bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Baroclinic Processes on Flushing Characteristics in a Highly Stratified Estuarine System, Mobile Bay, Alabama
Authors: Du Jiabi , Park Kyeong , Shen Jian , Dzwonkowski Brian , Yu Xin , Yoon Byung Il
Published: June 2018

Flushing of an estuary quantifies the overall water exchange between the estuary and coastal ocean and is crucially important for water quality as well as biological and geochemical processes within the system. Flushing times and freshwater age in Mobile Bay were numerically calculated under realistic and various controlled forcing conditions. Their responses to external forcing were explained by the three‐dimensional characteristics of general circulation in the system. The flushing time ranges from 10 to 33 days under the 25th–75th percentile river discharges, nearly half of the previous estimates based on barotropic processes only, suggesting the important contribution of baroclinic processes. Their influence, quantified as the “new ocean influx,” is on the same order of the river discharge under low to moderate river discharge conditions. The baroclinic influence increases and then decreases with increasing river discharge, aligning with the response of horizontal density gradient. By enhancing the net influx from the ocean mainly through density‐driven circulation, baroclinic processes contribute to reduce flushing times. The three‐dimensional circulation, which differs greatly between the wet and dry seasons, explains the temporal and spatial variations of the flushing characteristics. Wind forcing influences the three‐dimensional circulation in the system with easterly and northerly winds tending to reduce the flushing time, while southerly and westerly winds the opposite.
A New Centennial Sea‐Level Record for Antalya, Eastern Mediterranean
Authors: Ozturk U. , Marwan N. , von Specht S. , Korup O. , Jensen J.
Published: June 2018

Quantitative estimates of sea‐level rise in the Mediterranean Basin become increasingly accurate thanks to detailed satellite monitoring. However, such measuring campaigns cover several years to decades, while longer‐term sea‐level records are rare for the Mediterranean. We used a data archeological approach to reanalyze monthly mean sea‐level data of the Antalya‐I (1935–1977) tide gauge to fill this gap. We checked the accuracy and reliability of these data before merging them with the more recent records of the Antalya‐II (1985–2009) tide gauge, accounting for an eight‐year hiatus. We obtain a composite time series of monthly and annual mean sea levels spanning some 75 years, providing the longest record for the eastern Mediterranean Basin, and thus an essential tool for studying the region's recent sea‐level trends. We estimate a relative mean sea‐level rise of 2.2 ± 0.5 mm/year between 1935 and 2008, with an annual variability (expressed here as the standard deviation of the residuals,σresiduals = 41.4 mm) above that at the closest tide gauges (e.g., Thessaloniki, Greece,σresiduals = 29.0 mm). Relative sea‐level rise accelerated to 6.0 ± 1.5 mm/year at Antalya‐II; we attribute roughly half of this rate (~3.6 mm/year) to tectonic crustal motion and anthropogenic land subsidence. Our study highlights the value of data archeology for recovering and integrating historic tide gauge data for long‐term sea‐level and climate studies.
Effects of water-aging for 6 months on the durability of a novel antimicrobial and protein-repellent dental bonding agent
Authors: Zhang Ning , Zhang Ke , Weir Michael D. , Xu David J. , Reynolds Mark A. , Bai Yuxing , Xu Hockin H. K.
Published: June 2018

Biofilms at the tooth-restoration bonded interface can produce acids and cause recurrent caries. Recurrent caries is a primary reason for restoration failures. The objectives of this study were to synthesize a novel bioactive dental bonding agent containing dimethylaminohexadecyl methacrylate (DMAHDM) and 2-methacryloyloxyethyl phosphorylcholine (MPC) to inhibit biofilm formation at the tooth-restoration margin and to investigate the effects of water-aging for 6 months on the dentin bond strength and protein-repellent and antibacterial durability. A protein-repellent agent (MPC) and antibacterial agent (DMAHDM) were added to a Scotchbond multi-purpose (SBMP) primer and adhesive. Specimens were stored in water at 37 °C for 1, 30, 90, or 180 days (d). At the end of each time period, the dentin bond strength and protein-repellent and antibacterial properties were evaluated. Protein attachment onto resin specimens was measured by the micro-bicinchoninic acid approach. A dental plaque microcosm biofilm model was used to test the biofilm response. The SBMP + MPC + DMAHDM group showed no decline in dentin bond strength after water-aging for 6 months, which was significantly higher than that of the control (P < 0.05). The SBMP + MPC + DMAHDM group had protein adhesion that was only 1/20 of that of the SBMP control (P < 0.05). Incorporation of MPC and DMAHDM into SBMP provided a synergistic effect on biofilm reduction. The antibacterial effect and resistance to protein adsorption exhibited no decrease from 1 to 180 d (P > 0.1). In conclusion, a bonding agent with MPC and DMAHDM achieved a durable dentin bond strength and long-term resistance to proteins and oral bacteria. The novel dental bonding agent is promising for applications in preventive and restorative dentistry to reduce biofilm formation at the tooth-restoration margin.
Precision micro-mechanical components in single crystal diamond by deep reactive ion etching
Authors: Toros Adrien , Kiss Marcell , Graziosi Teodoro , Sattari Hamed , Gallo Pascal , Quack Niels
Published: June 2018

The outstanding material properties of single crystal diamond have been at the origin of the long-standing interest in its exploitation for engineering of high-performance micro- and nanosystems. In particular, the extreme mechanical hardness, the highest elastic modulus of any bulk material, low density, and the promise for low friction have spurred interest most notably for micro-mechanical and MEMS applications. While reactive ion etching of diamond has been reported previously, precision structuring of freestanding micro-mechanical components in single crystal diamond by deep reactive ion etching has hitherto remained elusive, related to limitations in the etch processes, such as the need of thick hard masks, micromasking effects, and limited etch rates. In this work, we report on an optimized reactive ion etching process of single crystal diamond overcoming several of these shortcomings at the same time, and present a robust and reliable method to produce fully released micro-mechanical components in single crystal diamond. Using an optimized Al/SiO2 hard mask and a high-intensity oxygen plasma etch process, we obtain etch rates exceeding 30 µm/h and hard mask selectivity better than 1:50. We demonstrate fully freestanding micro-mechanical components for mechanical watches made of pure single crystal diamond. The components with a thickness of 150 µm are defined by lithography and deep reactive ion etching, and exhibit sidewall angles of 82°–93° with surface roughness better than 200 nm rms, demonstrating the potential of this powerful technique for precision microstructuring of single crystal diamond.
Decrypting the sulfur cycle in oceanic oxygen minimum zones
Authors: Crowe Sean A , Cox Raymond P , Jones CarriAyne , Fowle David A , Santibañez-Bustos J F , Ulloa O , Canfield Donald E
Published: June 2018

Here we present ecophysiological studies of the anaerobic sulfide oxidizers considered critical to cryptic sulfur cycling in oceanic oxygen minimum zones (OMZs). We find that HS− oxidation rates by microorganisms in the Chilean OMZ offshore from Dichato are sufficiently rapid (18 nM h−1), even at HS− concentrations well below 100 nM, to oxidize all sulfide produced during sulfate reduction in OMZs. Even at 100 nM, HS− is well below published half-saturation concentrations and we conclude that the sulfide-oxidizing bacteria in OMZs (likely the SUP05/ARTIC96BD lineage of the gammaproteobacteria) have high-affinity (>105 g−1 wet cells h−1) sulfur uptake systems. These specific affinities for sulfide are higher than those recorded for any other organism on any other substrate. Such high affinities likely allow anaerobic sulfide oxidizers to maintain vanishingly low sulfide concentrations in OMZs driving marine cryptic sulfur cycling. If more broadly distributed, such high-affinity sulfur biochemistry could facilitate sulfide-based metabolisms and prominent S-cycles in many other ostensibly sulfide-free environments.
Bacterioplankton drawdown of coral mass-spawned organic matter
Authors: Guillemette Ryan , Kaneko Ryo , Blanton Jessica , Tan Jasmine , Witt Matthias , Hamilton Samantha , Allen Eric E , Medina Mónica , Hamasaki Koji , Koch Boris P , Azam Farooq
Published: June 2018

Coral reef ecosystems are highly sensitive to microbial activities that result from dissolved organic matter (DOM) enrichment of their surrounding seawater. However, the response to particulate organic matter (POM) enrichment is less studied. In a microcosm experiment, we tested the response of bacterioplankton to a pulse of POM from the mass-spawning of Orbicella franksi coral off the Caribbean coast of Panama. Particulate organic carbon (POC), a proxy measurement for POM, increased by 40-fold in seawater samples collected during spawning; 68% degraded within 66 h. The elevation of multiple hydrolases presumably solubilized the spawn-derived POM into DOM. A carbon budget constructed for the 275 µM of degraded POC showed negligible change to the concentration of dissolved organic carbon (DOC), indicating that the DOM was readily utilized. Fourier transform ion cyclotron resonance mass spectrometry shows that the DOM pool became enriched with heteroatom-containing molecules, a trend that suggests microbial alteration of organic matter. Our sensitivity analysis demonstrates that bacterial carbon demand could have accounted for a large proportion of the POC degradation. Further, using bromodeoxyuridine immunocapture in combination with 454 pyrosequencing of the 16S ribosomal RNA gene, we surmise that actively growing bacterial groups were the primary degraders. We conclude that coral gametes are highly labile to bacteria and that such large capacity for bacterial degradation and alteration of organic matter has implications for coral reef health and coastal marine biogeochemistry.
High-resolution melting analysis coupled with next-generation sequencing as a simple tool for the identification of a novel somatic BRCA2 variant: a case report
Authors: Costella Alessandra , De Leo Rossella , Guarino Donatella , D’Indinosante Marco , Concolino Paola , Mazzuccato Giorgia , Urbani Andrea , Scambia Giovanni , Capoluongo Ettore , Fagotti Anna , Minucci Angelo
Published: June 2018

In a 72-year-old woman with no associated personal or family history of breast and/or ovarian cancers, we identified a novel somatic pathogenic BRCA2 variant (c.18_28delAGAGAGGCCAA, p.Lys6Asnfs*4) using next-generation sequencing (NGS). The variant allele frequency (VAF) was 16%, and Sanger sequencing was unable to identify this variant. Adopting a high-resolution melting analysis strategy coupled with NGS, we successfully highlighted the presence of the c.18_28delAGAGAGGCCAA allele.
Two novel mutations of COMP in Japanese boys with pseudoachondroplasia
Authors: Ichihashi Yosuke , Takagi Masaki , Ishii Tomohiro , Watanabe Kenji , Nishimura Gen , Hasegawa Tomonobu
Published: June 2018

Mutations in the cartilage oligomeric matrix protein (COMP) gene cause both pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). Most mutations in COMP are located in the region encoding type 3 thrombospondin like domain (TSP3D). We report two Japanese boys with PSACH who had different novel in-frame deletions in TSP3D. The result recapitulates previous reports in that the in-frame deletions in TSP3D preferentially caused PSACH rather than MED.
Publisher Correction: Precisely printable and biocompatible silk fibroin bioink for digital light processing 3D printing
Authors: Kim Soon Hee , Yeon Yeung Kyu , Lee Jung Min , Chao Janet Ren , Lee Young Jin , Seo Ye Been , Sultan Md. Tipu , Lee Ok Joo , Lee Ji Seung , Yoon Sung-il , Hong In-Sun , Khang Gilson , Lee Sang Jin , Yoo James J. , Park Chan Hum
Published: June 2018

The original version of this Article contained errors in Figs. 5 and 6. In Fig. 5b, the second panel on the bottom row was stretched out of proportion. In Fig. 6d, the first panel was also stretched out of proportion. In Fig. 6f, the fifth panel inadvertently repeated the fourth. This has been corrected in both the PDF and HTML versions of the Article.
Chemical synthesis of perfectly isotactic and high melting bacterial poly(3-hydroxybutyrate) from bio-sourced racemic cyclic diolide
Authors: Tang Xiaoyan , Chen Eugene Y.-X.
Published: June 2018

Bacterial poly(3-hydroxybutyrate) (P3HB) is a perfectly isotactic, crystalline material possessing properties suitable for substituting petroleum plastics, but high costs and low volumes of its production are impractical for commodity applications. The chemical synthesis of P3HB via ring-opening polymerization (ROP) of racemic β-butyrolactone has attracted intensive efforts since the 1960s, but not yet produced P3HB with high isotacticity and molecular weight. Here, we report a route utilizing racemic cyclic diolide (rac-DL) derived from bio-sourced succinate. With stereoselective racemic catalysts, the ROP of rac-DL under ambient conditions produces rapidly P3HB with perfect isotacticity ([mm] > 99%), high melting temperature (Tm = 171 °C), and high molecular weight (Mn = 1.54 × 105 g mol−1, Đ = 1.01). With enantiomeric catalysts, kinetic resolution polymerizations of rac-DL automatically stops at 50% conversion and yields enantiopure (R,R)-DL and (S,S)-DL with >99% e.e. and the corresponding poly[(S)-3HB] and poly[(R)-3HB] with high Tm = 175 °C.
Quantitative in vivo whole genome motility screen reveals novel therapeutic targets to block cancer metastasis
Authors: Stoletov Konstantin , Willetts Lian , Paproski Robert J. , Bond David J. , Raha Srijan , Jovel Juan , Adam Benjamin , Robertson Amy E. , Wong Francis , Woolner Emma , Sosnowski Deborah L. , Bismar Tarek A. , Wong Gane Ka-Shu , Zijlstra Andries , Lewis John D.
Published: June 2018

Metastasis is the most lethal aspect of cancer, yet current therapeutic strategies do not target its key rate-limiting steps. We have previously shown that the entry of cancer cells into the blood stream, or intravasation, is highly dependent upon in vivo cancer cell motility, making it an attractive therapeutic target. To systemically identify genes required for tumor cell motility in an in vivo tumor microenvironment, we established a novel quantitative in vivo screening platform based on intravital imaging of human cancer metastasis in ex ovo avian embryos. Utilizing this platform to screen a genome-wide shRNA library, we identified a panel of novel genes whose function is required for productive cancer cell motility in vivo, and whose expression is closely associated with metastatic risk in human cancers. The RNAi-mediated inhibition of these gene targets resulted in a nearly total (>99.5%) block of spontaneous cancer metastasis in vivo.
Manipulation of emergent vortices in swarms of magnetic rollers
Authors: Kokot Gašper , Snezhko Alexey
Published: June 2018

Active colloids are an emergent class of out-of-equilibrium materials demonstrating complex collective phases and tunable functionalities. Microscopic particles energized by external fields exhibit a plethora of fascinating collective phenomena, yet mechanisms of control and manipulation of active phases often remains lacking. Here we report the emergence of unconfined macroscopic vortices in a system of ferromagnetic rollers energized by a vertical alternating magnetic field and elucidate the complex nature of a magnetic roller-vortex interactions with inert scatterers. We demonstrate that active self-organized vortices have an ability to spontaneously switch the direction of rotation and move across the surface. We reveal the capability of certain non-active particles to pin the vortex and manipulate its dynamics. Building on our findings, we demonstrate the potential of magnetic roller vortices to effectively capture and transport inert particles at the microscale.
Deciphering the late steps of rifamycin biosynthesis
Authors: Qi Feifei , Lei Chao , Li Fengwei , Zhang Xingwang , Wang Jin , Zhang Wei , Fan Zhen , Li Weichao , Tang Gong-Li , Xiao Youli , Zhao Guoping , Li Shengying
Published: June 2018

Rifamycin-derived drugs, including rifampin, rifabutin, rifapentine, and rifaximin, have long been used as first-line therapies for the treatment of tuberculosis and other deadly infections. However, the late steps leading to the biosynthesis of the industrially important rifamycin SV and B remain largely unknown. Here, we characterize a network of reactions underlying the biosynthesis of rifamycin SV, S, L, O, and B. The two-subunit transketolase Rif15 and the cytochrome P450 enzyme Rif16 are found to mediate, respectively, a unique C–O bond formation in rifamycin L and an atypical P450 ester-to-ether transformation from rifamycin L to B. Both reactions showcase interesting chemistries for these two widespread and well-studied enzyme families.
Cell entry of a host-targeting protein of oomycetes requires gp96
Authors: Trusch Franziska , Loebach Lars , Wawra Stephan , Durward Elaine , Wuensch Andreas , Iberahim Nurul Aqilah , de Bruijn Irene , MacKenzie Kevin , Willems Ariane , Toloczko Aleksandra , Diéguez-Uribeondo Javier , Rasmussen Tim , Schrader Thomas , Bayer Peter , Secombes Chris J. , van West Pieter
Published: June 2018

The animal-pathogenic oomyceteSaprolegnia parasiticacauses serious losses in aquaculture by infecting and killing freshwater fish. Like plant-pathogenic oomycetes,S. parasiticaemploys similar infection structures and secretes effector proteins that translocate into host cells to manipulate the host. Here, we show that the host-targeting protein SpHtp3 enters fish cells in a pathogen-independent manner. This uptake process is guided by a gp96-like receptor and can be inhibited by supramolecular tweezers. The C-terminus of SpHtp3 (containing the amino acid sequence YKARK), and not the N-terminal RxLR motif, is responsible for the uptake into host cells. Following translocation, SpHtp3 is released from vesicles into the cytoplasm by another host-targeting protein where it degrades nucleic acids. The effector translocation mechanism described here, is potentially also relevant for other pathogen–host interactions as gp96 is found in both animals and plants.
Nitrogen-fixing populations of Planctomycetes and Proteobacteria are abundant in surface ocean metagenomes
Authors: Delmont Tom O. , Quince Christopher , Shaiber Alon , Esen Özcan C. , Lee Sonny TM , Rappé Michael S. , McLellan Sandra L. , Lücker Sebastian , Eren A. Murat
Published: June 2018

Nitrogen fixation in the surface ocean impacts global marine nitrogen bioavailability and thus microbial primary productivity. Until now, cyanobacterial populations have been viewed as the main suppliers of bioavailable nitrogen in this habitat. Although PCR amplicon surveys targeting the nitrogenase reductase gene have revealed the existence of diverse non-cyanobacterial diazotrophic populations, subsequent quantitative PCR surveys suggest that they generally occur in low abundance. Here, we use state-of-the-art metagenomic assembly and binning strategies to recover nearly one thousand non-redundant microbial population genomes from the TARA Oceans metagenomes. Among these, we provide the first genomic evidence for non-cyanobacterial diazotrophs inhabiting surface waters of the open ocean, which correspond to lineages within the Proteobacteria and, most strikingly, the Planctomycetes. Members of the latter phylum are prevalent in aquatic systems, but have never been linked to nitrogen fixation previously. Moreover, using genome-wide quantitative read recruitment, we demonstrate that the discovered diazotrophs were not only widespread but also remarkably abundant (up to 0.3% of metagenomic reads for a single population) in both the Pacific Ocean and the Atlantic Ocean northwest. Our results extend decades of PCR-based gene surveys, and substantiate the importance of heterotrophic bacteria in the fixation of nitrogen in the surface ocean.
Acoustic impedance matched buffers enable separation of bacteria from blood cells at high cell concentrations
Authors: Ohlsson Pelle , Petersson Klara , Augustsson Per , Laurell Thomas
Published: June 2018

Sepsis is a common and often deadly systemic response to an infection, usually caused by bacteria. The gold standard for finding the causing pathogen in a blood sample is blood culture, which may take hours to days. Shortening the time to diagnosis would significantly reduce mortality. To replace the time-consuming blood culture we are developing a method to directly separate bacteria from red and white blood cells to enable faster bacteria identification. The blood cells are moved from the sample flow into a parallel stream using acoustophoresis. Due to their smaller size, the bacteria are not affected by the acoustic field and therefore remain in the blood plasma flow and can be directed to a separate outlet. When optimizing for sample throughput, 1 ml of undiluted whole blood equivalent can be processed within 12.5 min, while maintaining the bacteria recovery at 90% and the blood cell removal above 99%. That makes this the fastest label-free microfluidic continuous flow method per channel to separate bacteria from blood with high bacteria recovery (>80%). The high throughput was achieved by matching the acoustic impedance of the parallel stream to that of the blood sample, to avoid that acoustic forces relocate the fluid streams.
NaoXinTong Capsules inhibit the development of diabetic nephropathy in db/db mice
Authors: Yang Shu , Liu Mengyang , Chen Yuanli , Ma Chuanrui , Liu Lipei , Zhao Buchang , Wang Yong , Li Xiaoju , Zhu Yan , Gao Xiumei , Kong Deling , Duan Yajun , Han Jihong , Yang Xiaoxiao
Published: June 2018

NaoXinTong Capsule (NXT), a Chinese medicine, is currently used to treat patients with cardiovascular and cerebrovascular diseases. Clinical observations indicate its anti-diabetic functions with unclear mechanisms. Herein, we report the effect of NXT on diabetic nephropathy (DN). Type 2 diabeticdb/dbmice were treated with NXT for 14 weeks. In the course of treatment, NXT reduced diabetes-increased glucose levels and improved renal functions. At the end of treatment, we found that NXT ameliorated serum lipid profiles and other biochemical parameters. In the kidney, NXT inhibited mesangial matrix expansion, expression of vascular endothelial growth factor A, fibronectin, advanced glycation end product and its receptor. Meanwhile, it reduced the diabetes-induced podocyte injury by increasing WT1 and nephrin expression. In addition, NXT inhibited accumulation of extracellular matrix proteins by increasing MMP2/9 expression through inactivation of TGFβ/Smad pathway and CTGF expression. Mechanically, NXT activated insulin signaling pathway by increasing expression of INSR, IRS and FGF21, phosphorylation of Akt and AMPKα in the liver, INSR phosphorylation in the kidney, and FGF21 and GLUT4 expression in adipose tissue and skeletal muscle. Taken together, our study demonstrates that NXT inhibits DN by ameliorating glucose/lipid metabolism, maintaining tissue structure integrity, and correcting diabetes-induced renal dysfunctions.
Psoriasis risk in patients with diabetic retinopathy: A nationwide population-based study
Authors: Lee Ji Hyun , Han Ju Hee , Han Kyung Do , Park Young Min , Lee Jun Young , Park Yong-Gyu , Lee Young Bok
Published: June 2018

Psoriasis is a chronic cutaneous disease known to be related with systemic disease; however, the association between psoriasis and diabetic complications has not been previously reported. Diabetic microvascular complications include diabetic retinopathy (DR), nephropathy, and neuropathy, and overt diabetic nephropathy can lead to the end-stage renal disease (ESRD).The present study investigated the association between psoriasis and non-proliferative DR (NPDR) or proliferative DR (PDR) or ESRD. We analyzed the relationship between diabetic complication and psoriasis using data from the National Health Insurance Service between 2009 and 2015. During a mean follow-up of 5.18 years, 43,792 patients were newly diagnosed with psoriasis. In Cox proportional hazard models, patients with NPDR (hazard ratio [HR] 1.26) had a higher incidence of psoriasis and patients with PDR patients had a higher risk of psoriasis (HR 1.35). ESRD was defined by the ICD-10 code, including chronic kidney disease/renal failure, transplantation, and dialysis. The incidence of psoriasis increased in DR patients with ESRD (HR 2.99, 95% CI 2.49–3.59, p < 0.001) compared to non-DR patients without ESRD. This is the first association study between psoriasis and diabetic complications including DR and ESRD. DR and its severity were related to the onset of psoriasis. In addition, ESRD was related with an increased psoriasis in DR patients.
Distribution of reported syphilis cases in South China: spatiotemporal analysis
Authors: Wong Ngai Sze , Chen Lei , Tucker Joseph D. , Zhao Peizhen , Goh Beng Tin , Poon Chin Man , Yang Ligang , Yang Bin , Zheng Heping , Huang Shujie
Published: June 2018

There was a varied spatial distribution of reported syphilis cases across cities in South China. This study aims to identify and describe spatiotemporal clusters of primary and secondary syphilis (P/S) cases in this region. Reported syphilis cases in Guangdong Province, China, from January 2014 to June 2015 were collected from the national centralized reporting system. Spatiotemporal clusters of P/S were identified and cross-validated by calculating local Moran’s I, performing hotspot analysis (Getis-Ord Gi*), and constructing a discrete Poisson model in SaTScan. Reported cases within and outside the clusters were compared by bivariable and multivariable logistic regression. Out of 17,691 reported P/S cases, 11% were in the identified spatiotemporal clusters. The monthly P/S notification rate (per 100,000 persons) ranged between 0.6 and 1. The identified clusters were located in 14, out of 126, counties in eight, out of 21, cities. Cases of older age, living in rural area and taking self-initiated syphilis test were more likely to be in the clusters. Some areas bore a greater burden of P/S in Guangdong Province. Routine spatiotemporal analysis of P/S cases may be useful for enhancing syphilis control programs by strategic location-based service planning.
Parasite motility is critical for virulence of African trypanosomes
Authors: Shimogawa Michelle M. , Ray Sunayan S. , Kisalu Neville , Zhang Yibo , Geng Quanjie , Ozcan Aydogan , Hill Kent L.
Published: June 2018

African trypanosomes, Trypanosoma brucei spp., are lethal pathogens that cause substantial human suffering and limit economic development in some of the world’s most impoverished regions. The name Trypanosoma (“auger cell”) derives from the parasite’s distinctive motility, which is driven by a single flagellum. However, despite decades of study, a requirement for trypanosome motility in mammalian host infection has not been established. LC1 is a conserved dynein subunit required for flagellar motility. Prior studies with a conditional RNAi-based LC1 mutant, RNAi-K/R, revealed that parasites with defective motility could infect mice. However, RNAi-K/R retained residual expression of wild-type LC1 and residual motility, thus precluding definitive interpretation. To overcome these limitations, here we generate constitutive mutants in which both LC1 alleles are replaced with mutant versions. These double knock-in mutants show reduced motility compared to RNAi-K/R and are viable in culture, but are unable to maintain bloodstream infection in mice. The virulence defect is independent of infection route but dependent on an intact host immune system. By comparing different mutants, we also reveal a critical dependence on the LC1 N-terminus for motility and virulence. Our findings demonstrate that trypanosome motility is critical for establishment and maintenance of bloodstream infection, implicating dynein-dependent flagellar motility as a potential drug target.
Highly-efficient three-dimensional waveguide couplers using impedance-tunable transformation optics
Authors: Cao Jun , Qi Fenghua , Yan Senlin , Zhang Lifa
Published: June 2018

There is growing interest in designing waveguide couplers with low reflections. Using impedance-tunable transformation optics, we propose a coordinate transformation technique in the design of compact three-dimensional waveguide couplers. To transmit electromagnetic waves between two coaxial waveguides with different inner and outer radii in the microwave range, a suitable impedance function is derived to reduce the impedance mismatch at the boundary, which make the fabrication process being simplified due to the reduced set of transformation media(dielectric response materials only). A larger refractive index is set to raise the coupling performance in the low frequency range. Next we apply impedance-tunable transformation optics to the design of dielectric waveguide couplers, where only the core region be contained in the transformed space; by selecting a tunable impedance function, waves can transmit efficiently through waveguides with quite different cross sections and background media. The proposed impedance-tunable three-dimensional waveguide couplers are confirmed by the 3-dimensional numerical simulation with good performances, which can have potential applications in fiber-to-chip coupling.
Realization of an ultrathin acoustic lens for subwavelength focusing in the megasonic range
Authors: Hyun Jaeyub , Kim Yong Tae , Doh Il , Ahn Bongyoung , Baik Kyungmin , Kim Se-Hwa
Published: June 2018

In this study, we report the first experimental realization of an ultrathin (0.14λ, λ = 1.482 mm means wavelength at 1 MHz in the water medium) subwavelength focusing acoustic lens that can surpass the Rayleigh diffraction limit (0.61λ/NA, NA means numerical aperture). It is termed a Super-Oscillatory Acoustic Lens (SOAL), and it operates in the megasonic range. The SOAL represents an interesting feature allowing the achievement of subwavelength focusing without the need to operate in close proximity to the object to be imaged. The optimal layout of the SOAL is obtained by utilizing a systematic design approach, referred to here as topology optimization. To this end, the optimization formulation is newly defined. The optimized SOAL is fabricated using a photo-etching process and its subwavelength focusing performance is verified experimentally via an acoustic intensity measurement system. From these measurements, we found that the proposed optimized SOAL can achieve superior focusing features with a Full Width at Half Maximum (FWHM) of ~0.40λ/NA ≃ 0.84 mm (for our SOAL, NA = 0.707) with the transmission efficiency of 26.5%.
On the thermal shock resistance and mechanical properties of novel unidirectional UHTCMCs for extreme environments
Authors: Zoli Luca , Vinci Antonio , Galizia Pietro , Melandri Cesare , Sciti Diletta
Published: June 2018

Aerospace provides a strong driving force for technological development. Recently a novel class of composites for harsh environments, based on ultra-high temperature ceramic composites reinforced with continuous fibers (UHTCMC), is being developed. The goal of this work is to overcome the current data patchwork about their microstructural optimization and structural behavior, by showing a consistent mechanical characterization of well-defined and developed UHTCMCs based on ZrB2-matrix. The obtained composites have a density of 3.7 g/cm3 and porosity of less than 10%. The flexural strength increased from 360 to 550 MPa from room temperature to 1500 °C, showing a non-brittle behaviour. The composites were able to sustain a thermal shock severity as high as 1500 °C. The maximum decrease of strength at 1400 °C was 16% of the initial value, indicating that the samples could be shocked at even higher temperature. Flexural strength, Young’s modulus and coefficient of thermal expansions (CTE) of the composites were measured both along transverse and longitudinal direction and correlated to the microstructural features. The presented microstructural and mechanical characterization well defines the potentiality of the UHTCMCs and can be used as reference for the design and development of novel thermal protection systems and other structural components for harsh environments.
Pharmacological activation of epidermal growth factor receptor signaling inhibits colitis-associated cancer in mice
Authors: Dubé Philip E. , Liu Cambrian Y. , Girish Nandini , Washington M. Kay , Polk D. Brent
Published: June 2018

Current treatments for inflammatory bowel disease (IBD) target the overactive immune response of the intestinal mucosa. However, epidermal growth factor (EGF), an activating ligand of the EGF receptor (EGFR), has been shown to induce disease remission through direct targeting of intestinal mucosal healing. Despite promising preclinical and clinical results, this EGFR-activating therapy has not progressed, in part due to the potential for carcinogenesis associated with long-term use and the increased risk of colitis-associated cancer (CAC) in IBD. Here we tested whether pharmacological modulation of EGFR altered outcomes of CAC in the murine azoxymethane/dextran sulfate sodium model. We found that administering EGF during the period of maximum colitis severity (“early”), coincident with the initiation and early promotion of tumors, improved outcomes of colitis and reduced tumor size. In contrast, daily EGF administration beginning ~2 months after tumor initiation (“late”) increased tumor size. Administration of the EGFR kinase inhibitor gefitinib increased the tumor size when the drug was given early and decreased the tumor size when the drug was administered late. EGF administration not only reduced colonic cytokine and chemokine expression during injury, but also baseline chemokine expression in homeostasis. These results suggest that EGFR activation during acute bouts of colitis may reduce the long-term burden of CAC.
The role of miR-122 in the dysregulation of glucose-6-phosphate dehydrogenase (G6PD) expression in hepatocellular cancer
Authors: Barajas Juan M. , Reyes Ryan , Guerrero Maria J. , Jacob Samson T. , Motiwala Tasneem , Ghoshal Kalpana
Published: June 2018

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Thus, a better understanding of molecular aberrations involved in HCC pathogenesis is necessary for developing effective therapy. It is well established that cancer cells metabolize energy sources differently to rapidly generate biomass. Glucose-6-phosphate-dehydrogenase (G6PD), the rate-limiting enzyme of the Pentose Phosphate Pathway (PPP), is often activated in human malignancies to generate precursors for nucleotide and lipid synthesis. Here, we determined the clinical significance of G6PD in primary human HCC by analyzing RNA-seq and clinical data in The Cancer Genome Atlas. We found that the upregulation of G6PD correlates with higher tumor grade, increased tumor recurrence, and poor patient survival. Notably, liver-specific miR-122, which is essential for metabolic homeostasis, suppresses G6PD expression by directly interacting with its 3′UTR. Luciferase reporter assay confirmed two conserved functional miR-122 binding sites located in the 3′-UTR of G6PD. Furthermore, we show that ectopic expression of miR-122 and miR-1, a known regulator of G6PD expression coordinately repress G6PD expression in HCC cells. These miRNAs also reduced G6PD activity in HepG2 cells that express relatively high activity of this enzyme. Collectively, this study provides evidence that anti-HCC efficacy of miR122 and miR-1 could be mediated, at least in part, through inhibition of PPP by suppressing the expression of G6PD.
Complex history of dog (Canis familiaris) origins and translocations in the Pacific revealed by ancient mitogenomes
Authors: Greig K. , Gosling A. , Collins C. J. , Boocock J. , McDonald K. , Addison D. J. , Allen M. S. , David B. , Gibbs M. , Higham C. F. W. , Liu F. , McNiven I. J. , O’Connor S. , Tsang C. H. , Walter R. , Matisoo-Smith E.
Published: June 2018

Archaeological evidence suggests that dogs were introduced to the islands of Oceania via Island Southeast Asia around 3,300 years ago, and reached the eastern islands of Polynesia by the fourteenth century AD. This dispersal is intimately tied to human expansion, but the involvement of dogs in Pacific migrations is not well understood. Our analyses of seven new complete ancient mitogenomes and five partial mtDNA sequences from archaeological dog specimens from Mainland and Island Southeast Asia and the Pacific suggests at least three dog dispersal events into the region, in addition to the introduction of dingoes to Australia. We see an early introduction of dogs to Island Southeast Asia, which does not appear to extend into the islands of Oceania. A shared haplogroup identified between Iron Age Taiwanese dogs, terminal-Lapita and post-Lapita dogs suggests that at least one dog lineage was introduced to Near Oceania by or as the result of interactions with Austronesian language speakers associated with the Lapita Cultural Complex. We did not find any evidence that these dogs were successfully transported beyond New Guinea. Finally, we identify a widespread dog clade found across the Pacific, including the islands of Polynesia, which likely suggests a post-Lapita dog introduction from southern Island Southeast Asia.
Recurrence Quantification Analysis at work: Quasi-periodicity based interpretation of gait force profiles for patients with Parkinson disease
Authors: Afsar Ozgur , Tirnakli Ugur , Marwan Norbert
Published: June 2018

In this letter, making use of real gait force profiles of healthy and patient groups with Parkinson disease which have different disease severity in terms of Hoehn-Yahr stage, we calculate various heuristic complexity measures of the recurrence quantification analysis (RQA). Using this technique, we are able to evince that entropy, determinism and average diagonal line length (divergence) measures decrease (increases) with increasing disease severity. We also explain these tendencies using a theoretical model (based on the sine-circle map), so that we clearly relate them to decreasing degree of irrationality of the system as a course of gait’s nature. This enables us to interpret the dynamics of normal/pathological gait and is expected to increase further applications of this technique on gait timings, gait force profiles and combinations of them with various physiological signals.
WNK1 regulates skeletal muscle cell hypertrophy by modulating the nuclear localization and transcriptional activity of FOXO4
Authors: Mandai Shintaro , Mori Takayasu , Nomura Naohiro , Furusho Taisuke , Arai Yohei , Kikuchi Hiroaki , Sasaki Emi , Sohara Eisei , Rai Tatemitsu , Uchida Shinichi
Published: June 2018

With-no-lysine (K) (WNK) kinases, which are mutated in the inherited form of hypertension pseudohypoaldosteronism type II, are essential regulators of membrane ion transporters. Here, we report that WNK1 positively regulates skeletal muscle cell hypertrophy via mediating the function of the pro-longevity transcription factor forkhead box protein O4 (FOXO4) independent of the conventional WNK signaling pathway linking SPS/STE20-related proline-alanine–rich kinase (SPAK)/oxidative stress response kinase 1 (OSR1) to downstream effector ion transporters. Small interfering RNA (siRNA)-mediated silencing of WNK1, but not SPAK/OSR1 kinases, induced myotube atrophy and remarkable increases in the mRNA expression of the muscle atrophy ubiquitin ligases MAFbx and MuRF1 in C2C12 mouse skeletal muscle cells. WNK1 silencing also increased FOXO4 nuclear localization, and co-transfection of Foxo4-targeted siRNA completely reversed the myotube atrophy and upregulation of atrogene transcription induced by WNK1 silencing. We further illustrated that WNK1 protein abundance in skeletal muscle was increased by chronic voluntary wheel running exercise (hypertrophic stimulus) and markedly decreased by adenine-induced chronic kidney disease (atrophic stimulus) in mice. These findings suggest that WNK1 is involved in the physiological regulation of mammalian skeletal muscle hypertrophy and atrophy via interactions with FOXO4. The WNK1-FOXO4 axis may be a potential therapeutic target in human diseases causing sarcopenia.
Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice
Authors: Pievani A. , Michelozzi I. M. , Rambaldi B. , Granata V. , Corsi A. , Dazzi F. , Biondi A. , Serafini M.
Published: June 2018

There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice.
Role of disorder when upscaling magnetocaloric Ni-Co-Mn-Al Heusler alloys from thin films to ribbons
Authors: Weise B. , Dutta B. , Teichert N. , Hütten A. , Hickel T. , Waske A.
Published: June 2018

Research in functional magnetic materials often employs thin films as model systems for finding new chemical compositions with promising properties. However, the scale-up of thin films towards bulk-like structures is challenging, since the material synthesis conditions are entirely different for thin films and e.g. rapid quenching methods. As one of the consequences, the type and degree of order in thin films and melt-spun ribbons are usually different, leading to different magnetic properties. In this work, using the example of magnetocaloric Ni-Co-Mn-Al melt-spun ribbons and thin films, we show that the excellent functional properties of the films can be reproduced also in ribbons, if an appropriate heat treatment is applied, that installs the right degree of order in the ribbons. We show that some chemical disorder is needed to get a pronounced and sharp martensitic transition. Increasing the order with annealing improves the magnetic properties only up to a point where selected types of disorder survive, which in turn compromise the magnetic properties. These findings allow us to understand the impact of the type and degree of disorder on the functional properties, paving the way for a faster transfer of combinatorial thin film research towards bulk-like materials for magnetic Heusler alloys.
DPubChem: a web tool for QSAR modeling and high-throughput virtual screening
Authors: Soufan Othman , Ba-alawi Wail , Magana-Mora Arturo , Essack Magbubah , Bajic Vladimir B.
Published: June 2018

High-throughput screening (HTS) performs the experimental testing of a large number of chemical compounds aiming to identify those active in the considered assay. Alternatively, faster and cheaper methods of large-scale virtual screening are performed computationally through quantitative structure-activity relationship (QSAR) models. However, the vast amount of available HTS heterogeneous data and the imbalanced ratio of active to inactive compounds in an assay make this a challenging problem. Although different QSAR models have been proposed, they have certain limitations, e.g., high false positive rates, complicated user interface, and limited utilization options. Therefore, we developed DPubChem, a novel web tool for deriving QSAR models that implement the state-of-the-art machine-learning techniques to enhance the precision of the models and enable efficient analyses of experiments from PubChem BioAssay database. DPubChem also has a simple interface that provides various options to users. DPubChem predicted active compounds for 300 datasets with an average geometric mean and F1 score of 76.68% and 76.53%, respectively. Furthermore, DPubChem builds interaction networks that highlight novel predicted links between chemical compounds and biological assays. Using such a network, DPubChem successfully suggested a novel drug for the Niemann-Pick type C disease. DPubChem is freely available at www.cbrc.kaust.edu.sa/dpubchem.
Intra-individual Gene Expression Variability of Histologically Normal Breast Tissue
Authors: Sun Xuezheng , Shan Yue , Li Quefeng , Chollet-Hinton Lynn , Kirk Erin L. , Gierach Gretchen L. , Troester Melissa A.
Published: June 2018

Several studies have sought to identify novel transcriptional biomarkers in normal breast or breast microenvironment to predict tumor risk and prognosis. However, systematic efforts to evaluate intra-individual variability of gene expression within normal breast have not been reported. This study analyzed the microarray gene expression data of 288 samples from 170 women in the Normal Breast Study (NBS), wherein multiple histologically normal breast samples were collected from different block regions and different sections at a given region. Intra-individual differences in global gene expression and selected gene expression signatures were quantified and evaluated in association with other patient-level factors. We found that intra-individual reliability was relatively high in global gene expression, but differed by signatures, with composition-related signatures (i.e., stroma) having higher intra-individual variability and tumorigenesis-related signatures (i.e., proliferation) having lower intra-individual variability. Histological stroma composition was the only factor significantly associated with heterogeneous breast tissue (defined as > median intra-individual variation; high nuclear density, odds ratio [OR] = 3.42, 95% confidence interval [CI] = 1.15–10.15; low area, OR = 0.29, 95% CI = 0.10–0.86). Other factors suggestively influencing the variability included age, BMI, and adipose nuclear density. Our results underscore the importance of considering intra-individual variability in tissue-based biomarker development, and have important implications for normal breast research.