bluuebunny/crossref_metadata_2025 huggingface dataset:
An effect of flaps on the fourth formant in English
Authors: Warner Natasha , Tucker Benjamin V.
Published: July 2016

Very few segments of the world's languages have been shown to have a systematic effect on the fourth formant (F4). We investigate a large drop in F4 which sometimes occurs in conjunction with the flap in American English. The goal of the present work is to document this phenomenon, and to determine what phonological environments coincide with this large drop in F4. We measure data from six speakers producing words with medial flaps in various environments, such asparty, turtle, bottle, credit, harder. We find that the combination of flap with a rhotic and to a lesser extend a syllabic // leads to a larger drop in F4 than other flap combinations like a following /i/. Together with previous perceptual data, the findings support the conclusion that this feature of F4 results from transitions among articulations.
Distribution of grey wolves Canis lupus lupus in the Nepalese Himalaya: implications for conservation management
Authors: Subba Samundra Ambuhang , Shrestha Anil Kumar , Thapa Kanchan , Malla Sabita , Thapa Gokarna Jung , Shrestha Sujeet , Shrestha Shrota , Subedi Naresh , Bhattarai Gopal Prakash , Ottvall Richard
Published: July 2016

The grey wolf Canis lupus lupus is Critically Endangered in Nepal, and is a protected species there. Understanding the species’ status and distribution is critical for its conservation in the Nepalese Himalaya. We assessed the distribution of the grey wolf in the Himalayan and Trans-Himalayan regions using data from faecal and camera trap surveys and published data sources. We recorded 40 instances of wolf presence. Using these data we estimated a distribution of 28,553 km2, which includes potential as well as known habitat and comprises 73% of the Nepalese Himalaya. There is evidence of recovery of the grey wolf population in Kanchenjunga Conservation Area in the eastern portion of the species’ range. A livestock insurance scheme has been shown to be a viable option to reduce retaliatory killing of wolves as a result of livestock depredation. The wolf plays an important ecological role in the Himalaya, and its conservation should not be delayed by the ongoing taxonomic debate about its subspecific status.
AGING, THE GREAT MODERATION, AND BUSINESS-CYCLE VOLATILITY IN A LIFE-CYCLE MODEL
Authors: Heer Burkhard , Rohrbacher Stefan , Scharrer Christian
Published: July 2016

According to empirical studies, the life cycle of labor supply volatility exhibits a U-shaped pattern. This may lead to the conclusion that demographic change induces a drop in output volatility. We present an overlapping-generations model that replicates the empirically observed pattern and study the impact of demographic transition on output volatility. We find that the change in age composition itself has only a marginal influence on output volatility, as the mitigating effect of more individuals with lower labor supply volatilities is compensated for by higher age-specific labor shares. Instead, the driving force behind the Great Moderation in our model is the downward shift of the age-specific labor supply volatility curve.
GENEALOGICAL STELES IN NORTH CHINA DURING THE JIN AND YUAN DYNASTIES
Authors: Iiyama Tomoyasu
Published: July 2016

Using both long forgotten and newly available steles from North China, this article looks at these ancient monuments to explore the rise and evolution of an epigraphic practice under Jurchen and Mongol rules (1127–1368). In particular it looks at steles erected to record genealogical information (calledxianyingbeiin general) in north China during the twelfth to fourteenth centuries, which was a new usage for the stele in the area. The article's main aim is to demonstrate how cultural integration among different social strata was triggered by the invasions of the Jurchen and Mongol conquerors, which in turn led to the formation of a new and legitimate way to compile family genealogies in north China.
CLERGY, KINSHIP, AND CLOUT IN YUAN DYNASTY SHANXI
Authors: Wang Jinping
Published: July 2016

During the thirteenth and fourteenth centuries, people in north China took advantage of a Mongol policy that gave Buddhist officials a status equivalent to what civil officials enjoyed, as a strategy for family advancement. Monk Zhang Zhiyu and his family provide a case study of an emerging influential Buddhist order based at Mount Wutai that connected the Yuan regime with local communities through the kinship ties of prominent monks. Within this Buddhist order, powerful monks like Zhiyu used their prestigious positions in the clerical world to help the upward social mobility of their lay families, displaying a distinctive pattern of interpenetration between Buddhism and family. This new pattern also fit the way that northern Chinese families used Buddhist structures such as Zunsheng Dhāranῑ pillars and private Buddhist chapels to record their genealogies and consolidate kinship ties.
Integrated Marine Research for Sustainable Ocean Development
Authors: Braker Gesche , Visbeck Martin , Smith Nancy
Published: July 2016

Sustainable Ocean Development—A Perspective from Former, Current and Future Kiel Marine Scientists; New York, 28–30 September 2015
Post-translational modifications as key regulators of TNF-induced necroptosis
Authors: Liu X , Shi F , Li Y , Yu X , Peng S , Li W , Luo X , Cao Y
Published: July 2016

Necroptosis is a novel form of programmed cell death that is independent of caspase activity. Different stimuli can trigger necroptosis. At present, the most informative studies about necroptosis derive from the tumor necrosis factor (TNF)-triggered system. The initiation of TNF-induced necroptosis requires the kinase activity of receptor-interacting protein 1 and 3 (RIP1 and RIP3). Evidence now reveals that the ability of RIP1 and RIP3 to modulate this key cellular event is tightly controlled by post-translational modifications, including ubiquitination, phosphorylation, caspase 8-mediated cleavage and GlcNAcylation. These regulatory events coordinately determine whether a cell will survive or die by apoptosis or necroptosis. In this review, we highlight recent advances in the study of post-translational modifications during TNF-induced necroptosis and discuss how these modifications regulate the complex and delicate control of programmed necrosis.
Extra-coding RNAs regulate neuronal DNA methylation dynamics
Authors: Savell Katherine E. , Gallus Nancy V. N. , Simon Rhiana C. , Brown Jordan A. , Revanna Jasmin S. , Osborn Mary Katherine , Song Esther Y. , O’Malley John J. , Stackhouse Christian T. , Norvil Allison , Gowher Humaira , Sweatt J. David , Day Jeremy J.
Published: July 2016

Epigenetic mechanisms such as DNA methylation are essential regulators of the function and information storage capacity of neurons. DNA methylation is highly dynamic in the developing and adult brain, and is actively regulated by neuronal activity and behavioural experiences. However, it is presently unclear how methylation status at individual genes is targeted for modification. Here, we report that extra-coding RNAs (ecRNAs) interact with DNA methyltransferases and regulate neuronal DNA methylation. Expression of ecRNA species is associated with gene promoter hypomethylation, is altered by neuronal activity, and is overrepresented at genes involved in neuronal function. Knockdown of the Fos ecRNA locus results in gene hypermethylation and mRNA silencing, and hippocampal expression of Fos ecRNA is required for long-term fear memory formation in rats. These results suggest that ecRNAs are fundamental regulators of DNA methylation patterns in neuronal systems, and reveal a promising avenue for therapeutic targeting in neuropsychiatric disease states.
High potential for weathering and climate effects of non-vascular vegetation in the Late Ordovician
Authors: Porada P. , Lenton T. M. , Pohl A. , Weber B. , Mander L. , Donnadieu Y. , Beer C. , Pöschl U. , Kleidon A.
Published: July 2016

It has been hypothesized that predecessors of today’s bryophytes significantly increased global chemical weathering in the Late Ordovician, thus reducing atmospheric CO2 concentration and contributing to climate cooling and an interval of glaciations. Studies that try to quantify the enhancement of weathering by non-vascular vegetation, however, are usually limited to small areas and low numbers of species, which hampers extrapolating to the global scale and to past climatic conditions. Here we present a spatially explicit modelling approach to simulate global weathering by non-vascular vegetation in the Late Ordovician. We estimate a potential global weathering flux of 2.8 (km3 rock) yr−1, defined here as volume of primary minerals affected by chemical transformation. This is around three times larger than today’s global chemical weathering flux. Moreover, we find that simulated weathering is highly sensitive to atmospheric CO2 concentration. This implies a strong negative feedback between weathering by non-vascular vegetation and Ordovician climate.
Gene expression signatures of human cell and tissue longevity
Authors: Seim Inge , Ma Siming , Gladyshev Vadim N
Published: July 2016

Different cell types within the body exhibit substantial variation in the average time they live, ranging from days to the lifetime of the organism. The underlying mechanisms governing the diverse lifespan of different cell types are not well understood. To examine gene expression strategies that support the lifespan of different cell types within the human body, we obtained publicly available RNA-seq data sets and interrogated transcriptomes of 21 somatic cell types and tissues with reported cellular turnover, a bona fide estimate of lifespan, ranging from 2 days (monocytes) to a lifetime (neurons). Exceptionally long-lived neurons presented a gene expression profile of reduced protein metabolism, consistent with neuronal survival and similar to expression patterns induced by longevity interventions such as dietary restriction. Across different cell lineages, we identified a gene expression signature of human cell and tissue turnover. In particular, turnover showed a negative correlation with the energetically costly cell cycle and factors supporting genome stability, concomitant risk factors for aging-associated pathologies. In addition, the expression of p53 was negatively correlated with cellular turnover, suggesting that low p53 activity supports the longevity of post-mitotic cells with inherently low risk of developing cancer. Our results demonstrate the utility of comparative approaches in unveiling gene expression differences among cell lineages with diverse cell turnover within the same organism, providing insights into mechanisms that could regulate cell longevity.
Use of spirometry among chest physicians and primary care physicians in India
Authors: Vanjare Nitin , Chhowala Sushmeeta , Madas Sapna , Kodgule Rahul , Gogtay Jaideep , Salvi Sundeep
Published: July 2016

Although spirometry is the gold-standard diagnostic test for obstructive airways diseases, it remains poorly utilised in clinical practice. We aimed to investigate the use of spirometry across India, the change in its usage over a period of time and to understand the reasons for its under-utilisation. Two nationwide surveys were conducted in the years 2005 and 2013, among four groups of doctors: chest physicians (CPs), general physicians (GenPs), general practitioners (GPs) and paediatricians (Ps). A total of 1,000 physicians from each of the four groups were randomly selected from our database in the years 2005 and 2013. These surveys were conducted in 52 cities and towns across 15 states in India. A questionnaire was administered to the physicians, which captured information about their demographic details, type of practice and use of spirometry. The overall response rates of the physicians in 2005 and 2013 were 42.8% and 54.9%, respectively. Spirometry was reported to be used by 55% CPs, 20% GenPs, 10% GPs and 5% Ps in 2005, and this increased by 30.9% among CPs (P value <0.01), 18% among GenPs (P value=0.01), 20% among GPs (P value: not significant) and 224% among Ps (P value <0.01). The reasons for not using spirometry varied between 2005 and 2013. In all, 32.2% of physicians were unaware of which predicted equation they were using. The use of spirometry in India is low, although it seems to have improved over the years. The reasons identified in this study for under-utilisation should be used to address initiatives to improve the use of spirometry in clinical practice.
A method to identify and analyze biological programs through automated reasoning
Authors: Yordanov Boyan , Dunn Sara-Jane , Kugler Hillel , Smith Austin , Martello Graziano , Emmott Stephen
Published: July 2016

Predictive biology is elusive because rigorous, data-constrained, mechanistic models of complex biological systems are difficult to derive and validate. Current approaches tend to construct and examine static interaction network models, which are descriptively rich, but often lack explanatory and predictive power, or dynamic models that can be simulated to reproduce known behavior. However, in such approaches implicit assumptions are introduced as typically only one mechanism is considered, and exhaustively investigating all scenarios is impractical using simulation. To address these limitations, we present a methodology based on automated formal reasoning, which permits the synthesis and analysis of the complete set of logical models consistent with experimental observations. We test hypotheses against all candidate models, and remove the need for simulation by characterizing and simultaneously analyzing all mechanistic explanations of observed behavior. Our methodology transforms knowledge of complex biological processes from sets of possible interactions and experimental observations to precise, predictive biological programs governing cell function.
Controllable Molecule Transport and Release by a Restorable Surface-tethered DNA nanodevice
Authors: Wang Zhaoyin , Xu Yuanyuan , Wang Haiyan , Liu Fengzhen , Ren Zhenning , Wang Zhaoxia
Published: July 2016

In this paper, we report a novel surface-tethered DNA nanodevice that may present three states and undergo conformational changes under the operation of pH. Besides, convenient regulation on the electrode surface renders the construction and operation of this DNA nanodevice restorable. To make full use of this DNA nanodevice, ferrocene (Fc) has been further employed for the fabrication of the molecular device. On one hand, the state switches of the DNA nanodevice can be characterized conveniently and reliably by the obtained electrochemical signals from Fc. On the other hand, β-cyclodextrin-ferrocene (β-CD-Fc) host-guest system can be introduced by Fc, which functionalizes this molecular device. Based on different electrochemical behaviors of β-CD under different states, this DNA nanodevice can actualize directional loading, transporting and unloading of β-CD in nanoscale. Therefore, this DNA nanodevice bares promising applications in controllable molecular transport and release, which are of great value to molecular device design.
How antibodies alter the cell entry pathway of dengue virus particles in macrophages
Authors: Ayala-Nunez Nilda V. , Hoornweg Tabitha E. , van de Pol Denise P.I. , Sjollema Klaas A. , Flipse Jacky , van der Schaar Hilde M. , Smit Jolanda M.
Published: July 2016

Antibody-dependent enhancement of dengue virus (DENV) infection plays an important role in the exacerbation of DENV-induced disease. To understand how antibodies influence the fate of DENV particles, we explored the cell entry pathway of DENV in the absence and presence of antibodies in macrophage-like P388D1 cells. Recent studies unraveled that both mature and immature DENV particles contribute to ADE, hence, both particles were studied. We observed that antibody-opsonized DENV enters P388D1 cells through a different pathway than non-opsonized DENV. Antibody-mediated DENV entry was dependent on FcγRs, pH, Eps15, dynamin, actin, PI3K, Rab5 and Rab7. In the absence of antibodies, DENV cell entry was FcγR, PI3K and Rab5-independent. Live-cell imaging of fluorescently-labeled particles revealed that actin-mediated membrane protrusions facilitate virus uptake. In fact, actin protrusions were found to actively search and capture antibody-bound virus particles distantly located from the cell body, a phenomenon that is not observed in the absence of antibodies. Overall, similar results were seen for antibody-opsonized standard and antibody-bound immature DENV preparations, indicating that the maturation status of the virus does not control the entry pathway. Collectively, our findings suggest that antibodies alter the cell entry pathway of DENV and trigger a novel mechanism of initial virus-cell contact.
Stiffness of the microenvironment upregulates ERBB2 expression in 3D cultures of MCF10A within the range of mammographic density
Authors: Cheng Qingsu , Bilgin Cemal Cagatay , Fontenay Gerald , Chang Hang , Henderson Matthew , Han Ju , Parvin Bahram
Published: July 2016

The effects of the stiffness of the microenvironment on the molecular response of 3D colony organization, at the maximum level of mammographic density (MD), are investigated. Phenotypic profiling reveals that 3D colony formation is heterogeneous and increased stiffness of the microenvironment, within the range of the MD, correlates with the increased frequency of aberrant 3D colony formation. Further integrative analysis of the genome-wide transcriptome and phenotypic profiling hypothesizes overexpression of ERBB2 in the premalignant MCF10A cell lines at a stiffness value that corresponds to the collagen component at high mammographic density. Subsequently, ERBB2 overexpression has been validated in the same cell line. Similar experiments with a more genetically stable cell line of 184A1 also revealed an increased frequency of aberrant colony formation with the increased stiffness; however, 184A1 did not demonstrate overexpression of ERBB2 at the same stiffness value of the high MD. These results suggest that stiffness exacerbates premalignant cell line of MCF10A.
Neural networks within multi-core optic fibers
Authors: Cohen Eyal , Malka Dror , Shemer Amir , Shahmoon Asaf , Zalevsky Zeev , London Michael
Published: July 2016

Hardware implementation of artificial neural networks facilitates real-time parallel processing of massive data sets. Optical neural networks offer low-volume 3D connectivity together with large bandwidth and minimal heat production in contrast to electronic implementation. Here, we present a conceptual design for in-fiber optical neural networks. Neurons and synapses are realized as individual silica cores in a multi-core fiber. Optical signals are transferred transversely between cores by means of optical coupling. Pump driven amplification in erbium-doped cores mimics synaptic interactions. We simulated three-layered feed-forward neural networks and explored their capabilities. Simulations suggest that networks can differentiate between given inputs depending on specific configurations of amplification; this implies classification and learning capabilities. Finally, we tested experimentally our basic neuronal elements using fibers, couplers and amplifiers and demonstrated that this configuration implements a neuron-like function. Therefore, devices similar to our proposed multi-core fiber could potentially serve as building blocks for future large-scale small-volume optical artificial neural networks.
miR-7a/b attenuates post-myocardial infarction remodeling and protects H9c2 cardiomyoblast against hypoxia-induced apoptosis involving Sp1 and PARP-1
Authors: Li Rui , Geng Hai-hua , Xiao Jie , Qin Xiao-teng , Wang Fu , Xing Jun-hui , Xia Yan-fei , Mao Yang , Liang Jing-wen , Ji Xiao-ping
Published: July 2016

miRs (microRNAs, miRNAs) intricately regulate physiological and pathological processes. Although miR-7a/b protects against cardiomyocyte injury in ischemia/reperfusion injury, the function of miR-7a/b in myocardial infarction (MI)-induced cardiac remodeling remains unclear. Here, we sought to investigate the function of miR-7a/b in post-MI remodeling in a mouse model and to determine the underlying mechanisms involved. miR-7a/b overexpression improved cardiac function, attenuated cardiac remodeling and reduced fibrosis and apoptosis, whereas miR-7a/b silencing caused the opposite effects. Furthermore, miR-7a/b overexpression suppressed specific protein 1 (Sp1) and poly (ADP-ribose) polymerase (PARP-1) expression both in vivo and in vitro and a luciferase reporter activity assay showed that miR-7a/b could directly bind to Sp1. Mithramycin, an inhibitor of the DNA binding activity of Sp1, effectively repressed PARP-1 and caspase-3, whereas knocking down miR-7a/b partially counteracted these beneficial effects. Additionally, an immunoprecipitation assay indicated that hypoxia triggered activation of the binding activity of Sp1 to the promoters of PARP-1 and caspase-3, which is abrogated by miR-7a/b. In summary, these findings identified miR-7a/b as protectors of cardiac remodeling and hypoxia-induced injury in H9c2 cardiomyoblasts involving Sp1 and PARP-1.
Exome sequencing in pooled DNA samples to identify maternal pre-eclampsia risk variants
Authors: Kaartokallio Tea , Wang Jingwen , Heinonen Seppo , Kajantie Eero , Kivinen Katja , Pouta Anneli , Gerdhem Paul , Jiao Hong , Kere Juha , Laivuori Hannele
Published: July 2016

Pre-eclampsia is a common pregnancy disorder that is a major cause for maternal and perinatal mortality and morbidity. Variants predisposing to pre-eclampsia might be under negative evolutionary selection that is likely to keep their population frequencies low. We exome sequenced samples from a hundred Finnish pre-eclamptic women in pools of ten to screen for low-frequency, large-effect risk variants for pre-eclampsia. After filtering and additional genotyping steps, we selected 28 low-frequency missense, nonsense and splice site variants that were enriched in the pre-eclampsia pools compared to reference data, and genotyped the variants in 1353 pre-eclamptic and 699 non-pre-eclamptic women to test the association of them with pre-eclampsia and quantitative traits relevant for the disease. Genotypes from the SISu project (n = 6118 exome sequenced Finnish samples) were included in the binary trait association analysis as a population reference to increase statistical power. In these analyses, none of the variants tested reached genome-wide significance. In conclusion, the genetic risk for pre-eclampsia is likely complex even in a population isolate like Finland, and larger sample sizes will be necessary to detect risk variants.
Dipeptidyl peptidase-4 inhibitors and fracture risk: an updated meta-analysis of randomized clinical trials
Authors: Fu Jianying , Zhu Jianhong , Hao Yehua , Guo Chongchong , Zhou Zhikun
Published: July 2016

Data on the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on fracture risk are conflicting. Here, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of DPP-4 inhibitors. Electronic databases were searched for relevant published articles, and unpublished studies presented at ClinicalTrials.gov were searched for relevant clinical data. Eligible studies included prospective randomized trials evaluating DPP-4 inhibitors versus placebo or other anti-diabetic medications in patients with type 2 diabetes. Study quality was determined using Jadad scores. Statistical analyses were performed to calculate the risk ratios (RRs) and 95% confidence intervals (CIs) using fixed-effects models. There were 62 eligible RCTs with 62,206 participants, including 33,452 patients treated with DPP-4 inhibitors. The number of fractures was 364 in the exposed group and 358 in the control group. The overall risk of fracture did not differ between patients exposed to DPP-4 inhibitors and controls (RR, 0.95; 95% CI, 0.83–1.10; P = 0.50). The results were consistent across subgroups defined by type of DPP-4 inhibitor, type of control, and length of follow-up. The study showed that DPP-4 inhibitor use does not modify the risk of bone fracture compared with placebo or other anti-diabetic medications in patients with type 2 diabetes.
Airflow-aligned helical nanofilament (B4) phase in topographic confinement
Authors: Gim Min-Jun , Kim Hanim , Chen Dong , Shen Yongqiang , Yi Youngwoo , Korblova Eva , Walba David M. , Clark Noel A. , Yoon Dong Ki
Published: July 2016

We investigated a controlled helical nanofilament (HNF: B4) phase under topographic confinement with airflow that can induce a shear force and temperature gradient on the sample. The resulting orientation and ordering of the B4 phase in this combinational effort was directly investigated using microscopy. The structural freedom of the complex B7 phase, which is a higher temperature phase than the B4 phase, can result in relatively complex microscopic arrangements of HNFs compared with the B4 phase generated from the simple layer structure of the B2 phase. This interesting chiral/polar nanofilament behaviour offers new opportunities for further exploration of the exotic physical properties of the B4 phase.
Interactive Organization of the Circadian Core Regulators PER2, BMAL1, CLOCK and PML
Authors: Miki Takao , Zhao Zhaoyang , Lee Cheng Chi
Published: July 2016

The BMAL1 and CLOCK heterodimer in the mammalian circadian transcriptional complex is thought to be repressed by PER2 and CRY1 via direct interactions. We recently reported that PER2 is largely cytosolic in Pml−/− cells and did not co-immunoprecipitate (co-IP) with BMAL1 or CLOCK. Here, using multi-color immunofluorescence (IF) staining and co-IP, we observed a nuclear distribution of BMAL1 and a predominately cytosolic distribution of CLOCK in Pml−/− MEF. In the presence of WT PML, PER2 co-localized with BMAL1 in the nucleus. In Pml−/− MEF transfected with mutant K487R PML, we observed that BMAL1 and PER2 co-localized with K487R PML in the cytosol. Furthermore, cytosolic CLOCK and PER2 displayed a significant non-overlapping IF staining pattern. In Bmal1−/− MEF, CLOCK was primarily cytosolic while PML and PER2 were nuclear. Together, our studies suggest that PML mediates the binding of PER2 to BMAL1 in the BMAL1/CLOCK heterodimer and is an important component in the organization of a functional clock complex in the nucleus. Our studies also support that BMAL1 is important for CLOCK nuclear localization.
A novel Plasmodium falciparum rhoptry associated adhesin mediates erythrocyte invasion through the sialic-acid dependent pathway
Authors: Anand Gaurav , Reddy K. Sony , Pandey Alok Kumar , Mian Syed Yusuf , Singh Hina , Mittal Shivani Arora , Amlabu Emmanuel , Bassat Quique , Mayor Alfredo , Chauhan Virander Singh , Gaur Deepak
Published: July 2016

Erythrocyte invasion by Plasmodium falciparum merozoites is central to blood-stage infection and malaria pathogenesis. This intricate process is coordinated by multiple parasite adhesins that bind erythrocyte receptors and mediate invasion through several alternate pathways. P. falciparum expresses 2700 genes during the blood-stages, of which the identity and function of many remains unknown. Here, we have identified and characterized a novel P. falciparum rhoptry associated adhesin (PfRA) that mediates erythrocyte invasion through the sialic-acid dependent pathway. PfRA appears to play a significant functional role as it is conserved across different Plasmodium species. It is localized in the rhoptries and further translocated to the merozoite surface. Both native and recombinant PfRA specifically bound erythrocytes in a sialic-acid dependent, chymotrypsin and trypsin resistant manner, which was abrogated by PfRA antibodies confirming a role in erythrocyte invasion. PfRA antibodies inhibited erythrocyte invasion and in combination with antibodies against other parasite ligands produced an additive inhibitory effect, thus validating its important role in erythrocyte invasion. We have thus identified a novel P. falciparum adhesin that binds with a sialic acid containing erythrocyte receptor. Our observations substantiate the strategy to block P. falciparum erythrocyte invasion by simultaneously targeting multiple conserved merozoite antigens involved in alternate invasion pathways.
Macular sub-layer thinning and association with pulmonary function tests in Amyotrophic Lateral Sclerosis
Authors: Simonett Joseph M. , Huang Russell , Siddique Nailah , Farsiu Sina , Siddique Teepu , Volpe Nicholas J. , Fawzi Amani A.
Published: July 2016

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder that may have anterior visual pathway involvement. In this study, we compare the macular structure of patients with ALS to healthy controls and examine correlations between macular sub-layer thickness measurements and pulmonary function tests and disease duration. ALS patients underwent optical coherence tomography (OCT) imaging to obtain macular cube scans of the right eye. Macular cube OCT data from age-matched healthy subjects were provided by the OCT reading center. Semi-automated retinal segmentation software was used to quantify macular sub-layers. Pulmonary function tests and time since symptom onset were collected retrospectively from the electronic medical records of ALS patients. Macular retinal nerve fiber layer was significantly thinner in ALS patients compared to healthy controls (P < 0.05). Total macular and other sub-layer thicknesses were not reduced in the ALS cohort. Macular retinal nerve fiber layer thickness positively correlated with forced vital capacity % predicted and forced expiratory volume in 1 second % predicted (P < 0.05). In conclusion, analysis of OCT measurements supports the involvement of the anterior visual pathway in ALS. Subtle structural thinning in the macular retinal nerve fiber layer correlates with pulmonary function tests.
Estimation of brain network ictogenicity predicts outcome from epilepsy surgery
Authors: Goodfellow M. , Rummel C. , Abela E. , Richardson M. P. , Schindler K. , Terry J. R.
Published: July 2016

Surgery is a valuable option for pharmacologically intractable epilepsy. However, significant post-operative improvements are not always attained. This is due in part to our incomplete understanding of the seizure generating (ictogenic) capabilities of brain networks. Here we introduce an in silico, model-based framework to study the effects of surgery within ictogenic brain networks. We find that factors conventionally determining the region of tissue to resect, such as the location of focal brain lesions or the presence of epileptiform rhythms, do not necessarily predict the best resection strategy. We validate our framework by analysing electrocorticogram (ECoG) recordings from patients who have undergone epilepsy surgery. We find that when post-operative outcome is good, model predictions for optimal strategies align better with the actual surgery undertaken than when post-operative outcome is poor. Crucially, this allows the prediction of optimal surgical strategies and the provision of quantitative prognoses for patients undergoing epilepsy surgery.
Production of dumbbell probe through hairpin cleavage-ligation and increasing RCA sensitivity and specificity by circle to circle amplification
Authors: Wei Hua , Tang Suming , Hu Tianyu , Zhao Guojie , Guan Yifu
Published: July 2016

Dumbbell probe (DP) attracts increasing interests in rolling circle amplification (RCA). A universal DP production method through cleavage-ligation of hairpin was proposed and optimized. The production is characterized by restriction endonuclease (RE)-induced cleavage ends ligation. It has the advantage of phosphorylation-free, splint-free and purification-free. To optimize designing, we found that the position of RE cleavage sequence in the stem and the primer position in the loop affected the formation and amplification of DP obviously. Both sticky and blunt ends cleaved by RE produce DP efficiently. Moreover, we introduced this DP into circle to circle (C2C) RCA based on the same cleavage-ligation principle and acquired high sensitivity. By combining a two-ligation design and the C2C strategy, specificity for detecting let-7 family members was increased extremely. Furthermore, coreaction of different steps facilitated convenient formation and amplification process of DP.
Inverse scattering transform analysis of rogue waves using local periodization procedure
Authors: Randoux Stéphane , Suret Pierre , El Gennady
Published: July 2016

The nonlinear Schrödinger equation (NLSE) stands out as the dispersive nonlinear partial differential equation that plays a prominent role in the modeling and understanding of the wave phenomena relevant to many fields of nonlinear physics. The question of random input problems in the one-dimensional and integrable NLSE enters within the framework of integrable turbulence and the specific question of the formation of rogue waves (RWs) has been recently extensively studied in this context. The determination of exact analytic solutions of the focusing 1D-NLSE prototyping RW events of statistical relevance is now considered as the problem of central importance. Here we address this question from the perspective of the inverse scattering transform (IST) method that relies on the integrable nature of the wave equation. We develop a conceptually new approach to the RW classification in which appropriate, locally coherent structures are specifically isolated from a globally incoherent wave train to be subsequently analyzed by implementing a numerical IST procedure relying on a spatial periodization of the object under consideration. Using this approach we extend the existing classifications of the prototypes of RWs from standard breathers and their collisions to more general nonlinear modes characterized by their nonlinear spectra.
A high-sensitivity HPLC assay for measuring intracellular Na+ and K+ and its application to Plasmodium falciparum infected erythrocytes
Authors: Winterberg Markus , Kirk Kiaran
Published: July 2016

The measurement of intracellular ion concentrations, and the screening of chemical agents to identify molecules targeting ion transport, has traditionally involved low-throughput techniques. Here we present a novel HPLC method that allows the rapid, high-sensitivity measurement of cell Na+ and K+ content, demonstrating its utility by monitoring the ionic changes induced in the intracellular malaria parasite by the new spiroindolone antimalarial KAE609.
The role of interconnectivity in control of an Ebola epidemic
Authors: Blackwood J. C. , Childs L. M.
Published: July 2016

Several West African countries - Liberia, Sierra Leone and Guinea - experienced significant morbidity and mortality during the largest Ebola epidemic to date, from late 2013 through 2015. The extent of the epidemic was fueled by outbreaks in large urban population centers as well as movement of the pathogen between populations. During the epidemic there was no known vaccine or drug, so effective disease control required coordinated efforts that include both standard medical and community practices such as hospitalization, quarantine and safe burials. Due to the high connectivity of the region, control of the epidemic not only depended on internal strategies but also was impacted by neighboring countries. In this paper, we use a deterministic framework to examine the role of movement between two populations in the overall success of practices designed to minimize the extent of Ebola epidemics. We find that it is possible for even small amounts of intermixing between populations to positively impact the control of an epidemic on a more global scale.
Serum BAFF levels, Methypredsinolone therapy, Epstein-Barr Virus and Mycobacterium avium subsp. paratuberculosis infection in Multiple Sclerosis patients
Authors: Mameli Giuseppe , Cocco Eleonora , Frau Jessica , Arru Giannina , Caggiu Elisa , Marrosu Maria Giovanna , Sechi Leonardo A.
Published: July 2016

Elevated B lymphocyte activating factor BAFF levels have been reported in multiple sclerosis (MS) patients; moreover, disease-modifying treatments (DMT) have shown to influence blood BAFF levels in MS patients, although the significance of these changes is still controversial. In addition, BAFF levels were reported increased during infectious diseases. In our study, we wanted to investigate on the serum BAFF concentrations correlated to the antibody response against Mycobacterium avium subspecies paratuberculosis (MAP), Epstein-Barr virus (EBV) and their human homologous epitopes in MS and in patients affected with other neurological diseases (OND), divided in Inflammatory Neurological Diseases (IND), Non Inflammatory Neurological Diseases (NIND) and Undetermined Neurological Diseases (UND), in comparison to healthy controls (HCs). Our results confirmed a statistically significant high BAFF levels in MS and IND patients in comparison to HCs but not NIND and UND patients. Interestingly, BAFF levels were inversely proportional to antibodies level against EBV and MAP peptides and the BAFF levels significantly decreased in MS patients after methylprednisolone therapy. These results implicate that lower circulating BAFF concentrations were present in MS patients with humoral response against MAP and EBV. In conclusion MS patients with no IgGs against EBV and MAP may support the hypothesis that elevated blood BAFF levels could be associated with a more stable disease.
Caenorhabditis elegans employs innate and learned aversion in response to bacterial toxic metabolites tambjamine and violacein
Authors: Ballestriero Francesco , Nappi Jadranka , Zampi Giuseppina , Bazzicalupo Paolo , Di Schiavi Elia , Egan Suhelen
Published: July 2016

Bacteriovorus eukaryotes such as nematodes are one of the major natural predators of bacteria. In their defense bacteria have evolved a number of strategies to avoid predation, including the production of deterrent or toxic metabolites, however little is known regarding the response of predators towards such bacterial defenses. Here we use the nematode C. elegans as a model to study a predators’ behavioral response towards two toxic bacterial metabolites, tambjamine YP1 and violacein. We found that C. elegans displays an innate avoidance behavior towards tambjamine YP1, however requires previous exposure to violacein before learning to avoid this metabolite. The learned avoidance of violacein is specific, reversible, is mediated via the nematode olfactory apparatus (aversive olfactory learning) and is reduced in the absence of the neurotransmitter serotonin. These multiple strategies to evade bacterial toxic metabolites represent a valuable behavioral adaptation allowing bacteriovorus predators to distinguish between good and bad food sources, thus contributing to the understanding of microbial predator-prey interactions.
Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling
Authors: Clausen Bettina Hjelm , Degn Matilda , Sivasaravanaparan Mithula , Fogtmann Torben , Andersen Maria Gammelstrup , Trojanowsky Michelle D. , Gao Han , Hvidsten Svend , Baun Christina , Deierborg Tomas , Finsen Bente , Kristensen Bjarne Winther , Bak Sara Thornby , Meyer Morten , Lee Jae , Nedospasov Sergei A. , Brambilla Roberta , Lambertsen Kate Lykke
Published: July 2016

Microglia are activated following cerebral ischemia and increase their production of the neuro- and immunomodulatory cytokine tumor necrosis factor (TNF). To address the function of TNF from this cellular source in focal cerebral ischemia we used TNF conditional knock out mice (LysMcreTNFfl/fl) in which the TNF gene was deleted in cells of the myeloid lineage, including microglia. The deletion reduced secreted TNF levels in lipopolysaccharide-stimulated cultured primary microglia by ~93%. Furthermore, phosphorylated-ERK/ERK ratios were significantly decreased in naïve LysMcreTNFfl/fl mice demonstrating altered ERK signal transduction. Micro-PET using 18[F]-fluorodeoxyglucose immediately after focal cerebral ischemia showed increased glucose uptake in LysMcreTNFfl/fl mice, representing significant metabolic changes, that translated into increased infarct volumes at 24 hours and 5 days compared to littermates (TNFfl/fl). In naïve LysMcreTNFfl/fl mice cytokine levels were low and comparable to littermates. At 6 hours, TNF producing microglia were reduced by 56% in the ischemic cortex in LysMcreTNFfl/fl mice compared to littermate mice, whereas no TNF+ leukocytes were detected. At 24 hours, pro-inflammatory cytokine (TNF, IL-1β, IL-6, IL-5 and CXCL1) levels were significantly lower in LysMcreTNFfl/fl mice, despite comparable infiltrating leukocyte populations. Our results identify microglial TNF as beneficial and neuroprotective in the acute phase and as a modulator of neuroinflammation at later time points after experimental ischemia, which may contribute to regenerative recovery.
Point contact resistive switching memory based on self-formed interface of Al/ITO
Authors: Li Qiuhong , Qiu Linjun , Wei Xianhua , Dai Bo , Zeng Huizhong
Published: July 2016

Point contact resistive switching random access memory (RRAM) has been achieved by directly sputtering Al electrodes on indium tin oxide (ITO) conductive glasses. The room-temperature deposited Al/ITO shows an asymmetrical bipolar resistive switching (BRS) behavior after a process of initialization which induces a stable high resistive state (HRS). It might be caused by the in-situ formation of an ultra-thin layer (≈4 nm) at the interface. By comparison, the Al/ITO device after vacuum annealed exhibits typical symmetrical BRS without an initiation or electroforming process. This can be ascribed to the ex-situ thickening of the interfacial layer (≈9.2 nm) to achieve the stable HRS after heat treatment. This work suggests that the self-formed interface of active Al electrode/ITO would provide the simplest geometry to construct RRAM.
Adaptive immunity against gut microbiota enhances apoE-mediated immune regulation and reduces atherosclerosis and western-diet-related inflammation
Authors: Saita Diego , Ferrarese Roberto , Foglieni Chiara , Esposito Antonio , Canu Tamara , Perani Laura , Ceresola Elisa Rita , Visconti Laura , Burioni Roberto , Clementi Massimo , Canducci Filippo
Published: July 2016

Common features of immune-metabolic and inflammatory diseases such as metabolic syndrome, diabetes, obesity and cardiovascular diseases are an altered gut microbiota composition and a systemic pro-inflammatory state. We demonstrate that active immunization against the outer membrane protein of bacteria present in the gut enhances local and systemic immune control via apoE-mediated immune-modulation. Reduction of western-diet-associated inflammation was obtained for more than eighteen weeks after immunization. Immunized mice had reduced serum cytokine levels, reduced insulin and fasting glucose concentrations; and gene expression in both liver and visceral adipose tissue confirmed a reduced inflammatory steady-state after immunization. Moreover, both gut and atherosclerotic plaques of immunized mice showed reduced inflammatory cells and an increased M2 macrophage fraction. These results suggest that adaptive responses directed against microbes present in our microbiota have systemic beneficial consequences and demonstrate the key role of apoE in this mechanism that could be exploited to treat immune-metabolic diseases.
Structural Signature of Plasticity Unveiled by Nano-Scale Viscoelastic Contact in a Metallic Glass
Authors: Lu Y. M. , Zeng J. F. , Wang S. , Sun B. A. , Wang Q. , Lu J. , Gravier S. , Bladin J. J. , Wang W. H. , Pan M. X. , Liu C. T. , Yang Y.
Published: July 2016

Room-temperature plasticity in metallic glasses (MGs) is commonly associated with local structural heterogeneity; however, direct observation of the subtle structural change caused by plasticity is vitally important but the data are extremely scarce. Based on dynamic atomic force microscopy (DAFM), here we show that plasticity-induced structural evolution in a Zr-Ni MG can be revealed via nano-scale viscoelastic contacts between an AFM tip and plastically deformed MG surface layers. Our experimental results clearly show a spatial amplification of the nano-scale structural heterogeneity caused by the distributed plastic flow, which can be linked to the limited growth, reorientation and agglomeration of some nano-scale energy-absorbing regions, which are reminiscent of the behavior of the defect-like regions with non-affine deformation as conceived in many theories and models. Furthermore, we are able to experimentally extract the thermodynamic properties of these nano-scale regions, which possess an energy barrier of 0.3–0.5 eV, about half of that for a typical shear transformation event that usually occurs at the onset of plasticity. The outcome of our current work sheds quantitative insights into the correlation between plasticity and structural heterogeneity in MGs.
In-situ coupling between kinase activities and protein dynamics within single focal adhesions
Authors: Wu Yiqian , Zhang Kaiwen , Seong Jihye , Fan Jason , Chien Shu , Wang Yingxiao , Lu Shaoying
Published: July 2016

The dynamic activation of oncogenic kinases and regulation of focal adhesions (FAs) are crucial molecular events modulating cell adhesion in cancer metastasis. However, it remains unclear how these events are temporally coordinated at single FA sites. Therefore, we targeted fluorescence resonance energy transfer (FRET)-based biosensors toward subcellular FAs to report local molecular events during cancer cell adhesion. Employing single FA tracking and cross-correlation analysis, we quantified the dynamic coupling characteristics between biochemical kinase activities and structural FA within single FAs. We show that kinase activations and FA assembly are strongly and sequentially correlated, with the concurrent FA assembly and Src activation leading focal adhesion kinase (FAK) activation by 42.6 ± 12.6 sec. Strikingly, the temporal coupling between kinase activation and individual FA assembly reflects the fate of FAs at later stages. The FAs with a tight coupling tend to grow and mature, while the less coupled FAs likely disassemble. During FA disassembly, however, kinase activations lead the disassembly, with FAK being activated earlier than Src. Therefore, by integrating subcellularly targeted FRET biosensors and computational analysis, our study reveals intricate interplays between Src and FAK in regulating the dynamic life of single FAs in cancer cells.
Regional differences in health, diet and weaning patterns amongst the first Neolithic farmers of central Europe
Authors: Ash Abigail , Francken Michael , Pap Ildikó , Tvrdý Zdeněk , Wahl Joachim , Pinhasi Ron
Published: July 2016

Across much of central Europe, theLinearbandkeramik(LBK) represents the first Neolithic communities. Arising in Transdanubia around 5500 cal. BC the LBK spread west to the Rhine within two to three hundred years, carrying elements of a mixed agricultural economy and a relatively homogeneous material culture. Colonisation of new regions during this progress would have required economic adaptations to varied ecological conditions within the landscape. This paper investigates whether such adaptation at a local scale affected health patterns and altered the dietary habits of populations that otherwise shared a common cultural and biological origin. Analysis of non-specific stress (linear enamel hypoplasia, porotic hyperostosis, cribra orbitalia) within five LBK populations from across central Europe in conjunction with published carbon and nitrogen stable isotope data from each site revealed a high prevalence of porotic hyperostosis and cribra orbitalia in western populations that was associated with a lower animal protein intake. Hypoplastic enamel was more frequently observed in eastern populations however, and may reflect geographic differences in childhood morbidity and mortality as a result of variation in social practices relating to weaning. Local socio-economic adaptations within the LBK were therefore an important factor in the exposure of populations to non-specific stress.