bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations
Authors: Bianchi Sarah , van Riel Wilhelmina E. , Kraatz Sebastian H. W. , Olieric Natacha , Frey Daniel , Katrukha Eugene A. , Jaussi Rolf , Missimer John , Grigoriev Ilya , Olieric Vincent , Benoit Roger M. , Steinmetz Michel O. , Akhmanova Anna , Kammerer Richard A. 
Published: August 2016

AbstractTight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
Stochastic Induction of Long-Term Potentiation and Long-Term Depression
Authors: Antunes G. , Roque A. C. , Simoes-de-Souza F. M. 
Published: August 2016

AbstractLong-term depression (LTD) and long-term potentiation (LTP) of granule-Purkinje cell synapses are persistent synaptic alterations induced by high and low rises of the intracellular calcium ion concentration ([Ca2+]), respectively. The occurrence of LTD involves the activation of a positive feedback loop formed by protein kinase C, phospholipase A2 and the extracellular signal-regulated protein kinase pathway and its expression comprises the reduction of the population of synaptic AMPA receptors. Recently, a stochastic computational model of these signalling processes demonstrated that, in single synapses, LTD is probabilistic and bistable. Here, we expanded this model to simulate LTP, which requires protein phosphatases and the increase in the population of synaptic AMPA receptors. Our results indicated that, in single synapses, while LTD is bistable, LTP is gradual. Ca2+ induced both processes stochastically. The magnitudes of the Ca2+ signals and the states of the signalling network regulated the likelihood of LTP and LTD and defined dynamic macroscopic Ca2+ thresholds for the synaptic modifications in populations of synapses according to an inverse Bienenstock, Cooper and Munro (BCM) rule or a sigmoidal function. In conclusion, our model presents a unifying mechanism that explains the macroscopic properties of LTP and LTD from their dynamics in single synapses.
TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells
Authors: Liu Jun , Akanuma Naoki , Liu Chengyang , Naji Ali , Halff Glenn A. , Washburn William K. , Sun Luzhe , Wang Pei 
Published: August 2016

AbstractAnimal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.
Pathogenic Differences between Nipah Virus Bangladesh and Malaysia Strains in Primates: Implications for Antibody Therapy
Authors: Mire Chad E. , Satterfield Benjamin A. , Geisbert Joan B. , Agans Krystle N. , Borisevich Viktoriya , Yan Lianying , Chan Yee-Peng , Cross Robert W. , Fenton Karla A. , Broder Christopher C. , Geisbert Thomas W. 
Published: August 2016

AbstractNipah virus (NiV) is a paramyxovirus that causes severe disease in humans and animals. There are two distinct strains of NiV, Malaysia (NiVM) and Bangladesh (NiVB). Differences in transmission patterns and mortality rates suggest that NiVB may be more pathogenic than NiVM. To investigate pathogenic differences between strains, 4 African green monkeys (AGM) were exposed to NiVM and 4 AGMs were exposed to NiVB. While NiVB was uniformly lethal, only 50% of NiVM-infected animals succumbed to infection. Histopathology of lungs and spleens from NiVB-infected AGMs was significantly more severe than NiVM-infected animals. Importantly, a second study utilizing 11 AGMs showed that the therapeutic window for human monoclonal antibody m102.4, previously shown to rescue AGMs from NiVM infection, was much shorter in NiVB-infected AGMs. Together, these data show that NiVB is more pathogenic in AGMs under identical experimental conditions and suggests that postexposure treatments may need to be NiV strain specific for optimal efficacy.
Tin nanoparticles as an effective conductive additive in silicon anodes
Authors: Zhong L. , Beaudette C. , Guo J. , Bozhilov K. , Mangolini L. 
Published: August 2016

AbstractWe have found that the addition of tin nanoparticles to a silicon-based anode provides dramatic improvements in performance in terms of both charge capacity and cycling stability. Using a simple procedure and off-the-shelf additives and precursors, we developed a structure in which the tin nanoparticles are segregated at the interface between the silicon-containing active layer and the solid electrolyte interface. Even a minor addition of tin, as small as ∼2% by weight, results in a significant decrease in the anode resistance, as confirmed by electrochemical impedance spectroscopy. This leads to a decrease in charge transfer resistance, which prevents the formation of electrically inactive “dead spots” in the anode structure and enables the effective participation of silicon in the lithiation reaction.
Optimal Device Independent Quantum Key Distribution
Authors: Kamaruddin S. , Shaari J. S. 
Published: August 2016

AbstractWe consider an optimal quantum key distribution setup based on minimal number of measurement bases with binary yields used by parties against an eavesdropper limited only by the no-signaling principle. We note that in general, the maximal key rate can be achieved by determining the optimal tradeoff between measurements that attain the maximal Bell violation and those that maximise the bit correlation between the parties. We show that higher correlation between shared raw keys at the expense of maximal Bell violation provide for better key rates for low channel disturbance.
hiPSC-derived cardiomyocytes from Brugada Syndrome patients without identified mutations do not exhibit clear cellular electrophysiological abnormalities
Authors: Veerman Christiaan C. , Mengarelli Isabella , Guan Kaomei , Stauske Michael , Barc Julien , Tan Hanno L. , Wilde Arthur A. M. , Verkerk Arie O. , Bezzina Connie R. 
Published: August 2016

AbstractBrugada syndrome (BrS) is a rare cardiac rhythm disorder associated with sudden cardiac death. Mutations in the sodium channel gene SCN5A are found in ~20% of cases while mutations in other genes collectively account for <5%. In the remaining patients the genetic defect and the underlying pathogenic mechanism remain obscure. To provide insight into the mechanism of BrS in individuals without identified mutations, we here studied electrophysiological properties of cardiomyocytes (CMs) generated from human induced pluripotent stem cells (hiPSCs) from 3 BrS patients who tested negative for mutations in the known BrS-associated genes. Patch clamp studies revealed no differences in sodium current (INa) in hiPSC-CMs from the 3 BrS patients compared to 2 unrelated controls. Moreover, action potential upstroke velocity (Vmax), reflecting INa, was not different between hiPSC-CMs from the BrS patients and the controls. hiPSC-CMs harboring the BrS-associated SCN5A-1795insD mutation exhibited a reduction in both INa and Vmax, demonstrating our ability to detect reduced sodium channel function. hiPSC-CMs from one of the BrS lines demonstrated a mildly reduced action potential duration, however, the transient outward potassium current (Ito) and the L-type calcium current (ICa,L), both implicated in BrS, were not different compared to the controls. Our findings indicate that ion channel dysfunction, in particular in the cardiac sodium channel, may not be a prerequisite for BrS.
Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas
Authors: Malouf Gabriel G. , Compérat Eva , Yao Hui , Mouawad Roger , Lindner Veronique , Rioux-leclercq Nathalie , Verkarre Virginie , Leroy Xavier , Dainese Linda , Classe Marion , Descotes Jean-Luc , Barthelemy Philippe , Yacoub Mokrane , Rouprêt Morgan , Bernhard Jean-Christophe , Creighton Chad J. , Spano Jean-Philippe , Su Xiaoping , Khayat David 
Published: August 2016

AbstractCollecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients.
OpEx - a validated, automated pipeline optimised for clinical exome sequence analysis
Authors: Ruark Elise , Münz Márton , Clarke Matthew , Renwick Anthony , Ramsay Emma , Elliott Anna , Seal Sheila , Lunter Gerton , Rahman Nazneen 
Published: August 2016

AbstractWe present an easy-to-use, open-source Optimised Exome analysis tool, OpEx (http://icr.ac.uk/opex) that accurately detects small-scale variation, including indels, to clinical standards. We evaluated OpEx performance with an experimentally validated dataset (the ICR142 NGS validation series), a large 1000 exome dataset (the ICR1000 UK exome series), and a clinical proband-parent trio dataset. The performance of OpEx for high-quality base substitutions and short indels in both small and large datasets is excellent, with overall sensitivity of 95%, specificity of 97% and low false detection rate (FDR) of 3%. Depending on the individual performance requirements the OpEx output allows one to optimise the inevitable trade-offs between sensitivity and specificity. For example, in the clinical setting one could permit a higher FDR and lower specificity to maximise sensitivity. In contexts where experimental validation is not possible, minimising the FDR and improving specificity may be a preferable trade-off for slightly lower sensitivity. OpEx is simple to install and use; the whole pipeline is run from a single command. OpEx is therefore well suited to the increasing research and clinical laboratories undertaking exome sequencing, particularly those without in-house dedicated bioinformatics expertise.
Pituitary response to thyrotropin releasing hormone in children with overweight and obesity
Authors: Rijks Jesse , Penders Bas , Dorenbos Elke , Straetemans Saartje , Gerver Willem-Jan , Vreugdenhil Anita 
Published: August 2016

AbstractThyroid stimulating hormone (TSH) concentrations in the high normal range are common in children with overweight and obesity and associated with increased cardiovascular disease risk. Prior studies aiming at unravelling the mechanisms underlying these high TSH concentrations mainly focused on factors promoting thyrotropin releasing hormone (TRH) production as a cause for high TSH concentrations. However, it is unknown whether TSH release of the pituitary in response to TRH is affected in children with overweight and obesity. Here we describe TSH release of the pituitary in response to exogenous TRH in 73 euthyroid children (39% males) with overweight or (morbid) obesity. Baseline TSH concentrations (0.9–5.5 mU/L) were not associated with BMI z score, whereas these concentrations were positively associated with TSH concentrations 20 minutes after TRH administration (r2 = 0.484, p < 0.001) and the TSH incremental area under the curve during the TRH stimulation test (r2 = 0.307, p < 0.001). These results suggest that pituitary TSH release in response to TRH stimulation might be an important factor contributing to high normal serum TSH concentrations, which is a regular finding in children with overweight and obesity. The clinical significance and the intermediate factors contributing to pituitary TSH release need to be elucidated in future studies.
Left atrial enlargement is an independent predictor of stroke and systemic embolism in patients with non-valvular atrial fibrillation
Authors: Hamatani Yasuhiro , Ogawa Hisashi , Takabayashi Kensuke , Yamashita Yugo , Takagi Daisuke , Esato Masahiro , Chun Yeong-Hwa , Tsuji Hikari , Wada Hiromichi , Hasegawa Koji , Abe Mitsuru , Lip Gregory Y. H. , Akao Masaharu 
Published: August 2016

AbstractControversy exists regarding whether left atrial enlargement (LAE) is a predictor of stroke/systemic embolism (SE) in atrial fibrillation (AF) patients. The Fushimi AF Registry, a community-based prospective survey, enrolled all AF patients in Fushmi-ku, Japan, from March 2011. Follow-up data and baseline echocardiographic data were available for 2,713 patients by August 2015. We compared backgrounds and incidence of events over a median follow-up of 976.5 days between patients with LAE (left atrial diameter > 45 mm; LAE group) and those without in the Fushimi AF Registry. The LAE group accounted for 39% (n = 1,049) of cohort. The LAE group was older and had longer AF duration, with more prevalent non-paroxysmal AF, higher CHADS2/CHA2DS2-VASc score and oral anticoagulant (OAC) use. A higher risk of stroke/SE during follow-up in the LAE group was found (entire cohort; hazard ratio (HR): 1.92, 95% confidence interval (CI): 1.40–2.64; p < 0.01; without OAC; HR: 1.97, 95% CI: 1.18–3.25; p < 0.01; with OAC; HR: 1.83, 95% CI: 1.21–2.82; p < 0.01). LAE was independently associated with increased risk of stroke/SE (HR: 1.74, 95% CI: 1.25–2.42; p < 0.01) after adjustment by the components of CHA2DS2-VASc score and OAC use. In conclusion, LAE was an independent predictor of stroke/SE in large community cohort of AF patients.
Two-step crystal growth mechanism during crystallization of an undercooled Ni50Al50 alloy
Authors: An Simin , Li Jiahao , Li Yang , Li Shunning , Wang Qi , Liu Baixin 
Published: August 2016

AbstractCrystallization processes are always accompanied by the emergence of multiple intermediate states, of which the structures and transition dynamics are far from clarity, since it is difficult to experimentally observe the microscopic pathway. To insight the structural evolution and the crystallization dynamics, we perform large-scale molecular dynamics simulations to investigate the time-dependent crystallization behavior of the NiAl intermetallic upon rapid solidification. The simulation results reveal that the crystallization process occurs via a two-step growth mechanism, involving the formation of initial non-equilibrium long range order (NLRO) regions and of the subsequent equilibrium long range order (ELRO) regions. The formation of the NLRO regions makes the grains rather inhomogeneous, while the rearrangement of the NLRO regions into the ELRO regions makes the grains more ordered and compact. This two-step growth mechanism is actually controlled by the evolution of the coordination polyhedra, which are characterized predominantly by the transformation from five-fold symmetry to four-fold and six-fold symmetry. From liquids to NLRO and further to ELRO, the five-fold symmetry of these polyhedra gradually fades and finally vanishes when B2 structure is distributed throughout the grain bulk. The energy decrease along the pathway further implies the reliability of the proposed crystallization processes.
Anatomical imbalance between cortical networks in autism
Authors: Watanabe Takamitsu , Rees Geraint 
Published: August 2016

AbstractInfluential psychological models of autism spectrum disorder (ASD) have proposed that this prevalent developmental disorder results from impairment of global (integrative) information processing and overload of local (sensory) information. However, little neuroanatomical evidence consistent with this account has been reported. Here, we examined relative grey matter volumes (rGMVs) between three cortical networks, how they changed with age and their relationship with core symptomatology. Using public neuroimaging data of high-functioning ASD males and age-/sex-/IQ-matched controls, we first identified age-associated atypical increases in rGMVs of the regions of two sensory systems (auditory and visual networks) and an age-related aberrant decrease in rGMV of a task-control system (fronto-parietal network, FPN) in ASD children. While the enlarged rGMV of the auditory network in ASD adults was associated with the severity of autistic socio-communicational core symptom, that of the visual network was instead correlated with the severity of restricted and repetitive behaviours in ASD. Notably, the atypically decreased rGMV of FPN predicted both of the two core symptoms. These findings suggest that disproportionate undergrowth of a task-control system (FPN) may be a common anatomical basis for the two ASD core symptoms and relative overgrowth of the two different sensory systems selectively compounds the distinct symptoms.
High-brightness organic light-emitting diodes for optogenetic control of Drosophila locomotor behaviour
Authors: Morton Andrew , Murawski Caroline , Pulver Stefan R. , Gather Malte C. 
Published: August 2016

AbstractOrganic light emitting diodes (OLEDs) are in widespread use in today’s mobile phones and are likely to drive the next generation of large area displays and solid-state lighting. Here we show steps towards their utility as a platform technology for biophotonics, by demonstrating devices capable of optically controlling behaviour in live animals. Using devices with apinOLED architecture, sufficient illumination intensity (0.3 mW.mm−2) to activate channelrhodopsins (ChRs)in vivowas reliably achieved at low operating voltages (5 V). InDrosophila melanogasterthird instar larvae expressing ChR2(H134R) in motor neurons, we found that pulsed illumination from blue and green OLEDs triggered robust and reversible contractions in animals. This response was temporally coupled to the timing of OLED illumination. With blue OLED illumination, the initial rate and overall size of the behavioural response was strongest. Green OLEDs achieved roughly 70% of the response observed with blue OLEDs. Orange OLEDs did not produce contractions in larvae, in agreement with the spectral response of ChR2(H134R). The device configuration presented here could be modified to accommodate other small model organisms, cell cultures or tissue slices and the ability of OLEDs to provide patterned illumination and spectral tuning can further broaden their utility in optogenetics experiments.
Anti-photoaging properties of the phosphodiesterase 3 inhibitor cilostazol in ultraviolet B-irradiated hairless mice
Authors: Kim Ha Neui , Gil Chan Hee , Kim Yu Ri , Shin Hwa Kyoung , Choi Byung Tae 
Published: August 2016

AbstractWe investigated whether cilostazol, an activator of cyclic adenosine monophosphate (cAMP)-dependent intracellular signaling, could inhibit ultraviolet B (UVB) irradiation-induced photoaging in HR-1 hairless mice. Cilostazol decreased wrinkle formation and skin thickness in UVB-irradiated mice, as well as increased staining of collagen fibers and inhibition of reactive oxygen species (ROS) formation in the skin. Moreover, the proteolytic activities of gelatinase matrix metalloproteinase (MMP)-9 and collagenase MMP-3 were significantly decreased in UVB-irradiated mice treated with cilostazol. Western blotting showed that UVB-induced activation of p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-κB was significantly inhibited by cilostazol, whereas the activation of Akt was significantly enhanced by cilostazol. Confirmation of localized protein expression in the skin revealed marked p38 MAPK and NF-κB activation that was mainly detected in the dermis. Marked Akt activation was mainly detected in the epidermis. Our results suggest that cilostazol may have anti-photoaging effects on UVB-induced wrinkle formation by maintaining the extracellular matrix density in the dermis, which occurs via regulation of ROS and related p38 MAPK and NF-κB signaling, and subsequent down-regulation of MMPs. Therefore, cilostazol may protect against photoaging-induced wrinkle formation.
Configurationally Stable Doubly Bridged Biphenyl Azocines through Copper-Catalyzed Double Carbene Insertions into the Corresponding Azepines
Authors: Harthong Steven , Brun Elodie , Grass Stéphane , Besnard Céline , Bürgi Thomas , Lacour Jérôme 
Published: August 2016

Doubly bridged biphenyl azocines can be prepared in a single step through copper-catalyzed reactions of a doubly bridged biphenyl azepine and diazodiester reagents. Double [1,2]-Stevens rearrangements occur at 100 °C to afford doubly tethered eight-membered rings (49 to 61%) as trans and cis regioisomers (1:1 ratio). These products present an axial chirality. ECD and VCD analyses of the separated enantiomers (CSP-HPLC) were used to assign the absolute configuration. High configurational stability is observed for both regioisomers as racemization does not occur after 1 week of heating at 208 °C in dodecane (ΔG
‡ > 41 kcal·mol–1). Interestingly, reactions performed at 40 °C retain a certain level of enantiospecificity (82–86%), avoiding, for the most part, thermal racemization of the starting material.
Spatial organization of bacterial transcription and translation
Authors: Castellana Michele , Hsin-Jung Li Sophia , Wingreen Ned S. 
Published: August 2016

Significance
Protein synthesis is a mechanism of fundamental importance for life. The molecular components involved in this process are macromolecules called mRNAs and ribosomes. Here, we combine a theoretical and experimental analysis, and show that mRNAs congregate with ribosomes away from the nucleoid, namely at the cell poles. Overall, our model provides an understanding of the role of spatial localization in bacteria, providing potential insights on how such localization mechanisms may be useful to perform specific biological functions.