bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translationally controlled tumor protein (TCTP) plays a pivotal role in cardiomyocyte survival through a Bnip3-dependent mechanism
Authors: Cai Wenqian , Fujita Takayuki , Hidaka Yuko , Jin Huiling , Suita Kenji , Shigeta Mayo , Kiyonari Hiroshi , Umemura Masanari , Yokoyama Utako , Sadoshima Junichi , Ishikawa Yoshihiro 
Published: July 2019

AbstractPrevention of cardiomyocyte death is an important therapeutic strategy for heart failure. In this study, we focused on translationally controlled tumor protein (TCTP), a highly conserved protein that is expressed ubiquitously in mammalian tissues, including heart. TCTP plays pivotal roles in survival of certain cell types, but its function in cardiomyocytes has not been examined. We aimed to clarify the role of TCTP in cardiomyocyte survival and the underlying mechanism. Here, we demonstrated that downregulation of TCTP with siRNA induced cell death of cardiomyocytes with apoptotic and autophagic features, accompanied with mitochondrial permeability transition pore (mPTP) opening. TCTP loss did not induce cell death of cardiac fibroblasts. Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) was found to mediate the TCTP-loss-induced cardiomyocyte death. In exploring the clinical significance of the TCTP expression in the heart, we found that DOX treatment markedly downregulated the protein expression of TCTP in cultured cardiomyocytes and in mouse heart tissue. Exogenous rescue of TCTP expression attenuated DOX-induced cardiomyocyte death. In mice, cardiomyocyte-specific overexpression of TCTP resulted in decreased susceptibility to DOX-induced cardiac dysfunction, accompanied with attenuated induction of Bnip3. Dihydroartemisinin, a pharmacological TCTP inhibitor, induced development of heart failure and cardiomyocyte death in control mice, but not in mice with cardiomyocyte-specific TCTP overexpression. Our findings revealed TCTP has a pivotal role in cardiomyocyte survival, at least in part through a Bnip3-dependent mechanism. TCTP could be considered as a candidate therapeutic target to prevent DOX-induced heart failure.
Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells
Authors: Chandra Goutam , Defour Aurelia , Mamchoui Kamel , Pandey Kalpana , Mishra Soumya , Mouly Vincent , Sreetama SenChandra , Mahad Ahmad Mohammad , Mahjneh Ibrahim , Morizono Hiroki , Pattabiraman Nagarajan , Menon Anant K. , Jaiswal Jyoti K. 
Published: July 2019

AbstractAutosomal recessive mutations in Anoctamin 5 (ANO5/TMEM16E), a member of the transmembrane 16 (TMEM16) family of Ca2+-activated ion channels and phospholipid scramblases, cause adult-onset muscular dystrophies (limb girdle muscular dystrophy 2L (LGMD2L) and Miyoshi Muscular Dystrophy (MMD3). However, the molecular role of ANO5 is unclear and ANO5 knockout mouse models show conflicting requirements of ANO5 in muscle. To study the role of ANO5 in human muscle cells we generated a myoblast line from a MMD3-patient carrying the c.2272C>T mutation, which we find causes the mutant protein to be degraded. The patient myoblasts exhibit normal myogenesis, but are compromised in their plasma membrane repair (PMR) ability. The repair deficit is linked to the poor ability of the endoplasmic reticulum (ER) to clear cytosolic Ca2+ increase caused by focal plasma membrane injury. Expression of wild-type ANO5 or pharmacological prevention of injury-triggered cytosolic Ca2+ overload enable injured patient muscle cells to repair. A homology model of ANO5 shows that several of the known LGMD2L/MMD3 patient mutations line the transmembrane region of the protein implicated in its channel activity. These results point to a role of cytosolic Ca2+ homeostasis in PMR, indicate a role for ANO5 in ER-mediated cytosolic Ca2+ uptake and identify normalization of cytosolic Ca2+ homeostasis as a potential therapeutic approach to treat muscular dystrophies caused by ANO5 deficit.
Relationship between duration and extent of oedema and visual acuity outcome with ranibizumab in diabetic macular oedema: A post hoc analysis of Protocol I data
Authors: Sadda Srinivas R. , Campbell Joanna , Dugel Pravin U. , Holekamp Nancy M. , Kiss Szilárd , Loewenstein Anat , Augustin Albert J. , Shih Vanessa , Xu Xiaoshu , Wykoff Charles C. , Whitcup Scott M. 
Published: July 2019

Abstract
Background/objectives
This post hoc analysis explores the relationship between residual oedema exposure after ranibizumab treatment initiation and long-term visual acuity outcome in eyes with centre-involved diabetic macular oedema (DMO).

Subjects/methods
Eyes randomised to the ranibizumab + prompt or deferred laser treatment arms in the Protocol I trial and with observed central retinal thickness (CRT) readings at baseline and ≥1 follow-up visits (n = 367) were stratified by 1) oedema duration (number of study visits with CRT ≥ 250 µm during the first 52 weeks of ranibizumab treatment); and 2) oedema extent (amount of excess CRT [≥ 250 µm] at each study visit, averaged over the first 52 weeks). Associations between measures of residual oedema and best-corrected visual acuity (BCVA) were assessed in multiple regression analyses.

Results
Oedema duration and oedema extent during the first 52 weeks of ranibizumab treatment showed significant negative associations with BCVA improvement at weeks 52, 104 and 156. Eyes with the most persistent oedema gained (mean) 4.4 (95% CI 0.1─8.7) fewer Early Treatment Diabetic Retinopathy Study (ETDRS) letters at week 156 than eyes with the least persistent oedema (P = 0.044). Eyes with the greatest amount of oedema gained (mean) 9.3 (95% CI 4.0─14.5) fewer ETDRS letters at week 156 than eyes with the least amount of oedema (P < 0.001).

Conclusions
Macular oedema exposure over the first 52 weeks of ranibizumab treatment is a negative prognostic factor for long-term visual acuity improvement in centre-involved DMO.
Three-dimensional view of ultrafast dynamics in photoexcited bacteriorhodopsin
Authors: Nass Kovacs Gabriela , Colletier Jacques-Philippe , Grünbein Marie Luise , Yang Yang , Stensitzki Till , Batyuk Alexander , Carbajo Sergio , Doak R. Bruce , Ehrenberg David , Foucar Lutz , Gasper Raphael , Gorel Alexander , Hilpert Mario , Kloos Marco , Koglin Jason E. , Reinstein Jochen , Roome Christopher M. , Schlesinger Ramona , Seaberg Matthew , Shoeman Robert L. , Stricker Miriam , Boutet Sébastien , Haacke Stefan , Heberle Joachim , Heyne Karsten , Domratcheva Tatiana , Barends Thomas R. M. , Schlichting Ilme 
Published: July 2019

AbstractBacteriorhodopsin (bR) is a light-driven proton pump. The primary photochemical event upon light absorption is isomerization of the retinal chromophore. Here we used time-resolved crystallography at an X-ray free-electron laser to follow the structural changes in multiphoton-excited bR from 250 femtoseconds to 10 picoseconds. Quantum chemistry and ultrafast spectroscopy were used to identify a sequential two-photon absorption process, leading to excitation of a tryptophan residue flanking the retinal chromophore, as a first manifestation of multiphoton effects. We resolve distinct stages in the structural dynamics of the all-trans retinal in photoexcited bR to a highly twisted 13-cis conformation. Other active site sub-picosecond rearrangements include correlated vibrational motions of the electronically excited retinal chromophore, the surrounding amino acids and water molecules as well as their hydrogen bonding network. These results show that this extended photo-active network forms an electronically and vibrationally coupled system in bR, and most likely in all retinal proteins.
The post-abscission midbody is an intracellular signaling organelle that regulates cell proliferation
Authors: Peterman Eric , Gibieža Paulius , Schafer Johnathon , Skeberdis Vytenis Arvydas , Kaupinis Algirdas , Valius Mindaugas , Heiligenstein Xavier , Hurbain Ilse , Raposo Graca , Prekeris Rytis 
Published: July 2019

AbstractOnce thought to be a remnant of cell division, the midbody (MB) has recently been shown to have roles beyond its primary function of orchestrating abscission. Despite the emerging roles of post-abscission MBs, how MBs accumulate in the cytoplasm and signal to regulate cellular functions remains unknown. Here, we show that extracellular post-abscission MBs can be internalized by interphase cells, where they reside in the cytoplasm as a membrane-bound signaling structure that we have named the MBsome. We demonstrate that MBsomes stimulate cell proliferation and that MBsome formation is a phagocytosis-like process that depends on a phosphatidylserine/integrin complex, driven by actin-rich membrane protrusions. Finally, we show that MBsomes rely on dynamic actin coats to slow lysosomal degradation and propagate their signaling function. In summary, MBsomes may sometimes serve as intracellular organelles that signal via integrin and EGFR-dependent pathways to promote cell proliferation and anchorage-independent growth and survival.
Mixed topological semimetals driven by orbital complexity in two-dimensional ferromagnets
Authors: Niu Chengwang , Hanke Jan-Philipp , Buhl Patrick M. , Zhang Hongbin , Plucinski Lukasz , Wortmann Daniel , Blügel Stefan , Bihlmayer Gustav , Mokrousov Yuriy 
Published: July 2019

AbstractThe concepts of Weyl fermions and topological semimetals emerging in three-dimensional momentum space are extensively explored owing to the vast variety of exotic properties that they give rise to. On the other hand, very little is known about semimetallic states emerging in two-dimensional magnetic materials, which present the foundation for both present and future information technology. Here, we demonstrate that including the magnetization direction into the topological analysis allows for a natural classification of topological semimetallic states that manifest in two-dimensional ferromagnets as a result of the interplay between spin-orbit and exchange interactions. We explore the emergence and stability of such mixed topological semimetals in realistic materials, and point out the perspectives of mixed topological states for current-induced orbital magnetism and current-induced domain wall motion. Our findings pave the way to understanding, engineering and utilizing topological semimetallic states in two-dimensional spin-orbit ferromagnets.
Genomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases
Authors: Sun Jing , Wang Cheng , Zhang Yi , Xu Lingyan , Fang Weijia , Zhu Yuping , Zheng Yi , Chen Xiaofeng , Xie Xiju , Hu Xinhua , Hu Weidong , Zheng Jingyu , Li Ping , Yu Jian , Mei Zhu , Cai Xiaomin , Wang Biao , Hu Zhibin , Shu Yongqian , Shen Hongbing , Gu Yanhong 
Published: July 2019

AbstractBrain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue. Compared with primary CRC, BM exhibits elevated mutational signatures of homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRD). Further analysis reveals two DNA damage response (DDR) signatures could emerge early and are enhanced in BM tissues but are eliminated eventually in matched primary CRC tissues. BM-specific mutations in DDR genes and elevated microsatellite instability (MSI) levels support the importance of DDR in the brain metastasis of CRC. We also identify BM-related genes (e.g., SCN7A, SCN5A, SCN2A, IKZF1, and PDZRN4) that carry frequent BM-specific mutations. These results provide a better understanding of the BM mutational landscape and insights into treatment.
Multicenter study demonstrates radiomic features derived from magnetic resonance perfusion images identify pseudoprogression in glioblastoma
Authors: Elshafeey Nabil , Kotrotsou Aikaterini , Hassan Ahmed , Elshafei Nancy , Hassan Islam , Ahmed Sara , Abrol Srishti , Agarwal Anand , El Salek Kamel , Bergamaschi Samuel , Acharya Jay , Moron Fanny E. , Law Meng , Fuller Gregory N. , Huse Jason T. , Zinn Pascal O. , Colen Rivka R. 
Published: July 2019

AbstractPseudoprogression (PsP) is a diagnostic clinical dilemma in cancer. In this study, we retrospectively analyse glioblastoma patients, and using their dynamic susceptibility contrast and dynamic contrast-enhanced perfusion MRI images we build a classifier using radiomic features obtained from both Ktrans and rCBV maps coupled with support vector machines. We achieve an accuracy of 90.82% (area under the curve (AUC) = 89.10%, sensitivity = 91.36%, 67 specificity = 88.24%, p = 0.017) in differentiating between pseudoprogression (PsP) and progressive disease (PD). The diagnostic performances of the models built using radiomic features from Ktrans and rCBV separately were equally high (Ktrans: AUC = 94%, 69 p = 0.012; rCBV: AUC = 89.8%, p = 0.004). Thus, this MR perfusion-based radiomic model demonstrates high accuracy, sensitivity and specificity in discriminating PsP from PD, thus provides a reliable alternative for noninvasive identification of PsP versus PD at the time of clinical/radiologic question. This study also illustrates the successful application of radiomic analysis as an advanced processing step on different MR perfusion maps.
Mechanism of superconductivity and electron-hole doping asymmetry in κ-type molecular conductors
Authors: Watanabe Hiroshi , Seo Hitoshi , Yunoki Seiji 
Published: July 2019

AbstractUnconventional superconductivity in molecular conductors is observed at the border of metal-insulator transitions in correlated electrons under the influence of geometrical frustration. The symmetry as well as the mechanism of the superconductivity (SC) is highly controversial. To address this issue, we theoretically explore the electronic properties of carrier-doped molecular Mott system κ-(BEDT-TTF)2X. We find significant electron-hole doping asymmetry in the phase diagram where antiferromagnetic (AF) spin order, different patterns of charge order, and SC compete with each other. Hole-doping stabilizes AF phase and promotes SC with dxy-wave symmetry, which has similarities with high-Tc cuprates. In contrast, in the electron-doped side, geometrical frustration destabilizes the AF phase and the enhanced charge correlation induces another SC with extended-s + $$d_{x^2 - y^2}$$

d

x

2

-

y

2

wave symmetry. Our results disclose the mechanism of each phase appearing in filling-control molecular Mott systems, and elucidate how physics of different strongly-correlated electrons are connected, namely, molecular conductors and high-Tc cuprates.
Multifunctional cationic nanosystems for nucleic acid therapy of thoracic aortic dissection
Authors: Xu Chen , Zhang Yanzhenzi , Xu Ke , Nie Jing-Jun , Yu Bingran , Li Sijin , Cheng Gang , Li Yulin , Du Jie , Xu Fu-Jian 
Published: July 2019

AbstractThoracic aortic dissection (TAD) is an aggressive vascular disease that requires early diagnosis and effective treatment. However, due to the particular vascular structure and narrowness of lesion location, there are no effective drug delivery systems for the therapy of TAD. Here, we report a multifunctional delivery nanosystem (TP-Gd/miRNA-ColIV) composed of gadolinium-chelated tannic acid (TA), low-toxic cationic PGEA (ethanolamine-aminated poly(glycidyl methacrylate)) and type IV collagen targeted peptide (ColIV) for targeted nucleic acid therapy, early diagnosis and noninvasive monitoring of TAD. Such targeted therapy with miR-145 exhibits impressive performances in stabilizing the vascular structures and preventing the deterioration of TAD. After the treatment with TP-Gd/miR-145-ColIV, nearly no dissection occurs in the thoracic aortic arches of the mice with TAD model. Moreover, TP-Gd/miRNA-ColIV also demonstrates good magnetic resonance imaging (MRI) ability and can be used to noninvasively monitor the development conditions of TAD.
Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP
Authors: Abdul Azeez Kamal R. , Chatterjee Sneha , Yu Channing , Golub Todd R. , Sobott Frank , Elkins Jonathan M. 
Published: July 2019

AbstractAurora kinases B and C (AURKB/AURKC) are activated by binding to the C-terminal domain of INCENP. Full activation requires phosphorylation of two serine residues of INCENP that are conserved through evolution, although the mechanism of this activation has not been explained. Here we present crystal structures of the fully active complex of AURKC bound to INCENP, consisting of phosphorylated, activated, AURKC and INCENP phosphorylated on its TSS motif, revealing the structural and biochemical mechanism of synergistic activation of AURKC:INCENP. The structures show that TSS motif phosphorylation stabilises the kinase activation loop of AURKC. The TSS motif phosphorylations alter the substrate-binding surface consistent with a mechanism of altered kinase substrate selectivity and stabilisation of the protein complex against unfolding. We also analyse the binding of the most specific available AURKB inhibitor, BRD-7880, and demonstrate that the well-known Aurora kinase inhibitor VX-680 disrupts binding of the phosphorylated INCENP TSS motif.
Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life
Authors: Pineault Kyriel M. , Song Jane Y. , Kozloff Kenneth M. , Lucas Daniel , Wellik Deneen M. 
Published: July 2019

AbstractMultipotent mesenchymal stromal cells (MSCs) are required for skeletal formation, maintenance, and repair throughout life; however, current models posit that postnatally arising long-lived adult MSCs replace transient embryonic progenitor populations. We previously reported exclusive expression and function of the embryonic patterning transcription factor, Hoxa11, in adult skeletal progenitor-enriched MSCs. Here, using a newly generated Hoxa11-CreERT2 lineage-tracing system, we show Hoxa11-lineage marked cells give rise to all skeletal lineages throughout the life of the animal and persist as MSCs. Hoxa11 lineage-positive cells give rise to previously described progenitor-enriched MSC populations marked by LepR-Cre and Osx-CreER, placing them upstream of these populations. Our studies establish that Hox-expressing cells are skeletal stem cells that arise from the earliest stages of skeletal development and self-renew throughout the life of the animal.
Controls of soil organic matter on soil thermal dynamics in the northern high latitudes
Authors: Zhu Dan , Ciais Philippe , Krinner Gerhard , Maignan Fabienne , Jornet Puig Albert , Hugelius Gustaf 
Published: July 2019

AbstractPermafrost warming and potential soil carbon (SOC) release after thawing may amplify climate change, yet model estimates of present-day and future permafrost extent vary widely, partly due to uncertainties in simulated soil temperature. Here, we derive thermal diffusivity, a key parameter in the soil thermal regime, from depth-specific measurements of monthly soil temperature at about 200 sites in the high latitude regions. We find that, among the tested soil properties including SOC, soil texture, bulk density, and soil moisture, SOC is the dominant factor controlling the variability of diffusivity among sites. Analysis of the CMIP5 model outputs reveals that the parameterization of thermal diffusivity drives the differences in simulated present-day permafrost extent among these models. The strong SOC-thermics coupling is crucial for projecting future permafrost dynamics, since the response of soil temperature and permafrost area to a rising air temperature would be impacted by potential changes in SOC.
Empirical mean-noise fitness landscapes reveal the fitness impact of gene expression noise
Authors: Schmiedel Jörn M. , Carey Lucas B. , Lehner Ben 
Published: July 2019

AbstractThe effects of cell-to-cell variation (noise) in gene expression have proven difficult to quantify because of the mechanistic coupling of noise to mean expression. To independently quantify the effects of changes in mean expression and noise we determine the fitness landscapes in mean-noise expression space for 33 genes in yeast. For most genes, short-lived (noise) deviations away from the expression optimum are nearly as detrimental as sustained (mean) deviations. Fitness landscapes can be classified by a combination of each gene’s sensitivity to protein shortage or surplus. We use this classification to explore evolutionary scenarios for gene expression and find that certain landscape topologies can break the mechanistic coupling of mean and noise, thus promoting independent optimization of both properties. These results demonstrate that noise is detrimental for many genes and reveal non-trivial consequences of mean-noise-fitness topologies for the evolution of gene expression systems.
Divergent synthesis of chiral cyclic azides via asymmetric cycloaddition reactions of vinyl azides
Authors: Thirupathi Nuligonda , Wei Fang , Tung Chen-Ho , Xu Zhenghu 
Published: July 2019

AbstractVinyl azides, bearing conjugated azide and alkene functional groups, have been recognized as versatile building blocks in organic synthesis. In general vinyl azides act as 3-atom (CCN) synthons through the fast release of molecular nitrogen and have been extensively utilized in the construction of structurally diverse N-heterocycles. Keeping the azide moiety intact in organic transformations to synthesis chiral azides is an important but challenging task. Herein, we report an enantioselective copper(II)/BOX-catalyzed cycloaddition of vinyl azides, generating diverse chiral cyclic azides. α-Aryl substituted vinyl azides react with unsaturated keto esters through an inverse-electron-demand hetero-Diels-Alder reaction to afford chiral azido dihydropyrans with excellent enatioselectivities. In contrast, cyclohexenyl azides undergo a diastereo- and enantio-selective Diels-Alder reaction giving important azido octahydronaphthalenes with three continuous stereogenic centers. Notable features of these reactions include a very broad scope, mild reaction conditions and 100% atom economy.
Multifunctional and biodegradable self-propelled protein motors
Authors: Pena-Francesch Abdon , Giltinan Joshua , Sitti Metin 
Published: July 2019

AbstractA diversity of self-propelled chemical motors, based on Marangoni propulsive forces, has been developed in recent years. However, most motors are non-functional due to poor performance, a lack of control, and the use of toxic materials. To overcome these limitations, we have developed multifunctional and biodegradable self-propelled motors from squid-derived proteins and an anesthetic metabolite. The protein motors surpass previous reports in performance output and efficiency by several orders of magnitude, and they offer control of their propulsion modes, speed, mobility lifetime, and directionality by regulating the protein nanostructure via local and external stimuli, resulting in programmable and complex locomotion. We demonstrate diverse functionalities of these motors in environmental remediation, microrobot powering, and cargo delivery applications. These versatile and degradable protein motors enable design, control, and actuation strategies in microrobotics as modular propulsion sources for autonomous minimally invasive medical operations in biological environments with air-liquid interfaces.