial diversity, on the other hand, make a traditional and still the best platform to search for new chemical scaffolds and compounds. Here, we report the antimicrobial characteristics of novel bacterial isolate from a salt lake in India. We screened the bacterial isolates for their inhibitory activity against indicator bacteria and found that four novel species were able to prevent the growth of test strains studied in vitro. Further, we characterized one novel species (SMB1T = SL4-2) using polyphasic taxonomic approaches and also purified the active ingredient from this bacterium. We successfully characterized the antimicrobial compound using mass spectroscopy and amino acid analysis. We also allocated two novel biosynthetic gene clusters for putative bacteriocins and one novel non-ribosomal peptide gene cluster in its whole genome. We concluded that the strain SMB1T belonged to the genus Paenibacilllus with the pairwise sequence similarity of 98.67% with Paenibacillus tarimensis DSM 19409T and we proposed the name Paenibacillus sambharensis sp. nov. The type strain is SMB1T (=MTCC 12884 = KCTC 33895T).