bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parkin-dependent regulation of the MCU complex component MICU1
Authors: Matteucci Alessandra , Patron Maria , Vecellio Reane Denis , Gastaldello Stefano , Amoroso Salvatore , Rizzuto Rosario , Brini Marisa , Raffaello Anna , Calì Tito 
Published: September 2018

AbstractThe mitochondrial Ca2+ uniporter machinery is a multiprotein complex composed by the Ca2+ selective pore-forming subunit, the mitochondrial uniporter (MCU), and accessory proteins, including MICU1, MICU2 and EMRE. Their concerted action is required to fine-tune the uptake of Ca2+ into the mitochondrial matrix which both sustains cell bioenergetics and regulates the apoptotic response. To adequately fulfil such requirements and avoid impairment in mitochondrial Ca2+ handling, the intracellular turnover of all the MCU components must be tightly regulated. Here we show that the MCU complex regulator MICU1, but not MCU and MICU2, is rapidly and selectively degraded by the Ubiquitin Proteasome System (UPS). Moreover, we show that the multifunctional E3 ubiquitin ligase Parkin (PARK2), whose mutations cause autosomal recessive early-onset Parkinson’s disease (PD), is a potential candidate involved in this process since its upregulation strongly decreases the basal level of MICU1. Parkin was found to interact with MICU1 and, interestingly, Parkin Ubl-domain, but not its E3-ubquitin ligase activity, is required for the degradation of MICU1, suggesting that in addition to the well documented role in the control of Parkin basal auto-inhibition, the Ubl-domain might exert important regulatory functions by acting as scaffold for the proteasome-mediated degradation of selected substrates under basal conditions, i.e. to guarantee their turnover. We have found that also MICU2 stability was affected upon Parkin overexpression, probably as a consequence of increased MICU1 degradation. Our findings support a model in which the PD-related E3 ubiquitin ligase Parkin directly participates in the selective regulation of the MCU complex regulator MICU1 and, indirectly, also of the MICU2 gatekeeper, thus indicating that Parkin loss of function could contribute to the impairment of the ability of mitochondria to handle Ca2+ and consequently to the pathogenesis of PD.
c-Kit+ Cells in Adult Salivary Glands do not Function as Tissue Stem Cells
Authors: Kwak Mingyu , Ninche Ninche , Klein Sabine , Saur Dieter , Ghazizadeh Soosan 
Published: September 2018

AbstractA rare population of salivary gland cells isolated based on c-Kit immunoreactivity are thought to represent tissue stem cells since they exhibit the most robust proliferative and differentiation capacity ex vivo. Despite their high promise for cell-based therapies aimed at restoring salivary function, the precise location and in vivo function of c-Kit+ stem cells remain unclear. Here, by combining immunostaining with c-KitCreERT2-based genetic labeling and lineage tracing in the adult mouse salivary glands, we show that c-Kit is expressed in a relatively large and heterogeneous cell population that consists mostly of differentiated cells. Moreover, c-Kit does not mark ductal stem cells that are known to express cytokeratin K14. Tracking the fate of in vivo-labeled c-Kit+ or that of K14+ cells in spheroid cultures reveals a limited proliferative potential for c-Kit+ cells and identifies K14+ cells as the major source of salispheres in these cultures. Long-term in vivo lineage tracing studies indicate that although c-Kit marks at least two discrete ductal cell lineages, c-Kit+ cells do not contribute to the normal maintenance of any other cell lineages. Our results indicate that c-Kit is not a reliable marker for salivary gland stem cells, which has important implications for salivary gland regenerative therapies.
The pathogenesis linked to coenzyme Q10 insufficiency in iPSC-derived neurons from patients with multiple-system atrophy
Authors: Nakamoto Fumiko Kusunoki , Okamoto Satoshi , Mitsui Jun , Sone Takefumi , Ishikawa Mitsuru , Yamamoto Yorihiro , Kanegae Yumi , Nakatake Yuhki , Imaizumi Kent , Ishiura Hiroyuki , Tsuji Shoji , Okano Hideyuki 
Published: September 2018

AbstractMultiple-system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. We previously reported that functionally impaired variants of COQ2, which encodes an essential enzyme in the biosynthetic pathway of coenzyme Q10, are associated with MSA. Here, we report functional deficiencies in mitochondrial respiration and the antioxidative system in induced pluripotent stem cell (iPSC)-derived neurons from an MSA patient with compound heterozygous COQ2 mutations. The functional deficiencies were rescued by site-specific CRISPR/Cas9-mediated gene corrections. We also report an increase in apoptosis of iPSC-derived neurons from MSA patients. Coenzyme Q10 reduced apoptosis of neurons from the MSA patient with compound heterozygous COQ2 mutations. Our results reveal that cellular dysfunctions attributable to decreased coenzyme Q10 levels are related to neuronal death in MSA, particularly in patients with COQ2 variants, and may contribute to the development of therapy using coenzyme Q10 supplementation.
Chemotherapy payload of anti-insoluble fibrin antibody-drug conjugate is released specifically upon binding to fibrin
Authors: Fuchigami Hirobumi , Manabe Shino , Yasunaga Masahiro , Matsumura Yasuhiro 
Published: September 2018

AbstractCancer-induced blood coagulation in human tumour generates insoluble fibrin (IF)-rich cancer stroma in which uneven monoclonal antibody (mAb) distribution reduce the potential effectiveness of mAb-mediated treatments. Previously, we developed a mAb that reacts only with IF and not with fibrinogen (FNG) or the fibrin degradation product (FDP). Although IF, FNG and FDP share same amino acid sequences, the mAb is hardly neutralised by FNG and FDP in circulation and accumulates in fibrin clots within tumour tissue. Here, we created an antibody drug conjugate (ADC) using the anti-IF mAb conjugated with a chemotherapy payload (IF-ADC). The conjugate contains a linker severed specifically by plasmin (PLM), which is activated only on binding to IF. Imaging mass spectrometry showed the substantial intratumour distribution of the payload following the IF-ADC injection into mice bearing IF-rich 5–11 xenografts derived from pancreatic tumours of LSL-KrasG12D/+; LSL-Trp53R172H/+; Ptf1a-Cre (KPC) mice. IF-ADC treatment significantly extended the survival of the KPC mice. These data suggest that conjugating chemotherapy drugs to this IF-specific mAb could represent an effective means of treating stroma-rich tumours
Sun-induced fluorescence and gross primary productivity during a heat wave
Authors: Wohlfahrt G. , Gerdel K. , Migliavacca M. , Rotenberg E. , Tatarinov F. , Müller J. , Hammerle A. , Julitta T. , Spielmann F. M. , Yakir D. 
Published: September 2018

AbstractRemote sensing of sun-induced chlorophyll fluorescence (SIF) has been suggested as a promising approach for probing changes in global terrestrial gross primary productivity (GPP). To date, however, most studies were conducted in situations when/where changes in both SIF and GPP were driven by large changes in the absorbed photosynthetically active radiation (APAR) and phenology. Here we quantified SIF and GPP during a short-term intense heat wave at a Mediterranean pine forest, during which changes in APAR were negligible. GPP decreased linearly during the course of the heat wave, while SIF declined slightly initially and then dropped dramatically during the peak of the heat wave, temporally coinciding with a biochemical impairment of photosynthesis inferred from the increase in the uptake ratio of carbonyl sulfide to carbon dioxide. SIF thus accounted for less than 35% of the variability in GPP and, even though it responded to the impairment of photosynthesis, appears to offer limited potential for quantitatively monitoring GPP during heat waves in the absence of large changes in APAR.
Examining the Role of Cone-expressed RPE65 in Mouse Cone Function
Authors: Kolesnikov Alexander V. , Tang Peter H. , Kefalov Vladimir J. 
Published: September 2018

AbstractEfficient chromophore supply is paramount for the continuous function of vertebrate cone photoreceptors. It is well established that isomerization of all-trans- to 11-cis- retinoid in the retinal pigmented epithelium by RPE65 is a key reaction in this process. Mutations in RPE65 result in a disrupted chromophore supply, retinal degeneration, and blindness. Interestingly, RPE65 has recently been found to also be expressed in cone photoreceptors in several species, including mouse and human. However, the functional role of cone-expressed RPE65 has remained unknown. Here, we used loss and gain of function approaches to investigate this issue. First, we compared the function of cones from control and RPE65-deficient mice. Although we found that deletion of RPE65 partially suppressed cone dark adaptation, the interpretation of this result was complicated by the abnormal cone structure and function caused by the chromophore deficiency in the absence of RPE65 in the pigmented epithelium. As an alternative approach, we generated transgenic mice to express human RPE65 in the cones of mice where RPE65 expression is normally restricted to the pigmented epithelium. Comparison of control (RPE65-deficient) and transgenic (RPE65-expressing) cones revealed no morphological or functional changes, with only a slight delay in dark adaptation, possibly caused by the buffering of retinoids by RPE65. Together, our results do not provide any evidence for a functional role of RPE65 in mouse cones. Future studies will have to determine whether cone-expressed RPE65 plays a role in maintaining the long-term homeostasis of retinoids in cones and their function and survival, particularly in humans.
High cadence, linear, and circular polarization monitoring of OJ 287
Authors: Myserlis I. , Komossa S. , Angelakis E. , Gómez J. L. , Karamanavis V. , Krichbaum T. P. , Bach U. , Grupe D. 
Published: September 2018

Aims. We present a multifrequency, dense radio monitoring program of the blazar OJ 287 using the 100-m Effelsberg radio telescope. The program aims to test different binary supermassive black hole (SMBH) scenarios and studying the physical conditions in the central region of this bright blazar. Here, we analyze the evolution in total flux density, linear and circular polarization as a means to study the OJ 287 jet structure and its magnetic field geometry.
Methods. We used a recently developed, high-precision data analysis methodology to recover all four Stokes parameters. We measured the total flux density of OJ 287 at nine bands from 2.64 GHz to 43 GHz, the linear polarization parameters at four bands between 2.64 GHz and 10.45 GHz, and the circular polarization at two bands, 4.85 GHz and 8.35 GHz. The mean cadence of our measurements is ten days.
Results. Between December 2015 and January 2017 (MJD 57370–57785), OJ 287 showed flaring activity and complex linear and circular polarization behavior. The radio electric vector position angle (EVPA) showed a large clockwise (CW) rotation by ∼340° with a mean rate of −1.04°/day. Based on concurrent very long baseline interferometric (VLBI) polarization data at 15 GHz and 43 GHz, the rotation seems to originate within the jet core at 43 GHz (projected angular size ≤0.15 mas or 0.67 pc at the redshift of the source). Moreover, optical polarization data show a similar monotonic CW rotation with a rate of about −1.1°/day which is superposed with shorter and faster rotations that exhibit rates of about 7.8°/day, mainly in the CW sense.
Conclusions. The flux density and polarization variability of the single dish, VLBI and optical data is consistent with a polarized emission component propagating on a helical trajectory within a bent jet. We constrained the helix arc length to 0.26 pc and radius to ≤0.04 pc as well as the jet bending arc length projected on the plane of the sky to ≤1.9–7.6 pc. A similar bending has been observed also in high angular resolution VLBI images of the OJ 287 jet at its innermost regions. The helical trajectory covers only a part of the jet width, possibly its spine. In addition, our results indicate the presence of a stable polarized emission component. Its EVPA (−10°) is oriented perpendicular to the large scale jet, suggesting dominance of the poloidal magnetic field component. Finally, the EVPA rotation begins simultaneously with an optical flare and hence the two might be physically connected. That optical flare has been suggested to be linked to the interaction of a secondary SMBH with the inner accretion disk or originating in the jet of the primary.
High frequency saltwater intrusion monitoring using borehole geophysical tools (SMD)
Authors: Baïsset M. , Neyens D. 
Published: September 2018

In February 2016, two remote controlled geophysical monitoring tools (SMD) have been installed for the first time in the Reunion Island. Settled into two piezometers drilled into a basaltic coastal aquifer, between the ocean and a production well, they allow the record of groundwater electrical conductivity (ECw) logs on a 30 min basis. Thanks to those two tools, water operator continuously knows the shape and the position of the SWI as data are available online on a secured web application designed especially for SWI data management.
During the observation period a 5,15 m rise of SWI interface has been recorded. Knowing the average porosity, water table elevation and SWI interface position it is possible to estimate available fresh groundwater volume. Along a 1 km band between extraction well and the ocean, available fresh groundwater volume was found to be 1 259 000 m3 in June 2016. In June 2017, due to SWI progression this volume was found to be 777 000 m3, that to say a 480 000 m3 volume of freshwater replaced by brackish water.
SMD network will now be spread in the Reunion Island to improve coastal extraction well management knowing SWI shape and position on a high frequency basis.
Modeling saltwater intrusion scenarios for a coastal aquifer at the German North Sea
Authors: Schneider A. , Zhao H. , Wolf J. , Logashenko D. , Reiter S. , Howahr M. , Eley M. , Gelleszun M. , Wiederhold H. 
Published: September 2018

A 3d regional density-driven flow model of a heterogeneous aquifer system at the German North Sea Coast is set up within the joint project NAWAK (“Development of sustainable adaption strategies for the water supply and distribution infrastructure on condition of climatic and demographic change”). The development of the freshwater-saltwater interface is simulated for three climate and demographic scenarios.
Groundwater flow simulations are performed with the finite volume code d3f++ (distributed density driven flow) that has been developed with a view to the modelling of large, complex, strongly density-influenced aquifer systems over long time periods.
Merging Transition-Metal Catalysis with Phthalimides: A New Entry to Useful Building Blocks
Authors: Gramage-Doria Rafael , Yuan Yu-Chao , Bruneau Christian 
Published: September 2018

Phthalimides have found their main application in organic synthesis as protecting groups for primary amines during the multistep synthesis of biologically relevant targets. On the other hand, phthalimide functionalization is rather challenging and it is traditionally associated with the use of over-stoichiometric amounts of environmentally hazardous reagents. In this short review, we describe and discuss how, in the last decades, transition-metal catalysts have provided useful organic building blocks after selective transformation of the phthalimide skeleton in a more efficient and sustainable manner.1	Introduction2	Partial Carbonyl Reduction3	Full Carbonyl Reduction4	Aromatic Ring Reduction5	Five-Membered-Ring Opening6	Conclusion
Die Erfindung der Psychotherapie – das erste Jahrhundert. Deutschland 1695-1808
Authors: Peters U. H. 
Published: September 2018

ZusammenfassungViele Historiker meinen, die Psychotherapie sei von Sigmund Freud erfunden worden, wieder andere glauben, die Psychotherapie habe um 1800 begonnen. Das eine ist so wenig zutreffend wie das andere. Die Psychotherapie ist ab 1700 unmittelbar mit dem Beginn der Aufklärung in Deutschland entstanden, als Georg Ernst Stahl 1695 als erster eine Theorie darüber veröffentliche, wie Körper und Psyche aufeinander wirken. Die Psychotherapie besteht nun bereits in ihrem 4. Jahrhundert und findet in Deutschland allgemeine Anerkennung. Im Folgenden soll nun ihr erstes Jahrhundert näher beleuchtet werden. Es ist die Phase der Entstehung der Psychotherapie bis hin zur Prägung ihres Namens zu Beginn 1800. Ihre Entwicklung, ihre Lehre und ihre Techniken und Anwendung werden hier im Einzelnen dargestellt.
Agomelatin – update aktueller Daten
Authors: Volz H.-P. 
Published: September 2018

ZusammenfassungAgomelatin ist ein Antidepressivum mit einem neuartigen Wirkansatz: Es wirkt an melatonergen MT1- und MT2-Rezeptoren agonistisch, an dem serotonergen 5-HT2c-Rezeptor antagonistisch und beeinflusst - anders als monaminerge Substanzen - positiv die bei Depressiven gestörten zirkadianen Parameter wie Affekt, Schlaf und Aktivitätszyklus. Die Wirksamkeit auf alle Kernsymptome der Depression ist mit anderen modernen Antidepressiva mindestens vergleichbar. 2010 wurde diese Substanz vom Autor in diesem Journal in einem Überblicksartikel vorgestellt, nun sollen neue und auch seinerzeit unberücksichtigte Erkenntnisse über diese Substanz ergänzt werden. Aus den Arbeiten wird ersichtlich, dass Agomelatin spezifische Vorteile im Bereich der Schlafstörungen und der sexuellen Funktionsstörungen besitzt, dabei gut antidepressiv wirkt. Offene Studien zeigen die gute Anwendbarkeit der Substanz unter Praxisbedingungen sowie potenziell interessante Einsatzgebiete im Bereich der therapieresistenten Depression und der postremissiven Depression bei schizophren Erkrankten.
Psychotherapeutische Versorgung in Deutschland
Authors: Herpertz S. C. , Roth-Sackenheim Ch. 
Published: September 2018

ZusammenfassungMehr als 3% der Deutschen erhalten eine psychotherapeutische Behandlung. Dabei verteilt sich die Versorgungslandschaft auf eine Reihe unterschiedlicher Berufsgruppen, wobei das Verhältnis von Ärzten und Psychologen derzeit bei 1:1,7 liegt. Das deutsche Krankenver-sicherungssystem verteilt seine Ressourcen unter der Leitidee, dass psychisch Kranke mit einem der zugelassenen Richtlinienverfahren „Kognitive Verhaltenstherapie, Tiefenpsychologie oder Psychoanalyse“ behandelt werden sollen; so entfallen ungefähr die Hälfte aller Ausgaben für Psychiatrie und Neurologie auf die Finanzierung der Richtlinienverfahren. Der ambulant tätige Facharzt für Psychiatrie und Psychotherapie versorgt dagegen mit Abstand die meisten Patienten und übernimmt damit die Verantwortung für die Versorgungssicherung der psychisch Kranken in Deutschland. Allerdings geht die sehr hohe Fallzahl auf Kosten der Zeitintensität der Behandlung des einzelnen Patienten. Dies dürfte nur sehr eingeschränkt dem Selbstbild und der Kompetenz der Mehrzahl der Psychiater und Psychotherapeuten entsprechen, erbringen sie doch oft auch Richtlinienpsychotherapien. Laufende Forschungsprojekte, z.T. unterstützt von der Bundesärztekammer, werden hoffentlich mehr Klarheit darüber bringen, welche psychotherapeutischen Leistungen von Ärzten im Allgemeinen und Psychiatern im Besonderen neben der Richtlinienpsychotherapie erbracht werden.
Uneven balance of power between hypothalamic peptidergic neurons in the control of feeding
Authors: Wei Qiang , Krolewski David M. , Moore Shannon , Kumar Vivek , Li Fei , Martin Brian , Tomer Raju , Murphy Geoffrey G. , Deisseroth Karl , Watson Stanley J. , Akil Huda 
Published: September 2018

Significance
The interplay between the anorexigenic and orexigenic neurons in the arcuate nucleus that contributes to the control of feeding remains elusive. Using optogenetic stimulation, we show that activation of POMC neurons rapidly inhibits feeding behavior in fasted animals. However, simultaneous stimulation of both POMC neurons and a subset of the orexigenic neurons that express AgRP is sufficient to reverse that inhibition and trigger intense feeding behavior. We used 3D imaging and functional studies to illuminate the anatomical underpinning of both the inhibitory and excitatory events. Our work suggests that translational applications that aim to control appetite need to target the activation rather than the inhibition mechanisms.
Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins
Authors: Li Ben B. , Qian Changli , Gameiro Paulo A. , Liu Chin-Chih , Jiang Tao , Roberts Thomas M. , Struhl Kevin , Zhao Jean J. 
Published: September 2018

Significance
The PI3K-Akt-mTOR pathway integrates signaling information from various mitogen and nutrient sensors to regulate cell growth and proliferation. Hyperactivation of this pathway has been observed in a number of diseases, including many cancers. Pharmacological inhibition of mechanistic target of rapamycin (mTOR) causes immediate suppression of cell-wide protein synthesis; interestingly, this effect is not uniform across all transcripts, but is biased toward mRNAs encoding ribosomal proteins. In this study, we developed a rapid, scalable, and targeted assay for RNA translation that enabled us to identify translation modulators of ribosomal proteins that act independent of mTOR signaling. These modulators include chemical compounds, acting via their “off-target” effects, as well as certain metabolic perturbations, and together, they represent a noncanonical mode of regulating ribosome biogenesis and protein synthesis capacity.
Phospho-dependent recruitment of the yeast NuA4 acetyltransferase complex by MRX at DNA breaks regulates RPA dynamics during resection
Authors: Cheng Xue , Jobin-Robitaille Olivier , Billon Pierre , Buisson Rémi , Niu Hengyao , Lacoste Nicolas , Abshiru Nebiyu , Côté Valérie , Thibault Pierre , Kron Stephen J. , Sung Patrick , Brandl Christopher J. , Masson Jean-Yves , Côté Jacques 
Published: September 2018

Significance
Double-strand breaks (DSBs) in the DNA are the most dangerous type of damage and must be repaired to maintain genome integrity, avoiding disease-linked mutations and cancer initiation/progression. The NuA4 histone acetyltransferase complex is recruited to DNA DSBs to facilitate repair through modification of the chromatin surrounding the damage, but its recruitment mechanism is poorly understood. Here, we report that the DNA damage sensor complex Mre11-Rad50-Xrs2 physically recruits NuA4 to the break sites followed by bidirectional spreading linked to the DNA end resection required for error-free repair by homologous recombination. During that process, NuA4 can acetylate ssDNA-binding replication protein A (RPA), leading to its displacement.
Metabolic regulation and glucose sensitivity of cortical radial glial cells
Authors: Rash Brian G. , Micali Nicola , Huttner Anita J. , Morozov Yury M. , Horvath Tamas L. , Rakic Pasko 
Published: September 2018

Significance
Metabolic abnormalities during gestation have been previously linked to increased likelihood of dyslexia, autism, and attention deficit hyperactivity disorder, but the factors involved and how they may act during cortical development is unknown. Here, we found in rodents that obesity and hyperglycemia affect the primary stem cells of the cortex (radial glial cells), reducing their ability to perform neurogenesis and form the radial scaffold needed for neuronal migration. At the subcellular level, excess glucose degraded calcium activity and the transport of mitochondria in the radial scaffold. Consequent delayed neuronal production and migration were observed. These results reveal aspects of neurogenesis as well as the sensitivity of the cortical development process to certain gestational metabolic influences.