bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of High-Quality Random Number Generators
Authors: James Frederick , Moneta Lorenzo
Published: January 2020

This is a review of pseudorandom number generators (RNG’s) of the highest quality, suitable for use in the most demanding Monte Carlo calculations. All the RNG’s we recommend here are based on the Kolmogorov–Anosov theory of mixing in classical mechanical systems, which guarantees under certain conditions and in certain asymptotic limits, that points on the trajectories of these systems can be used to produce random number sequences of exceptional quality. We outline this theory of mixing and establish criteria for deciding which RNG’s are sufficiently good approximations to the ideal mathematical systems that guarantee highest quality. The well-known RANLUX (at highest luxury level) and its recent variant RANLUX++ are seen to meet our criteria, and some of the proposed versions of MIXMAX can be modified easily to meet the same criteria.
Effect of new olivacine derivatives on p53 protein level
Authors: Gębarowski Tomasz , Wiatrak Benita , Gębczak Katarzyna , Tylińska Beata , Gąsiorowski Kazimierz
Published: January 2020

Background

The p53 protein is a transcription factor for many genes, including genes involved in inhibiting cell proliferation and inducing apoptosis in genotoxically damaged and tumor-transformed cells. In more than 55% of cases of human cancers, loss of the essential function of p53 protein is found. In numerous reports, it has been shown that small molecules (chemical compounds) can restore the suppressor function of the mutant p53 protein in tumor cells. The aim of this study was to evaluate the potential anticancer activity of three newly synthesized olivacine derivatives.

Methods

The study was performed using two cell lines—CCRF/CEM (containing the mutant p53 protein) and A549 (containing a non-mutant, wild-type p53 protein). The cells were incubated with olivacine derivatives for 18 h and then assays were carried out: measurement of the amount of p53 and p21 proteins, detection of apoptosis, cell cycle analysis, and rhodamine 123 accumulation assay (evaluation of P-glycoprotein inhibition). Multiple-criteria decision analysis was used to compare the anticancer activity of the tested compounds.

Results

Each tested compound caused the reconstitution of suppressor activity of the p53 protein in cells with the mutant protein. In addition, one of the compounds showed significant antitumor activity in both wild-type and mutant cells. For all compounds, a stronger effect on the level of the p53 protein was observed than for the reference compound—ellipticine.

Conclusions

The observed effects of the tested new olivacine derivatives (pyridocarbazoles) suggest that they are good candidates for new anticancer drugs.
Can helping others strengthen teens? Character strengths as mediators between prosocial behavior and adolescents’ internalizing symptoms
Authors: Padilla‐Walker Laura M. , Millett Mallory A. , Memmott‐Elison Madison K.
Published: January 2020

Introduction

Identifying protective factors against internalizing behaviors during adolescence is a public health priority, as rates of depression and anxiety are rising. As such, the purpose of this study was to examine whether prosocial engagement toward strangers and family members is protective against depressive and anxiety symptoms, and whether this link is mediated by character strengths (i.e., hope, persistence, gratitude, and self‐esteem).

Method

The sample consisted of 500 US adolescents (52% female; 66% European American; 33% from single‐parent families). Data across three consecutive yearly waves were utilized in the current study (Mage Time 1 = 13.32).

Results

Results of a longitudinal structural equation model revealed prosocial behavior toward strangers and family members were differentially related to character strengths, and that prosocial behavior toward strangers was indirectly associated with depressive symptoms via self‐esteem.

Conclusion

Taken together, findings extend the Developmental Cascades model and suggest that prosocial behavior and character strengths protect against depressive symptoms during the adolescent period. Findings are discussed in the context of relevant research and theory, and implications for future research and intervention programs are presented.
Ten‐eleven translocation‐2 affects the fate of cells and has therapeutic potential in digestive tumors
Authors: Wang Feng , Zhang Jing , Qi Jian
Published: January 2020

Ten‐eleven translocation (TET) methylcytosine dioxygenases catalyze the oxidative reactions of 5‐methylcytosine (5‐mC) to 5‐hydroxymethylcytosine (5‐hmC), 5‐formylcytosine (5‐fC), and 5‐carboxylcytosine (5‐caC), which are intermediate steps during DNA demethylation. It is reported that somatic mutations of TET2 gene are identified in a variety of human tumors, especially in hematological malignancies. The tendency and mechanism of cellular differentiation in different systems are affected by TET2 via regulation of associated gene expression or maintenance of demethylated state. TET2 acts as a critical driver of tumorigenesis through the conversion of 5‐mC to 5‐hmC and successive oxidation products. Sometimes, it requires special interactions and cofactors. Here, we reviewed recent advances in understanding the function of TET2 proteins in regulating cell differentiation, and its role in various tumors focusing on several digestive cancers.
ALGEBRAIC STRUCTURE OF THE RANGE OF A TRIGONOMETRIC POLYNOMIAL
Authors: KOVALEV LEONID V. , YANG XUERUI
Published: January 2020

The range of a trigonometric polynomial with complex coefficients can be interpreted as the image of the unit circle under a Laurent polynomial. We show that this range is contained in a real algebraic subset of the complex plane. Although the containment may be proper, the difference between the two sets is finite, except for polynomials with a certain symmetry.
TRANSFORMATION FORMULAS FOR THE NUMBER OF REPRESENTATIONS OF BY LINEAR COMBINATIONS OF FOUR TRIANGULAR NUMBERS
Authors: SUN ZHI-HONG
Published: January 2020

Let $\mathbb{Z}$ and $\mathbb{Z}^{+}$ be the set of integers and the set of positive integers, respectively. For $a,b,c,d,n\in \mathbb{Z}^{+}$, let $t(a,b,c,d;n)$ be the number of representations of $n$ by $\frac{1}{2}ax(x+1)+\frac{1}{2}by(y+1)+\frac{1}{2}cz(z+1)+\frac{1}{2}dw(w+1)$ with $x,y,z,w\in \mathbb{Z}$. Using theta function identities we prove 13 transformation formulas for $t(a,b,c,d;n)$ and evaluate $t(2,3,3,8;n)$, $t(1,1,6,24;n)$ and $t(1,1,6,8;n)$.
Dietary intake of phloridzin from natural occurrence in foods
Authors: Niederberger Katherine E. , Tennant David R. , Bellion Phillip
Published: January 2020

Type 2 diabetes mellitus (T2DM) is one of the major diseases of our times. Besides being a considerable inconvenience for the patient, the associated healthcare expenses are tremendous. One of the cornerstones of T2DM prevention is a healthy diet, including a variety of fruits and vegetables. Apples are touted to have health benefits, and the apple polyphenol, phloridzin, has gained interest in recent years as it can reduce intestinal sugar uptake by inhibition of the Na/glucose cotransporter 1. By researching the amount of phloridzin in different food sources and linking them to their consumption data, we could estimate the average and high-level phloridzin consumption in Europe. On average, European people consume 0·7–7·5 mg/d phloridzin, the main contributors being apples and apple juice. High-level consumers may get up to 52 mg/d of phloridzin. Older people are more at risk of developing T2DM, yet they consume less phloridzin than adolescents and adults, as determined by our survey. Management of blood glucose levels might be improved by the consumption of phloridzin, as has been shown in recent clinical trials; these trials used phloridzin-enriched apple extract at doses exceeding those from normal food consumption. There are, however, indications that consumption of average to high levels of phloridzin via food might also contribute to reduced sugar load and a reduction in T2DM risk.
The utility of computed tomography and diffusion-weighted magnetic resonance imaging fusion in cholesteatoma: illustration with a UK case series
Authors: Hall A , St Leger D , Singh A , Lingam R K
Published: January 2020

Objective

Post-processing imaging techniques allow high-resolution computed tomography and diffusion-weighted magnetic resonance imaging of the temporal bone to be superimposed and viewed simultaneously (fusion imaging). This study aimed to highlight the practical utility of fusion imaging for disease localisation and evaluation in a UK case series of primary and post-operative cholesteatoma.

Method

Fusion of computed tomography and diffusion-weighted magnetic resonance b1000 images was performed using specific software. Axial computed tomography images and coronal b1000 images were selected for fusion.

Results

A case series of primary and post-operative cholesteatoma in which computed tomography and magnetic resonance imaging fusion assisted the management of both the patient pathway and surgical approach is reviewed.

Conclusion

Computed tomography and magnetic resonance imaging fusion can assist in pre-operative surgical planning and patient counselling through assessment of disease in both primary and revision scenarios. Computed tomography and magnetic resonance imaging fusion can assist the operative surgeon through accurate localisation that can influence both the operative technique and optimise operation theatre utilisation.
Nierenbiopsie-Diagnostik: Was muss ich wissen und was ist neu?
Authors: Menter Thomas , Hirt-Minkowski Patricia , Hopfer Helmut
Published: January 2020

Zusammenfassung. Nierenbiopsien gelten als sichere Methode, um die Differentialdiagnose einer Hämaturie, einer Proteinurie und eines akuten renalen Nierenversagens aufzuklären. Bedingt durch die aufwendige Aufarbeitung mit Lichtmikroskopie, Immunhistologie und Elektronenmikroskopie ist die Nephropathologie «hochspezialisiert» und deshalb in der Regel nur in grösseren Zentren verfügbar. Sie leistet einen entscheidenden Beitrag in der diagnostischen Abklärung von Nierenkranken und deren Therapie. Immunhistochemische Marker helfen uns zunehmend, Erkrankungen ätiologisch zuzuordnen. Ausführlicher diskutieren wir in unserem Artikel Paraprotein-assoziierte Nierenerkrankungen. Diese sind relativ häufig, jedoch erfüllen viele der Patienten die diagnostischen Kriterien eines Plasmazellmyeloms nicht. Für sie wurde vor wenigen Jahren der Begriff «monoklonale Gammopathie renaler Signifikanz» (MGRS) und gleichzeitig eine Therapie, die sich an die Tumortherapie anlehnt, eingeführt – mit Verbesserung des Mortalitäts- und Morbiditätsrisikos dieser Patienten. Ausserdem gehen wir auf die neue Gruppe der Komplement C3-Glomerulopathien ein. Diese sind zwar selten, zeigen aber eine interessante Pathophysiologie und es zeichnen sich neue Therapieansätzen am Horizont ab.
The Nitrogen Isotopic Composition of Tissue and Shell‐Bound Organic Matter of Planktic Foraminifera in Southern Ocean Surface Waters
Authors: Smart Sandi M. , Fawcett Sarah E. , Ren Haojia , Schiebel Ralf , Tompkins Emily M. , Martínez‐García Alfredo , Stirnimann Luca , Roychoudhury Alakendra , Haug Gerald H. , Sigman Daniel M.
Published: January 2020

We present the first nitrogen isotope (δ15N) measurements of planktic foraminifera, paleoceanographically important zooplankton, from the nutrient‐rich waters of the modern Southern Ocean. Foraminifera were collected from net tows in the Subantarctic and Polar Frontal Zones (SAZ and PFZ, respectively) south of Africa during winter 2015 and late summer 2016. In late summer, consistent with preferential uptake of 14N‐nitrate and the progressive, northward depletion of nitrate by phytoplankton across the Southern Ocean, foraminifer tissue and shell‐bound δ15N rise equatorward along with nitrate δ15N. However, foraminifer δ15N is ~3‰ lower than expected for heterotrophs relying on photosynthetic biomass generated directly from nitrate. This discrepancy appears to originate with the particulate organic N (PON) in late‐summer surface waters, the δ15N of which is lowered by ammonium recycling. In winter, when overall productivity and foraminifer production are reduced, foraminifer δ15N is higher (by 4.6 ± 0.8‰ for tissue and by 4.0 ± 1.5‰ for shell‐bound N compared to late summer) and exhibits no clear north‐south trend. These characteristics can also be explained by the feeding‐driven connection of foraminifera to PON, which is elevated in δ15N by net degradation in winter. Therefore, foraminifer δ15N is more closely tied to PON δ15N than to nitrate δ15N in the Southern Ocean mixed layer. Combining our isotope data with previously reported sediment trap fluxes from the western Pacific SAZ/PFZ suggests that, under modern conditions, the late‐summer ammonium recycling signal outweighs that of wintertime decomposition on the annually integrated δ15N of sinking foraminifera.
Atmospheric Sulfuric Acid‐Dimethylamine Nucleation Enhanced by Trifluoroacetic Acid
Authors: Lu Yiqun , Liu Ling , Ning An , Yang Gan , Liu Yiliang , Kurtén Theo , Vehkamäki Hanna , Zhang Xiuhui , Wang Lin
Published: January 2020

Sulfuric acid (SA)‐dimethylamine (DMA)‐H2O cluster formation has been proven to be responsible for a significant part of new particle formation (NPF) in a Chinese megacity. However, the possible involvement of common atmospheric acids in the subsequent growth of SA‐DMA clusters remains elusive. We simulated formation and growth of clusters using atmospheric relevant concentrations of SA, DMA, and trifluoroacetic acid (TFA), a commonly observed atmospheric perfluorocarboxylic acid, using Density Functional Theory combined with Atmospheric Cluster Dynamics Code. The presence of TFA leads to complex cluster formation routes and an enhancement of NPF rates by up to 2.3 ([TFA] = 5.0 × 106 molecules cm−3, [SA] = 1.0 × 106 molecules cm−3, and [DMA] = 1.5 × 109 molecules cm−3). The agreement of (SA)1·(DMA)1‐2·(TFA)1 concentrations between simulations and ambient measurements during NPF events validates model predictions and implies that perfluorocarboxylic acids could potentially boost atmospheric SA‐DMA NPF rates.
Comparative Rock Magnetic Study of Eocene Volcanogenic and Sedimentary Rocks From Yunnan, Southeastern Tibetan Plateau, and Its Geological Implications
Authors: Shen Miaomiao , Zan Jinbo , Yan Maodu , Zhang Weilin , Fang Xiaomin , Zhang Dawen , Zhang Tao
Published: January 2020

Many recent biomagnetostratigraphic studies within and around the Tibetan Plateau have resulted in significant age differences, due to lack of radiometric age constraints. It has hindered the knowledge on the tectonic and paleoclimate evolutions of the Tibetan Plateau. Identifying barely visible tephra‐bearing layers is urgent to solve the debate. Here we carry out a comparative rock magnetic study of Eocene volcanogenic and sedimentary rocks from the Jianchuan and Qujing Basins of the Yunnan Plateau. Our aim is to establish an effective method for tephra identification in sedimentary sequences. Petrographic and rare earth element analyses demonstrate that the volcanogenic rocks are of basic‐intermediate magmatic origin with no sign of deformation or alteration, and the sedimentary rocks are unaffected by volcanic disturbance. Rock magnetic analyses reveal that the primary ferrimagnetic minerals of the volcanogenic rocks are Ti‐poor titanomagnetite and/or magnetite, including pseudo‐single‐domain, viscous superparamagnetic and ultrafine superparamagnetic (true superparamagnetic, nonviscous around room temperature) grains. Hematite is the dominant magnetic mineral in the sedimentary rocks, and paramagnetic minerals are also abundant; pseudo‐single‐domain/single‐domain magnetite and maghemite are also present. The enrichment of ultrafine superparamagnetic grains in the volcanogenic rocks may induce strikingly peaked signals in low‐temperature frequency‐dependent susceptibility measurement, in sharp contrast with pedogenically produced viscous superparamagnetic particles that show no peaks. Therefore, we attribute the low‐temperature frequency‐dependent susceptibility parameters to the effective and sensitive magnetic parameters for identifying tephra‐bearing layers within the sedimentary sequences of the Yunnan Plateau.
Present‐Day Crustal Deformation of Continental China Derived From GPS and Its Tectonic Implications
Authors: Wang Min , Shen Zheng‐Kang
Published: January 2020

We process rigorously GPS data observed during the past 25 years from continental China to derive site secular velocities. Analysis of the velocity solution leads to the following results. (a) The deformation field inside the Tibetan plateau and Tien Shan is predominantly continuous, and large deformation gradients only exist perpendicular to the Indo‐Eurasian relative plate motion and are associated with a few large strike‐slip faults. (b) Lateral extrusions occur on both the east and west sides of the plateau. The westward extrusion peaks at ~6 mm/yr in the Pamir‐Hindu Kush region. A bell‐shaped eastward extrusion involves most of the plateau at a maximum rate of ~20 mm/yr between the Jiali and Ganzi‐Yushu faults, and the pattern is consistent with gravitational flow in southern and southeastern Tibet where the crust shows widespread dilatation at 10–20 nanostrain/yr. (c) The southeast borderland of Tibet rotates clockwise around the eastern Himalaya syntaxis, with sinistral and dextral shear motions along faults at the outer and inner flanks of the rotation terrane. The result suggests gravitational flow accomplished through rotation and translation of smaller subblocks in the upper crust. (d) Outside of the Tibetan plateau and Tien Shan, deformation field is block‐like. However, unnegligible internal deformation on the order of a couple of nanostrain/yr is found for all blocks. The North China block, under a unique tectonic loading environment, deforms and rotates at rates significantly higher than its northern and southern neighboring blocks, attesting its higher seismicity rate and earthquake hazard potential than its neighbors.
Time‐Dependent Hydraulic Fracture Initiation
Authors: Lu Guanyi , Gordeliy Elizaveta , Prioul Romain , Aidagulov Gallyam , Uwaifo Efosa C. , Ou Qihang , Bunger Andrew P.
Published: January 2020

Rocks are known to fail in a time‐dependent manner similar to many brittle and quasi‐brittle materials. However, observed time dependence of hydraulic fracture initiation has ubiquitously been attributed to fluid flow‐related mechanisms without consideration of the intrinsic time dependence of rock failure. Laboratory delayed hydraulic fracturing breakdown experiments on three rocks (granite, sandstone, and limestone) show sensitivity to rock properties associated with subcritical crack growth as well as fluid viscosity and ambient confining pressure applied to the specimens. A new hydraulic fracture initiation model accounting for subcritical crack growth and fluid flow in a poroelastic medium, as well as the additional energy dissipation required for fluid flow in the rough fracture tip, is then used to estimate the value of the subcritical index n based on characterization experiments. Given this characterization data, the model is shown to be capable of predicting time‐dependent hydraulic fracture initiation with variation of fluid viscosity and confining stress.
Convective‐Stratiform Rainfall of Typhoon Fitow (2013): Sensitivity to Rainfall Partitioning Methods
Authors: Shu Shoujuan , Xu Huiyan , Zhang Wenjuan
Published: January 2020

Rainfall separation methods are widely used in literatures, with some algorithms applied to surface rainfall and some applied to radar or other observations. How the effectiveness or practicability of these rainfall partitioning algorithms when applied to model results is not well known. In this study, three convective‐stratiform rainfall partitioning methods are compared and evaluated by analyzing cloud properties and associated precipitation budgets based on both observations and grid‐scale simulations from a three‐dimensional Weather Research and Forecasting modeling of Typhoon Fitow (2013). Results show that convective‐stratiform rainfall separation based on surface rain rate is generally more reasonable than that based on radar reflectivity in terms of statistics of vertical velocity and raindrop microphysical budgets. The radar reflectivity partition method does not conduct an exact demarcation between convective and stratiform regions, since the rainfall in stratiform region has similar characteristics as convective rainfall, whereas the rainfall classified as convective rainfall has similar characteristics as stratiform rainfall. Observational analysis based on satellite and lightning confirms these results and shows that the rainfall separation based on surface rain rate generally detects the cellular convective rainfall near eyewall and isolated convection in spiral rainbands, whereas the rainfall separation based on radar reflectivity not only fails to identify the scattered convective rainfall but also overestimates the convective rainfall embedded among the stratiform regions. Above all, the method based on surface rainfall produces more reasonable statistical and microphysical characteristics for both convective and stratiform regions of precipitation, which generally agree with the real rainfall distributions from satellite and lightning observations.
Mid‐Neoproterozoic Tectonics of Northwestern India: Evidence of Stitching Pluton along 810 Ma Phulad Shear Zone
Authors: Chatterjee Sadhana M. , Sarkar Ayan Kumar , Roy Alip , Manna Anirban
Published: January 2020

In northwestern India, Phulad Shear Zone (PSZ, ~810 Ma) demarcates the boundary between South Delhi Fold Belt to the east and Marwar craton to the west. This shear zone has regional NE‐SW trend with small bends of N‐S orientations. PSZ is characterized by steep southeasterly dipping mylonitic foliation with steep oblique stretching lineation. The PSZ has developed in a ductile transpression with top‐to‐the‐NNW reverse sense of movement associated with a component of sinistral‐slip movement on horizontal section. The 200 by 6 km porphyritic Phulad granite occurs along and across the PSZ, and it is variably deformed. Phulad granite shows evidence of magmatic foliation with preservation of parallel alignment of euhedral feldspars phenocrysts and microgranitoid enclaves. The feldspar phenocrysts show simple twin interfaces parallel to the direction of elongation. This granite also shows development of solid‐state foliation parallel to this magmatic foliation. Detailed study of structural elements suggests that Phulad granite has formed during the regional deformation in the country rock shear zone prior to its complete crystallization. Our data indicate that the releasing bends of N‐S orientation within the PSZ have provided the space required for emplacement of Phulad granite in a transpressional regime. EPMA U‐Pb‐Th monazite and U‐Pb LA‐ICP‐MS zircon ages in Phulad granite indicate a magmatic age of 819.1 ± 4 and 818 ± 18 Ma, respectively. PSZ represents the suture along which Marwar craton accreted with remaining India to form the Greater India landmass. The present study suggests that Phulad granite acted as a stitching pluton during this suturing along PSZ at 810–820 Ma.
Proinflammatory cytokine TNFα promotes HPV-associated oral carcinogenesis by increasing cancer stemness
Authors: Hong Hannah S. , Akhavan Jonathan , Lee Sung Hee , Kim Reuben H. , Kang Mo K. , Park No-Hee , Shin Ki-Hyuk
Published: January 2020

High-risk human papillomaviruses (HPVs) are involved in the development of several human cancers, including oropharyngeal squamous cell carcinomas. However, many studies have demonstrated that HPV alone is not sufficient for the oncogenic transformation of normal human epithelial cells, indicating that additional cofactors are required for the oncogenic conversion of HPV-infected cells. Inasmuch as chronic inflammation is also closely associated with carcinogenesis, we investigated the effect of chronic exposure to tumor necrosis factor α (TNFα), the major proinflammatory cytokine, on oncogenesis in two immortalized oral keratinocyte cell lines, namely, HPV16-immortalized and human telomerase reverse transcriptase (hTERT)-immortalized cells. TNFα treatment led to the acquisition of malignant growth properties in HPV16-immortalized cells, such as (1) calcium resistance, (2) anchorage independence, and (3) increased cell proliferation in vivo. Moreover, TNFα increased the cancer stem cell-like population and stemness phenotype in HPV16-immortalized cells. However, such transforming effects were not observed in hTERT-immortalized cells, suggesting an HPV-specific role in TNFα-promoted oncogenesis. We also generated hTERT-immortalized cells that express HPV16 E6 and E7. Chronic TNFα exposure successfully induced the malignant growth and stemness phenotype in the E6-expressing cells but not in the control and E7-expressing cells. We further demonstrated that HPV16 E6 played a key role in TNFα-induced cancer stemness via suppression of the stemness-inhibiting microRNAs miR-203 and miR-200c. Overexpression of miR-203 and miR-200c suppressed cancer stemness in TNFα-treated HPV16-immortalized cells. Overall, our study suggests that chronic inflammation promotes cancer stemness in HPV-infected cells, thereby promoting HPV-associated oral carcinogenesis.
Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis
Authors: Herster Franziska , Bittner Zsofia , Archer Nathan K. , Dickhöfer Sabine , Eisel David , Eigenbrod Tatjana , Knorpp Thomas , Schneiderhan-Marra Nicole , Löffler Markus W. , Kalbacher Hubert , Vierbuchen Tim , Heine Holger , Miller Lloyd S. , Hartl Dominik , Freund Lukas , Schäkel Knut , Heister Martin , Ghoreschi Kamran , Weber Alexander N. R.
Published: January 2020

Psoriasis is an inflammatory skin disease with strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37. LL37 in complex with DNA and RNA is thought to initiate disease exacerbation via plasmacytoid dendritic cells. However, the source of nucleic acids supposed to start this initial inflammatory event remains unknown. We show here that primary murine and human PMNs mount a fulminant and self-propagating neutrophil extracellular trap (NET) and cytokine response, but independently of the canonical NET component, DNA. Unexpectedly, RNA, which is abundant in NETs and psoriatic but not healthy skin, in complex with LL37 triggered TLR8/TLR13-mediated cytokine and NET release by PMNs in vitro and in vivo. Transfer of NETs to naive human PMNs prompts additional NET release, promoting further inflammation. Our study thus uncovers a self-propagating vicious cycle contributing to chronic inflammation in psoriasis, and NET-associated RNA (naRNA) as a physiologically relevant NET component.
5-fluorocytosine resistance is associated with hypermutation and alterations in capsule biosynthesis in Cryptococcus
Authors: Billmyre R. Blake , Applen Clancey Shelly , Li Lucy X. , Doering Tamara L. , Heitman Joseph
Published: January 2020

Patients infected with the fungal pathogen Cryptococcus are most effectively treated with a combination of 5-fluorocytosine (5FC) and amphotericin B. 5FC acts as a prodrug, which is converted into toxic 5-fluorouracil (5FU) upon uptake into fungal cells. However, the pathogen frequently develops resistance through unclear mechanisms. Here we show that resistance to 5FC in Cryptococcus deuterogattii is acquired more frequently in isolates with defects in DNA mismatch repair that confer an elevated mutation rate. We use whole genome sequencing of 16 independent isolates to identify mutations associated with 5FC resistance in vitro. We find mutations in known resistance genes (FUR1 and FCY2) and in a gene UXS1, previously shown to encode an enzyme that converts UDP-glucuronic acid to UDP-xylose for capsule biosynthesis, but not known to play a role in 5FC metabolism. Mutations in UXS1 lead to accumulation of UDP-glucuronic acid and alterations in nucleotide metabolism, which appear to suppress toxicity of both 5FC and its toxic derivative 5FU.
Predicting optical coherence tomography-derived diabetic macular edema grades from fundus photographs using deep learning
Authors: Varadarajan Avinash V. , Bavishi Pinal , Ruamviboonsuk Paisan , Chotcomwongse Peranut , Venugopalan Subhashini , Narayanaswamy Arunachalam , Cuadros Jorge , Kanai Kuniyoshi , Bresnick George , Tadarati Mongkol , Silpa-archa Sukhum , Limwattanayingyong Jirawut , Nganthavee Variya , Ledsam Joseph R. , Keane Pearse A. , Corrado Greg S. , Peng Lily , Webster Dale R.
Published: January 2020

Center-involved diabetic macular edema (ci-DME) is a major cause of vision loss. Although the gold standard for diagnosis involves 3D imaging, 2D imaging by fundus photography is usually used in screening settings, resulting in high false-positive and false-negative calls. To address this, we train a deep learning model to predict ci-DME from fundus photographs, with an ROC–AUC of 0.89 (95% CI: 0.87–0.91), corresponding to 85% sensitivity at 80% specificity. In comparison, retinal specialists have similar sensitivities (82–85%), but only half the specificity (45–50%, p < 0.001). Our model can also detect the presence of intraretinal fluid (AUC: 0.81; 95% CI: 0.81–0.86) and subretinal fluid (AUC 0.88; 95% CI: 0.85–0.91). Using deep learning to make predictions via simple 2D images without sophisticated 3D-imaging equipment and with better than specialist performance, has broad relevance to many other applications in medical imaging.
Electrically-driven Yagi-Uda antennas for light
Authors: Kullock René , Ochs Maximilian , Grimm Philipp , Emmerling Monika , Hecht Bert
Published: January 2020

Yagi-Uda antennas are a key technology for efficiently transmitting information from point to point using radio waves. Since higher frequencies allow higher bandwidths and smaller footprints, a strong incentive exists to shrink Yagi-Uda antennas down to the optical regime. Here we demonstrate electrically-driven Yagi-Uda antennas for light with wavelength-scale footprints that exhibit large directionalities with forward-to-backward ratios of up to 9.1 dB. Light generation is achieved via antenna-enhanced inelastic tunneling of electrons over the antenna feed gap. We obtain reproducible tunnel gaps by means of feedback-controlled dielectrophoresis, which precisely places single surface-passivated gold nanoparticles in the antenna gap. The resulting antennas perform equivalent to radio-frequency antennas and combined with waveguiding layers even outperform RF designs. This work paves the way for optical on-chip data communication that is not restricted by Joule heating but also for advanced light management in nanoscale sensing and metrology as well as light emitting devices.
Emerging regenerative medicine and tissue engineering strategies for Parkinson’s disease
Authors: Harris James P. , Burrell Justin C. , Struzyna Laura A. , Chen H. Isaac , Serruya Mijail D. , Wolf John A. , Duda John E. , Cullen D. Kacy
Published: January 2020

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, affecting 1–2% of people over 65. The classic motor symptoms of PD result from selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in a loss of their long axonal projections to the striatum. Current treatment strategies such as dopamine replacement and deep brain stimulation (DBS) can only minimize the symptoms of nigrostriatal degeneration, not directly replace the lost pathway. Regenerative medicine-based solutions are being aggressively pursued with the goal of restoring dopamine levels in the striatum, with several emerging techniques attempting to reconstruct the entire nigrostriatal pathway—a key goal to recreate feedback pathways to ensure proper dopamine regulation. Although many pharmacological, genetic, and optogenetic treatments are being developed, this article focuses on the evolution of transplant therapies for the treatment of PD, including fetal grafts, cell-based implants, and more recent tissue-engineered constructs. Attention is given to cell/tissue sources, efficacy to date, and future challenges that must be overcome to enable robust translation into clinical use. Emerging regenerative medicine therapies are being developed using neurons derived from autologous stem cells, enabling the construction of patient-specific constructs tailored to their particular extent of degeneration. In the upcoming era of restorative neurosurgery, such constructs may directly replace SNpc neurons, restore axon-based dopaminergic inputs to the striatum, and ameliorate motor deficits. These solutions may provide a transformative and scalable solution to permanently replace lost neuroanatomy and improve the lives of millions of people afflicted by PD.
Pulsed atom-mechanical quantum non-demolition gate
Authors: Manukhova A. D. , Rakhubovsky A. A. , Filip R.
Published: January 2020

Hybridization of quantum science and technology crucially depends on quantum gates between various physical systems. The different platforms have different fundamental physics and, therefore, diverse advantages in various applications. Many applications require nearly ideal quantum gates with variable large interaction gain and sufficient entangling power. Moreover, pulsed gates are advantageous for fast quantum circuits. For quantum systems with continuous variables, the quantum non-demolition (QND) gate is the most basic. It is an entangling gate that simultaneously keeps a variable of the interacting system unchanged. This feature is useful for quantum circuits from quantum sensing to continuous variable quantum computing. Currently, atomic ensembles storing quantum states of radiation and mechanical oscillators transducing them are two major but very different continuous-variable matter platforms. We propose a high-quality continuous-variable QND gate between an atomic ensemble and a mechanical oscillator in the separated optical cavities connected by propagating optical pulses. We demonstrate that squeezing of light pulses, homodyne measurement, and optimized feedforward control used to build the gate are sufficient to reach an interaction gain up to 50 with nearly ideal entangling power.
A quantum solution for efficient use of symmetries in the simulation of many-body systems
Authors: Schmitz Albert T. , Johri Sonika
Published: January 2020

A many-body Hamiltonian can be block-diagonalized by expressing it in terms of symmetry-adapted basis states. Finding the group orbit representatives of these basis states and their corresponding symmetries is currently a memory/computational bottleneck on classical computers during exact diagonalization. We apply Grover’s search in the form of a minimization procedure to solve this problem. Our quantum solution provides an exponential reduction in memory, and a quadratic speedup in time over classical methods. We discuss explicitly the full circuit implementation of Grover minimization as applied to this problem, finding that the oracle only scales as polylog in the size of the group, which acts as the search space. Further, we design an error mitigation scheme that, with no additional qubits, reduces the impact of bit-flip errors on the computation, with the magnitude of mitigation directly correlated with the error rate, improving the utility of the algorithm in the Noisy Intermediate Scale Quantum era.
Clinical Implications of Suspended Scattering Particles in Motion Observed by Optical Coherence Tomography Angiography
Authors: Ahn Jaemoon , Han Sangheon , Ahn So Min , Kim Seong-Woo , Oh Jaeryung
Published: January 2020

The objective of this study was to investigate the relationship between suspended scattering particles in motion (SSPiM) in optical coherence tomography angiography (OCTA) and treatment response in diabetic macular edema (DME). We retrospectively reviewed the medical records of patients diagnosed with DME who had undergone intravitreal injection. The optical density ratio (ODR) of the intraretinal cyst and the numbers of hyperreflective foci from OCT images and SSPiM from OCTA images were compared, and their association with treatment response was analyzed. Forty-five eyes from 45 patients were included in this study. Twenty-four patients were treated with anti-vascular endothelial growth factor, and 21 patients were treated with a steroid. Binary logistic regression model showed that SSPiM in OCTA images was associated with hyperreflective foci numbers (P = 0.038) and mean ODR of the intraretinal cyst (P = 0.006). Linear regression model showed that SSPiM in the inner nuclear layer was related to treatment response (P = 0.006). SSPiM on OCTA images is related to the poor structural response to treatment in DME.
Methanogenic Archaea Can Produce Methane in Deliquescence-Driven Mars Analog Environments
Authors: Maus Deborah , Heinz Jacob , Schirmack Janosch , Airo Alessandro , Kounaves Samuel P. , Wagner Dirk , Schulze-Makuch Dirk
Published: January 2020

The current understanding of the Martian surface indicates that briny environments at the near-surface are temporarily possible, e.g. in the case of the presumably deliquescence-driven Recurring Slope Lineae (RSL). However, whether such dynamic environments are habitable for terrestrial organisms remains poorly understood. This hypothesis was tested by developing a Closed Deliquescence System (CDS) consisting of a mixture of desiccated Martian Regolith Analog (MRA) substrate, salts, and microbial cells, which over the course of days became wetted through deliquescence. The methane produced via metabolic activity for three methanogenic archaea: Methanosarcina mazei, M. barkeri and M. soligelidi, was measured after exposing them to three different MRA substrates using either NaCl or NaClO4 as a hygroscopic salt. Our experiments showed that (1) M. soligelidi rapidly produced methane at 4 °C, (2) M. barkeri produced methane at 28 °C though not at 4 °C, (3) M. mazei was not metabolically reactivated through deliquescence, (4) none of the species produced methane in the presence of perchlorate, and (5) all species were metabolically most active in the phyllosilicate-containing MRA. These results emphasize the importance of the substrate, microbial species, salt, and temperature used in the experiments. Furthermore, we show here for the first time that water provided by deliquescence alone is sufficient to rehydrate methanogenic archaea and to reactivate their metabolism under conditions roughly analogous to the near-subsurface Martian environment.
Selection and functional identification of a synthetic partial ABA agonist, S7
Authors: Min Myung Ki , Kim Rigyeong , Moon Seok-Jun , Lee Yongsang , Han Seungsu , Lee Sangho , Kim Beom-Gi
Published: January 2020

The stress hormone abscisic acid (ABA) helps plants to survive under abiotic stresses; however, its use as an agrochemical is limited by its chemical instability and expense. Here, we report the development of an in vivo screening system to isolate chemicals able to induce ABA signalling responses in rice (Oryza sativa) protoplasts. This system consists of an ABA-hypersensitive synthetic promoter containing ABRE and DRE motifs driving a luciferase reporter gene. After efficiently transfecting rice protoplasts with this construct, we screened chemicals library with a similar molecular weight and chemical structure to ABA and identified one chemical, S7, that induced ABA signalling by mediating interactions between the group I and II OsPYL receptors and certain OsPP2CAs in a yeast two-hybrid assay. In an in vitro pulldown assay, S7 was found to mediate a weak interaction between OsPYL5/8 and various OsPP2CAs. S7 treatments did not affect seedling growth or seed germination, but could reduce water loss. Rice seedlings treated with S7 exhibited transcriptome profiles that partially overlapped those treated with ABA. Taken together, we concluded that S7 is a new partial ABA agonist, which has potential use in future dissections of ABA signalling and as an agrochemical.
An Amazon stingless bee foraging activity predicted using recurrent artificial neural networks and attribute selection
Authors: Gomes Pedro A. B. , Suhara Yoshihiko , Nunes-Silva Patrícia , Costa Luciano , Arruda Helder , Venturieri Giorgio , Imperatriz-Fonseca Vera Lucia , Pentland Alex , Souza Paulo de , Pessin Gustavo
Published: January 2020

Bees play a key role in pollination of crops and in diverse ecosystems. There have been multiple reports in recent years illustrating bee population declines worldwide. The search for more accurate forecast models can aid both in the understanding of the regular behavior and the adverse situations that may occur with the bees. It also may lead to better management and utilization of bees as pollinators. We address an investigation with Recurrent Neural Networks in the task of forecasting bees’ level of activity taking into account previous values of level of activity and environmental data such as temperature, solar irradiance and barometric pressure. We also show how different input time windows, algorithms of attribute selection and correlation analysis can help improve the accuracy of our model.
Association between excessive daytime sleepiness, REM phenotype and severity of obstructive sleep apnea
Authors: Gabryelska Agata , Białasiewicz Piotr
Published: January 2020

The aim of the study was to compare REM-dependent and REM-independent, obstructive sleep apnea syndrome (OSA) patients in relation to their daily sleepiness assessed by Epworth sleepiness scale (ESS). The study included 1863 consecutive patients, who were referred to a sleep centre with a presumed diagnosis of OSA. Following polysomnography, 292 patients fulfilled criteria for either REM-dependent OSA (REM-OSA, n = 102) or REM-independent OSA (nREM-OSA, n = 190). Both study groups were matched regarding sex and age. REM-OSA group had two times lower median apnoea-hypopnea index (AHI) compared to nREM-OSA (p < 0.001), yet day-time sleepiness measured by ESS was similar: median score 9.0 (6.0–11.0) and 8.0 (4.8–11.0), p = 0.109, respectively. Subsequent post-hoc ANCOVA analysis, with covariates (BMI, percent of total sleep time spent in REM stage, percent of total sleep time spent in the supine position), has shown statistically significant difference between study groups regarding AHI (p < 0.001) and no difference regarding ESS score (p = 0.063). Despite two times lower AHI, patients with REM-OSA present with similar day-time sleepiness as those with REM independent OSA. Daily sleepiness may be stronger associated with apneas/hypopneas occurring in REM than nREM sleep.
Comparison between 5-day decitabine and 7-day azacitidine for lower-risk myelodysplastic syndromes with poor prognostic features: a retrospective multicentre cohort study
Authors: Lee Byung-Hyun , Kang Ka-Won , Jeon Min Ji , Yu Eun Sang , Kim Dae Sik , Choi Hojoon , Lee Se Ryeon , Sung Hwa Jung , Kim Byung Soo , Choi Chul Won , Park Yong
Published: January 2020

Numerous studies have analysed the clinical efficacies of hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS). However, reports that compare the two HMAs, decitabine and azacitidine, in patients with lower-risk (low and intermediate-1) MDS are limited. We compared 5-day decitabine and 7-day azacitidine regimens in terms of treatment responses, survival outcomes, and adverse events in patients with lower-risk MDS with poor prognostic features. The overall response rates (ORRs) were 67.2% and 44.0% in the patients treated with decitabine and azacitidine, respectively (P = 0.014). While the median progression-free survival (PFS) was significantly better in the patients treated with decitabine than in those treated with azacitidine (P = 0.019), no significant differences in event-free and overall survival rates were observed between the two groups. Multivariate analysis revealed that compared with azacitidine treatment, decitabine treatment is significantly associated with a higher ORR (P = 0.026) and longer PFS (P = 0.037). No significant differences were observed in the incidence of grade 3 or higher haematologic adverse events in response to the two HMAs. In conclusion, in lower-risk MDS, especially with poor prognostic features, ORR and PFS were significantly better with 5-day decitabine treatment than with 7-day azacitidine treatment, with comparable safety.
Endoscopic diagnosis and treatment planning for colorectal polyps using a deep-learning model
Authors: Song Eun Mi , Park Beomhee , Ha Chun-Ae , Hwang Sung Wook , Park Sang Hyoung , Yang Dong-Hoon , Ye Byong Duk , Myung Seung-Jae , Yang Suk-Kyun , Kim Namkug , Byeon Jeong-Sik
Published: January 2020

We aimed to develop a computer-aided diagnostic system (CAD) for predicting colorectal polyp histology using deep-learning technology and to validate its performance. Near-focus narrow-band imaging (NBI) pictures of colorectal polyps were retrieved from the database of our institution. Of these, 12480 image patches of 624 polyps were used as a training set to develop the CAD. The CAD performance was validated with two test datasets of 545 polyps. Polyps were classified into three histological groups: serrated polyp (SP), benign adenoma (BA)/mucosal or superficial submucosal cancer (MSMC), and deep submucosal cancer (DSMC). The overall kappa value measuring the agreement between the true polyp histology and the expected histology by the CAD was 0.614–0.642, which was higher than that of trainees (n = 6, endoscopists with experience of 100 NBI colonoscopies in <6 months; 0.368–0.401) and almost comparable with that of the experts (n = 3, endoscopists with experience of 2,500 NBI colonoscopies in ≥5 years) (0.649–0.735). The areas under the receiver operating curves for CAD were 0.93–0.95, 0.86–0.89, and 0.89–0.91 for SP, BA/MSMC, and DSMC, respectively. The overall diagnostic accuracy of the CAD was 81.3–82.4%, which was significantly higher than that of the trainees (63.8–71.8%, P < 0.01) and comparable with that of experts (82.4–87.3%). The kappa value and diagnostic accuracies of the trainees improved with CAD assistance: that is, the kappa value increased from 0.368 to 0.655, and the overall diagnostic accuracy increased from 63.8–71.8% to 82.7–84.2%. CAD using a deep-learning model can accurately assess polyp histology and may facilitate the diagnosis of colorectal polyps by endoscopists.
Origin of tuberculosis in the Paleolithic predicts unprecedented population growth and female resistance
Authors: Cardona Pere-Joan , Català Martí , Prats Clara
Published: January 2020

Current data estimate the origin of Mycobacterium tuberculosis complex (MtbC) infection around 73,000 years before the common era (BCE), and its evolution to “modern” lineages around 46,000 BCE. Being MtbC a major killer of humanity, the question is how both species could persist. To answer this question, we have developed two new epidemiological models (SEIR type), adapted to sex dimorphism and comparing coinfection and superinfection for different MtbC lineages. We have attributed a higher resistance/tolerance to females to explain the lower incidence noted in this sex, a better health status in the Paleolithic compared to the Neolithic, and a higher dissemination of “modern” lineages compared to “ancient” ones. Our findings show the extraordinary impact caused by “modern” lineages, provoking the extinction of the groups infected. This could only be overcomed by an unprecedented population increase (x20 times in 100 years) and helped with the protection generated by previous infection with “ancient” lineages. Our findings also suggest a key role of female resistance against MtbC. This data obliges us to rethink the growth population parameters in the Paleolithic, which is crucial to understanding the survival of both MtbC and humans, and to decipher the nature of human female resistance against TB.