bluuebunny/crossref_metadata_2025 huggingface dataset:
Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons
Authors: Alquezar Carolina , Felix Jessica B. , McCandlish Elizabeth , Buckley Brian T. , Caparros-Lefebvre Dominique , Karch Celeste M. , Golbe Lawrence I. , Kao Aimee W.
Published: January 2020

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death.
Facile and efficient 3-chlorophenol sensor development based on photolumenescent core-shell CdSe/ZnS quantum dots
Authors: Rahman Mohammed M. , Karim Mohammad Rezaul , Alam M. M. , Zaman M. Badruz , Alharthi Nabeel , Alharbi Hamad , Asiri Abdullah M.
Published: January 2020

Quantum dots (QDs) are semiconducting inorganic nanoparticles, tiny molecules of 2–10 nm sizes to strength the quantum confinements of electrons. The QDs are good enough to emit light onto electrons for exciting and returning to the ground state. Here, CdSe/ZnS core/shell QDs have been prepared and applied for electrochemical sensor development in this approach. Flat glassy carbon electrode (GCE) was coated with CdSe/ZnS QDs as very thin uniform layer to result of the selective and efficient sensor of 3-CP (3-chlorophenol). The significant analytical parameters were calculated from the calibration plot such as sensitivity (3.6392 µA µM−1 cm−2) and detection limit (26.09 ± 1.30 pM) with CdSe/ZnS/GCE sensor probe by electrochemical approach. The calibration curve was fitted with the regression co-efficient r2 = 0.9906 in the range of 0.1 nM ∼ 0.1 mM concentration, which denoted as linear dynamic range (LDR). Besides these, it was performed the reproducibility in short response time and successfully validated the fabricated sensor for 3-CP in the real environmental and extracted samples. It is introduced as a noble route to detect the environmental phenolic contaminants using CdSe/ZnS QDs modified sensor by electrochemical method for the safety of healthcare and environmental fields at broad scales.
Establishment of novel long-term cultures from EpCAM positive and negative circulating tumour cells from patients with metastatic gastroesophageal cancer
Authors: Brungs Daniel , Minaei Elahe , Piper Ann-Katrin , Perry Jay , Splitt Ashleigh , Carolan Martin , Ryan Shantay , Wu Xiao Juan , Corde Stéphanie , Tehei Moeava , Aghmesheh Morteza , Vine Kara L. , Becker Therese M. , Ranson Marie
Published: January 2020

Circulating tumour cell (CTC) enumeration and profiling has been established as a valuable clinical tool in many solid malignancies. A key challenge in CTC research is the limited number of cells available for study. Ex vivo CTC culture permits expansion of these rare cell populations for detailed characterisation, functional assays including drug sensitivity testing, and investigation of the pathobiology of metastases. We report for the first time the establishment and characterisation of two continuous CTC lines from patients with gastroesophageal cancer. The two cell lines (designated UWG01CTC and UWG02CTC) demonstrated rapid tumorigenic growth in immunodeficient mice and exhibit distinct genotypic and phenotypic profiles which are consistent with the tumours of origin. UWG02CTC exhibits an EpCAM+, cytokeratin+, CD44+ phenotype, while UWG01CTC, which was derived from a patient with metastatic neuroendocrine cancer, displays an EpCAM−, weak cytokeratin phenotype, with strong expression of neuroendocrine markers. Further, the two cell lines show distinct differences in drug and radiation sensitivity which match differential cancer-associated gene expression pathways. This is strong evidence implicating EpCAM negative CTCs in metastasis. These novel, well characterised, long-term CTC cell lines from gastroesophageal cancer will facilitate ongoing research into metastasis and the discovery of therapeutic targets.
In situ Rb-Sr dating of slickenfibres in deep crystalline basement faults
Authors: Tillberg Mikael , Drake Henrik , Zack Thomas , Kooijman Ellen , Whitehouse Martin J. , Åström Mats E.
Published: January 2020

Establishing temporal constraints of faulting is of importance for tectonic and seismicity reconstructions and predictions. Conventional fault dating techniques commonly use bulk samples of syn-kinematic illite and other K-bearing minerals in fault gouges, which results in mixed ages of repeatedly reactivated faults as well as grain-size dependent age variations. Here we present a new approach to resolve fault reactivation histories by applying high-spatial resolution Rb-Sr dating to fine-grained mineral slickenfibres in faults occurring in Paleoproterozoic crystalline rocks. Slickenfibre illite and/or K-feldspar together with co-genetic calcite and/or albite were targeted with 50 µm laser ablation triple quadrupole inductively coupled plasma mass spectrometry analyses (LA-ICP-MS/MS). The ages obtained disclose slickenfibre growth at several occasions spanning over 1 billion years, from at least 1527 Ma to 349 ± 9 Ma. The timing of these growth phases and the associated structural orientation information of the kinematic indicators on the fracture surfaces are linked to far-field tectonic events, including the Caledonian orogeny. Our approach links faulting to individual regional deformation events by minimizing age mixing through micro-scale analysis of individual grains and narrow crystal zones in common fault mineral assemblages.
Novel Chimeric Multiepitope Vaccine for Streptococcosis Disease in Nile Tilapia (Oreochromis niloticus Linn.)
Authors: Pumchan Ansaya , Krobthong Sucheewin , Roytrakul Sittiruk , Sawatdichaikul Orathai , Kondo Hidehiro , Hirono Ikuo , Areechon Nontawith , Unajak Sasimanas
Published: January 2020

Streptococcus agalactiae is a causative agent of streptococcosis disease in various fish species, including Nile tilapia (Oreochromis niloticus Linn.). Vaccination is an effective disease prevention and control method, but limitations remain for protecting against catastrophic mortality of fish infected with different strains of streptococci. Immunoproteomics analysis of S. agalactiae was used to identify antigenic proteins and construct a chimeric multiepitope vaccine. Epitopes from five antigenic proteins were shuffled in five helices of a flavodoxin backbone, and in silico analysis predicted a suitable RNA and protein structure for protein expression. 45F2 and 42E2 were identified as the best candidates for a chimeric multiepitope vaccine. Recombinant plasmids were constructed to produce a recombinant protein vaccine and DNA vaccine system. Overexpressed proteins were determined to be 30 kDa and 25 kDa in the E. coli and TK1 systems, respectively. The efficacy of the chimeric multiepitope construct as a recombinant protein vaccine and DNA vaccine was evaluated in Nile tilapia, followed by S. agalactiae challenge at 1 × 107 CFU/mL. Relative percentage survival (RPS) and cumulative mortality were recorded at approximately 57–76% and 17–30%, respectively. These chimeric multiepitope vaccines should be applied in streptococcosis disease control and developed into a multivalent vaccine to control multiple diseases.
Dose-dependent effect of cannabinoid WIN-55,212-2 on myelin repair following a demyelinating insult
Authors: Tomas-Roig J. , Agbemenyah H. Y. , Celarain N. , Quintana E. , Ramió-Torrentà Ll. , Havemann-Reinecke U.
Published: January 2020

Dysfunctions in the endocannabinoid system have been associated with experimental animal models and multiple sclerosis patients. Interestingly, the endocannabinoid system has been reported to confer neuroprotection against demyelination. The present study aims to assess the effects of the cannabinoid agonist WIN-55,212-2 in cuprizone fed animals on myelin repair capacity. Animals exposed to cuprizone were simultaneously treated withWIN-55,212-2, behaviorally tested and finally the corpus callosum was exhaustively studied by Western blotting, qRT-PCR and a myelin staining procedure. We report that the long-term administration of WIN-55,212-2 reduced the global amount of CB1 protein. Histological analysis revealed clear demyelination after being fed cuprizone for three weeks. However, cuprizone-fed mice subjected to 0.5 mg/Kg of WIN-55,212-2 displayed no differences when compared to controls during demyelination, although there was a robust increase in the myelinated axons during the remyelination phase. These animals displayed better performance on contextual fear conditioning which was in turn non-attributable to an antinociceptive effect. In contrast, a 1 mg/Kg dosage caused a remarkable demyelination accompanied by limited potential for myelin repair. Upon drug administration while mice ongoing demyeliniation, the expression of Aif1 (microglia) and Gfap (astrocytes) followed a dose-dependent manner whereas the expression of both markers was apparently attenuated during remyelination. Treatment with vehicle or 0.5 mg/Kg of the drug during demyelination increased the expression of Pdgfra (oligodendrocyte precursor cells) but this did not occur when 1 mg/Kg was administered. In conclusion, the drug at 0.5 mg/Kg did not alter myelin architecture while 1 mg/Kg had a deleterious effect in this model.
NIHSS is not enough for cognitive screening in acute stroke: A cross-sectional, retrospective study
Authors: Abzhandadze Tamar , Reinholdsson Malin , Stibrant Sunnerhagen Katharina
Published: January 2020

The aim of this study was to investigate whether the cognitive subscale of the National Institute of Health Stroke Scale (NIHSS), the Cog-4, can detect cognitive deficits in acute stroke. This was a cross-sectional, retrospective study. The study sample consisted of people with stroke enrolled in an acute stroke unit. The index test Cog-4 was calculated based on admission NIHSS score. The reference standard instrument, the Montreal Cognitive Assessment (MoCA), was performed within 36–48 h of admission. Non-parametric statistics were used for data analyses. The study included 531 participants with a mean age of 69 years. The Cog-4 failed to identify cognitive deficits in 65%, 58%, and 53% of patients when the MoCA thresholds for impaired cognition were set at ≤25 p, ≤23 p, and ≤19 p, respectively, were chosen for impaired cognition. The agreement between the Cog-4 and the MoCA was poor; Cohen’s kappa was from −0.210 to −0.109, depending on the MoCA cut-offs. The sensitivity of the Cog-4 was 35%, 42% and 48% for the MoCA thresholds for impaired cognition ≤25, ≤23 and ≤19 points, respectively. The Cog-4 has a limited ability to identify cognitive deficits in acute stroke. More structured and comprehensive tests should be employed as diagnostic tools.
Biomechanical comparison of the use of different surgical suture techniques for continuous loop tendon grafts preparation
Authors: Zhang Chen , Götschi Tobias , Li Xiang , Snedeker Jess G. , Fucentese Sandro F.
Published: January 2020

We introduce a new approach for a continuous loop tendon-graft preparation, benchmarking it against established graft preparation techniques widely used in conjunction with non-adjustable interference screw fixation. A four-strand bovine tendon graft was prepared using the following graft preparation techniques: standard graft using the baseball stitch technique (M-tech group); continuous loop graft using the GraftLinkTM technique (Arthrex-tech group); continuous loop graft using the Kessler anastomosis technique (Kessler-tech group); and continuous loop graft using a Double-Z anastomosis technique (Double Z-tech group). Each group of eight specimens underwent cyclic loading followed by a load-to-failure test. The M–technique yielded a smaller graft diameter (8.4 ± 0.5 mm) compared to the statistically equivalent diameters of the three continuous loop techniques (8.9 ± 0.6 mm of Arthrex-tech group, 9.1 ± 0.4 mm of Kessler-tech group and 9.2 ± 0.6 mm of Double Z-Tech group). The continuous loop grafts formed by the Double Z-Technique showed outstanding performance among the tested techniques in terms of ultimate failure load (982 ± 121 N) and cyclic elongation (3.7 ± 1.0 mm). There was no significant difference between the four groups in cyclic stiffness. Of the assessed techniques, the Arthrex technique resulted in the lowest ultimate elongation (2.0 ± 0.7 mm), followed by the Double Z-tech (4.5 ± 1.8 mm), the M-tech (5.2 ± 3.9 mm), and the Kessler-tech (5.3 ± 2.4 mm). The Arthrex-tech group (5.98 ± 0.38 min) displayed the shortest graft preparation time, followed by the M-Tech (7.94 ± 0.58 min), Kessler-tech (9.03 ± 0.39 min) and Double Z-Tech (13.29 ± 1.14 min). Double Z-Tech can improve the construct of continuous loop tendon graft with regard to mechanical performance.
High H2O Content in Pyroxenes of Residual Mantle Peridotites at a Mid Atlantic Ridge Segment
Authors: Li Pei , Xia Qun-Ke , Dallai Luigi , Bonatti Enrico , Brunelli Daniele , Cipriani Anna , Ligi Marco
Published: January 2020

Global correlations of mid-ocean-ridges basalt chemistry, axial depth and crustal thickness have been ascribed to mantle temperature variations affecting degree of melting. However, mantle H2O content and elemental composition may also play a role. How H2O is distributed in the oceanic upper mantle remains poorly constrained. We tackled this problem by determining the H2O content of orthopyroxenes (opx) and clinopyroxenes (cpx) of peridotites from a continuous lithospheric section created during 26 Ma at a 11°N Mid-Atlantic Ridge segment, and exposed along the Vema Transform. The H2O content of opx ranges from 119 ppm to 383 ppm; that of cpx from 407 ppm to 1072 ppm. We found anomalous H2O-enriched peridotites with their H2O content not correlating inversely with their degree of melting, although H2O is assumed to be incompatible during melting. Inverse correlation of H2O with Ce, another highly incompatible component, suggests post-melting H2O enrichment. We attribute a major role to post-melting temperature-dependent diffusion of hydrogen occurring above the melting region, where water-rich melt flows faster than residual peridotites through dunitic conduits cross-cutting the uprising mantle. Accordingly, estimates of the H2O content of the MORB mantle source based on H2O in abyssal peridotites can be affected by strong uncertainties.
Identification of genetic polymorphisms modulating nausea and vomiting in two series of opioid-treated cancer patients
Authors: Colombo Francesca , Pintarelli Giulia , Galvan Antonella , Noci Sara , Corli Oscar , Skorpen Frank , Klepstad Pål , Kaasa Stein , Pigni Alessandra , Brunelli Cinzia , Roberto Anna , Piazza Rocco , Pirola Alessandra , Gambacorti-Passerini Carlo , Caraceni Augusto Tommaso
Published: January 2020

Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.
No Evidence of Off-label Use of Olodaterol and Indacaterol in Denmark, France, and the Netherlands: A Drug Utilization Study
Authors: Rebordosa Cristina , Houben Eline , Laugesen Kristina , Bothner Ulrich , Montonen Jukka , Aguado Jaume , Overbeek Jetty A. , Ehrenstein Vera , Asmar Joelle , Wallace Laura , Gilsenan Alicia W.
Published: January 2020

To characterize the use of olodaterol and indacaterol in clinical practice and to quantify the off-label use in asthma. Drug utilization study of new users of olodaterol or indacaterol between 2014 and 2017 in the PHARMO Database Network in the Netherlands, the Danish population registers, and the IMS Real-World Evidence Longitudinal Patient Database panels in France. On-label use was defined as use among adults with a recorded diagnosis of COPD. Off-label use was defined as use among adults with a recorded diagnosis of asthma without a recorded diagnosis of COPD or as use among patients aged ≤18 years. Potential off-label use was defined as no recorded diagnosis of either COPD or asthma. The study included 4,158 new users of olodaterol and 9,966 new users of indacaterol. Prevalence of off-label use ranged from 3.5% for both drugs to 12.4% for olodaterol and 11.9% for indacaterol. Prevalence of on-label use ranged from 47.8% to 77.7% for olodaterol and from 28.7% to 70.1% for indacaterol. The remaining new users of olodaterol and indacaterol were classified as potential off-label users, with prevalence ranging from 17.3% to 48.6% for olodaterol and from 20.5% to 66.6% for indacaterol. This study provides no evidence of a major concern in Europe for olodaterol or indacaterol for off-label use in asthma or for pediatric use.
Development of Tripolymeric Triaxial Electrospun Fibrous Matrices for Dual Drug Delivery Applications
Authors: Nagiah Naveen , Murdock Christopher J. , Bhattacharjee Maumita , Nair Lakshmi , Laurencin Cato T.
Published: January 2020

Since the first work by Laurencin and colleagues on the development of polymeric electrospinning for biomedical purposes, the use of electrospinning technology has found broad applications in such areas of tissue regeneration and drug delivery. More recently, coaxial electrospinning has emerged as an important technique to develop scaffolds for regenerative engineering incorporated with drug(s). However, the addition of a softer core layer leads to a reduction in mechanical properties. Here, novel robust tripolymeric triaxially electrospun fibrous scaffolds were developed with a polycaprolactone (PCL) (core layer), a 50:50 poly (lactic-co-glycolic acid) (PLGA) (sheath layer) and a gelatin (intermediate layer) with a dual drug delivery capability was developed through modified electrospinning. A sharp increase in elastic modulus after the incorporation of PCL in the core of the triaxial fibers in comparison with uniaxial PLGA (50:50) and coaxial PLGA (50:50) (sheath)-gelatin (core) fibers was observed. Thermal analysis of the fibrous scaffolds revealed an interaction between the core-intermediate and sheath-intermediate layers of the triaxial fibers contributing to the higher tensile modulus. A simultaneous dual release of model small molecule Rhodamine B (RhB) and model protein Fluorescein isothiocynate (FITC) Bovine Serum Albumin (BSA) conjugate incorporated in the sheath and intermediate layers of triaxial fibers was achieved. The tripolymeric, triaxial electrospun systems were seen to be ideal for the support of mesenchymal stem cell growth, as shrinkage of fibers normally found with conventional electrospun systems was minimized. These tripolymeric triaxial electrospun fibers that are biomechanically competent, biocompatible, and capable of dual drug release are designed for regenerative engineering and drug delivery applications.
Early-Onset Osteoarthritis originates at the chondrocyte level in Hip Dysplasia
Authors: Hernandez Paula A. , Wells Joel , Usheva Emiliya , Nakonezny Paul A. , Barati Zahra , Gonzalez Roberto , Kassem Layla , Henson Frances M. D.
Published: January 2020

Subjects with developmental dysplasia of the hip (DDH) often show early-onset osteoarthritis (OA); however, the molecular mechanisms underlying this pathology are not known. We investigated whether cellular changes in chondrocytes from OA cartilage can be detected in chondrocytes from DDH cartilage before histological manifestations of degeneration. We characterized undamaged and damaged articular cartilage from 22 participants having hip replacement surgery with and without DDH (9 DDH-OA, 12 OA-only, one femoral fracture). Tissue immunostaining revealed changes in damaged OA-only cartilage that was also found in undamaged DDH-OA cartilage. Chondrocytes in situ from both groups show: (i) thicker fibers of vimentin intermediate filaments, (ii) clusters of integrin α5β1, (iii) positive MMP13 staining and (iv) a higher percentage of cells expressing the serine protease HtrA1. Further characterization of the extracellular matrix showed strong aggrecan and collagen II immunostaining in undamaged DDH cartilage, with no evidence of augmented cell death by activation of caspase 3. These findings suggest that early events in DDH cartilage originate at the chondrocyte level and that DDH cartilage may provide a novel opportunity to study these early changes for the development of therapeutic targets for OA.
FQSqueezer: k-mer-based compression of sequencing data
Authors: Deorowicz Sebastian
Published: January 2020

The amount of data produced by modern sequencing instruments that needs to be stored is huge. Therefore it is not surprising that a lot of work has been done in the field of specialized data compression of FASTQ files. The existing algorithms are, however, still imperfect and the best tools produce quite large archives. We present FQSqueezer, a novel compression algorithm for sequencing data able to process single- and paired-end reads of variable lengths. It is based on the ideas from the famous prediction by partial matching and dynamic Markov coder algorithms known from the general-purpose-compressors world. The compression ratios are often tens of percent better than offered by the state-of-the-art tools. The drawbacks of the proposed method are large memory and time requirements.
Quantitation of deoxynucleoside triphosphates by click reactions
Authors: Huang Chang-Yu , Yagüe-Capilla Miriam , González-Pacanowska Dolores , Chang Zee-Fen
Published: January 2020

The levels of the four deoxynucleoside triphosphates (dNTPs) are under strict control in the cell, as improper or imbalanced dNTP pools may lead to growth defects and oncogenesis. Upon treatment of cancer cells with therapeutic agents, changes in the canonical dNTPs levels may provide critical information for evaluating drug response and mode of action. The radioisotope-labeling enzymatic assay has been commonly used for quantitation of cellular dNTP levels. However, the disadvantage of this method is the handling of biohazard materials. Here, we described the use of click chemistry to replace radioisotope-labeling in template-dependent DNA polymerization for quantitation of the four canonical dNTPs. Specific oligomers were designed for dCTP, dTTP, dATP and dGTP measurement, and the incorporation of 5-ethynyl-dUTP or C8-alkyne-dCTP during the polymerization reaction allowed for fluorophore conjugation on immobilized oligonucleotides. The four reactions gave a linear correlation coefficient >0.99 in the range of the concentration of dNTPs present in 106 cells, with little interference of cellular rNTPs. We present evidence indicating that data generated by this methodology is comparable to radioisotope-labeling data. Furthermore, the design and utilization of a robust microplate assay based on this technology evidenced the modulation of dNTPs in response to different chemotherapeutic agents in cancer cells.
Evidence of altered mucosa-associated and fecal microbiota composition in patients with Irritable Bowel Syndrome
Authors: Sundin Johanna , Aziz Imran , Nordlander Sofia , Polster Annikka , Hu Yue O. O. , Hugerth Luisa W. , Pennhag Alexandra A. L. , Engstrand Lars , Törnblom Hans , Simrén Magnus , Öhman Lena
Published: January 2020

Altered bacterial composition and small intestinal bacterial overgrowth (SIBO) may be associated with irritable bowel syndrome (IBS). This study aimed to determine the fecal and mucosa-associated bacterial composition along the gastrointestinal (GI) tract and to assess SIBO in IBS. Bacterial composition of feces, and mucosa of the duodenum and sigmoid colon was determined by 16S rRNA-amplicon-sequencing. SIBO was evaluated by bacterial culture of duodenal aspirate, glucose and lactulose breath tests. Mucosal antibacterial gene expression was assessed by PCR Array. The bacterial profiles of feces and the mucosa of sigmoid colon, but not duodenum, differed between IBS patients (n = 17) and HS (n = 20). The IBS specific bacterial profiles were linked to the colonic antibacterial gene expression. Fecal bacterial profile differed between IBS subtypes, while the mucosa-associated bacterial profile was associated with IBS symptom severity and breath tests results at baseline (H2 and/or CH4 ≥ 15 ppm). The prevalence of SIBO was similar between IBS patients and HS. This study demonstrates that alterations in the bacterial composition of the sigmoid colon of IBS patients were linked to symptoms and immune activation. While breath tests reflected the mucosa-associated bacterial composition, there was no evidence for high prevalence of SIBO or small intestinal bacterial alterations in IBS.
Latency and interval therapy affect the evolution in metastatic colorectal cancer
Authors: Nikbakht Hamid , Jessa Selin , Sukhai Mahadeo A. , Arseneault Madeleine , Zhang Tong , Letourneau Louis , Thomas Mariam , Bourgey Mathieu , Roehrl Michael H. A. , Eveleigh Robert , Chen Eric X. , Krzyzanowska Monika , Moore Malcolm J. , Giesler Amanda , Yu Celeste , Bedard Philippe L. , Kamel-Reid Suzanne , Majewski Jacek , Siu Lillian L. , Riazalhosseini Yasser , Graham Donna M.
Published: January 2020

While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g., those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of latency in the evolutionary path of metastatic CRC and may have implications for future treatment options.
Differential interaction of Or proteins with the PSY enzymes in saffron
Authors: Ahrazem Oussama , López Alberto José , Argandoña Javier , Castillo Raquel , Rubio-Moraga Ángela , Gómez-Gómez Lourdes
Published: January 2020

Colored apocarotenoids accumulate at high concentrations in few plant species, where display a role in attraction of pollinators and seed dispersers. Among these apocarotenoids, crocins accumulate at high concentrations in the stigma of saffron and are responsible for the organoleptic and medicinal properties of this spice. Phytoene synthase and Orange protein are key for carotenoid biosynthesis and accumulation. We previously isolated four phytoene synthase genes from saffron with differential roles in carotenoid and apocarotenoid biosynthesis. However, the implications of Orange genes in the regulation of apocarotenoid accumulation are unknown. Here, we have identified two Orange genes from saffron, with different expression patterns. CsOr-a was mainly expressed in vegetative tissues and was induced by light and repressed by heat stress. Both CsOr-a and CsOr-b were expressed in stigmas but showed a different profile during the development of this tissue. The interactions of CsOr-a and CsOr-b were tested with all the four phytoene synthase proteins from saffron and with CsCCD2. None interactions were detected with CCD2 neither with the phytoene synthase 2, involved in apocarotenoid biosynthesis in saffron. The obtained results provide evidence of different mechanisms regulating the phytoene synthase enzymes in saffron by Orange for carotenoid and apocarotenoid accumulation in saffron.
Components of partial resistance to Plasmopara viticola enable complete phenotypic characterization of grapevine varieties
Authors: Bove Federica , Rossi Vittorio
Published: January 2020

Six components of partial resistance (RCs) were studied in 15 grapevine varieties with partial resistance to Plasmopara viticola: (i) infection frequency (IFR, proportion of inoculation sites showing sporulation), (ii) latent period (LP50, degree-days between inoculation and appearance of 50% of the final number of sporulating lesions), (iii) lesion size (LS, area of single lesions in mm2), (iv) production of sporangia (SPOR, number of sporangia produced per lesion, and SPOR’, number of sporangia produced per mm2 of lesion), (v) infectious period (IP, number of sporulation events on a lesion), and (vi) infectivity of sporangia (INF, infection efficiency of sporangia produced on resistant varieties). Artificial inoculation monocycle experiments were conducted for a 3-year period on leaves collected at leaf development, flowering, and fruit development. Compared to the susceptible variety ‘Merlot’, the partially resistant varieties showed reduced IFR, longer LP, smaller LS, fewer SPOR and SPOR’, shorter IP, and lower INF. At leaf development, IFR, SPOR, and INF were higher and LP was shorter than at flowering and fruit development. RCs analysis through monocyclic experiments provides reliable assessments of the resistance response of grapevine accessions. The workload required for routine assessment in breeding programs could be reduced by measuring IFR and SPOR, while producing robust results.
Brain mechanisms in motor control during reaching movements: Transition of functional connectivity according to movement states
Authors: Yeom Hong Gi , Kim June Sic , Chung Chun Kee
Published: January 2020

Understanding how the brain controls movements is a critical issue in neuroscience. The role of brain changes rapidly according to movement states. To elucidate the motor control mechanism of brain, it is essential to investigate the changes in brain network in motor-related regions according to movement states. Therefore, the objective of this study was to investigate the brain network transitions according to movement states. We measured whole brain magnetoencephalography (MEG) signals and extracted source signals in 24 motor-related areas. Functional connectivity and centralities were calculated according to time flow. Our results showed that brain networks differed between states of motor planning and movement. Connectivities between most motor-related areas were increased in the motor-planning state. In contrast, only connectivities with cerebellum and basal ganglia were increased while those of other motor-related areas were decreased during movement. Our results indicate that most processes involved in motor control are completed before movement. Further, brain developed network related to feedback rather than motor decision during movements. Our findings also suggest that neural signals during motor planning might be more predictive than neural signals during movement. They facilitate accurate prediction of movement for brain-machine interfaces and provide insight into brain mechanisms in motor control.
Comparative Proteomics Reveal Me31B’s Interactome Dynamics, Expression Regulation, and Assembly Mechanism into Germ Granules during Drosophila Germline Development
Authors: McCambridge Aidan , Solanki Dhruv , Olchawa Nicholas , Govani Neal , Trinidad Jonathan C. , Gao Ming
Published: January 2020

Me31B is a protein component of Drosophila germ granules and plays an important role in germline development by interacting with other proteins and RNAs. To understand the dynamic changes that the Me31B interactome undergoes from oogenesis to early embryogenesis, we characterized the early embryo Me31B interactome and compared it to the known ovary interactome. The two interactomes shared RNA regulation proteins, glycolytic enzymes, and cytoskeleton/motor proteins, but the core germ plasm proteins Vas, Tud, and Aub were significantly decreased in the embryo interactome. Our follow-up on two RNA regulations proteins present in both interactomes, Tral and Cup, revealed that they colocalize with Me31B in nuage granules, P-bodies/sponge bodies, and possibly in germ plasm granules. We further show that Tral and Cup are both needed for maintaining Me31B protein level and mRNA stability, with Tral’s effect being more specific. In addition, we provide evidence that Me31B likely colocalizes and interacts with germ plasm marker Vas in the ovaries and early embryo germ granules. Finally, we show that Me31B’s localization in germ plasm is likely independent of the Osk-Vas-Tud-Aub germ plasm assembly pathway although its proper enrichment in the germ plasm may still rely on certain conserved germ plasm proteins.
Incidence and treatment outcomes of secondary epiretinal membrane following intravitreal injection for diabetic macular edema
Authors: Kang Yong Koo , Park Han Sang , Park Dong Ho , Shin Jae Pil
Published: January 2020

The purpose of this study was to investigate the incidence of secondary epiretinal membrane (ERM) after intravitreal injection and the effect of ERM on visual acuity and central macular thickness (CMT) in patients with diabetic macular edema (DME). We included 147 eyes of 95 patients over 18 years old who were diagnosed with DME from 2012 to 2016, treated with intravitreal injection, and followed-up more than 24 months. Mean CMT in the ERM group was significantly thicker than in the non-ERM group after 9, 12, 18, and 24 months. Secondary ERM developed in 9.5% of patients during follow-up. Compared to other agents, the incidence of secondary ERM was significantly higher after intravitreal injection of dexamethasone implant. Among patients in the ERM group, the mean decrease of CMT between pre-injection and 2 weeks post-injection was significantly less after secondary ERM formation than before ERM formation. Secondary ERM formation was significantly associated with the number of intravitreal injections and the use of dexamethasone implant. Therefore, secondary ERM develops more frequently as the number of intravitreal injections increases and after intravitreal dexamethasone implant injection. The therapeutic effects of intravitreal injections for DME patients decrease after secondary ERM formation.
Exploration of a New Source of Sustainable Nanomaterial from the Koh-e-Suleiman Mountain Range of Pakistan for Industrial Applications
Authors: Nirwan J. S. , Farhaj S. , Chaudhary M. M. , Khizer Z. , Hasan S. S. , Angelis-Dimakis A. , Gill A. , Rasheed H. , Abbas N. , Arshad M. S. , Hussain T. , Shahzad Y. , Yousaf A. M. , Chohan T. A. , Hussain T. , Merchant H. A. , Akram M. R. , Khan T. M. , Ashraf M. , Conway B. R. , Ghori M. U.
Published: January 2020

The present study aimed to explore a new source of montmorillonite and to develop an extraction and purification protocol for its isolation from raw clay samples acquired from the Koh-e-Suleiman mountain range in Pakistan. The process involved the collection of raw clay from the source, identification and quantification of montmorillonite. Granulometric extraction and purification protocols increased the montmorillonite content from 21.8–25.1% in the raw clay to 90.1–93.9% after small-scale extraction and 85.33–89.33% on a larger scale. A techno-economic analysis highlighted the practicality and economic benefits of large-scale extraction for industrial applications. This study highlights the existence of a substantial new source of this valuable clay which is currently used across multiple industries including construction, pottery making, pharmaceuticals, cosmetics and engineering. It is intuitively expected that the large-scale extraction of the material will improve the economic condition of the region by providing employment opportunities to locals and may be a valuable resource for export.
Reduced Expression of Genes Regulating Cohesion Induces Chromosome Instability that May Promote Cancer and Impact Patient Outcomes
Authors: Leylek Tarik R. , Jeusset Lucile M. , Lichtensztejn Zelda , McManus Kirk J.
Published: January 2020

Chromosome instability (CIN), or continual changes in chromosome complements, is an enabling feature of cancer; however, the molecular determinants of CIN remain largely unknown. Emerging data now suggest that aberrant sister chromatid cohesion may induce CIN and contribute to cancer. To explore this possibility, we employed clinical and fundamental approaches to systematically assess the impact reduced cohesion gene expression has on CIN and cancer. Ten genes encoding critical functions in cohesion were evaluated and remarkably, each exhibits copy number losses in 12 common cancer types, and reduced expression is associated with worse patient survival. To gain mechanistic insight, we combined siRNA-based silencing with single cell quantitative imaging microscopy to comprehensively assess the impact reduced expression has on CIN in two karyotypically stable cell lines. We show that reduced expression induces CIN phenotypes, namely increases in micronucleus formation and nuclear areas. Subsequent direct tests involving a subset of prioritized genes also revealed significant changes in chromosome numbers with corresponding increases in moderate and severe cohesion defects within mitotic chromosome spreads. Collectively, our clinical and fundamental findings implicate reduced sister chromatid cohesion, resulting from gene copy number losses, as a key pathogenic event in the development and progression of many cancer types.
Large-scale Analyses of Disease Biomarkers and Apremilast Pharmacodynamic Effects
Authors: Medvedeva Irina V. , Stokes Matthew E. , Eisinger Dominic , LaBrie Samuel T. , Ai Jing , Trotter Matthew W. B. , Schafer Peter , Yang Robert
Published: January 2020

Finding biomarkers that provide shared link between disease severity, drug-induced pharmacodynamic effects and response status in human trials can provide number of values for patient benefits: elucidating current therapeutic mechanism-of-action, and, back-translating to fast-track development of next-generation therapeutics. Both opportunities are predicated on proactive generation of human molecular profiles that capture longitudinal trajectories before and after pharmacological intervention. Here, we present the largest plasma proteomic biomarker dataset available to-date and the corresponding analyses from placebo-controlled Phase III clinical trials of the phosphodiesterase type 4 inhibitor apremilast in psoriasis (PSOR), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) from 526 subjects overall. Using approximately 150 plasma analytes tracked across three time points, we identified IL-17A and KLK-7 as biomarkers for disease severity and apremilast pharmacodynamic effect in psoriasis patients. Combined decline rate of KLK-7, PEDF, MDC and ANGPTL4 by Week 16 represented biomarkers for the responder subgroup, shedding insights into therapeutic mechanisms. In ankylosing spondylitis patients, IL-6 and LRG-1 were identified as biomarkers with concordance to disease severity. Apremilast-induced LRG-1 increase was consistent with the overall lack of efficacy in ankylosing spondylitis. Taken together, these findings expanded the mechanistic knowledge base of apremilast and provided translational foundations to accelerate future efforts including compound differentiation, combination, and repurposing.
Deep neural networks for automated detection of marine mammal species
Authors: Shiu Yu , Palmer K. J. , Roch Marie A. , Fleishman Erica , Liu Xiaobai , Nosal Eva-Marie , Helble Tyler , Cholewiak Danielle , Gillespie Douglas , Klinck Holger
Published: January 2020

Deep neural networks have advanced the field of detection and classification and allowed for effective identification of signals in challenging data sets. Numerous time-critical conservation needs may benefit from these methods. We developed and empirically studied a variety of deep neural networks to detect the vocalizations of endangered North Atlantic right whales (Eubalaena glacialis). We compared the performance of these deep architectures to that of traditional detection algorithms for the primary vocalization produced by this species, the upcall. We show that deep-learning architectures are capable of producing false-positive rates that are orders of magnitude lower than alternative algorithms while substantially increasing the ability to detect calls. We demonstrate that a deep neural network trained with recordings from a single geographic region recorded over a span of days is capable of generalizing well to data from multiple years and across the species’ range, and that the low false positives make the output of the algorithm amenable to quality control for verification. The deep neural networks we developed are relatively easy to implement with existing software, and may provide new insights applicable to the conservation of endangered species.
Author Correction: Increase in the Population of Patients with Neovascular Age-Related Macular Degeneration Who Underwent Long-Term Active Treatment
Authors: Baek Seung Kook , Kim Jae Hui , Kim Jong Woo , Kim Chul Gu
Published: January 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Stochastic nucleation processes and substrate abundance explain time-dependent freezing in supercooled droplets
Authors: Knopf Daniel A. , Alpert Peter A. , Zipori Assaf , Reicher Naama , Rudich Yinon
Published: January 2020

Atmospheric immersion freezing (IF), a heterogeneous ice nucleation process where an ice nucleating particle (INP) is immersed in supercooled water, is a dominant ice formation pathway impacting the hydrological cycle and climate. Implementation of IF derived from field and laboratory data in cloud and climate models is difficult due to the high variability in spatio-temporal scales, INP composition, and morphological complexity. We demonstrate that IF can be consistently described by a stochastic nucleation process accounting for uncertainties in the INP surface area. This approach accounts for time-dependent freezing, a wide range of surface areas and challenges phenomenological descriptions typically used to interpret IF. The results have an immediate impact on the current description, interpretation, and experiments of IF and its implementation in models. The findings are in accord with nucleation theory, and thus should hold for any supercooled liquid material that nucleates in contact with a substrate.
mHealth and wearable technology should replace motor diaries to track motor fluctuations in Parkinson’s disease
Authors: Erb M. Kelley , Karlin Daniel R. , Ho Bryan K. , Thomas Kevin C. , Parisi Federico , Vergara-Diaz Gloria P. , Daneault Jean-Francois , Wacnik Paul W. , Zhang Hao , Kangarloo Tairmae , Demanuele Charmaine , Brooks Chris R. , Detheridge Craig N. , Shaafi Kabiri Nina , Bhangu Jaspreet S. , Bonato Paolo
Published: January 2020

Accurately monitoring motor and non-motor symptoms as well as complications in people with Parkinson’s disease (PD) is a major challenge, both during clinical management and when conducting clinical trials investigating new treatments. A variety of strategies have been relied upon including questionnaires, motor diaries, and the serial administration of structured clinical exams like part III of the MDS-UPDRS. To evaluate the potential use of mobile and wearable technologies in clinical trials of new pharmacotherapies targeting PD symptoms, we carried out a project (project BlueSky) encompassing four clinical studies, in which 60 healthy volunteers (aged 23–69; 33 females) and 95 people with PD (aged 42–80; 37 females; years since diagnosis 1–24 years; Hoehn and Yahr 1–3) participated and were monitored in either a laboratory environment, a simulated apartment, or at home and in the community. In this paper, we investigated (i) the utility and reliability of self-reports for describing motor fluctuations; (ii) the agreement between participants and clinical raters on the presence of motor complications; (iii) the ability of video raters to accurately assess motor symptoms, and (iv) the dynamics of tremor, dyskinesia, and bradykinesia as they evolve over the medication cycle. Future papers will explore methods for estimating symptom severity based on sensor data. We found that 38% of participants who were asked to complete an electronic motor diary at home missed ~25% of total possible entries and otherwise made entries with an average delay of >4 h. During clinical evaluations by PD specialists, self-reports of dyskinesia were marked by ~35% false negatives and 15% false positives. Compared with live evaluation, the video evaluation of part III of the MDS-UPDRS significantly underestimated the subtle features of tremor and extremity bradykinesia, suggesting that these aspects of the disease may be underappreciated during remote assessments. On the other hand, live and video raters agreed on aspects of postural instability and gait. Our results highlight the significant opportunity for objective, high-resolution, continuous monitoring afforded by wearable technology to improve upon the monitoring of PD symptoms.
Fingerprints of a second order critical line in developing neural networks
Authors: Kanders Karlis , Lee Hyungsub , Hong Nari , Nam Yoonkey , Stoop Ruedi
Published: January 2020

Patterns of biological activity with properties similar to critical states of statistical mechanics have received much attention, as they were mostly seen as indicators of computational optimality. Commonly, a single regime around an isolated critical point is expected. Our experimental data and our network simulations of developing neural cultures indicate the possibility of transitions between different critical regimes. In the latter, the addition of further fundamental neurophysiological principles to the standard neurodynamics branching model generates steeper power laws that have been observed in various experiments. Our analysis exhibits two populations of neurons, each composed of inhibitory and excitatory sites, that have distinct dynamical and topological properties. This generates a line of second order critical points, similar to what is known from the thermodynamics of two-component alloys. An analysis of two major critical regimes found in the experiments suggests that different critical regimes may express distinct computational roles.