bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vps34-mediated macropinocytosis in Tuberous Sclerosis Complex 2-deficient cells supports tumorigenesis
Authors: Filippakis Harilaos , Belaid Amine , Siroky Brian , Wu Constance , Alesi Nicola , Hougard Thomas , Nijmeh Julie , Lam Hilaire C. , Henske Elizabeth P. 
Published: September 2018

AbstractTuberous Sclerosis Complex (TSC), a rare genetic disorder with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivation, is characterized by multi-organ hamartomatous benign tumors including brain, skin, kidney, and lung (Lymphangioleiomyomatosis). mTORC1 hyperactivation drives metabolic reprogramming including glucose and glutamine utilization, protein, nucleic acid and lipid synthesis. To investigate the mechanisms of exogenous nutrients uptake in Tsc2-deficient cells, we measured dextran uptake, a polysaccharide internalized via macropinocytosis. Tsc2-deficient cells showed a striking increase in dextran uptake (3-fold, p < 0.0001) relative to Tsc2-expressing cells, which was decreased (3-fold, p < 0.0001) with mTOR inhibitor, Torin1. Pharmacologic and genetic inhibition of the lipid kinase Vps34 markedly abrogated uptake of Dextran in Tsc2-deficient cells. Macropinocytosis was further increased in Tsc2-deficient cells that lack autophagic mechanisms, suggesting that autophagy inhibition leads to dependence on exogenous nutrient uptake in Tsc2-deficient cells. Treatment with a macropinocytosis inhibitor, ethylisopropylamiloride (EIPA), resulted in selective growth inhibition of Atg5-deficient, Tsc2-deficient cells (50%, p < 0.0001). Genetic inhibition of autophagy (Atg5−/− MEFs) sensitized cells with Tsc2 downregulation to the Vps34 inhibitor, SAR405, resulting in growth inhibition (75%, p < 0.0001). Finally, genetic downregulation of Vps34 inhibited tumor growth and increased tumor latency in an in vivo xenograft model of TSC. Our findings show that macropinocytosis is upregulated with Tsc2-deficiency via a Vps34-dependent mechanism to support their anabolic state. The dependence of Tsc2-deficient cells on exogenous nutrients may provide novel approaches for the treatment of TSC.
New transgenic NIS reporter rats for longitudinal tracking of fibrogenesis by high-resolution imaging
Authors: Brunton Bethany , Suksanpaisan Lukkana , Li Hongtao , Liu Qian , Yu Yinxian , Vrieze Alyssa , Zhang Lianwen , Jenks Nathan , Jiang Huailei , DeGrado Timothy R. , Zhao Chunfeng , Russell Stephen J. , Peng Kah-Whye 
Published: September 2018

AbstractFibrogenesis is the underlying mechanism of wound healing and repair. Animal models that enable longitudinal monitoring of fibrogenesis are needed to improve traditional tissue analysis post-mortem. Here, we generated transgenic reporter rats expressing the sodium iodide symporter (NIS) driven by the rat collagen type-1 alpha-1 (Col1α1) promoter and demonstrated that fibrogenesis can be visualized over time using SPECT or PET imaging following activation of NIS expression by rotator cuff (RC) injury. Radiotracer uptake was first detected in and around the injury site day 3 following surgery, increasing through day 7–14, and declining by day 21, revealing for the first time, the kinetics of Col1α1 promoter activity in situ. Differences in the intensity and duration of NIS expression/collagen promoter activation between individual RC injured Col1α1-hNIS rats were evident. Dexamethasone treatment delayed time to peak NIS signals, showing that modulation of fibrogenesis by a steroid can be imaged with exquisite sensitivity and resolution in living animals. NIS reporter rats would facilitate studies in physiological wound repair and pathological processes such as fibrosis and the development of anti-fibrotic drugs.
Steeper structure-function relationship in eyes with than without a parapapillary deep-layer microvasculature dropout
Authors: Kim Ji-Ah , Lee Eun Ji , Kim Hyunjoong , Kim Tae-Woo 
Published: September 2018

AbstractThe degree of visual field (VF) loss can vary widely at a given level of retinal nerve fiber layer (RNFL) thickness. The cause of this variability is not fully understood. This cross-sectional study investigated whether the presence of choroidal microvasculature dropout (MvD) influences on the structure-function relationship among glaucomatous eyes. Seventy-one primary open-angle glaucoma (POAG) patients with choroidal MvD as determined by optical coherence tomography angiography (MvD+ group), and 71 age- and inferotemporal (IT) RNFL thickness-matched POAG patients without MvD (MvD– group) were included. VF sensitivity within the region corresponding to the IT RNFL sector was averaged using the total and pattern deviation fields. The slope of log-scale RNFL thickness versus VF defect was significantly steeper for the MvD+ than the MvD– group, as determined by both total and pattern deviation maps (P = 0.004 and <0.001, respectively). Both total and pattern VF deviation were significantly worse in the MvD+ than in the MvD– group (P = 0.002 and 0.007, respectively). Same results were obtained in subgroup analyses for eyes with thick and thin RNFL thickness (all P ≤ 0.027). These data suggest that parapapillary MvD is associated with poorer function of the remaining axons in eyes with POAG.
HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver
Authors: Arai Takatomo , Tanaka Masako , Goda Nobuhito 
Published: September 2018

AbstractAdaptive responses to hypoxia regulate hepatic lipid metabolism, but their consequences in nonalcoholic fatty liver disease (NAFLD) are largely unknown. Here, we show that hypoxia inducible factor-1 (HIF-1), a key determinant of hypoxic adaptations, prevents excessive hepatic lipid accumulation in the progression of NAFLD. When exposed to a choline-deficient diet (CDD) for 4 weeks, the loss of hepatic Hif-1α gene accelerated liver steatosis with enhanced triglyceride accumulation in the liver compared to wild-type (WT) livers. Expression of genes involved in peroxisomal fatty acid oxidation was suppressed significantly in CDD-treated WT livers, whereas this reduction was further enhanced in Hif-1α-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPARα/PGC-1α pathway, could be attributed to impaired peroxisomal β-oxidation in Hif-1α-deficient livers. The lipin1-mediated binding of PPARα to the acyl CoA oxidase promoter was markedly reduced in Hif-1α-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1α deletion in cells incubated in a choline-deficient medium. These results strongly suggest that HIF-1 plays a crucial role in the regulation of peroxisomal lipid metabolism by activating the expression and nuclear accumulation of lipin1 in NAFLD.
Robust metric for quantifying the importance of stochastic effects on nanoparticle growth
Authors: Olenius Tinja , Pichelstorfer Lukas , Stolzenburg Dominik , Winkler Paul M. , Lehtinen Kari E. J. , Riipinen Ilona 
Published: September 2018

AbstractComprehensive representation of nanoparticle dynamics is necessary for understanding nucleation and growth phenomena. This is critical in atmospheric physics, as airborne particles formed from vapors have significant but highly uncertain effects on climate. While the vapor–particle mass exchange driving particle growth can be described by a macroscopic, continuous substance for large enough particles, the growth dynamics of the smallest nanoparticles involve stochastic fluctuations in particle size due to discrete molecular collision and decay processes. To date, there have been no generalizable methods for quantifying the particle size regime where the discrete effects become negligible and condensation models can be applied. By discrete simulations of sub-10 nm particle populations, we demonstrate the importance of stochastic effects in the nanometer size range. We derive a novel, theory-based, simple and robust metric for identifying the exact sizes where these effects cannot be omitted for arbitrary molecular systems. The presented metric, based on examining the second- and first-order derivatives of the particle size distribution function, is directly applicable to experimental size distribution data. This tool enables quantifying the onset of condensational growth without prior information on the properties of the vapors and particles, thus allowing robust experimental resolving of nanoparticle formation physics.
Differential expression of the adult specifier E93 in the strepsipteran Xenos vesparum Rossi suggests a role in female neoteny
Authors: Chafino S. , López-Escardó D. , Benelli G. , Kovac H. , Casacuberta E. , Franch-Marro X. , Kathirithamby J. , Martín D. 
Published: September 2018

AbstractHolometaboly is a key evolutionary innovation that has facilitated the spectacular radiation of insects. Despite the undeniable advantage of complete metamorphosis, the female of some holometabolous species have lost the typical holometabolous development through neoteny. In Xenos vesparum Rossi (Strepsiptera: Stylopidae), a derived species of the holometabolous endoparasitic order Strepsiptera, neotenic females reach sexual maturity without the pupal and the imaginal stages, thus retaining their larval morphology (with the exception of the anterior part of the body or cephalothorax), while males undergo normal pupal-based metamorphosis. Expression of the “adult-specifier” E93 factor has been shown to be required for proper metamorphosis in holometabolous insects. Here, we investigated the involvement of E93 in female neoteny by cloning XvE93. Interestingly, while we detected a clear up-regulation of XvE93 expression in pupal and adult stages of males, persistent low levels of XvE93 were detected in X. vesparum females. However, a specific up-regulation of XvE93 was observed in the cephalothorax of late 4th female instar larva, which correlates with the occurrence of neotenic-specific features in the anterior part of the female body. Moreover, the same expression dynamic in the cephalothorax and abdomen was also observed for other two critical metamorphic regulators, the anti-metamorphic XvKr-h1 and the pupal specifier XvBr-C. The specific up-regulation of XvE93 and XvBr-C in the female cephalothorax seems to be the result of an increase in 20-hydroxyecdysone (20E) signaling in this region for we detected higher expression levels of the 20E-dependent nuclear receptors XvHR3 and XvE75 in the cephalothorax. Overall, our results detect a sex-specific expression pattern of critical metamorphic genes in X. vesparum, suggesting that neoteny in Strepsiptera results from the modification of the normal expression of E93, Br-C and Kr-h1 genes.
Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans
Authors: Yen Kelvin , Wan Junxiang , Mehta Hemal H. , Miller Brendan , Christensen Amy , Levine Morgan E. , Salomon Matthew P. , Brandhorst Sebastian , Xiao Jialin , Kim Su-Jeong , Navarrete Gerardo , Campo Daniel , Harry G. Jean , Longo Valter , Pike Christian J. , Mack Wendy J. , Hodis Howard N. , Crimmins Eileen M. , Cohen Pinchas 
Published: September 2018

AbstractAdvanced age is associated with a decline in cognitive function, likely caused by a combination of modifiable and non-modifiable factors such as genetics and lifestyle choices. Mounting evidence suggests that humanin and other mitochondrial derived peptides play a role in several age-related conditions including neurodegenerative disease. Here we demonstrate that humanin administration has neuroprotective effects in vitro in human cell culture models and is sufficient to improve cognition in vivo in aged mice. Furthermore, in a human cohort, using mitochondrial GWAS, we identified a specific SNP (rs2854128) in the humanin-coding region of the mitochondrial genome that is associated with a decrease in circulating humanin levels. In a large, independent cohort, consisting of a nationally-representative sample of older adults, we find that this SNP is associated with accelerated cognitive aging, supporting the concept that humanin is an important factor in cognitive aging.
Comprehensive Evolutionary Analysis of the Major RNA-Induced Silencing Complex Members
Authors: Zhang Rui , Jing Ying , Zhang Haiyang , Niu Yahan , Liu Chang , Wang Jin , Zen Ke , Zhang Chen-Yu , Li Donghai 
Published: September 2018

AbstractRNA-induced silencing complex (RISC) plays a critical role in small interfering RNA (siRNA) and microRNAs (miRNA) pathways. Accumulating evidence has demonstrated that the major RISC members (AGO, DICER, TRBP, PACT and GW182) represent expression discrepancies or multiple orthologues/paralogues in different species. To elucidate their evolutionary characteristics, an integrated evolutionary analysis was performed. Here, animal and plant AGOs were divided into three classes (multifunctional AGOs, siRNA-associated AGOs and piRNA-associated AGOs for animal AGOs and multifunctional AGOs, siRNA-associated AGOs and complementary functioning AGOs for plant AGOs). Animal and plant DICERs were grouped into one class (multifunctional DICERs) and two classes (multifunctional DICERs and siRNA-associated DICERs), respectively. Protista/fungi AGOs or DICERs were specifically associated with the siRNA pathway. Additionally, TRBP/PACT/GW182 were identified only in animals, and all of them functioned in the miRNA pathway. Mammalian AGOs, animal DICERs and chordate TRBP/PACT were found to be monophyletic. A large number of gene duplications were identified in AGO and DICER groups. Taken together, we provide a comprehensive evolutionary analysis, describe a phylogenetic tree-based classification of the major RISC members and quantify their gene duplication events. These findings are potentially useful for classifying RISCs, optimizing species-specific RISCs and developing research model organisms.
Machine learning inverse problem for topological photonics
Authors: Pilozzi Laura , Farrelly Francis A. , Marcucci Giulia , Conti Claudio 
Published: September 2018

AbstractTopology opens many new horizons for photonics, from integrated optics to lasers. The complexity of large-scale devices asks for an effective solution of the inverse problem: how best to engineer the topology for a specific application? We introduce a machine-learning approach applicable in general to numerous topological problems. As a toy model, we train a neural network with the Aubry–Andre–Harper band structure model and then adopt the network for solving the inverse problem. Our application is able to identify the parameters of a complex topological insulator in order to obtain protected edge states at target frequencies. One challenging aspect is handling the multivalued branches of the direct problem and discarding unphysical solutions. We overcome this problem by adopting a self-consistent method to only select physically relevant solutions. We demonstrate our technique in a realistic design and by resorting to the widely available open-source TensorFlow library.
Anisotropic turbulent transport in stably stratified rotating stellar radiation zones
Authors: Mathis S. , Prat V. , Amard L. , Charbonnel C. , Palacios A. , Lagarde N. , Eggenberger P. 
Published: September 2018

Context. Rotation is one of the key physical mechanisms that deeply impact the evolution of stars. Helio- and asteroseismology reveal a strong extraction of angular momentum from stellar radiation zones over the whole Hertzsprung–Russell diagram.
Aims. Turbulent transport in differentially rotating, stably stratified stellar radiation zones should be carefully modelled and its strength evaluated. Stratification and rotation imply that this turbulent transport is anisotropic. So far only phenomenological prescriptions have been proposed for the transport in the horizontal direction. This, however, constitutes a cornerstone in current theoretical formalisms for stellar hydrodynamics in evolution codes. We aim to improve its modelling.
Methods. We derived a new theoretical prescription for the anisotropy of the turbulent transport in radiation zones using a spectral formalism for turbulence that takes simultaneously stable stratification, rotation, and a radial shear into account. Then, the horizontal turbulent transport resulting from 3D turbulent motions sustained by the instability of the radial differential rotation is derived. We implemented this framework in the stellar evolution code STAREVOL and quantified its impact on the rotational and structural evolution of solar metallicity low-mass stars from the pre-main-sequence to the red giant branch.
Results. The anisotropy of the turbulent transport scales as N4τ2/(2Ω2), N and Ω being the buoyancy and rotation frequencies respectively and τ a time characterizing the source of turbulence. This leads to a horizontal turbulent transport of similar strength in average that those obtained with previously proposed prescriptions even if it can be locally larger below the convective envelope. Hence the models computed with the new formalism still build up too steep internal rotation gradients compared to helioseismic and asteroseismic constraints. As a consequence, a complementary transport mechanism such as internal gravity waves or magnetic fields is still needed to explain the observed strong transport of angular momentum along stellar evolution.
Conclusions. The new prescription links for the first time the anisotropy of the turbulent transport in radiation zones to their stratification and rotation. This constitutes important theoretical progress and demonstrates how turbulent closure models should be improved to get firm conclusions on the potential importance of other processes that transport angular momentum and chemicals inside stars along their evolution.
Stellenwert der Abdomensonografie in der Hämatologie
Authors: Trenker Corinna , Görg Christian , Jenssen Christian , Klein Stefan , Neubauer Andreas , Dietrich Christoph 
Published: September 2018

ZusammenfassungBei Erstdiagnose hämatologischer Systemerkrankungen liegen oft nur unspezifische Symptome vor, sodass eine Abdomensonografie häufig im Rahmen der primären Abklärung erfolgt. Die Detektion einer Splenomegalie und pathologischer Lymphome, aber auch anderer Befunde kann wertvolle Hinweise auf die Grunderkrankung geben. Auch bei vermuteten Lymphknotenvergrößerungen wird häufig primär eine Sonografie durchgeführt, die bei Nachweis lymphomverdächtiger Befunde in gleicher Sitzung ein initiales Staging ermöglicht und zur Planung des diagnostischen Vorgehens beiträgt. Aufgrund ihrer schnellen und auch bettseitigen Verfügbarkeit, fehlenden Strahlenbelastung sowie unlimitierten Wiederholbarkeit sind sonografische Untersuchungen auch in der initialen Abklärung von Anämie, Leukopenie, Leukozytose und Thrombozytopenie sowie bei hämatologischen Erkrankungen in der Detektion von Komplikationen, der Verlaufsbeobachtung und Nachsorge ein wertvolles diagnostisches Instrument.
Posterior Tibial Neuropathy Secondary to Pseudoaneurysm of the Proximal Segment of the Anterior Tibial Artery with Delayed Onset
Authors: Rahimizadeh Abolfazl , Davaee Manuchehr , Shariati Majid , Rahimizadeh Shaghayegh 
Published: September 2018

AbstractAnterior tibial artery is a nonvital artery which is one of the three arteries of the leg. This artery has a short proximal l segment in the popliteal region and a long segment in the anterior compartment of the leg designated as distal segment. With consideration of the deep location of the proximal segment in the popliteal fossa, it is less susceptible to trauma and subsequent formation of an aneurysm. On the contrary, the superficial long distal segment is more susceptible to trauma with high chance of pseudoaneurysm formation at the site of unrecognized injury. In this article, a 38-year-old military man being manifested about a decade after a trivial missile fragment injury with progressive posterior tibial neuropathy is presented. A giant pseudoaneurysm arising from the proximal segment of the anterior tibial artery was confirmed with angiography and the exact size of this pathology was documented with contrasted computed tomographic scan. The aneurysmal sac removal was accomplished after ligation of the corresponding artery proximal and distal to the sac followed by tibial nerve neurolysis which result in full recovery. In careful review we found that neither pseudoaneurysm arising from the proximal tibial artery nor posterior tibial neuropathy due to the compressive effect of the aneurysmal sac of this segment has been reported previously. Our primary purpose for reporting this case is not to describe the rarity of pseudoaneurysm formation at proximal segment of this artery but rather to describe delayed-onset posterior tibial vascular compressive neuropathy due to such an aneurysm. Eventually due to the potential sequel of a pseudoaneurysm, it is important for the surgeons to have high index of suspicion to prevent a missed or delayed diagnosis.
Concomitant Occlusive Vascular Lesions of Legs in Patients with Degenerative Lumbar Diseases: Do These Lesions Influence Treatment?
Authors: Lee Dong , Heo Dong , Cho Kyoung 
Published: September 2018

Background and Study Aims Vascular narrowing or obstruction reduces blood flow to the lower limbs during exercise or at rest. Symptoms may range from intermittent claudication to pain at rest. Narrowing of these arteries may produce pain in the buttocks, thighs, or legs. These symptoms may resemble those of lumbar radicular pain. Spine surgeons may overlook obstructive vascular lesions of the lower limbs in patients with lumbar degenerative diseases such as spinal stenosis and spondylolisthesis. We investigated the clinical and radiologic risk factors of concomitant vascular pathologic lesions in patients with degenerative lumbar diseases.
Materials and Methods If patients presented with a weak or absent dorsalis pedis artery pulse, edema of both legs, and a past history related to vascular lesions of the lower limbs, we evaluated the veins and arteries of the lower extremities using Doppler sonography. If abnormal vascular findings were detected, computed tomography angiography (CTA) of the lower extremities was performed. Radiologic and clinical risk factors of concomitant occlusive arterial lesions of the lower limb were analyzed by logistic regression analysis.
Results In 2013, 335 patients suspected of having vascular lesions underwent Doppler sonography. Among them, CTA of the lower extremities was performed in 58 patients. The mean age was 69.4 years (35 men and 23 women). Severe narrowing or total occlusion of the leg arteries was detected in 23 patients. Partial obstructive arterial disease of the legs was detected in 14 patients. Occlusion but with good collateral circulation of the leg was found in three patients. Surgical treatment plans were cancelled or changed in 28 patients. The risk factors for occlusive arterial lesions of the legs were an abnormal ankle-brachial pressure index (ABPI), absent dorsalis pedis artery pulse, and lack of response after a pain-blocking procedure.
Conclusion If patients present with a weak or absent dorsalis pedis artery pulse, abnormal ABPI ratio, and no response after a pain-blocking procedure, the clinician should consider the possibility of severe arterial occlusion of the legs. We suggest that the differential diagnosis of obstructive arterial lesions of the legs from lumbar degenerative diseases is important to prevent unnecessary invasive surgical treatment of the lumbar spine.