bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects and acceptability of implementing improved cookstoves and heaters to reduce household air pollution: a FRESH AIR study
Authors: van Gemert Frederik , de Jong Corina , Kirenga Bruce , Musinguzi Patrick , Buteme Shamim , Sooronbaev Talant , Tabyshova Aizhamal , Emilov Berik , Mademilov Maamed , Le An Pham , Quynh Nguyen Nhat , Dang Tran Ngoc , Hong Le Huynh Thi Cam , Chartier Ryan , Brakema Evelyn A. , van Boven Job F. M. ,   FRESH AIR, Kocks Janwillem , Nantanda Rebecca , Katagira Winceslaus , Ndeezi Grace , Tumwine James , Walusimbi Simon , Akylbekov Azamat , Binh Pham Duong Uyen , Tuan Tran Diep , Lan Le Thi Tuyet , Linh Tran Thanh Duv , Loan Kim Xuan , Van Le Thanh , Vinh Nguyen Nhu , Chavannes Niels H. , van der Kleij Rianne M. J. J. , Poot Charlotte , Anastasaki Marilena , Bertsias Antonios , Chatzea Vasiliki E. , Lionis Christos , Papadakis Sophia , Sifaki-Pistolla Dimitra , Tsiligianni Ioanna , Singh Sally , Burges Dennis , Hedrick Ben , Stout James , Warren Louise , Ferarrio Irene , Powell Pippa , Barton Andy , Cartwright Lucy , Kampen Sanne van , Jones Rupert , Pooler Jillian , Poulsen Anja , Kjærgaard Jesper , Hopkinson Nick , Cragg Liza , Pinnock Hilary , Williams Sian , McEwen Andy , Reventlow Susanne , Stubbe-Østergaard Marianne , Postma Maarten J. , de Sousa Jaime Correia
Published: August 2019

The objective was to evaluate the effectiveness and acceptability of locally tailored implementation of improved cookstoves/heaters in low- and middle-income countries. This interventional implementation study among 649 adults and children living in rural communities in Uganda, Vietnam and Kyrgyzstan, was performed after situational analyses and awareness programmes. Outcomes included household air pollution (PM2.5 and CO), self-reported respiratory symptoms (with CCQ and MRC-breathlessness scale), chest infections, school absence and intervention acceptability. Measurements were conducted at baseline, 2 and 6–12 months after implementing improved cookstoves/heaters. Mean PM2.5 values decrease by 31% (to 95.1 µg/m3) in Uganda (95%CI 71.5–126.6), by 32% (to 31.1 µg/m3) in Vietnam (95%CI 24.5–39.5) and by 65% (to 32.4 µg/m3) in Kyrgyzstan (95%CI 25.7–40.8), but all remain above the WHO guidelines. CO-levels remain below the WHO guidelines. After intervention, symptoms and infections diminish significantly in Uganda and Kyrgyzstan, and to a smaller extent in Vietnam. Quantitative assessment indicates high acceptance of the new cookstoves/heaters. In conclusion, locally tailored implementation of improved cookstoves/heaters is acceptable and has considerable effects on respiratory symptoms and indoor pollution, yet mean PM2.5 levels remain above WHO recommendations.
Entanglement stabilization using ancilla-based parity detection and real-time feedback in superconducting circuits
Authors: Andersen Christian Kraglund , Remm Ants , Lazar Stefania , Krinner Sebastian , Heinsoo Johannes , Besse Jean-Claude , Gabureac Mihai , Wallraff Andreas , Eichler Christopher
Published: August 2019

Fault-tolerant quantum computing relies on the ability to detect and correct errors, which in quantum error correction codes is typically achieved by projectively measuring multi-qubit parity operators and by conditioning operations on the observed error syndromes. Here, we experimentally demonstrate the use of an ancillary qubit to repeatedly measure the ZZ and XX parity operators of two data qubits and to thereby project their joint state into the respective parity subspaces. By applying feedback operations conditioned on the outcomes of individual parity measurements, we demonstrate the real-time stabilization of a Bell state with a fidelity of F ≈ 74% in up to 12 cycles of the feedback loop. We also perform the protocol using Pauli frame updating and, in contrast to the case of real-time stabilization, observe a steady decrease in fidelity from cycle to cycle. The ability to stabilize parity over multiple feedback rounds with no further reduction in fidelity provides strong evidence for the feasibility of executing stabilizer codes on timescales much longer than the intrinsic coherence times of the constituent qubits.
Ferritin RNA interference inhibits the formation of iron granules in the trophocytes of worker honey bees (Apis mellifera)
Authors: Hsu Chin-Yuan , Lo Hsiao-Fan , Mutti Navdeep S. , Amdam Gro V.
Published: August 2019

Iron granules containing superparamagnetic magnetite act as magnetoreceptor for magnetoreception in honey bees. Biomineralization of iron granules occurs in the iron deposition vesicles of trophocytes and requires the participation of actin, myosin, ferritin2, and ATP synthase. The mechanism of magnetoreception in honey bees can be explored by suppressing the formation of iron granules. Toward this goal, we injected double-stranded RNA of ferritin2 and ferritin1 into newly emerged worker honey bees to knock down these genes via RNA interference. We confirmed that mRNA and protein production of the ferritins was inhibited, leading to immature iron granules. Downregulating ferritin2 and ferritin1, moreover, leads to different deposition morphology of 7.5-nm diameter iron particles, indicating that the two genes play different roles in the formation of iron granules in worker honey bees.
Large-scale mitogenomic analysis of the phylogeography of the Late Pleistocene cave bear
Authors: Gretzinger Joscha , Molak Martyna , Reiter Ella , Pfrengle Saskia , Urban Christian , Neukamm Judith , Blant Michel , Conard Nicholas J. , Cupillard Christophe , Dimitrijević Vesna , Drucker Dorothée G. , Hofman-Kamińska Emilia , Kowalczyk Rafał , Krajcarz Maciej T. , Krajcarz Magdalena , Münzel Susanne C. , Peresani Marco , Romandini Matteo , Rufí Isaac , Soler Joaquim , Terlato Gabriele , Krause Johannes , Bocherens Hervé , Schuenemann Verena J.
Published: August 2019

The cave bear (Ursus spelaeus) is one of the Late Pleistocene megafauna species that faced extinction at the end of the last ice age. Although it is represented by one of the largest fossil records in Europe and has been subject to several interdisciplinary studies including palaeogenetic research, its fate remains highly controversial. Here, we used a combination of hybridisation capture and next generation sequencing to reconstruct 59 new complete cave bear mitochondrial genomes (mtDNA) from 14 sites in Western, Central and Eastern Europe. In a Bayesian phylogenetic analysis, we compared them to 64 published cave bear mtDNA sequences to reconstruct the population dynamics and phylogeography during the Late Pleistocene. We found five major mitochondrial DNA lineages resulting in a noticeably more complex biogeography of the European lineages during the last 50,000 years than previously assumed. Furthermore, our calculated effective female population sizes suggest a drastic cave bear population decline starting around 40,000 years ago at the onset of the Aurignacian, coinciding with the spread of anatomically modern humans in Europe. Thus, our study supports a potential significant human role in the general extinction and local extirpation of the European cave bear and illuminates the fate of this megafauna species.
Evolutionary drivers of protein shape
Authors: Shannon Gareth , Marples Callum R. , Toofanny Rudesh D. , Williams Philip M.
Published: August 2019

Diffusional motion within the crowded environment of the cell is known to be crucial to cellular function as it drives the interactions of proteins. However, the relationships between protein diffusion, shape and interaction, and the evolutionary selection mechanisms that arise as a consequence, have not been investigated. Here, we study the dynamics of triaxial ellipsoids of equivalent steric volume to proteins at different aspect ratios and volume fractions using a combination of Brownian molecular dynamics and geometric packing. In general, proteins are found to have a shape, approximately Golden in aspect ratio, that give rise to the highest critical volume fraction resisting gelation, corresponding to the fastest long-time self-diffusion in the cell. The ellipsoidal shape also directs random collisions between proteins away from sites that would promote aggregation and loss of function to more rapidly evolving nonsticky regions on the surface, and further provides a greater tolerance to mutation.
Extracellular endonucleases in the midgut of Myzus persicae may limit the efficacy of orally delivered RNAi
Authors: Ghodke Amol Bharat , Good Robert Trygve , Golz John F. , Russell Derek A. , Edwards Owain , Robin Charles
Published: August 2019

Myzus persicae is a major pest of many crops including canola and Brassica vegetables, partly because it vectors plant viruses. Previously it has been reported that double-stranded RNA delivered to aphids by injection, artificial diet or transgenic plants has knocked down target genes and caused phenotypic effects. While these studies suggest that RNA interference (RNAi) might be used to suppress aphid populations, none have shown effects sufficient for field control. The current study analyses the efficacy of dsRNA directed against previously reported gene-targets on Green peach aphid (Myzus persicae) strains. No silencing effect was observed when dsRNA was delivered in artificial diet with or without transfection reagents. dsRNA produced in planta also failed to induce significant RNAi in M. persicae. Transcriptome analyses of the midgut suggested other potential targets including the Ferritin heavy chain transcripts, but they also could not be knocked down with dsRNA. Here we show that dsRNA is rapidly degraded by midgut secretions of Myzus persicae. Analysis of the transcriptome of the M. persicae midgut revealed that an ortholog of RNases from other insects was abundant.
Serum and brain natural copper stable isotopes in a mouse model of Alzheimer’s disease
Authors: Moynier Frédéric , Creech John , Dallas Jessica , Le Borgne Marie
Published: August 2019

Alzheimer’s disease is associated with the production of Cu rich aβ fibrils. Because monitoring the changes in Cu level of organs has been proposed to follow the evolution of the disease, we analyzed the copper isotopic composition of serum and brain of APPswe/PSEN1dE9 transgenic mice, a model of Alzheimer’s disease, and wild-type (WT) controls. Serum composition of 3, 6, 9 and 12-month-old mice, as well as the composition of 9 brains of 12-month-old mice are reported. In WT mice, brains were ~1‰ isotopically heavier than serum, and the Cu isotopic composition of the serum was isotopically different between males and females. We propose that this effect of sex on the Cu isotopic budget of the serum may be related to a difference of Cu speciation and relative abundance of Cu carriers. Brains of APPswe/PSEN1dE9 mice were slightly lighter than brains of WT mice, while not statistically significant. This trend may reflect an increase of Cu(I) associated with the formation of Aβ fibrils. The Cu isotopic composition of the brains and serum were correlated, implying copper transport between these two reservoirs, in particular a transfer of Cu(I) from the brain to the serum. Altogether, these data suggest that Cu stable isotopic composition of body fluid may have the potential to be used as detection tools for the formation of Aβ fibrils in the brain, but further work has to be done.
Widespread Wolbachia infection in an insular radiation of damselflies (Odonata, Coenagrionidae)
Authors: Lorenzo-Carballa M. O. , Torres-Cambas Y. , Heaton K. , Hurst G. D. D. , Charlat S. , Sherratt T. N. , Van Gossum H. , Cordero-Rivera A. , Beatty C. D.
Published: August 2019

Wolbachia is one of the most common endosymbionts found infecting arthropods. Theory predicts symbionts like Wolbachia will be more common in species radiations, as host shift events occur with greatest frequency between closely related species. Further, the presence of Wolbachia itself may engender reproductive isolation, and promote speciation of their hosts. Here we screened 178 individuals belonging to 30 species of the damselfly genera Nesobasis and Melanesobasis — species radiations endemic to the Fiji archipelago in the South Pacific — for Wolbachia, using multilocus sequence typing to characterize bacterial strains. Incidence of Wolbachia was 71% in Nesobasis and 40% in Melanesobasis, and prevalence was also high, with an average of 88% in the Nesobasis species screened. We identified a total of 25 Wolbachia strains, belonging to supergroups A, B and F, with some epidemic strains present in multiple species. The occurrence of Wolbachia in both males and females, and the similar global prevalence found in both sexes rules out any strong effect of Wolbachia on the primary sex-ratio, but are compatible with the phenotype of cytoplasmic incompatibility. Nesobasis has higher species richness than most endemic island damselfly genera, and we discuss the potential for endosymbiont-mediated speciation within this group.
An S-cone circuit for edge detection in the primate retina
Authors: Patterson Sara S. , Kuchenbecker James A. , Anderson James R. , Bordt Andrea S. , Marshak David W. , Neitz Maureen , Neitz Jay
Published: August 2019

Midget retinal ganglion cells (RGCs) are the most common RGC type in the primate retina. Their responses have been proposed to mediate both color and spatial vision, yet the specific links between midget RGC responses and visual perception are unclear. Previous research on the dual roles of midget RGCs has focused on those comparing long (L) vs. middle (M) wavelength sensitive cones. However, there is evidence for several other rare midget RGC subtypes receiving S-cone input, but their role in color and spatial vision is uncertain. Here, we confirm the existence of the single S-cone center OFF midget RGC circuit in the central retina of macaque monkey both structurally and functionally. We investigated the receptive field properties of the S-OFF midget circuit with single cell electrophysiology and 3D electron microscopy reconstructions of the upstream circuitry. Like the well-studied L vs. M midget RGCs, the S-OFF midget RGCs have a center-surround receptive field consistent with a role in spatial vision. While spectral opponency in a primate RGC is classically assumed to contribute to hue perception, a role supporting edge detection is more consistent with the S-OFF midget RGC receptive field structure and studies of hue perception.
Functional Transcriptome Analysis in ARSACS KO Cell Model Reveals a Role of Sacsin in Autophagy
Authors: Morani Federica , Doccini Stefano , Sirica Roberto , Paterno Marta , Pezzini Francesco , Ricca Ivana , Simonati Alessandro , Delledonne Massimo , Santorelli Filippo Maria
Published: August 2019

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurological disease caused by mutations in SACS, which encodes sacsin. The complex architecture of sacsin suggests that it could be a key player in cellular protein quality control system. Molecular chaperones that operate in protein folding/unfolding and assembly/disassembly patterns have been described as essential modulators of selectivity during the autophagy process. We performed RNA-sequencing analysis to generate a whole-genome molecular signature profile of sacsin knockout cells. Using data analysis of biological processes significantly disrupted due to loss of sacsin, we confirmed the presence of decreased mitochondrial function associated with increased oxidative stress, and also provided a demonstration of a defective autophagic pathway in sacsin-depleted cells. Western blotting assays revealed decreased expression of LC3 and increased levels of p62 even after treatment with the lysosomal inhibitor bafilomycin A1, indicating impairment of the autophagic flux. Moreover, we found reduced co-immunolocalization of the autophagosome marker LC3 with lysosomal and mitochondrial markers suggesting fusion inhibition of autophagic compartments and subsequent failed cargo degradation, in particular failed degradation of damaged mitochondria. Pharmacological up-regulation of autophagy restored correct autophagic flux in sacsin knockout cells. These results corroborate the hypothesis that sacsin may play a role in autophagy. Chemical manipulation of this pathway might represent a new target to alleviate clinical and pathological symptoms, delaying the processes of neurodegeneration in ARSACS.
Author Correction: 3D shear wave velocity model of the crust and uppermost mantle beneath the Tyrrhenian basin and margins
Authors: Manu-Marfo D. , Aoudia A. , Pachhai S. , Kherchouche R.
Published: August 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper
Increasing altruistic and cooperative behaviour with simple moral nudges
Authors: Capraro Valerio , Jagfeld Glorianna , Klein Rana , Mul Mathijs , de Pol Iris van
Published: August 2019

The conflict between pro-self and pro-social behaviour is at the core of many key problems of our time, as, for example, the reduction of air pollution and the redistribution of scarce resources. For the well-being of our societies, it is thus crucial to find mechanisms to promote pro-social choices over egoistic ones. Particularly important, because cheap and easy to implement, are those mechanisms that can change people’s behaviour without forbidding any options or significantly changing their economic incentives, the so-called “nudges”. Previous research has found that moral nudges (e.g., making norms salient) can promote pro-social behaviour. However, little is known about whether their effect persists over time and spills across context. This question is key in light of research showing that pro-social actions are often followed by selfish actions, thus suggesting that some moral manipulations may backfire. Here we present a class of simple moral nudges that have a great positive impact on pro-sociality. In Studies 1–4 (total N = 1,400), we use economic games to demonstrate that asking subjects to self-report “what they think is the morally right thing to do” does not only increase pro-sociality in the choice immediately after, but also in subsequent choices, and even when the social context changes. In Study 5, we explore whether moral nudges promote charity donations to humanitarian organisations in a large (N = 1,800) crowdfunding campaign. We find that, in this context, moral nudges increase donations by about 44 percent.
Mapping behaviorally relevant light pollution levels to improve urban habitat planning
Authors: Schirmer Aaron E. , Gallemore Caleb , Liu Ting , Magle Seth , DiNello Elisabeth , Ahmed Humerah , Gilday Thomas
Published: August 2019

Artificial nighttime lights have important behavioral and ecological effects on wildlife. Combining laboratory and field techniques, we identified behaviorally relevant levels of nighttime light and mapped the extent of these light levels across the city of Chicago. We began by applying a Gaussian finite mixture model to 998 sampled illumination levels around Chicago to identify clusters of light levels. A simplified sample of these levels was replicated in the laboratory to identify light levels at which C57BL/6J mice exhibited altered circadian activity patterns. We then used camera trap and high-altitude photographic data to compare our field and laboratory observations, finding activity pattern changes in the field consistent with laboratory observations. Using these results, we mapped areas across Chicago exposed to estimated illumination levels above the value associated with statistically significant behavioral changes. Based on this measure, we found that as much as 36% of the greenspace in the city is in areas illuminated at levels greater than or equal to those at which we observe behavioral differences in the field and in the laboratory. Our findings provide evidence that artificial lighting patterns may influence wildlife behavior at a broad scale throughout urban areas, and should be considered in urban habitat planning.
Novel method for action potential measurements from intact cardiac monolayers with multiwell microelectrode array technology
Authors: Hayes Heather B. , Nicolini Anthony M. , Arrowood Colin A. , Chvatal Stacie A. , Wolfson David W. , Cho Hee Cheol , Sullivan Denise D. , Chal Jérome , Fermini Bernard , Clements Mike , Ross James D. , Millard Daniel C.
Published: August 2019

The cardiac action potential (AP) is vital for understanding healthy and diseased cardiac biology and drug safety testing. However, techniques for high throughput cardiac AP measurements have been limited. Here, we introduce a novel technique for reliably increasing the coupling of cardiomyocyte syncytium to planar multiwell microelectrode arrays, resulting in a stable, label-free local extracellular action potential (LEAP). We characterized the reliability and stability of LEAP, its relationship to the field potential, and its efficacy for quantifying AP morphology of human induced pluripotent stem cell derived and primary rodent cardiomyocytes. Rise time, action potential duration, beat period, and triangulation were used to quantify compound responses and AP morphology changes induced by genetic modification. LEAP is the first high throughput, non-invasive, label-free, stable method to capture AP morphology from an intact cardiomyocyte syncytium. LEAP can accelerate our understanding of stem cell models, while improving the automation and accuracy of drug testing.
Short-term influences of radiation on musculofascial healing in a laparotomy rat model
Authors: Chen Youbai , Zhang Qixu , Wu Yewen , Branch-Brooks Cynthia D. , Butler Charles E.
Published: August 2019

Preoperative radiation is associated with an increased risk of wound complications. However, the influences of radiation on musculofascial wound healing remains unclear. The purpose of the study was to investigate the short-term effects of preoperative local radiation on the musculofascial healing of laparotomy incisions in a rat model. Eighteen Fischer 344 rats received radiation doses of 0, 10, or 20 Gy to the abdominal wall and underwent laparotomy 4 weeks later. Two weeks after laparotomy, samples of irradiated muscle were harvested for mechanical tests, histological (Hematoxylin & Eosin, and Masson’s Trichrome) and immunohistochemical analyses using KI67, CD31, TGF-β, and MYOD1 antibodies. The elastic modulus (EM), maximum strain (MS), and ultimate tensile strength (UTS) in the 20-Gy group were significantly weaker than those in the 0-Gy group. The EM and UTS in the 20-Gy group were significantly lower than those in the 10-Gy group. The UTS and MS in the 10-Gy group were significantly lower than those in the 0-Gy group. The mean number of inflammatory cells per mm2 in the 20-Gy group was significantly larger than those in the 10- and 0-Gy groups. The mean numbers of CD31-, KI67-, and MYOD1-positive cells, the optical density of TGF-β, and the microvessel density in the 20-Gy group were significantly smaller than those in the 10- and 0-Gy groups. These results indicated that radiation delays musculofascial healing and decreases mechanical strength of the laparotomy incision by creating a chronic inflammatory environment, inhibiting cell proliferation, angiogenesis, granulation maturation, collagen deposition, and muscular regeneration in a dose-dependent manner. The impaired biomechanical, histological and molecular properties may be associated with the higher risk of wound complications in patients who undergo radiotherapy prior to laparotomy.
Hydro-ecological controls on riverine organic carbon dynamics in the tropical monsoon region
Authors: Zhang Qianzhu , Tao Zhen , Ma Zanwen , Gao Quanzhou , Deng Haojun , Xu Peng , Ding Jian , Wang Zhengang , Lin Youwen
Published: August 2019

Transport fluxes and properties of riverine organic carbon in the tropical monsoon region were the vital parameters in the global riverine organic carbon fluxes budget. The study focused on the riverine organic carbon in the Changhuajiang River (CHJR), locating at the mid-west of the Hainan Island, China. Dissolved organic carbon (DOC) concentrations in the CHJR ranged from 0.22 mg/L to 11.75 mg/L with an average of 1.75 mg/L, which was lower than the average of global rivers and had a significantly temporal and spatial variation. Output flux of riverine DOC was calculated as 0.55 t/km2/y, which could be revised up to 1.03 t/km2/y, considering that the riverine discharge before dam construction. A linear model of riverine DOC flux suitable in CHJR basin was established, which involved the factors, such as soil organic carbon, runoff depth and slope, etc. There was a large variation of POC concentrations in the CHJR where the average POC concentration in the dry season was 2.41 times of the wet season. Riverine POC flux in CHJR basin was calculated as 1.78 t/km2/y, higher than the average of global rivers and far lower than those in other domestic larger rivers. About 8.28 × 103 t POC were exported yearly in CHJR, of which, 7.15 × 103 t originated from terrestrial ecosystem and 1.13 × 103 t stemmed from aquatic ecosystem. Meanwhile, about 87.74% of terrestrial source happened in the wet season and 12.26% in the dry season. This research revealed that the riverine organic carbon mainly stemmed from the surface erosion processes in the drainage basin during the wet season.
Double Pinned Perpendicular-Magnetic-Tunnel-Junction Spin-Valve Providing Multi-level Resistance States
Authors: Choi Jin-Young , Jun Hansol , Ashiba Kei , Baek Jong-Ung , Shim Tae-Hun , Park Jea-Gun
Published: August 2019

A new design for high density integration greater than gigabits of perpendicular-magnetic-tunnel-junction (p-MTJ) spin-valve, called the double pinned (i.e., bottom and top pinned structures) p-MTJ spin-valve achieved a multi-level memory-cell operation exhibiting four-level resistances. Three key magnetic properties, the anisotropy exchange field (Hex) of the bottom pinned structure, the coercivity (Hc) of the double free-layer, and the Hc of the top pinned structure mainly determined four-level resistances producing tunneling-magnetoresistance (TMR) ratios of 152.6%, 33.6%, and 166.5%. The three key-design concepts are: i) the bottom pinned structure with a sufficiently large Hex to avoid a write-error, ii) the Hc of the double free-layer (i.e., ~0.1 kOe) much less than the Hc of the top pinned structure (i.e., ~1.0 kOe), and iii) the top pinned structure providing different electron spin directions.
Allometric Scaling of physiologically-relevant organoids
Authors: Magliaro Chiara , Rinaldo Andrea , Ahluwalia Arti
Published: August 2019

The functional and structural resemblance of organoids to mammalian organs suggests that they might follow the same allometric scaling rules. However, despite their remarkable likeness to downscaled organs, non-luminal organoids are often reported to possess necrotic cores due to oxygen diffusion limits. To assess their potential as physiologically relevant in vitro models, we determined the range of organoid masses in which quarter power scaling as well as a minimum threshold oxygen concentration is maintained. Using data on brain organoids as a reference, computational models were developed to estimate oxygen consumption and diffusion at different stages of growth. The results show that mature brain (or other non-luminal) organoids generated using current protocols must lie within a narrow range of masses to maintain both quarter power scaling and viable cores. However, micro-fluidic oxygen delivery methods could be designed to widen this range, ensuring a minimum viable oxygen threshold throughout the constructs and mass dependent metabolic scaling. The results provide new insights into the significance of the allometric exponent in systems without a resource-supplying network and may be used to guide the design of more predictive and physiologically relevant in vitro models, providing an effective alternative to animals in research.
11PS04 is a new chemical entity identified by microRNA-based biosensing with promising therapeutic potential against cancer stem cells
Authors: Aguado Tania , Romero-Revilla José A. , Granados Rosario , Campuzano Susana , Torrente-Rodríguez Rebeca M. , Cuesta Ángel M. , Albiñana Virginia , Botella Luisa María , Santamaría Silvia , Garcia-Sanz Jose A. , Pingarrón José Manuel , Sánchez-Sancho Francisco , Sánchez-Puelles José-María
Published: August 2019

Phenotypic drug discovery must take advantage of the large amount of clinical data currently available. In this sense, the impact of microRNAs (miRs) on human disease and clinical therapeutic responses is becoming increasingly well documented. Accordingly, it might be possible to use miR-based signatures as phenotypic read-outs of pathological status, for example in cancer. Here, we propose to use the information accumulating regarding the biology of miRs from clinical research in the preclinical arena, adapting it to the use of miR biosensors in the earliest steps of drug screening. Thus, we have used an amperometric dual magnetosensor capable of monitoring a miR-21/miR-205 signature to screen for new drugs that restore these miRs to non-tumorigenic levels in cell models of breast cancer and glioblastoma. In this way we have been able to identify a new chemical entity, 11PS04 ((3aR,7aS)-2-(3-propoxyphenyl)-7,7a-dihydro-3aH-pyrano[3,4-d]oxazol-6(4H)-one), the therapeutic potential of which was suggested in mechanistic assays of disease models, including 3D cell culture (oncospheres) and xenografts. These assays highlighted the potential of this compound to attack cancer stem cells, reducing the growth of breast and glioblastoma tumors in vivo. These data demonstrate the enhanced chain of translatability of this strategy, opening up new perspectives for drug-discovery pipelines and highlighting the potential of miR-based electro-analytical sensors as efficient tools in modern drug discovery.
Left ventricular mass estimation by real-time 3D echocardiography favourably competes with CMR in congenital left ventricular disease
Authors: Michel Miriam , Shabanah Wael , Körperich Hermann , Kelter-Klöpping Andrea , Entenmann Andreas , Racolta Anca , Laser Kai Thorsten
Published: August 2019

Assessment of left ventricular mass (LVM) is important in the evaluation of patients with congenital heart disease (CHD) and cardiac magnetic resonance imaging (CMR) is the gold standard. Recent software allows LVM calculation by real-time 3-dimensional echocardiography (RT3DE). We investigated the impact of different software analysis tools on LVM determination by CMR or RT3DE in a cohort of patients with heterogeneous left ventricular (LV) disease. 37 subjects (17 patients, mean age 18.7 y; 20 controls, mean age 13.2 y) underwent CMR and RT3DE. CMR LVM and RT3DE calculations were done using two different LV-analysis software packages for each modality: CMR i) customized software “CMR HDZ”, CMR ii) “CMR ISP”; RT3DE i) “Toshiba”, RT3DE ii) “Tomtec”, 4D LV-Analysis Version 3.1 (built 3.1.0.258661). Intra- and interobserver variabilities were calculated. Only RT3DE-derived LVM showed significant software-dependent differences. RT3DE-derived LVM (both softwares) was significantly higher than CMR-derived LVM (both softwares). The two different methods and four evaluation software packages for LVM assessment were well correlated with each other. Intra- and interobserver variability of LVM as assessed by each single modality or software was low. Despite software dependency and overestimation of RT3DE-assessed LVM by 5 to 10%, RT3DE still competes with the gold standard, CMR, even in patients with various forms of LV disease. The use of optimized software, especially for RT3DE, should improve the accuracy of LVM assessment, overcoming LVM overestimation.
Morphological and Molecular Changes in Juvenile Normal Human Fibroblasts Exposed to Simulated Microgravity
Authors: Buken Christoph , Sahana Jayashree , Corydon Thomas J. , Melnik Daniela , Bauer Johann , Wehland Markus , Krüger Marcus , Balk Silke , Abuagela Nauras , Infanger Manfred , Grimm Daniela
Published: August 2019

The literature suggests morphological alterations and molecular biological changes within the cellular milieu of human cells, exposed to microgravity (µg), as many cell types assemble to multicellular spheroids (MCS). In this study we investigated juvenile normal human dermal fibroblasts (NHDF) grown in simulated µg (s-µg) on a random positioning machine (RPM), aiming to study changes in cell morphology, cytoskeleton, extracellular matrix (ECM), focal adhesion and growth factors. On the RPM, NHDF formed an adherent monolayer and compact MCS. For the two cell populations we found a differential regulation of fibronectin, laminin, collagen-IV, aggrecan, osteopontin, TIMP-1, integrin-β1, caveolin-1, E-cadherin, talin-1, vimentin, α-SM actin, TGF-β1, IL-8, MCP-1, MMP-1, and MMP-14 both on the transcriptional and/or translational level. Immunofluorescence staining revealed only slight structural changes in cytoskeletal components. Flow cytometry showed various membrane-bound proteins with considerable variations. In silico analyses of the regulated proteins revealed an interaction network, contributing to MCS growth via signals mediated by integrin-β1, E-cadherin, caveolin-1 and talin-1. In conclusion, s-µg-conditions induced changes in the cytoskeleton, ECM, focal adhesion and growth behavior of NHDF and we identified for the first time factors involved in fibroblast 3D-assembly. This new knowledge might be of importance in tissue engineering, wound healing and cancer metastasis.
Preclinical Evaluation of a Noncontact Simultaneous Monitoring Method for Respiration and Carotid Pulsation Using Impulse-Radio Ultra-Wideband Radar
Authors: Park Jun-Young , Lee Yonggu , Choi Yeon-Woo , Heo Ran , Park Hyun-Kyung , Cho Seok-Hyun , Cho Sung Ho , Lim Young-Hyo
Published: August 2019

There has been the possibility for respiration and carotid pulsation to be simultaneously monitored from a distance using impulse-radio ultra-wideband (IR-UWB) radar. Therefore, we investigated the validity of simultaneous respiratory rates (RR), pulse rates (PR) and R-R interval measurement using IR-UWB radar. We included 19 patients with a normal sinus rhythm (NSR) and 14 patients with persistent atrial fibrillation (PeAF). The RR, PR, R-R interval and rhythm were obtained simultaneously from the right carotid artery area in a supine position and under normal breathing conditions using IR-UWB radar. There was excellent agreement between the RR obtained by IR-UWB radar and that manually counted by a physician (intraclass correlation coefficient [ICC] 0.852). In the NSR group, there was excellent agreement between the PR (ICC 0.985), average R-R interval (ICC 0.999), and individual R-R interval (ICC 0.910) measured by IR-UWB radar and electrocardiography. In the PeAF group, PR (ICC 0.930), average R-R interval (ICC 0.957) and individual R-R interval (ICC 0.701) also agreed well between the two methods. These results demonstrate that IR-UWB radar can simultaneously monitor respiration, carotid pulse and heart rhythm with high precision and may thus be utilized as a noncontact continuous vital sign monitoring in clinical practice.
Design of high-order antibiotic combinations against M. tuberculosis by ranking and exclusion
Authors: Yilancioglu Kaan , Cokol Murat
Published: August 2019

Combinations of more than two drugs are routinely used for the treatment of pathogens and tumors. High-order combinations may be chosen due to their non-overlapping resistance mechanisms or for favorable drug interactions. Synergistic/antagonistic interactions occur when the combination has a higher/lower effect than the sum of individual drug effects. The standard treatment of Mycobacterium tuberculosis (Mtb) is an additive cocktail of three drugs which have different targets. Herein, we experimentally measured all 190 pairwise interactions among 20 antibiotics against Mtb growth. We used the pairwise interaction data to rank all possible high-order combinations by strength of synergy/antagonism. We used drug interaction profile correlation as a proxy for drug similarity to establish exclusion criteria for ideal combination therapies. Using this ranking and exclusion design (R/ED) framework, we modeled ways to improve the standard 3-drug combination with the addition of new drugs. We applied this framework to find the best 4-drug combinations against drug-resistant Mtb by adding new exclusion criteria to R/ED. Finally, we modeled alternating 2-order combinations as a cycling treatment and found optimized regimens significantly reduced the overall effective dose. R/ED provides an adaptable framework for the design of high-order drug combinations against any pathogen or tumor.
Distribution and dynamics of mitochondrial DNA methylation in oocytes, embryos and granulosa cells
Authors: Sirard Marc-André
Published: August 2019

Comparison of mitochondrial DNA (mtDNA) methylation patterns in oocytes, blastocysts and ovarian granulosa cells indicates hitherto unsuspected dynamics. Oocytes and blastocysts recovered from cows subjected to ovarian stimulation and from non-stimulated abattoir ovaries were analyzed using bisulphite transformation of DNA followed by whole genome sequencing. The cow is a recognized as a good model for human oocyte and pre-implantation development. The number of mtDNA copies is high in oocytes (200,000–400,000) and early embryos, resulting in very high coverage (>3000x) and very low p values for each of 716 cytosine-based nucleosides. Methylation ratio was lowest in oocytes, following by blastocysts then granulosa cells and was not restricted to CG sites but was found also at CHG and CHH sites. The initial methylation pattern is conserved during the first week of life but not in somatic cells. RNA analysis of mitochondria encoded genes showed a significant inverse correlation between methylation and expression for almost all sequences. Methylation was more extensive in somatic tissues from mature animals than in immature pre-pubertal animals. Our findings suggest that mtDNA methylation might play a programming role during gametogenesis and would be subject to epigenetic regulation according to environment and/or maternal maturity.
An empirical assessment of research practices across 163 clinical trials of tumor-bearing companion dogs
Authors: Tan Yuan Jin , Crowley Ryan J. , Ioannidis John P. A.
Published: August 2019

Comparative clinical trials of domestic dogs with spontaneously-occurring cancers are increasingly common. Canine cancers are likely more representative of human cancers than induced murine tumors. These trials could bridge murine models and human trials and better prioritize drug candidates. Such investigations also benefit veterinary patients. We aimed to evaluate the design and reporting practices of clinical trials containing ≥2 arms and involving tumor-bearing dogs. 163 trials containing 8552 animals were systematically retrieved from PubMed (searched 1/18/18). Data extracted included sample sizes, response criteria, study design, and outcome reporting. Low sample sizes were prevalent (median n = 33). The median detectable hazard ratio was 0.3 for overall survival and 0.06 for disease progression. Progressive disease thresholds for studies that did not adopt VCOG-RECIST guidelines varied in stringency. Additionally, there was significant underreporting across all Cochrane risk of bias categories. The proportion of studies with unclear reporting ranged from 44% (randomization) to 94% (selective reporting). 72% of studies also failed to define a primary outcome. The present study confirms previous findings that clinical trials in dogs need to be improved, particularly regarding low statistical power and underreporting of design and outcomes.
Molecular analysis and epidemiological typing of Vancomycin-resistant Enterococcus outbreak strains
Authors: Rangberg Anbjørg , Larsen Astri Lervik , Kacelnik Oliver , Sæther Hanne Skarpodde , Bjørland Marthe , Ringstad Jetmund , Jonassen Christine Monceyron
Published: August 2019

Outbreaks of multidrug resistant bacteria including vancomycin-resistant enterococci (VRE) in healthcare institutions are increasing in Norway, despite a low level of resistance compared to other European countries. In this study, we describe epidemiological relatedness of vancomycin-resistant Enterococcus faecium isolated during an outbreak at a Norwegian hospital in 2012–2013. During the outbreak, 9454 fecal samples were screened for VRE by culture and/or PCR. Isolates from 86 patients carrying the vanA resistance gene were characterized using pulsed-field gel electrophoresis (PFGE), MALDI-TOF mass spectrometry and single nucleotide polymorphism typing. PFGE revealed two main clusters, the first comprised 56 isolates related to an initial outbreak strain, and the second comprised 21 isolates originating from a later introduced strain, together causing two partly overlapping outbreaks. Nine isolates, including the index case were not related to the two outbreak clusters. In conclusion, the epidemiological analyses show that the outbreak was discovered by coincidence, and that infection control measures were successful. All typing methods identified the two outbreak clusters, and the experiment congruence between the MALDI-TOF and the PFGE clustering was 63.2%, with a strong correlation (r = 72.4%). Despite lower resolution compared to PFGE, MALDI-TOF may provide an efficient mean for real-time monitoring spread of infection.
Prioritization of solid concentration and temperature for solid state anaerobic digestion of pearl millet straw employing multi-criteria assessment tool
Authors: Paritosh Kunwar , Pareek Nidhi , Chawade Aakash , Vivekanand Vivekanand
Published: August 2019

India produces huge quantities of agricultural residues and stubbles and mainly disposed by burning on site causing air pollution. The organic matter present in the residues and stubble may be utilized by anaerobic digestion as a source of renewable energy subsequently reducing emission of greenhouse gases caused by burning. In the present study, solid state anaerobic digestion (SSAD) of pearl millet straw was investigated at mesophilic and thermophilic temperature with four different total solid (TS) content (15, 20, 25 and 30%). Results showed that 20 and 25% TS generated maximum methane (124.1 ± 7 and 162.4 ± 9L/kg VS) at mesophilic and thermophilic temperature respectively. However, increasing TS content beyond 25% did not show significant increment on methane yield. Analytical analysis showed correlation between the reduction of volatile solids and methane yield as well as VFA (volatile fatty acid) accumulation at high TS content. Also, VlseKriterijuska Optimizacija Komoromisno Resenje (VIKOR) and Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) methods as MultiCriteria Decision Making modelling (MCDM) applied to select best possible alternative for SSAD of pearl millet. MCDM analysis showed that VIKOR method endorsed the experimental results.
Enhancing the Thermal Stability of Carbon Nanomaterials with DNA
Authors: Safaee Mohammad Moein , Gravely Mitchell , Lamothe Adeline , McSweeney Megan , Roxbury Daniel
Published: August 2019

Single-walled carbon nanotubes (SWCNTs) have recently been utilized as fillers that reduce the flammability and enhance the strength and thermal conductivity of material composites. Enhancing the thermal stability of SWCNTs is crucial when these materials are applied to high temperature applications. In many instances, SWCNTs are applied to composites with surface coatings that are toxic to living organisms. Alternatively, single-stranded DNA, a naturally occurring biological polymer, has recently been utilized to form singly-dispersed hybrids with SWCNTs as well as suppress their known toxicological effects. These hybrids have shown unrivaled stabilities in both aqueous suspension or as a dried material. Furthermore, DNA has certain documented flame-retardant effects due to the creation of a protective char upon heating in the presence of oxygen. Herein, using various thermogravimetric analytical techniques, we find that single-stranded DNA has a significant flame-retardant effect on the SWCNTs, and effectively enhances their thermal stability. Hybridization with DNA results in the elevation of the thermal decomposition temperature of purified SWCNTs in excess of 200 °C. We translate this finding to other carbon nanomaterials including multi-walled carbon nanotubes (MWCNTs), reduced graphene oxide (RGO) and fullerene (C60), and show similar effects upon complexation with DNA. The rate of thermal decomposition of the SWCNTs was also explored and found to significantly depend upon the sequence of DNA that was used.
Clinical and genetic characteristics of pachydrusen in patients with exudative age-related macular degeneration
Authors: Fukuda Yoshiko , Sakurada Yoichi , Yoneyama Seigo , Kikushima Wataru , Sugiyama Atsushi , Matsubara Mio , Tanabe Naohiko , Iijima Hiroyuki
Published: August 2019

We investigated the clinical and genetic characteristics of patients with unilateral exudative age-related macular degeneration (AMD), including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation, in whom pachydrusen was seen. Patients with unilateral exudative AMD with at least a 12-month follow-up period were included. According to the fellow eye condition, 327 consecutive patients were classified into 4 groups: Group 0: no drusen (42.8%), Group 1: pachydrusen (12.2%), Group 2: soft drusen (30.3%), Group 3: pseudodrusen with or without soft drusen (14.7%). Development of exudative AMD in the fellow eye was retrospectively studied for a 60-month period and this inter-group comparisons were performed. Genotyping was performed for ARMS2 A69S and CFH I62V. The thickness of the choroid in the fellow eyes increased significantly in Group 1 than in other groups (all P < 1.0 × 10−7). The development of exudative AMD in the fellow eye was significantly less frequent in Group 1 than in Groups 2 or 3 (P = 0.022 and 0.0015, respectively). Risk allele frequency of ARMS2 A69S was significantly lower in Group 1 than in Group 2 and 3 (all P < 1.0 × 10−4). Patients with pachydrusen have genetic and clinical characteristics distinct from those of soft drusen and pseudodrusen.
Dark air–liquid interfacial chemistry of glyoxal and hydrogen peroxide
Authors: Zhang Fei , Yu Xiaofei , Chen Jianmin , Zhu Zihua , Yu Xiao-Ying
Published: August 2019

The air–liquid (a–l) interfacial chemistry of glyoxal is of great interest in atmospheric chemistry. We present molecular imaging of glyoxal and hydrogen peroxide (H2O2) dark aging using in situ time-of-flight secondary ion mass spectrometry (ToF-SIMS). More organic peroxides and cluster ions are observed at the a–l interface in dark aging compared to UV aging. Cluster ions formed with more water molecules in dark aging indicate that the aqueous secondary organic aerosol (aqSOA) could form hydrogen bond with water molecules, suggesting that aqSOAs at the aqueous phase are more hydrophilic. Thus the interfacial aqSOA in dark aging could increase hygroscopic growth. Strong contribution of cluster ions and large water clusters in dark aging indicates change of solvation shells at the a–l interface. The observation of organic peroxides and cluster ions indicates that the aqueous surface could be a reservoir of organic peroxides and odd hydrogen radicals at night. Our findings provide new understandings of glyoxal a–l interfacial chemistry and fill in the gap between field measurements and the climate model simulation of aqSOAs.
Study on the affinity characteristics of proteins on the immobilized metal affinity chromatography column
Authors: Li Rong , Chen Peng , Zhang Ning , Chen Bin
Published: August 2019

Study on affinity characteristic paramaters (KPML&ΛPML) of proteins on the iminodisuccinic acid metal chelate copper column by frontal chromatography.
Molecular sieving property adjusted by the encapsulation of Ag nanoparticles into ZnO@ZIF-71 nanorod arrays
Authors: Zhou Tingting , Qin Ziyu , Wang Xiaoxia , Wu Congyi , Tang Xing , Zhang Tian , Wang Hao , Xie Changsheng , Zeng Dawen
Published: August 2019

Ag NPs are encapsulated into ZIF-71 serving as an adjustable molecular sieving layer to hydrogen and acetone.