bluuebunny/crossref_metadata_2025 huggingface dataset:
ON CONTRA-CLASSICAL VARIANTS OF NELSON LOGIC N4 AND ITS CLASSICAL EXTENSION
Authors: OMORI HITOSHI , WANSING HEINRICH
Published: October 2018

In two recent articles, Norihiro Kamide introduces unusual variants of Nelson’s paraconsistent logic and its classical extension. Kamide’s systems, IP and CP, are unusual insofar as double negations in these logics behave as intuitionistic and classical negations, respectively. In this article we present Hilbert-style axiomatizations of both IP and CP. The axiom system for IP is shown to be sound and complete with respect to a four-valued Kripke semantics, and the axiom system for CP is characterized by four-valued truth tables. Moreover, we note some properties of IP and CP, and emphasize that these logics are unusual also because they are contra-classical and inconsistent but nontrivial. We point out that Kamide’s approach exemplifies a general method for obtaining contra-classical logics, and we briefly speculate about a linguistic application of Kamide’s logics.
A Comparative Assessment of the Impact of Climate Change and Energy Policies on Alpine Hydropower
Authors: Anghileri D. , Botter M. , Castelletti A. , Weigt H. , Burlando P.
Published: October 2018

Scientific literature has mostly focused on the analysis of climate change impacts on hydropower operations, underrating the consequences of energy policies, for example, increase in Variable Renewable Sources (VRSs) and CO2 emission permit price, on hydropower productivity and profitability. We contribute a modeling framework to assess the impacts of different climate change and energy policies on the operations of hydropower reservoir systems in the Alps. Our approach is characterized by the following: (i) the use of a physically explicit hydrological model to assess future water availability; (ii) the consideration of electricity price scenarios obtained from an electricity market model accounting for the future projected European energy strategies; and (iii) the use of optimization techniques to design hydropower system operations in response to the projected changes. Through the application to the Mattmark system, a snow‐ and ice‐dominated hydropower system in Switzerland, we demonstrate how the framework is effective in exploring the sensitivity of Alpine hydropower to changes in water availability and electricity price, in quantifying the uncertainties associated to these projections and in identifying the value of reoperation strategies. Results show that energy policies may have more significant impacts on hydropower operations than climate change and, as such, are worth considering in impact assessments studies. The reduction of water availability due to climate change is expected to induce a loss in electricity production down to −27% by 2050. Changes in electricity price, instead, may have up to 6 times stronger impact than climate change, leading to an increase in hydropower revenue up to about +181%.
Along‐Strike Variation in the Magmatic Tempo of the Coast Mountains Batholith, British Columbia, and Implications for Processes Controlling Episodicity in Arcs
Authors: Cecil M. R. , Rusmore M. E. , Gehrels G. E. , Woodsworth G. J. , Stowell H. H. , Yokelson I. N. , Chisom C. , Trautman M. , Homan E.
Published: October 2018

The growth of the Coast Mountains batholith has been documented as episodic through time, and it has become a type example of a continental arc system that developed through non‐steady‐state magmatism. The magmatic record, however, is not well known along the length of the arc, hindering evaluation of the processes controlling the tempo and patterns of batholith growth. A new, robust geochronologic database (485 U‐Pb zircon and titanite ages, 120 of which are newly presented herein) covering nearly 1,000 km of arc length reveals significant along‐strike variation in the tempo of batholith emplacement, the timing of arc cessation, and the arc cooling history. Zircon ages range from ~180 to 40 Ma along the length of the arc and overlap with titanite ages, with the exception of parts of the central batholith where Eocene extension and exhumation of lower crustal rocks led to a more complex history. New analysis of zircon ages reveals significant along‐strike differences in the timing of high flux magmatic events. Small‐scale (<150 km) intra‐arc variations in magmatic tempo suggest that small‐scale processes, likely operating within the arc system, appear to have driven the episodic growth of the Coast Mountains batholith. In contrast, rates of Cretaceous‐Paleogene eastward arc migration are consistently ~2.5 km/Myr along the length of the arc. These rates are similar to those documented in North American arc systems, which suggests that arc migration has an external, plate‐scale driver and/or is an intrinsic, self‐modulating feature of most continental arcs.
Observed Variation of Three‐Dimensional Return Stroke Speeds Along the Channel in Rocket‐Triggered Lightning
Authors: Li Yun , Qiu Shi , Shi Lihua , Wang Tao , Zhang Qi , Lei Qi , Sun Zheng
Published: October 2018

An improved very high frequency location system, multiple antenna radiation continuous observation system (MARCOS), is combined with high‐speed video observation to explore radiation source evolution during return stroke (RS) stages in triggered lightning. A three‐dimensional (3‐D) channel reconstruction is performed for speed measurement of the RS processes. The 3‐D average speeds for the two selected strokes (RS1 and RS3) over the bottom channel within 1 km are 9.24 × 107 m/s and 1.07 × 108 m/s, respectively. The high temporal‐spatial resolution of MARCOS permits thorough examination of the speed variation. Our observation shows that the 3‐D RS speeds of both RS1 and RS3 are increased initially with height for the first several hundred meters, maximized, and then decreased with height. To the best of our knowledge, this is the first evidence regarding nonmonotonic 3‐D RS speed variation in triggered lightning.
Effect of the Decadal Kuroshio Extension Variability on the Seasonal Changes of the Mixed‐Layer Salinity Anomalies in the Kuroshio‐Oyashio Confluence Region
Authors: Geng Yu , Wang Qiang , Mu Mu
Published: October 2018

This study investigates the seasonal variations of the mixed‐layer salinity anomalies (MLSAs) under the decadal variability of the Kuroshio Extension (KE) in the Kuroshio‐Oyashio Confluence Region (KOCR: 35–40°N, 140–150°E). Our analysis reveals that the seasonal variation trend of the MLSA is almost opposite in the stable and unstable states of the KE. In the stable (unstable) state, the increasing (decreasing) MLSA in the KOCR reaches its maximal positive (minimal negative) value in late summer and then decreases (increases) gradually. An exploration of the budget of the MLSA shows that ocean dynamics explain more than half of the seasonal MLSA changes in the two states and exceed the contribution of atmospheric forcing (approximately 18%). The leading oceanic processes include advection of the mean mixed‐layer salinity by anomalous Ekman and geostrophic currents and advection of the MLSA by mean geostrophic currents, which explain 13.80%, 12.90%, and 20.73% (11.59%, 13.36%, and 24.90%) of the MLSA temporal changes in the stable (unstable) states, respectively. The difference in the MLSA between the two states is primarily derived from the discrepancies in the anomalous ocean currents in the KOCR and south of Japan, salinity anomalies in the south of Japan, and sea surface temperature anomalies affecting atmospheric forcing between the two modes of the KE. Moreover, the most apparent influences are concentrated in summer and early autumn because of the shallower mixed layer in terms of atmospheric forcing and obvious velocity changes and the distribution of climatological salinity for ocean processes.
How Important Is Humidity in Heat Stress?
Authors: Sherwood Steven C.
Published: October 2018

Recent studies highlight the importance of humidity in accounting for extreme values of wet‐bulb temperature, a proposed indicator of heat stress. But this result may be sensitive to the measure of heat stress used—an ongoing source of confusion.
Life Cycle of Atmospheric Rivers: Identification and Climatological Characteristics
Authors: Zhou Yang , Kim Hyemi , Guan Bin
Published: October 2018

An atmospheric river (AR) event is a strong poleward moisture transport that is composed of a series of spatiotemporally connected instantaneous AR objects. A new object‐based tracking algorithm is developed in this study, which aims to identify an AR event and investigate its life cycle from origin to termination. The algorithm identifies duration, intensity, propagation speed and direction, and the traveled distance throughout the life cycle of the AR event. The tracking algorithm is applied to 6‐hourly column‐integrated water vapor flux from November to March during the period of 1979–2017, with a focus on the North Pacific. Most North Pacific AR events originate in the subtropics over the Northwest Pacific and terminate at higher latitudes over the Northeast Pacific including western North America. On average, long AR events that last more than 72 hrs travel 7 times longer in distance and have stronger intensity than short AR events that last less than 24 hrs. Finally, a new accumulated AR intensity index is developed, which summarizes the overall impact of AR events over a given domain during a certain period by incorporating number, lifetime, and intensities of AR events.
Physical and Chemical Controls on the Simultaneous Occurrence of Young and Old Groundwater Inferred From Multiple Age Tracers
Authors: Underwood S. C. , McCallum J. L. , Cook P. G. , Simmons C. T. , Dogramaci S. , Purtschert R. , Siade A. J. , Prommer H.
Published: October 2018

Understanding groundwater ages within an aquifer system has the potential to better constrain estimates of groundwater recharge and flow rates and therefore increase the reliability of groundwater models. Groundwater ages are generally interpreted from field‐observed environmental tracer concentrations, but in many cases in which multiple groundwater age tracers have been analyzed simultaneously the results show significant disparities among tracer‐specific estimated ages. The disparities are generally attributed to physical mixing between waters of different ages. However, especially in the geochemical literature environmental tracer concentrations are often analyzed with simplistic models in which the degree of the simulated mixing might be considered unrealistic for natural heterogeneous geologic media. In this study we use numerical experiments to examine under which physical conditions measured concentrations of selected environmental tracers (CFC‐12, 39Ar, and 14C) may return discrepant ages. Our model simulations suggest that matrix diffusion has the greatest potential to cause mixing of different‐aged water and to generate age biases between tracers. The multitracer simulations also suggest that there is a limit to the magnitude of the discrepancies that can be attributed to physical processes. When comparing data collected from the Pilbara region of Western Australia with our numerical modeling studies, it was found that a dual‐domain mass transfer model was required to explain the field‐observed age discrepancies.
An electrochemical thermal transistor
Authors: Sood Aditya , Xiong Feng , Chen Shunda , Wang Haotian , Selli Daniele , Zhang Jinsong , McClellan Connor J. , Sun Jie , Donadio Davide , Cui Yi , Pop Eric , Goodson Kenneth E.
Published: October 2018

The ability to actively regulate heat flow at the nanoscale could be a game changer for applications in thermal management and energy harvesting. Such a breakthrough could also enable the control of heat flow using thermal circuits, in a manner analogous to electronic circuits. Here we demonstrate switchable thermal transistors with an order of magnitude thermal on/off ratio, based on reversible electrochemical lithium intercalation in MoS2 thin films. We use spatially-resolved time-domain thermoreflectance to map the lithium ion distribution during device operation, and atomic force microscopy to show that the lithiated state correlates with increased thickness and surface roughness. First principles calculations reveal that the thermal conductance modulation is due to phonon scattering by lithium rattler modes, c-axis strain, and stacking disorder. This study lays the foundation for electrochemically-driven nanoscale thermal regulators, and establishes thermal metrology as a useful probe of spatio-temporal intercalant dynamics in nanomaterials.
The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism
Authors: Iadanza Matthew G. , Silvers Robert , Boardman Joshua , Smith Hugh I. , Karamanos Theodoros K. , Debelouchina Galia T. , Su Yongchao , Griffin Robert G. , Ranson Neil A. , Radford Sheena E.
Published: October 2018

All amyloid fibrils contain a cross-β fold. How this structure differs in fibrils formed from proteins associated with different diseases remains unclear. Here, we combine cryo-EM and MAS-NMR to determine the structure of an amyloid fibril formed in vitro from β2-microglobulin (β2m), the culprit protein of dialysis-related amyloidosis. The fibril is composed of two identical protofilaments assembled from subunits that do not share β2m’s native tertiary fold, but are formed from similar β-strands. The fibrils share motifs with other amyloid fibrils, but also contain unique features including π-stacking interactions perpendicular to the fibril axis and an intramolecular disulfide that stabilises the subunit fold. We also describe a structural model for a second fibril morphology and show that it is built from the same subunit fold. The results provide insights into the mechanisms of fibril formation and the commonalities and differences within the amyloid fold in different protein sequences.
M-Phase Phosphoprotein 9 regulates ciliogenesis by modulating CP110-CEP97 complex localization at the mother centriole
Authors: Huang Ning , Zhang Donghui , Li Fangyuan , Chai Peiyuan , Wang Song , Teng Junlin , Chen Jianguo
Published: October 2018

The primary cilium is elongated from the mother centriole and has diverse signaling roles during development and disease. The CP110-CEP97 complex functions as a negative regulator of ciliogenesis, although the mechanisms regulating its mother centriole localization are poorly understood. Here we show that M-Phase Phosphoprotein 9 (MPP9) is recruited by Kinesin Family Member 24 (KIF24) to the distal end of mother centriole where it forms a ring-like structure and recruits CP110-CEP97 by directly binding CEP97. Loss of MPP9 causes abnormal primary cilia formation in growing cells and mouse kidneys. After phosphorylation by Tau Tubulin Kinase 2 (TTBK2) at the beginning of ciliogenesis, MPP9 is targeted for degradation via the ubiquitin-proteasome system, which facilitates the removal of CP110 and CEP97 from the distal end of the mother centriole. Thus, MPP9 acts as a regulator of ciliogenesis by regulating the localization of CP110-CEP97 at the mother centriole.
A perivascular niche for multipotent progenitors in the fetal testis
Authors: Kumar Deepti L. , DeFalco Tony
Published: October 2018

Androgens responsible for male sexual differentiation in utero are produced by Leydig cells in the fetal testicular interstitium. Leydig cells rarely proliferate and, hence, rely on constant differentiation of interstitial progenitors to increase their number during fetal development. The cellular origins of fetal Leydig progenitors and how they are maintained remain largely unknown. Here we show that Notch-active, Nestin-positive perivascular cells in the fetal testis are a multipotent progenitor population, giving rise to Leydig cells, pericytes, and smooth muscle cells. When vasculature is disrupted, perivascular progenitor cells fail to be maintained and excessive Leydig cell differentiation occurs, demonstrating that blood vessels are a critical component of the niche that maintains interstitial progenitor cells. Additionally, our data strongly supports a model in which fetal Leydig cell differentiation occurs by at least two different means, with each having unique progenitor origins and distinct requirements for Notch signaling to maintain the progenitor population.
Interplay between sympathetic nervous system and inflammation in aseptic loosening of hip joint replacement
Authors: Ribeiro-da-Silva M. , Vasconcelos D. M. , Alencastre I. S. , Oliveira M. J. , Linhares D. , Neves N. , Costa G. , Henrique R. , Lamghari M. , Alves C. J.
Published: October 2018

Inflammation is a common symptom in joint disorders such as rheumatoid arthritis, osteoarthritis (OA) and implant aseptic loosening (AL). The sympathetic nervous system is well known to play a critical role in regulating inflammatory conditions, and imbalanced sympathetic activity has been observed in rheumatoid arthritis. In AL it is not clear whether the sympathetic nervous system is altered. In this study we evaluated the systemic and local profile of neuroimmune molecules involved in the interplay between the sympathetic nervous system and the periprosthetic inflammation in hip AL. Our results showed that periprosthetic inflammation does not trigger a systemic response of the sympathetic nervous system, but is mirrored rather by the impairment of the sympathetic activity locally in the hip joint. Moreover, macrophages were identified as key players in the local regulation of inflammation by the sympathetic nervous system in a process that is implant debris-dependent and entails the reduction of both adrenergic and Neuropetide Y (NPY)-ergic activity. Additionally, our results showed a downregulation of semaphorin 3A (SEMA3A) that may be part of the mechanism sustaining the periprosthetic inflammation. Overall, the local sympathetic nervous system emerges as a putative target to mitigate the inflammatory response to debris release and extending the lifespan of orthopedic implants.
Publisher Correction: How morphological development can guide evolution
Authors: Kriegman Sam , Cheney Nick , Bongard Josh
Published: October 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Emotion-Specific Affective Theory of Mind Impairment in Parkinson’s Disease
Authors: Yu Rwei-Ling , Chen Po See , Tu Shao-Ching , Tsao Wei-Chia , Tan Chun-Hsiang
Published: October 2018

The neuropathology of Parkinson’s disease (PD) involves the frontal-subcortical circuit, an area responsible for processing affective theory of mind (ToM). Patients with PD are expected to experience deficits in the affective ToM. This study aims to investigate whether the ability to infer emotion in others is affected in either young-onset Parkinson’s disease (YOPD) or middle-onset PD (MOPD) patients and to test whether the impairments in affective ToM are associated with the motor symptoms. The affective ToM, global mental abilities, and clinical symptoms were assessed in a total of 107 MOPD, 30 YOPD, and 30 normal controls (NCs). The MOPD patients exhibited deficits in affective ToM to the negative and neutral valences, when compared to the participants in the NCs and YOPD group. By conducting gender-stratified analysis, the deficits in affective ToM was only found in female participants. After adjusting for demographic variables, the multiple linear regression model revealed that affective ToM predicted motor symptoms, especially in female MOPD patients. The present study may aid in the development of medical care programs by advocating for a more comprehensive therapeutic plan that includes continuous disease progression monitoring and social skills training for female MOPD patients or their caregivers.
Chemically monoubiquitinated PEX5 binds to the components of the peroxisomal docking and export machinery
Authors: Hagmann Vera , Sommer Stefanie , Fabian Patrick , Bierlmeier Jan , van Treel Nadine , Mootz Henning D. , Schwarzer Dirk , Azevedo Jorge E. , Dodt Gabriele
Published: October 2018

Peroxisomal matrix proteins contain either a peroxisomal targeting sequence 1 (PTS1) or a PTS2 that are recognized by the import receptors PEX5 and PEX7, respectively. PEX5 transports the PTS1 proteins and the PEX7/PTS2 complex to the docking translocation module (DTM) at the peroxisomal membrane. After cargo release PEX5 is monoubiquitinated and extracted from the peroxisomal membrane by the receptor export machinery (REM) comprising PEX26 and the AAA ATPases PEX1 and PEX6. Here, we investigated the protein interactions of monoubiquitinated PEX5 with the docking proteins PEX13, PEX14 and the REM. “Click” chemistry was used to synthesise monoubiquitinated recombinant PEX5. We found that monoubiquitinated PEX5 binds the PEX7/PTS2 complex and restores PTS2 protein import in vivo in ΔPEX5 fibroblasts. In vitro pull-down assays revealed an interaction of recombinant PEX5 and monoubiquitinated PEX5 with PEX13, PEX14 and with the REM components PEX1, PEX6 and PEX26. The interactions with the docking proteins were independent of the PEX5 ubiquitination status whereas the interactions with the REM components were increased when PEX5 is ubiquitinated.
Selective adsorption of 1,3-dimethyltrisulfane (DMTS) responsible for aged odour in Japanese sake using supported gold nanoparticles
Authors: Murayama Haruno , Yamamoto Yusuke , Tone Misaki , Hasegawa Takayuki , Kimura Moemi , Ishida Tamao , Isogai Atsuko , Fujii Tsutomu , Okumura Mitsutaka , Tokunaga Makoto
Published: October 2018

Gold (Au) nanoparticles (NPs) supported on SiO2 (Au/SiO2) were prepared by a practical impregnation method and applied as an adsorbent for 1,3-dimethyltrisulfane (DMTS), which is responsible for an unpleasant odour in drinks, especially Japanese sake. Compared with a conventional adsorbent, activated carbon, Au/SiO2 selectively reduced the DMTS concentration in Japanese sake without decreasing the concentrations of other aromatic components. DFT calculations revealed that the selective adsorption of DMTS occurred through the formation of a stable intermediate. The size of the supported Au NPs was controlled by the preparation conditions and determined from TEM observations and XRD measurements, and the size was ranged from 2.4 nm to 30 nm. Au/SiO2 having Au NPs with a diameter of 2.4 nm adsorbed DMTS the most efficiently. Smaller Au NPs showed better DMTS adsorption capabilities because larger amounts of Au atoms were exposed on their surfaces in the size range of this study. Langmuir-type monolayer adsorption and one-to-one binding of Au–S are proposed to occur based on an adsorption isotherm experiment. Even though significant differences of the fruity aroma score were not observed in the sensory evaluation between Au/SiO2 and activated carbon for this less aromatic Japanese sake, Au/SiO2 selectively decreased the DMTS concentration in the instrumental analysis.
Subcortical structural changes along the menstrual cycle: beyond the hippocampus
Authors: Pletzer Belinda , Harris TiAnni , Hidalgo-Lopez Esmeralda
Published: October 2018

Animal studies have robustly shown hormone related changes in spine density in various brain areas, specifically the hippocampus. Literature on hormone dependent gray matter volume changes in humans is however less consistent. While various areas have been reported to change along the menstrual cycle in women, many do not survive multiple-comparisons correction and only hippocampal changes have been replicated. We attribute these problems to small sample sizes and inconsistent definitions of menstrual cycle phases. In the present study a large sample of 55 women was scanned three times along their menstrual cycle in concisely defined time windows of hormonal changes. Accordingly this is the first study using a large enough sample size to assess menstrual cycle dependent changes in human brain structure with sufficient power. Results confirm a significant estradiol-dependent pre-ovulatory increase in gray matter volumes of the bilateral hippocampus, but also show a significant, progesterone-dependent increase in gray matter volumes of the right basal ganglia after ovulation. No other areas were affect by hormonal changes along the menstrual cycle. These hormone driven menstrual cycle changes in human brain structure are small, but may be the underlying cause of menstrual cycle dependent changes in cognition and emotion.
Facile Microwave-assisted Synthesis Manganese Doped Zinc Sulfide Nanoparticles
Authors: Sousa David Magalhães , Alves Luís Cerqueira , Marques Ana , Gaspar Guilherme , Lima João Carlos , Ferreira Isabel
Published: October 2018

Undoped and manganese doped zinc sulfide nanoparticles were produced by a fast, one-step and two-component microwave-assisted synthesis method. The solid phase retains around 78% of the initial Mn concentration, as revealed by Particle Induced X-ray Emission analysis. X-ray diffraction patterns confirmed zinc blende structure and in the transmission electron microscopy images, nanoparticles with triangular prism and cube shapes were observed, respectively with an average particle size around 7 nm and 13 nm. Dried powders of zinc sulfide nanoparticles, doped with 0.1 mol% and 0.7 mol% of Mn ions, show highest brilliance of luminescence under UV light. Increasing dopant levels resulted in a diminishing emission that vanishes above 4% of dopant concentration. The synthesis of ZnS was monitored and two main events were detected, one at 145 °C corresponding to the sol-gel phase formation and another after ~3 min at 300 °C where the precipitation of the zinc sulfide nanoparticles occurs.
Quantitative evaluation of incomplete preweaning lethality in mice by using the CRISPR/Cas9 system
Authors: Nakamura Takumi , Nakajima Kazuo , Ohnishi Tetsuo , Yoshikawa Takeo , Nakanishi Moe , Takumi Toru , Tsuboi Takashi , Kato Tadafumi
Published: October 2018

Various molecular biology techniques implementing genome editing have made it possible to generate mouse mutants for nearly all known genes; as a result, the International Mouse Phenotyping Consortium (IMPC) database listing the phenotypes of genetically modified mice has been established. Among mouse phenotypes, lethality is crucial to evaluate the importance of genes in mouse survival. Although many genes are reported to show “preweaning lethality, incomplete penetrance” in the IMPC database, the survival rates of homozygous knockout mice are highly variable. Here, we propose the lethal allele index (LAI), the ratio of the observed number of mice with homozygous knockout (KO) to the theoretically predicted number of homozygous KO mice, as a simple quantitative indicator of preweaning lethality. Among the mice mutants registered as incompletely lethal in IMPC, the LAI calculated from the genotypes of F1 mice tended to be lower in disease-related genes, and correlated with the frequency of loss-of-function (LOF) alleles in humans. In genome-edited mice using CRISPR/Cas9, the number of mice with homozygous frameshift alleles seemed to be associated with lethality. We edited the Ehd1 gene in cell lines as well as mice using CRISPR/Cas9, and found that the genotype distribution was significantly different. The LAI calculated from these data was similar to the value calculated from the IMPC data. These findings support the potential usefulness of the LAI as an index of preweaning lethality in genome-edited mice.
Opsin gene expression regulated by testosterone level in a sexually dimorphic lizard
Authors: Tseng Wen-Hsuan , Lin Jhan-Wei , Lou Chen-Han , Lee Ko-Huan , Wu Leang-Shin , Wang Tzi-Yuan , Wang Feng-Yu , Irschick Duncan J. , Lin Si-Min
Published: October 2018

Expression of nuptial color is usually energetically costly, and is therefore regarded as an ‘honest signal’ to reflect mate quality. In order to choose a mate with high quality, both sexes may benefit from the ability to precisely evaluate their mates through optimizing visual systems which is in turn partially regulated by opsin gene modification. However, how terrestrial vertebrates regulate their color vision sensitivity is poorly studied. The green-spotted grass lizard Takydromus viridipunctatus is a sexually dimorphic lizard in which males exhibit prominent green lateral colors in the breeding season. In order to clarify relationships among male coloration, female preference, and chromatic visual sensitivity, we conducted testosterone manipulation with mate choice experiments, and evaluated the change of opsin gene expression from different testosterone treatments and different seasons. The results indicated that males with testosterone supplementation showed a significant increase in nuptial color coverage, and were preferred by females in mate choice experiments. By using quantitative PCR (qPCR), we also found that higher levels of testosterone may lead to an increase in rhodopsin-like 2 (rh2) and a decrease in long-wavelength sensitive (lws) gene expression in males, a pattern which was also observed in wild males undergoing maturation as they approached the breeding season. In contrast, females showed the opposite pattern, with increased lws and decreased rh2 expression in the breeding season. We suggest this alteration may facilitate the ability of male lizards to more effectively evaluate color cues, and also may provide females with the ability to more effectively evaluate the brightness of potential mates. Our findings suggest that both sexes of this chromatically dimorphic lizard regulate their opsin expression seasonally, which might play an important role in the evolution of nuptial coloration.
Drug survival of biologics in treating psoriasis: a meta-analysis of real-world evidence
Authors: Lin Pei-Tzu , Wang Shu-Hui , Chi Ching-Chi
Published: October 2018

Drug survival of biologics represents their real-world effectiveness and safety. We conducted a meta-analysis of real-world evidence on the drug survival of biologics in treating psoriasis. We searched the PubMed, CENTRAL, and EMBASE databases from inception to 7th October 2017 for studies reporting the annual drug survival for at least 1 year. Two authors independently screened and selected relevant studies, and assessed their risk of bias. A third author was available for arbitrating discrepancies. We conducted a random-effects model meta-analysis to obtain the respective pooled drug survival from year 1 to 4. We conducted subgroup analysis on biologic-naïve subjects, discontinuation for loss of efficacy and adverse effects. We included 37 studies with 32,631 subjects. The drug survival for all biologics decreased with time, dropping from 66% at year 1 to 41% at year 4 for etanercept, from 69% to 47% for adalimumab, from 61% to 42% for infliximab, and from 82% to 56% for ustekinumab. Ustekinumab was associated with the highest drug survival in all and biologic-naïve subjects. Etanercept was associated with the lowest drug survival and was most commonly discontinued for loss of efficacy. Infliximab was most frequently associated with discontinuation for adverse effects. Clinicians may use this study as a reference in treating psoriasis.
Intravital imaging with two-photon microscopy reveals cellular dynamics in the ischeamia-reperfused rat heart
Authors: Matsuura Ryohei , Miyagawa Shigeru , Fukushima Satsuki , Goto Takasumi , Harada Akima , Shimozaki Yuri , Yamaki Kazumasa , Sanami Sho , Kikuta Junichi , Ishii Masaru , Sawa Yoshiki
Published: October 2018

Recent advances in intravital microscopy have provided insight into dynamic biological events at the cellular level in both healthy and pathological tissue. However, real-time in vivo cellular imaging of the beating heart has not been fully established, mainly due to the difficulty of obtaining clear images through cycles of cardiac and respiratory motion. Here we report the successful recording of clear in vivo moving images of the beating rat heart by two-photon microscopy facilitated by cardiothoracic surgery and a novel cardiac stabiliser. Subcellular dynamics of the major cardiac components including the myocardium and its subcellular structures (i.e., nuclei and myofibrils) and mitochondrial distribution in cardiac myocytes were visualised for 4–5 h in green fluorescent protein-expressing transgenic Lewis rats at 15 frames/s. We also observed ischaemia/reperfusion (I/R) injury-induced suppression of the contraction/relaxation cycle and the consequent increase in cell permeability and leukocyte accumulation in cardiac tissue. I/R injury was induced in other transgenic mouse lines to further clarify the biological events in cardiac tissue. This imaging system can serve as an alternative modality for real time monitoring in animal models and cardiological drug screening, and can contribute to the development of more effective treatments for cardiac diseases.
Genetic and functional diversity of double-stranded DNA viruses in a tropical monsoonal estuary, India
Authors: Jasna Vijayan , Parvathi Ammini , Dash Abhinandita
Published: October 2018

The present study illustrates the genetic diversity of four uncultured viral communities from the surface waters of Cochin Estuary (CE), India. Viral diversity inferred using Illumina HiSeq paired-end sequencing using a linker-amplified shotgun library (LASL) revealed different double-stranded DNA (dsDNA) viral communities. The water samples were collected from four stations PR1, PR2, PR3, and PR4, during the pre-monsoon (PRM) season. Analysis of virus families indicated that the Myoviridae was the most common viral community in the CE followed by Siphoviridae and Podoviridae. There were significant (p < 0.05) spatial variations in the relative abundance of dominant families in response to the salinity regimes. The relative abundance of Myoviridae and Podoviridae were high in the euryhaline region and Siphoviridae in the mesohaline region of the estuary. The predominant phage type in CE was phages that infected Synechococcus. The viral proteins were found to be involved in major functional activities such as ATP binding, DNA binding, and DNA replication. The study highlights the genetic diversity of dsDNA viral communities and their functional protein predictions from a highly productive estuarine system. Further, the metavirome data generated in this study will enhance the repertoire of publicly available dataset and advance our understanding of estuarine viral ecology.
Mutations of FAM111B gene are not associated with Systemic Sclerosis
Authors: Gcelu A. , Deshpande G. , Shaboodien G. , Spracklen T. F. , Kalla A. , Tikly M. , Mayosi B. M. , Hodkinson B
Published: October 2018

Systemic sclerosis (SSc) is a prototypic systemic fibrotic disease with unclearly characterized genetic basis. We have discovered that mutations in family with sequence similarity 111, member B (FAM111B) gene cause hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis, a multisystem fibrotic condition with clinical similarities to SSc. This observation has established FAM111B as a candidate gene for SSc. Patients and Methods: Demographic and clinical characteristics of consenting adults with definite SSc were recorded. Blood DNA analysis was performed using the High-Resolution Melt technique, and samples with abnormal electropherograms were selected for Sanger sequencing to identify mutations. Ethnically-matched controls from the general South African population were used to verify the frequency of variants in FAM111B. Public databases such as 1000 Genomes and ExAC were also used to verify the frequency of variants in FAM111B. Results: Of 131 patients, 118 (90.1%) were female, and 78 (59.5%) were black Africans. Genetic analysis revealed two FAM111B genetic variants. The c.917 A > G variant (rs200497516) was found in one SSc patients, and one control, and was classified as a missense variant of unknown significance. The c.988 C > T variant (rs35732637) occurred in three SSc patients and 42/243 (17.3%) of healthy controls, and is a known polymorphism. Conclusion: One rare variant was found in a patient with SSc but has no functional or structural impact on the FAM111B gene. In this cohort, FAM111B gene mutations are not associated with SSc.
Long-ranged Protein-glycan Interactions Stabilize von Willebrand Factor A2 Domain from Mechanical Unfolding
Authors: Dong Chuqiao , Lee Jumin , Kim Seonghoon , Lai Whitney , Webb Edmund B. , Oztekin Alparslan , Zhang X. Frank , Im Wonpil
Published: October 2018

von Willebrand Factor (vWF) is a large multimeric protein that binds to platelets and collagen in blood clotting. vWF A2 domain hosts a proteolytic site for ADAMTS13 (A Disintegrin and Metalloprotease with a ThromboSpondin type 1 motif, member 13) to regulate the size of vWF multimers. This regulation process is highly sensitive to force conditions and protein-glycan interactions as the process occurs in flowing blood. There are two sites on A2 domain (N1515 and N1574) bearing various N-linked glycan structures. In this study, we used molecular dynamics (MD) simulation to study the force-induced unfolding of A2 domain with and without a single N-linked glycan type on each site. The sequential pullout of β-strands was used to represent a characteristic unfolding sequence of A2. This unfolding sequence varied due to protein-glycan interactions. The force-extension and total energy-extension profiles also show differences in magnitude but similar characteristic shapes between the systems with and without glycans. Systems with N-linked glycans encountered higher energy barriers for full unfolding and even for unfolding up to the point of ADAMTS13 cleavage site exposure. Interestingly, there is not much difference observed for A2 domain structure itself with and without glycans from standard MD simulations, suggesting roles of N-glycans in A2 unfolding through long-ranged protein-glycan interactions.
Quantitative study of 18F-(+)DTBZ image: comparison of PET template-based and MRI based image analysis
Authors: Jung Lung Hsu , Weng Yi-Hsin , Wen Ming-Ching , Hsiao Ing-Tsung , Lin Kun-Ju
Published: October 2018

[18F]9-fluoropropyl-(+)-dihydrotetrabenazine (18F-(+)DTBZ) is a recently developed PET tracer to investigate the vesicular monoamine transporter type 2 (VMAT2) activity in measuring dopaminergic degeneration in vivo and monitoring the severity of Parkinson’s disease (PD). However, manual drawing of the striatal regions is time consuming and prone to human bias. In the current study, we developed an automated method to quantify the signals of the striatum on 18F-(+)DTBZ images. 39 patients with PD and 26 controls were enrolled. Traditional brain magnetic resonance imaging (MRI) and 18F-(+)DTBZ PET were acquired. Both indirect normalization of native PET images to the standard space through individual brain MRI and directly coregistration of native images to the transporter-specific PET template in standard space were performed. Specific uptake ratios (SURs) in 10 predefined regions were used as indicators of VMAT2 activities to correlate with motor severity. Our results showed patients with PD had significant lower SURs in the bilateral putamina, caudates and globus pallidi than controls. SURs in the caudate and putamen were significantly correlated with motor severity. The contralateral putaminal region performed best in discriminating between PD patients and controls. Finally, the results from the application of the 18F-(+)DTBZ PET template were comparable to those derived from the traditional MRI based method. Thus, 18F-(+)DTBZ PET imaging holds the potential to effectively differentiate PD patients from controls. The 18F-(+)DTBZ PET template-based method for automated quantification of presynaptic VMAT2 transporter density is easier to implement and may facilitate efficient, robust and user-independent image analysis.
A neural network based model effectively predicts enhancers from clinical ATAC-seq samples
Authors: Thibodeau Asa , Uyar Asli , Khetan Shubham , Stitzel Michael L. , Ucar Duygu
Published: October 2018

Enhancers are cis-acting sequences that regulate transcription rates of their target genes in a cell-specific manner and harbor disease-associated sequence variants in cognate cell types. Many complex diseases are associated with enhancer malfunction, necessitating the discovery and study of enhancers from clinical samples. Assay for Transposase Accessible Chromatin (ATAC-seq) technology can interrogate chromatin accessibility from small cell numbers and facilitate studying enhancers in pathologies. However, on average, ~35% of open chromatin regions (OCRs) from ATAC-seq samples map to enhancers. We developed a neural network-based model, Predicting Enhancers from ATAC-Seq data (PEAS), to effectively infer enhancers from clinical ATAC-seq samples by extracting ATAC-seq data features and integrating these with sequence-related features (e.g., GC ratio). PEAS recapitulated ChromHMM-defined enhancers in CD14+ monocytes, CD4+ T cells, GM12878, peripheral blood mononuclear cells, and pancreatic islets. PEAS models trained on these 5 cell types effectively predicted enhancers in four cell types that are not used in model training (EndoC-βH1, naïve CD8+ T, MCF7, and K562 cells). Finally, PEAS inferred individual-specific enhancers from 19 islet ATAC-seq samples and revealed variability in enhancer activity across individuals, including those driven by genetic differences. PEAS is an easy-to-use tool developed to study enhancers in pathologies by taking advantage of the increasing number of clinical epigenomes.
Opposite Carcinogenic Effects of Circadian Clock Gene BMAL1
Authors: Korkmaz Tuba , Aygenli Fatih , Emisoglu Handan , Ozcelik Gozde , Canturk Asena , Yilmaz Secil , Ozturk Nuri
Published: October 2018

The circadian clock confers daily rhythmicity on many biochemical and physiological functions and its disruption is associated with increased risks of developing obesity, diabetes, heart disease and cancer. Although, there are studies on the role of Bmal1 in carcinogenesis using germline, conditional or tissue-specific knockouts, it is still not well understood how BMAL1 gene affects cancer-related biological events at the molecular level. We, therefore, took an in vitro approach to understand the contribution of BMAL1 in this molecular mechanism using human breast epithelial cell lines by knocking out BMAL1 gene with CRISPR technology. We preferred epithelial cells over fibroblasts as the most of cancers originate from epithelial cells. After obtaining BMAL1 knockouts by targeting the gene at two different sites from non-tumorigenic MCF10A and invasive tumorigenic MDA-MB-231 cells, we analysed apoptosis and invasion properties of the cell lines as representative events in tumor development. BMAL1 disruption sensitized both cell lines to a bulky-DNA adduct forming agent (cisplatin) and a double-strand break-inducing agent (doxorubicin), while it enhanced the invasive properties of MDA-MB-231 cells. These results show that the disruption of clock genes may have opposing carcinogenic effects.
Standardized phytotherapic extracts rescue anomalous locomotion and electrophysiological responses of TDP-43 Drosophila melanogaster model of ALS
Authors: Maccioni Riccardo , Setzu Maria Dolores , Talani Giuseppe , Solari Paolo , Kasture Ameya , Sucic Sonja , Porru Simona , Muroni Patrizia , Sanna Enrico , Kasture Sanjay , Acquas Elio , Liscia Anna
Published: October 2018

Findings from studies using animal models expressing amyotrophic lateral sclerosis (ALS) mutations in RNA-binding proteins, such as Transactive Response DNA-binding protein-43 (TDP-43), indicate that this protein, which is involved in multiple functions, including transcriptional regulation and pre-mRNA splicing, represents a key candidate in ALS development. This study focuses on characterizing, in a Drosophila genetic model of ALS (TDP-43), the effects of Mucuna pruriens (Mpe) and Withania somnifera (Wse). Electrophysiological and behavioural data in TDP-43 mutant flies revealed anomalous locomotion (i.e. impaired climbing with unexpected hyperactivity) and sleep dysregulation. These features, in agreement with previous findings with a different ALS model, were at least partially, rescued by treatment with Mpe and Wse. In addition, electrophysiological recordings from dorsal longitudinal muscle fibers and behavioral observations of TDP-43 flies exposed to the volatile anaesthetics, diethyl ether or chloroform, showed paradoxical responses, which were normalized upon Mpe or Wse treatment. Hence, given the involvement of some potassium channels in the effects of anaesthetics, our results also hint toward a possible dysregulation of some potassium channels in the ALS-TDP-43 Drosophila model, that might shed new light on future therapeutic strategies pertaining to ALS.
Association of domain-specific physical activity and cardiorespiratory fitness with all-cause and cause-specific mortality in two population-based cohort studies
Authors: Bahls Martin , Groß Stefan , Baumeister Sebastian E. , Völzke Henry , Gläser Sven , Ewert Ralf , Markus Marcello R. P. , Medenwald Daniel , Kluttig Alexander , Felix Stephan B. , Dörr Marcus
Published: October 2018

Physical activity (PA) reduces the risk for mortality. Whether the beneficial effects of PA are domain specific is unclear. We associated leisure time (LTPA), sports (SPA) and work (WPA) related PA and cardiorespiratory fitness (CRF) with all-cause mortality in two German population-based cohorts. We used data of the Study of Health in Pomerania (SHIP, n = 2,935, median age 53; 48% male) and the Cardiovascular Disease, Living and Ageing in Halle study (CARLA, n = 1,776, median age 64 and 54% male). Mortality was determined after a median follow-up of 8.2 years in SHIP (n = 332) and 11.5 years in CARLA (n = 409). LTPA (SHIP: hazard ratio [HR] per standard deviation [SD] 0.82 95%-CI 0.73 to 0.91 and CARLA: HR per SD 0.70: 95%-CI 0.59 to 0.82) and SPA (SHIP: HR per SD 0.80 95%-CI 0.71 to 0.91 and CARLA: HR per SD 0.70 95%-CI 0.60 to 0.82) but not WPA were inversely associated with all-cause mortality. In a subsample CRF was inversely related to mortality and positively to LTPA and sports SPA. No association was found for WPA. Our results may suggest that the inverse association between PA and mortality are partly influenced by higher CRF.
Chronic p27Kip1 Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor
Authors: Patki Mugdha , McFall Thomas , Rosati Rayna , Huang Yanfang , Malysa Agnes , Polin Lisa , Fielder Abigail , Wilson Mike R. , Lonardo Fulvio , Back Jessica , Li Jing , Matherly Larry H. , Bepler Gerold , Ratnam Manohar
Published: October 2018

Dexamethasone (Dex), co-administered to lung adenocarcinoma patients with pemetrexed chemotherapy, protects against pemetrexed cytotoxicity by inducing reversible G1 arrest, reflected by the effect of Dex on FLT-PET images of patient tumors. However, perioperative Dex treatment increases survival but the mechanism is unknown. In cells with glucocorticoid receptor-α (GR) expression corresponding to higher clinical tumor levels, Dex-induced growth arrest was followed by marked cell expansion, beta-galactosidase expression and Ki67 negativity, despite variable p53 and K-RAS status. Dex induced a transient early surge in p21Cip1. However, a progressive, irreversible loss of clonogenic growth, whose time of onset was dependent on GR level and Dex dose, was independent of p21Cip1and caused by gradual accumulation of p27Kip1 due to transcriptional activation of p27Kip1 by Dex. This effect was independent of canonical pathways of senescence or p27Kip1 regulation. The in vitro observations were reflected by growth suppression and P27Kip1 induction in GR-overexpressing tumor xenografts compared with isogenic low-GR tumors. Extended Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in GR overexpressing lung tumor cell populations and hence could improve outcome of surgery/pemetrexed chemotherapy and sensitize tumors to immunotherapy.