bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
Authors: Montero-Melendez Trinidad , Nagano Ai , Chelala Claude , Filer Andrew , Buckley Christopher D. , Perretti Mauro
Published: February 2020

Rheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC1, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC1is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.
Enhanced eddy activity in the Beaufort Gyre in response to sea ice loss
Authors: Armitage Thomas W. K. , Manucharyan Georgy E. , Petty Alek A. , Kwok Ron , Thompson Andrew F.
Published: February 2020

The Beaufort Gyre freshwater content has increased since the 1990s, potentially stabilizing in recent years. The mechanisms proposed to explain the stabilization involve either mesoscale eddy activity that opposes Ekman pumping or the reduction of Ekman pumping due to reduced sea ice–ocean surface stress. However, the relative importance of these mechanisms is unclear. Here, we present observational estimates of the Beaufort Gyre mechanical energy budget and show that energy dissipation and freshwater content stabilization by eddies increased in the late-2000s. The loss of sea ice and acceleration of ocean currents after 2007 resulted in enhanced mechanical energy input but without corresponding increases in potential energy storage. To balance the energy surplus, eddy dissipation and its role in gyre stabilization must have increased after 2007. Our results imply that declining Arctic sea ice will lead to an increasingly energetic Beaufort Gyre with eddies playing a greater role in its stabilization.
The role of side-branching in microstructure development in laser powder-bed fusion
Authors: Pham Minh-Son , Dovgyy Bogdan , Hooper Paul A. , Gourlay Christopher M. , Piglione Alessandro
Published: February 2020

In-depth understanding of microstructure development is required to fabricate high quality products by additive manufacturing (for example, 3D printing). Here we report the governing role of side-branching in the microstructure development of alloys by laser powder bed fusion. We show that perturbations on the sides of cells (or dendrites) facilitate crystals to change growth direction by side-branching along orthogonal directions in response to changes in local heat flux. While the continuous epitaxial growth is responsible for slender columnar grains confined to the centreline of melt pools, side-branching frequently happening on the sides of melt pools enables crystals to follow drastic changes in thermal gradient across adjacent melt pools, resulting in substantial broadening of grains. The variation of scan pattern can interrupt the vertical columnar microstructure, but promotes both in-layer and out-of-layer side-branching, in particular resulting in the helical growth of microstructure in a chessboard strategy with 67° rotation between layers.
The empirical basis for modelling glacial erosion rates
Authors: Cook Simon J. , Swift Darrel A. , Kirkbride Martin P. , Knight Peter G. , Waller Richard I.
Published: February 2020

Glaciers are highly effective agents of erosion that have profoundly shaped Earth’s surface, but there is uncertainty about how glacial erosion should be parameterised in landscape evolution models. Glacial erosion rate is usually modelled as a function of glacier sliding velocity, but the empirical basis for this relationship is weak. In turn, climate is assumed to control sliding velocity and hence erosion, but this too lacks empirical scrutiny. Here, we present statistically robust relationships between erosion rates, sliding velocities, and climate from a global compilation of 38 glaciers. We show that sliding is positively and significantly correlated with erosion, and derive a relationship for use in erosion models. Our dataset further demonstrates that the most rapid erosion is achieved at temperate glaciers with high mean annual precipitation, which serve to promote rapid sliding. Precipitation has received little attention in glacial erosion studies, but our data illustrate its importance.
Integrative genomic study of Chinese clear cell renal cell carcinoma reveals features associated with thrombus
Authors: Wang Xiang-Ming , Lu Yang , Song Yi-Meng , Dong Jun , Li Ruo-Yan , Wang Guo-Liang , Wang Xu , Zhang Shu-Dong , Dong Zhou-Huan , Lu Min , Wang Shi-Yu , Ge Li-Yuan , Luo Guang-Da , Ma Run-Zhuo , George Rozen Steve , Bai Fan , Wu Di , Ma Lu-Lin
Published: February 2020

Clear cell renal cell carcinoma (ccRCC) is a heterogeneous disease with features that vary by ethnicity. A systematic characterization of the genomic landscape of Chinese ccRCC is lacking, and features of ccRCC associated with tumor thrombus (ccRCC-TT) remain poorly understood. Here, we applied whole-exome sequencing on 110 normal-tumor pairs and 42 normal-tumor-thrombus triples, and transcriptome sequencing on 61 tumor-normal pairs and 30 primary-thrombus pairs from 152 Chinese patients with ccRCC. Our analysis reveals that a mutational signature associated with aristolochic acid (AA) exposure is widespread in Chinese ccRCC. Tumors from patients with ccRCC-TT show a higher mutational burden and genomic instability; in addition, mutations in BAP1 and SETD2 are highly enriched in patients with ccRCC-TT. Moreover, patients with/without TT show distinct molecular characteristics. We reported the integrative genomic sequencing of Chinese ccRCC and identified the features associated with tumor thrombus, which may facilitate ccRCC diagnosis, prognosis and treatment.
Mechanistic insight into carbon-carbon bond formation on cobalt under simulated Fischer-Tropsch synthesis conditions
Authors: Weststrate C. J. , Sharma Devyani , Garcia Rodriguez Daniel , Gleeson Michael A. , Fredriksson Hans O. A. , Niemantsverdriet J. W.
Published: February 2020

Facile C-C bond formation is essential to the formation of long hydrocarbon chains in Fischer-Tropsch synthesis. Various chain growth mechanisms have been proposed previously, but spectroscopic identification of surface intermediates involved in C-C bond formation is scarce. We here show that the high CO coverage typical of Fischer-Tropsch synthesis affects the reaction pathways of C2Hx adsorbates on a Co(0001) model catalyst and promote C-C bond formation. In-situ high resolution x-ray photoelectron spectroscopy shows that a high CO coverage promotes transformation of C2Hx adsorbates into the ethylidyne form, which subsequently dimerizes to 2-butyne. The observed reaction sequence provides a mechanistic explanation for CO-induced ethylene dimerization on supported cobalt catalysts. For Fischer-Tropsch synthesis we propose that C-C bond formation on the close-packed terraces of a cobalt nanoparticle occurs via methylidyne (CH) insertion into long chain alkylidyne intermediates, the latter being stabilized by the high surface coverage under reaction conditions.
Genetic screens in isogenic mammalian cell lines without single cell cloning
Authors: DeWeirdt Peter C. , Sangree Annabel K. , Hanna Ruth E. , Sanson Kendall R. , Hegde Mudra , Strand Christine , Persky Nicole S. , Doench John G.
Published: February 2020

Isogenic pairs of cell lines, which differ by a single genetic modification, are powerful tools for understanding gene function. Generating such pairs of mammalian cells, however, is labor-intensive, time-consuming, and, in some cell types, essentially impossible. Here, we present an approach to create isogenic pairs of cells that avoids single cell cloning, and screen these pairs with genome-wide CRISPR-Cas9 libraries to generate genetic interaction maps. We query the anti-apoptotic genes BCL2L1 and MCL1, and the DNA damage repair gene PARP1, identifying both expected and uncharacterized buffering and synthetic lethal interactions. Additionally, we compare acute CRISPR-based knockout, single cell clones, and small-molecule inhibition. We observe that, while the approaches provide largely overlapping information, differences emerge, highlighting an important consideration when employing genetic screens to identify and characterize potential drug targets. We anticipate that this methodology will be broadly useful to comprehensively study gene function across many contexts.
Reflection of strengthening results in values of generalized degrees of metallicity and covalence is principle to new strategy of designing alloys
Authors: Protopopov Evgeny , Dobrykh Syuzanna , Trofimova Yulia , Malenko Pavel , Valter Alexander , Protopopov Alexander
Published: February 2020

To the best of our knowledge, the general approach of designing alloys with specified mechanical properties does not exist. This is due to the unresolved problem of analysing the set of heterogeneous variables that affect the mechanical properties along its production line from the smelting of the alloy to the manufacture of the final product. Here, we show that in principle this problem can be solved by analysing all the strengthening mechanisms in a common reference frame with reference to the single factor namely, the generalized degree of metallicity and covalence, which characterizes the entire interatomic bonds in all phases of the alloy. Such factors are able to reflect the results of hardening by various mechanisms because of the correlation with the mechanical properties. From the energy view point, these factors correspond to the proportion of the metallic and covalent bonds energy in the total energy of all chemical bonds in the alloy. Based on the approach being developed, we considered a method for predicting new doping systems for dispersively strengthening aluminum alloys according to the criterion of a given strength and have considered the methodology of optimizing chemical composition in steel smelting which is used for mass production of parts according to the criterion of the desired mechanical properties obtained due to solid solution hardening.
A three-dimensional momentum-space calculation of three-body bound state in a relativistic Faddeev scheme
Authors: Hadizadeh M. R. , Radin M. , Mohseni K.
Published: February 2020

In this paper, we study the relativistic effects in a three-body bound state. For this purpose, the relativistic form of the Faddeev equations is solved in momentum space as a function of the Jacobi momentum vectors without using a partial wave decomposition. The inputs for the three-dimensional Faddeev integral equation are the off-shell boost two-body t–matrices, which are calculated directly from the boost two-body interactions by solving the Lippmann-Schwinger equation. The matrix elements of the boost interactions are obtained from the nonrelativistic interactions by solving a nonlinear integral equation using an iterative scheme. The relativistic effects on three-body binding energy are calculated for the Malfliet-Tjon potential. Our calculations show that the relativistic effects lead to a roughly 2% reduction in the three-body binding energy. The contribution of different Faddeev components in the normalization of the relativistic three-body wave function is studied in detail. The accuracy of our numerical solutions is tested by calculation of the expectation value of the three-body mass operator, which shows an excellent agreement with the relativistic energy eigenvalue.
Subsurface Cooling Rates and Microstructural Response during Laser Based Metal Additive Manufacturing
Authors: Thampy Vivek , Fong Anthony Y. , Calta Nicholas P. , Wang Jenny , Martin Aiden A. , Depond Philip J. , Kiss Andrew M. , Guss Gabe , Xing Qingfeng , Ott Ryan T. , van Buuren Anthony , Toney Michael F. , Weker Johanna Nelson , Kramer Matthew J. , Matthews Manyalibo J. , Tassone Christopher J. , Stone Kevin H.
Published: February 2020

Laser powder bed fusion (LPBF) is a method of additive manufacturing characterized by the rapid scanning of a high powered laser over a thin bed of metallic powder to create a single layer, which may then be built upon to form larger structures. Much of the melting, resolidification, and subsequent cooling take place at much higher rates and with much higher thermal gradients than in traditional metallurgical processes, with much of this occurring below the surface. We have used in situ high speed X-ray diffraction to extract subsurface cooling rates following resolidification from the melt and above the β-transus in titanium alloy Ti-6Al-4V. We observe an inverse relationship with laser power and bulk cooling rates. The measured cooling rates are seen to correlate to the level of residual strain borne by the minority β-Ti phase with increased strain at slower cooling rates. The α-Ti phase shows a lattice contraction which is invariant with cooling rate. We also observe a broadening of the diffraction peaks which is greater for the β-Ti phase at slower cooling rates and a change in the relative phase fraction following LPBF. These results provide a direct measure of the subsurface thermal history and demonstrate its importance to the ultimate quality of additively manufactured materials.
Statin treatment can reduce incidence of early seizure in acute ischemic stroke: A propensity score analysis
Authors: Matsubara Soichiro , Tanaka Tomotaka , Tomari Shinya , Fukuma Kazuki , Ishiyama Hiroyuki , Abe Soichiro , Arimizu Takuro , Yamaguchi Yoshitaka , Ogata Soshiro , Nishimura Kunihiro , Koga Masatoshi , Ando Yukio , Toyoda Kazunori , Ihara Masafumi
Published: February 2020

A previous study showed early statin administration in patients with acute ischemic stroke (AIS) was associated with a lower risk of early-onset seizure (ES), which is a high risk of epilepsy, but this retrospective study design may not have eliminated confounding factor effects. We aimed to verify the determinants and prognostic significance of ES and clarify the effects of statin administration. Consecutive AIS patients without a history of epilepsy were enrolled. The relationship between ES (within 7 days of index-stroke) and statin treatment was assessed using multivariate and propensity scores (PS). Of 2,969 patients with AIS, 1,623 (54.6%) were treated with statin, and 66 (2.2%) developed ES. In logistic regression models, cortical stroke lesion [odds ratio (OR), 2.82; 95% confidence interval (CI), 1.29–7.28) and pre-morbid modified Rankin Scale (per 1 point) (OR, 1.39; 95% CI, 1.18–1.65) were higher risks for ES, while statin significantly reduced the risk of ES (OR, 0.44; 95% CI, 0.24–0.79). In accordance with PS-matching, statin treatment produced consistent results for ES after adjusting by inverse probability of treatment-weighting PS (OR, 0.41; 95% CI, 0.22–0.75). In conclusion, as previously, statin treatment was independently associated with a lower risk of ES in AIS.
Ocular Manifestations of Leukemia and Results of Treatment with Intravitreal Methotrexate
Authors: Vishnevskia-Dai Vicktoria , Sella King Sara , Lekach Ruth , Fabian Ido Didi , Zloto Ofira
Published: February 2020

Ocular involvement in leukemia is considered rare. Ocular symptoms can be the presenting signs of leukemia, they can appear after diagnosis has been established, or they can be the first manifestation of a relapse after remission. We report, to the best of our knowledge for the first time, the ocular manifestation of a series of patients with ocular leukemia and the result of their treatment with intravitreal methotrexate (MTX) injections. This is a retrospective cohort study. The medical records of 12 consecutive patients with ocular leukemia (24 eyes, 11 eyes treated with MTX) treated at the Sheba Medical Center from January 2010 to December 2017 were retrospectively reviewed. Details on ocular inflammatory reaction and tumor cell infiltration at presentation and the end of follow-up were recorded as main outcome measures. The 12 patients included 7 women and 5 men (mean age ± standard deviation at diagnosis 25.92 ± 23.91 years, range 2–82 years). Eleven eyes of 6 patients were treated with intravitreal MTX injections. The indication for treatment was biopsy proven, tumor cell infiltration. The mean number of MTX injections was 3.37 ± 5.35 (range 1–18). The mean follow-up was 27.08 ± 36.79 months (range 1–93). All treated eyes showed improvement in the inflammatory reaction and tumor cell infiltration. In conclusion we found that Intravitreal MTX injections may be an effective therapeutic approach for eyes with intraocular leukemic tumor cell infiltration.
Charge transport mechanism in networks of armchair graphene nanoribbons
Authors: Richter Nils , Chen Zongping , Tries Alexander , Prechtl Thorsten , Narita Akimitsu , Müllen Klaus , Asadi Kamal , Bonn Mischa , Kläui Mathias
Published: February 2020

In graphene nanoribbons (GNRs), the lateral confinement of charge carriers opens a band gap, the key feature that enables novel graphene-based electronics. Despite great progress, reliable and reproducible fabrication of single-ribbon field-effect transistors (FETs) is still a challenge, impeding the understanding of the charge transport. Here, we present reproducible fabrication of armchair GNR-FETs based on networks of nanoribbons and analyze the charge transport mechanism using nine-atom wide and, in particular, five-atom-wide GNRs with large conductivity. We show formation of reliable Ohmic contacts and a yield of functional FETs close to unity by lamination of GNRs to electrodes. Modeling the charge transport in the networks reveals that transport is governed by inter-ribbon hopping mediated by nuclear tunneling, with a hopping length comparable to the physical GNR length. Overcoming the challenge of low-yield single-ribbon transistors by the networks and identifying the corresponding charge transport mechanism is a key step forward for functionalization of GNRs.
First Report of Kosakonia radicincitans Bacteraemia from Europe (Austria) - Identification and Whole-Genome Sequencing of Strain DSM 107547
Authors: Mertschnigg Tanja , Patz Sascha , Becker Matthias , Feierl Gebhard , Ruppel Silke , Bunk Boyke , Spröer Cathrin , Overmann Jörg , Zarfel Gernot
Published: February 2020

Kosakonia radicincitans is a species within the new genus Kosakonia. Many strains of this genus have been isolated from plants, but some strains are assumed to act as facultative human pathogens. In this study, an in-depth analysis of a Kosakonia isolate from human blood was performed. The strain was originally isolated from blood and identified as a member of the Enterobacter cloacae complex, exhibiting an atypical result in susceptibility testing. Therefore, the genetic background was examined, including phylogenetic classification and screening for virulence factors. Using whole-genome sequencing, the isolate was identified as a K. radicincitans strain, revealing a virulence gene cluster for yersiniabactin biosynthesis in contrast to all other strains of the species. Whole-genome sequencing was the perfect method for identifying putative virulence factors of a particular Kosakonia strain and will help distinguish beneficial strains from pathogenic strains in the future. To our knowledge, this is the first report of Kosakonia-related bacteraemia from Europe.
Robust RNA-Seq of aRNA-amplified single cell material collected by patch clamp
Authors: Kim Jae Mun “Hugo” , Camarena Adrian , Walker Christopher , Lin Ming Yi , Wolseley Victoria , Souaiaia Tade , Thornton Matthew , Grubbs Brendan , Chow Robert H. , Evgrafov Oleg V. , Knowles James A.
Published: February 2020

Most single cell RNA sequencing protocols start with single cells dispersed from intact tissue. High-throughput processing of the separated cells is enabled using microfluidics platforms. However, dissociation of tissue results in loss of information about cell location and morphology and potentially alters the transcriptome. An alternative approach for collecting RNA from single cells is to re-purpose the electrophysiological technique of patch clamp recording. A hollow patch pipette is attached to individual cells, enabling the recording of electrical activity, after which the cytoplasm may be extracted for single cell RNA-Seq (“Patch-Seq”). Since the tissue is not disaggregated, the location of cells is readily determined, and the morphology of the cells is maintained, making possible the correlation of single cell transcriptomes with cell location, morphology and electrophysiology. Recent Patch-Seq studies utilizes PCR amplification to increase amount of nucleic acid material to the level required for current sequencing technologies. PCR is prone to create biased libraries – especially with the extremely high degrees of exponential amplification required for single cell amounts of RNA. We compared a PCR-based approach with linear amplifications and demonstrate that aRNA amplification (in vitro transcription, IVT) is more sensitive and robust for single cell RNA collected by a patch clamp pipette.
Manganese-enhanced T1 mapping to quantify myocardial viability: validation with 18F-fluorodeoxyglucose positron emission tomography
Authors: Spath Nick , Tavares Adriana , Gray Gillian A. , Baker Andrew H. , Lennen Ross J. , Alcaide-Corral Carlos J. , Dweck Marc R. , Newby David E. , Yang Phillip C. , Jansen Maurits A. , Semple Scott I.
Published: February 2020

Gadolinium chelates are widely used in cardiovascular magnetic resonance imaging (MRI) as passive intravascular and extracellular space markers. Manganese, a biologically active paramagnetic calcium analogue, provides novel intracellular myocardial tissue characterisation. We previously showed manganese-enhanced MRI (MEMRI) more accurately quantifies myocardial infarction than gadolinium delayed-enhancement MRI (DEMRI). Here, we evaluated the potential of MEMRI to assess myocardial viability compared to gold-standard 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) viability. Coronary artery ligation surgery was performed in male Sprague-Dawley rats (n = 13) followed by dual MEMRI and 18F-FDG PET imaging at 10–12 weeks. MEMRI was achieved with unchelated (EVP1001-1) or chelated (mangafodipir) manganese. T1 mapping MRI was followed by 18F-FDG micro-PET, with tissue taken for histological correlation. MEMRI and PET demonstrated good agreement with histology but native T1 underestimated infarct size. Quantification of viability by MEMRI, PET and MTC were similar, irrespective of manganese agent. MEMRI showed superior agreement with PET than native T1. MEMRI showed excellent agreement with PET and MTC viability. Myocardial MEMRI T1 correlated with 18F-FDG standard uptake values and influx constant but not native T1. Our findings indicate that MEMRI identifies and quantifies myocardial viability and has major potential for clinical application in myocardial disease and regenerative therapies.
Claudin-1 decrease impacts epidermal barrier function in atopic dermatitis lesions dose-dependently
Authors: Bergmann Sophia , von Buenau Barbara , Vidal-y-Sy Sabine , Haftek Marek , Wladykowski Ewa , Houdek Pia , Lezius Susanne , Duplan Hélène , Bäsler Katja , Dähnhardt-Pfeiffer Stephan , Gorzelanny Christian , Schneider Stefan W. , Rodriguez Elke , Stölzl Dora , Weidinger Stephan , Brandner Johanna M.
Published: February 2020

The transmembrane protein claudin-1 is a major component of epidermal tight junctions (TJs), which create a dynamic paracellular barrier in the epidermis. Claudin-1 downregulation has been linked to atopic dermatitis (AD) pathogenesis but variable levels of claudin-1 have also been observed in healthy skin. To elucidate the impact of different levels of claudin-1 in healthy and diseased skin we determined claudin-1 levels in AD patients and controls and correlated them to TJ and skin barrier function. We observed a strikingly broad range of claudin-1 levels with stable TJ and overall skin barrier function in healthy and non-lesional skin. However, a significant decrease in TJ barrier function was detected in lesional AD skin where claudin-1 levels were further reduced. Investigations on reconstructed human epidermis expressing different levels of claudin-1 revealed that claudin-1 levels correlated with inside-out and outside-in barrier function, with a higher coherence for smaller molecular tracers. Claudin-1 decrease induced keratinocyte-autonomous IL-1β expression and fostered inflammatory epidermal responses to non-pathogenic Staphylococci. In conclusion, claudin-1 decrease beyond a threshold level results in TJ and epidermal barrier function impairment and induces inflammation in human epidermis. Increasing claudin-1 levels might improve barrier function and decrease inflammation and therefore be a target for AD treatment.
AMST: Alignment to Median Smoothed Template for Focused Ion Beam Scanning Electron Microscopy Image Stacks
Authors: Hennies Julian , Lleti José Miguel Serra , Schieber Nicole L. , Templin Rachel M. , Steyer Anna M. , Schwab Yannick
Published: February 2020

Alignment of stacks of serial images generated by Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) is generally performed using translations only, either through slice-by-slice alignments with SIFT or alignment by template matching. However, limitations of these methods are two-fold: the introduction of a bias along the dataset in the z-direction which seriously alters the morphology of observed organelles and a missing compensation for pixel size variations inherent to the image acquisition itself. These pixel size variations result in local misalignments and jumps of a few nanometers in the image data that can compromise downstream image analysis. We introduce a novel approach which enables affine transformations to overcome local misalignments while avoiding the danger of introducing a scaling, rotation or shearing trend along the dataset. Our method first computes a template dataset with an alignment method restricted to translations only. This pre-aligned dataset is then smoothed selectively along the z-axis with a median filter, creating a template to which the raw data is aligned using affine transformations. Our method was applied to FIB-SEM datasets and showed clear improvement of the alignment along the z-axis resulting in a significantly more accurate automatic boundary segmentation using a convolutional neural network.
Excessive antibiotics use increased in-hospital mortality in intracerebral hemorrhage patients with stroke-associated infection
Authors: Wang Fei , Wang Yinghua , Shi Junfeng , Shen Lijuan , Xu Xinyu , Jiang Ting-ting , Wang Li , Chang Qing , Hu Shanyou , Wu Xiao
Published: February 2020

Intracerebral hemorrhage (ICH) is associated with higher incidence of stroke-associated infection (SAI) as well as antibiotic use. However, there were few methods for judging proper antibiotic use in clinical manner. We introduce an index of antibiotic use, called personal antibiotic use density (PAUD), to evaluate the relation between antibiotic use and prognosis of ICH patients with SAI. A total of 162 in 570 ICH patients were observed to diagnose as SAI. Comparing with the survival patients, PAUD, ICH volume, National Institutes of Health Stroke Scale (NIHSS) score and ICH score were significantly higher among those who died, while the Glasgow Coma Scale score and the length of stay were significantly lower (P < 0.05). PAUD was identified as an independent risk factor of in-hospital death (OR 2.396, 95% CI 1.412–4.067, P = 0.001). In-hospital mortality was significantly lower in the low (P = 0.027) and intermediate PAUD (P < 0.001) groups than that in the high PAUD group. Cumulative in-hospital survival was significantly higher in low and intermediate PAUD groups (log rank test, P < 0.001). PAUD correlated positively with NIHSS score (r = 0.224, P < 0.001) and in-hospital mortality (r = 0.268, P = 0.001). The study indicated that PAUD is closely related to in-hospital prognosis of ICH patients with SAI. Higher PAUD may not be associated with better prognosis, but instead, higher risk of death.
Assessing right ventricular deformation in hypertrophic cardiomyopathy patients with preserved right ventricular ejection fraction: a 3.0-T cardiovascular magnetic resonance study
Authors: Li Xiang , Shi Ke , Yang Zhi-gang , Guo Ying-kun , Huang Shan , Xia Chun-chao , He Sen , Li Zhen-lin , Li Chen , He Yong
Published: February 2020

To assess the global and regional right ventricular (RV) deformation in hypertrophic cardiomyopathy (HCM) patients with preserved right ventricular ejection fraction (RVEF) using 3.0-T cardiovascular magnetic resonance tissue tracking (CMR-TT). Eighty-two HCM patients and 32 age- and sex-matched healthy controls were enrolled. HCM patients were divided into groups depending on the presence or absence of right ventricular hypertrophy (RVH), RV late gadolinium enhancement (RV-LGE), and left ventricular outflow tract obstruction (LVOTO), respectively. The RV global and apical longitudinal peak strain (LPS) in HCM patients with RVH were significantly lower than that in HCM patients without RVH and controls (P < 0.05). The global, apical and mid-ventricular LPS in HCM patients with RV-LGE were significantly lower than that in HCM patients without RV-LGE and controls (P < 0.05). Lower LPS was demonstrated in HCM patients without RV-LGE compared with controls in apical and mid-ventricular levels (P < 0.05). No significant difference was found regarding global and regional LPS in HCM patients with LVOTO compared without LVOTO (all P > 0.05). CMR-TT was able to detect subclinical RV myocardial deformation prior to RVEF impairment, which was more severe in the presence of RVH and RV-LGE.
Identifying multi-hit carcinogenic gene combinations: Scaling up a weighted set cover algorithm using compressed binary matrix representation on a GPU
Authors: Al Hajri Qais , Dash Sajal , Feng Wu-chun , Garner Harold R. , Anandakrishnan Ramu
Published: February 2020

Despite decades of research, effective treatments for most cancers remain elusive. One reason is that different instances of cancer result from different combinations of multiple genetic mutations (hits). Therefore, treatments that may be effective in some cases are not effective in others. We previously developed an algorithm for identifying combinations of carcinogenic genes with mutations (multi-hit combinations), which could suggest a likely cause for individual instances of cancer. Most cancers are estimated to require three or more hits. However, the computational complexity of the algorithm scales exponentially with the number of hits, making it impractical for identifying combinations of more than two hits. To identify combinations of greater than two hits, we used a compressed binary matrix representation, and optimized the algorithm for parallel execution on an NVIDIA V100 graphics processing unit (GPU). With these enhancements, the optimized GPU implementation was on average an estimated 12,144 times faster than the original integer matrix based CPU implementation, for the 3-hit algorithm, allowing us to identify 3-hit combinations. The 3-hit combinations identified using a training set were able to differentiate between tumor and normal samples in a separate test set with 90% overall sensitivity and 93% overall specificity. We illustrate how the distribution of mutations in tumor and normal samples in the multi-hit gene combinations can suggest potential driver mutations for further investigation. With experimental validation, these combinations may provide insight into the etiology of cancer and a rational basis for targeted combination therapy.
Trazodone Loaded Lipid Core Poly (ε-caprolactone) Nanocapsules: Development, Characterization and in Vivo Antidepressant Effect Evaluation
Authors: Elhesaisy Nahla , Swidan Shady
Published: February 2020

Trazodone hydrochloride (TRH) is a lipophilic drug which is used effectively as an antidepressant. Its poor solubility and short half-life represent an obstacle for its successful use. Nanocapsules with biodegradable polymeric shell are successful drug delivery systems for controlling the release of drugs. To enhance the entrapment of lipophilic drugs, oils can be added forming a lipophilic core in which the drug is more soluble. The aim of this study was to enhance the efficacy of TRH and prolong its action by formulating it into lipid core polymeric shell nanocapsules. Nanocapules were prepared using nanoprecipitation technique. All prepared formulations were in nano size range and negatively charged. The TRH entrapment efficiency (EE%) in lipid core nanocapsules was up to 74.8 ± 0.5% when using Labrafac lipophile as a lipid core compared to only 55.7 ± 0.9% in lipid free polymeric nanospheres. Controlled TRH release was achieved for all prepared formulations. Forced swim test results indicated the significant enhancement of antidepressant effect of the selected TRH loaded Labrafac lipophile core nanocapsules formulation compared to control and TRH dispersion in phosphate buffer. It is concluded that lipid core nanocapsules is a promising carrier for the enhancement of TRH efficacy.
Identification of gene signature for treatment response to guide precision oncology in clear-cell renal cell carcinoma
Authors: D’Costa Ninadh M. , Cina Davide , Shrestha Raunak , Bell Robert H. , Lin Yen-Yi , Asghari Hossein , Monjaras-Avila Cesar U. , Kollmannsberger Christian , Hach Faraz , Chavez-Munoz Claudia I. , So Alan I.
Published: February 2020

Clear-cell renal cell carcinoma (ccRCC) is a common therapy resistant disease with aberrant angiogenic and immunosuppressive features. Patients with metastatic disease are treated with targeted therapies based on clinical features: low-risk patients are usually treated with anti-angiogenic drugs and intermediate/high-risk patients with immune therapy. However, there are no biomarkers available to guide treatment choice for these patients. A recently published phase II clinical trial observed a correlation between ccRCC patients’ clustering and their response to targeted therapy. However, the clustering of these groups was not distinct. Here, we analyzed the gene expression profile of 469 ccRCC patients, using featured selection technique, and have developed a refined 66-gene signature for improved sub-classification of patients. Moreover, we have identified a novel comprehensive expression profile to distinguish between migratory stromal and immune cells. Furthermore, the proposed 66-gene signature was validated using a different cohort of 64 ccRCC patients. These findings are foundational for the development of reliable biomarkers that may guide treatment decision-making and improve therapy response in ccRCC patients.
Serum Metabolic Profiles of the Tryptophan-Kynurenine Pathway in the high risk subjects of major depressive disorder
Authors: Sakurai Masashi , Yamamoto Yasuko , Kanayama Noriyo , Hasegawa Masaya , Mouri Akihiro , Takemura Masao , Matsunami Hidetoshi , Miyauchi Tomoya , Tokura Tatsuya , Kimura Hiroyuki , Ito Mikiko , Umemura Eri , (Boku) Aiji Sato , Nagashima Wataru , Tonoike Takashi , Kurita Kenichi , Ozaki Norio , Nabeshima Toshitaka , Saito Kuniaki
Published: February 2020

Previous reports have shown that during chronic inflammation, the tryptophan (TRP)-kynurenine (KYN) pathway plays a pivotal role in the onset of depression. The aim of this study was to investigate the characteristics of the serum TRP-KYN pathway metabolite profile in high-risk subjects of major depressive disorder (HRMDD) defined by depression scores. The concentrations of TRP-KYN pathway metabolites {TRP, KYN, 3-hydroxyanthranilic acid (3HAA), 3-hydroxykynurenine (3HK), kynurenic acid (KYNA) and anthranilic acid (AA)} were assessed in serum from HRMDD, chronic pain disorder patients and healthy controls. In serum from HRMDD, elevated levels of AA and decreased levels of TRP were observed, but the levels of other metabolites were not changed. Furthermore, the change in the AA2nd/AA1st ratio in subjects who progressed from a healthy state to a depressive state was correlated with an increase in the CES-D score. The level of IL-1 receptor antagonist (IL-1RA) was negatively correlated with that of AA. Interestingly, we confirmed AA as a possible biomarker for depression-related symptoms, since the metabolite profiles in the chronic pain disorder group and chronic unpredictable mild stress model mice were similar to those in the HRMDD. These results suggest that AA may be an effective marker for HRMDD.
Psychosocial stress and longitudinally measured gestational weight gain throughout pregnancy: The Ulm SPATZ Health Study
Authors: Braig S. , Logan C. A. , Reister F. , Rothenbacher D. , Genuneit J.
Published: February 2020

Psychosocial stress is thought to influence gestational weight gain (GWG), but results are inconsistent. We investigated the relationship of questionnaire-based maternal stress and related constructs assessed at childbirth with maternal weight measured throughout pregnancy. Data were derived from the Ulm SPATZ Health Study, a birth cohort recruited from the general population (04/2012–05/2013, Ulm, Germany). Adjusted generalized estimating equations were performed. Regression coefficients (b) and 95% confidence intervals, each highest versus lowest tertile of stress or related constructs, are presented. In 748 women, we observed positive associations for maternal chronic stress (b = 4.36 kg (1.77; 6.95)), depressive symptoms (b = 2.50 kg (0.14; 4.86)), anxiety symptoms (b = 3.26 kg (0.62, 5.89)), and hair cortisol (b = 3.35 kg (0.86; 5.83)) with maternal weight at the first gestational month. GWG was considerably lower in mothers with higher chronic stress. Pregnancy-related anxiety was positively related to weight at first month (b = 4.16 kg (1.74; 6.58)) and overall GWG. In contrast, no association was observed between anxiety symptoms and GWG. Odds ratios for association with inadequate weight gain according to Institute of Medicine recommended cutoffs differed from the results presented obove. There is evidence of an association between stress and weight gain lying beyond the recommended cut-offs, which however needs further corroboration.
High hydrostatic pressure induces vigorous flagellar beating in Chlamydomonas non-motile mutants lacking the central apparatus
Authors: Yagi Toshiki , Nishiyama Masayoshi
Published: February 2020

The beating of eukaryotic flagella (also called cilia) depends on the sliding movements between microtubules powered by dynein. In cilia/flagella of most organisms, microtubule sliding is regulated by the internal structure of cilia comprising the central pair of microtubules (CP) and radial spokes (RS). Chlamydomonas paralyzed-flagella (pf) mutants lacking CP or RS are non-motile under physiological conditions. Here, we show that high hydrostatic pressure induces vigorous flagellar beating in pf mutants. The beating pattern at 40 MPa was similar to that of wild type at atmospheric pressure. In addition, at 80 MPa, flagella underwent an asymmetric-to-symmetric waveform conversion, similar to the one triggered by an increase in intra-flagella Ca2+ concentration during cell’s response to strong light. Thus, our study establishes that neither beating nor waveform conversion of cilia/flagella requires the presence of CP/RS in the axoneme.
Diagnostic performance of magnetic resonance imaging for colorectal liver metastasis: A systematic review and meta-analysis
Authors: Mao Yitao , Chen Bin , Wang Haofan , Zhang Youming , Yi Xiaoping , Liao Weihua , Zhao Luqing
Published: February 2020

The prognosis of colorectal cancer (CRC) is largely dependent on the early detection of hepatic metastases. With the advantages of nonradioactivity and the availability of multiple scanning sequences, the efficacy of magnetic resonance imaging (MRI) in the detection of colorectal liver metastases (CRLM) is not yet clear. We performed this meta-analysis to address this issue. PubMed, Embase, and the Cochrane Library were searched for studies reporting diagnostic performance of MRI for CRLM. Descriptive and quantitative data were extracted. The study quality was evaluated for the identified studies and a random effects model was used to determine the integrated diagnosis estimation. Meta-regression and subgroup analyses were implemented to investigate the potential contributors to heterogeneity. As a result, seventeen studies were included for analysis (from the year 1996 to 2018), comprising 1121 patients with a total of 3279 liver lesions. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.90 (95% confidence intervals (CI): 0.81–0.95), 0.88 (0.80–0.92), and 62.19 (23.71–163.13), respectively. The overall weighted area under the curve was 0.94 (0.92–0.96). Using two or more imaging planes and a quantitative/semiquantitative interpretation method showed higher diagnostic performance, although only the latter demonstrated statistical significance (P < 0.05). Advanced scanning sequences with DWI and liver-specific contrast media tended to increase the sensitivity for CRLM detection. We therefore concluded that contemporary MRI has high sensitivity and specificity for screening CRLM, especially for those with advanced scanning sequences. Using two or more imaging planes and adopting a quantitative/semiquantitative imaging interpretation may further improve diagnosis. However, the MRI results should be interpreted with caution because of substantial heterogeneity among studies.
On the relevance of cocaine detection in a fingerprint
Authors: Jang M. , Costa C. , Bunch J. , Gibson B. , Ismail M. , Palitsin V. , Webb R. , Hudson M. , Bailey M. J.
Published: February 2020

The finding that drugs and metabolites can be detected from fingerprints is of potential relevance to forensic science and as well as toxicology and clinical testing. However, discriminating between dermal contact and ingestion of drugs has never been verified experimentally. The inability to interpret the result of finding a drug or metabolite in a fingerprint has prevented widespread adoption of fingerprints in drug testing and limits the probative value of detecting drugs in fingermarks. A commonly held belief is that the detection of metabolites of drugs of abuse in fingerprints can be used to confirm a drug has been ingested. However, we show here that cocaine and its primary metabolite, benzoylecgonine, can be detected in fingerprints of non-drug users after contact with cocaine. Additionally, cocaine was found to persist above environmental levels for up to 48 hours after contact. Therefore the detection of cocaine and benzoylecgonine (BZE) in fingermarks can be forensically significant, but do not demonstrate that a person has ingested the substance. In contrast, the data here shows that a drug test from a fingerprint (where hands can be washed prior to donating a sample) CAN distinguish between contact and ingestion of cocaine. If hands were washed prior to giving a fingerprint, BZE was detected only after the administration of cocaine. Therefore BZE can be used to distinguish cocaine contact from cocaine ingestion, provided donors wash their hands prior to sampling. A test based on the detection of BZE in at least one of two donated fingerprint samples has accuracy 95%, sensitivity 90% and specificity of 100% (n = 86).
Preferential uptake of polyunsaturated fatty acids by colorectal cancer cells
Authors: Mika Adriana , Kobiela Jaroslaw , Pakiet Alicja , Czumaj Aleksandra , Sokołowska Ewa , Makarewicz Wojciech , Chmielewski Michał , Stepnowski Piotr , Marino-Gammazza Antonella , Sledzinski Tomasz
Published: February 2020

Although a growing body of evidence suggests that colorectal cancer (CRC) is associated with alterations of fatty acid (FA) profiles in serum and tumor tissues, available data about polyunsaturated fatty acid (PUFA) content in CRC patients are inconclusive. Our study showed that CRC tissues contained more PUFAs than normal large intestinal mucosa. However, serum levels of PUFAs in CRC patients were lower than in healthy controls. To explain the mechanism of PUFA alterations in CRC, we measured FA uptake by the colon cancer cells and normal colon cells. The levels of PUFAs in colon cancer cell culture medium decreased significantly with incubation time, while no changes were observed in the medium in which normal colon cells were incubated. Our findings suggest that the alterations in tumor and serum PUFA profiles result from preferential uptake of these FAs by cancer cells; indeed, PUFAs are essential for formation of cell membrane phospholipids during rapid proliferation of cancer cells. This observation puts into question potential benefits of PUFA supplementation in CRC patients.
Genome mining of biosynthetic and chemotherapeutic gene clusters in Streptomyces bacteria
Authors: Belknap Kaitlyn C. , Park Cooper J. , Barth Brian M. , Andam Cheryl P.
Published: February 2020

Streptomyces bacteria are known for their prolific production of secondary metabolites, many of which have been widely used in human medicine, agriculture and animal health. To guide the effective prioritization of specific biosynthetic gene clusters (BGCs) for drug development and targeting the most prolific producer strains, knowledge about phylogenetic relationships of Streptomyces species, genome-wide diversity and distribution patterns of BGCs is critical. We used genomic and phylogenetic methods to elucidate the diversity of major classes of BGCs in 1,110 publicly available Streptomyces genomes. Genome mining of Streptomyces reveals high diversity of BGCs and variable distribution patterns in the Streptomyces phylogeny, even among very closely related strains. The most common BGCs are non-ribosomal peptide synthetases, type 1 polyketide synthases, terpenes, and lantipeptides. We also found that numerous Streptomyces species harbor BGCs known to encode antitumor compounds. We observed that strains that are considered the same species can vary tremendously in the BGCs they carry, suggesting that strain-level genome sequencing can uncover high levels of BGC diversity and potentially useful derivatives of any one compound. These findings suggest that a strain-level strategy for exploring secondary metabolites for clinical use provides an alternative or complementary approach to discovering novel pharmaceutical compounds from microbes.