bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model
Authors: Weber Nicholas D. , Odriozola Leticia , Martínez-García Javier , Ferrer Veronica , Douar Anne , Bénichou Bernard , González-Aseguinolaza Gloria , Smerdou Cristian
Published: December 2019

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4−/− mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.
Author Correction: Macrophage-associated wound healing contributes to African green monkey SIV pathogenesis control
Authors: Barrenas Fredrik , Raehtz Kevin , Xu Cuiling , Law Lynn , Green Richard R. , Silvestri Guido , Bosinger Steven E. , Nishida Andrew , Li Qingsheng , Lu Wuxun , Zhang Jianshui , Thomas Matthew J. , Chang Jean , Smith Elise , Weiss Jeffrey M. , Dawoud Reem A. , Richter George H. , Trichel Anita , Ma Dongzhu , Peng Xinxia , Komorowski Jan , Apetrei Cristian , Pandrea Ivona , Gale Michael
Published: December 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
E-cigarette flavored pods induce inflammation, epithelial barrier dysfunction, and DNA damage in lung epithelial cells and monocytes
Authors: Muthumalage Thivanka , Lamb Thomas , Friedman Michelle R. , Rahman Irfan
Published: December 2019

E-cigarette flavored pods are increasing in use among young adults. Although marketed as a safer alternative to conventional cigarettes, the health effects of e-cigarette flavored pods are unknown. We hypothesized that e-cigarette flavored pods would cause oxidative stress, barrier dysfunction, and an inflammatory response in monocytes and lung epithelial cells. JUUL pod flavors (Fruit Medley, Virginia Tobacco, Cool Mint, Crème Brulee, Cool Cucumber, Mango, and Classic Menthol) and similar pod flavors (Just Mango-Strawberry Coconut and Caffé Latte) were tested. These pod flavors generated significant amounts of acellular ROS and induced significant mitochondrial superoxide production in bronchial epithelial cells (16-HBE). Lung epithelial cells (16-HBE, BEAS-2B) and monocytes (U937) exposed to various pod aerosols resulted in increased inflammatory mediators, such as IL-8 or PGE2. JUUL pod flavors, Crème Brulee and Cool Cucumber, caused epithelial barrier dysfunction in 16-HBE cells. Moreover, tested flavors also showed DNA damage upon exposure in monocytes. We determined the chemical constituents present in various flavors. Our data suggest that these constituents in flavored pods induce oxidative stress, inflammation, epithelial barrier dysfunction, and DNA damage in lung cells. These data provide insights into the regulation of e-cigarette flavored pods, as well as constituents in these flavors.
Optical experiment to test negative probability in context of quantum-measurement selection
Authors: Ryu Junghee , Hong Sunghyuk , Lee Joong-Sung , Seol Kang Hee , Jae Jeongwoo , Lim James , Lee Jiwon , Lee Kwang-Geol , Lee Jinhyoung
Published: December 2019

Negative probability values have been widely employed as an indicator of the nonclassicality of quantum systems. Known as a quasiprobability distribution, they are regarded as a useful tool that provides significant insight into the underlying fundamentals of quantum theory when compared to the classical statistics. However, in this approach, an operational interpretation of these negative values with respect to the definition of probability—the relative frequency of occurred event—is missing. An alternative approach is therefore considered where the quasiprobability operationally reveals the negativity of measured quantities. We here present an experimental realization of the operational quasiprobability, which consists of sequential measurements in time. To this end, we implement two sets of polarization measurements of single photons. We find that the measured negativity can be interpreted in the context of selecting measurements, and it reflects the nonclassical nature of photons. Our results suggest a new operational way to unravel the nonclassicality of photons in the context of measurement selection.
Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel Elecsys Aβ(1–42), pTau and tTau CSF immunoassays
Authors: Blennow Kaj , Shaw Leslie M. , Stomrud Erik , Mattsson Niklas , Toledo Jon B. , Buck Katharina , Wahl Simone , Eichenlaub Udo , Lifke Valeria , Simon Maryline , Trojanowski John Q. , Hansson Oskar
Published: December 2019

We evaluated the performance of CSF biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients with cognitive symptoms. CSF samples from patients in two multicentre longitudinal studies (ADNI, n = 619; BioFINDER, n = 431) were analysed. Aβ(1–42), tTau and pTau CSF concentrations were measured using Elecsys CSF immunoassays, and tTau/Aβ(1–42) and pTau/Aβ(1–42) ratios calculated. Patients were classified as biomarker (BM)-positive or BM-negative at baseline. Ability of biomarkers to predict risk of clinical decline and conversion to AD/dementia was assessed using pre-established cut-offs for Aβ(1–42) and ratios; tTau and pTau cut-offs were determined. BM-positive patients showed greater clinical decline than BM-negative patients, demonstrated by greater decreases in MMSE scores (all biomarkers: –2.10 to –0.70). Risk of conversion to AD/dementia was higher in BM-positive patients (HR: 1.67 to 11.48). Performance of Tau/Aβ(1–42) ratios was superior to single biomarkers, and consistent even when using cut-offs derived in a different cohort. Optimal pTau and tTau cut-offs were approximately 27 pg/mL and 300 pg/mL in both BioFINDER and ADNI. Elecsys pTau/Aβ(1–42) and tTau/Aβ(1–42) are robust biomarkers for predicting risk of clinical decline and conversion to dementia in non-demented patients, and may support AD diagnosis in clinical practice.
Investigating the drivers of the spatio-temporal patterns of genetic differences between Plasmodium falciparum malaria infections in Kilifi County, Kenya
Authors: Malinga Josephine , Mogeni Polycarp , Omedo Irene , Rockett Kirk , Hubbart Christina , Jeffreys Anne , Williams Thomas N. , Kwiatkowski Dominic , Bejon Philip , Ross Amanda
Published: December 2019

Knowledge of how malaria infections spread locally is important both for the design of targeted interventions aiming to interrupt malaria transmission and the design of trials to assess the interventions. A previous analysis of 1602 genotypedPlasmodium falciparumparasites in Kilifi, Kenya collected over 12 years found an interaction between time and geographic distance: the mean number of single nucleotide polymorphism (SNP) differences was lower for pairs of infections which were both a shorter time interval and shorter geographic distance apart. We determine whether the empiric pattern could be reproduced by a simple model, and what mean geographic distances between parent and offspring infections and hypotheses about genotype-specific immunity or a limit on the number of infections would be consistent with the data. We developed an individual-based stochastic simulation model of households, people and infections. We parameterized the model for the total number of infections, and population and household density observed in Kilifi. The acquisition of new infections, mutation, recombination, geographic location and clearance were included. We fit the model to the observed numbers of SNP differences between pairs of parasite genotypes. The patterns observed in the empiric data could be reproduced. Although we cannot rule out genotype-specific immunity or a limit on the number of infections per individual, they are not necessary to account for the observed patterns. The mean geographic distance between parent and offspring malaria infections for the base model was 0.4 km (95% CI 0.24, 1.20), for a distribution with 58% of distances shorter than the mean. Very short mean distances did not fit well, but mixtures of distributions were also consistent with the data. For a pathogen which undergoes meiosis in a setting with moderate transmission and a low coverage of infections, analytic methods are limited but an individual-based model can be used with genotyping data to estimate parameter values and investigate hypotheses about underlying processes.
Omega-3 Fatty Acids Effects on Inflammatory Biomarkers and Lipid Profiles among Diabetic and Cardiovascular Disease Patients: A Systematic Review and Meta-Analysis
Authors: Natto Zuhair S. , Yaghmoor Wael , Alshaeri Heba K. , Van Dyke Thomas E.
Published: December 2019

The purpose of this systematic review and meta-analysis was to investigate omega-3 fatty acids’ influence on 12 inflammatory biomarkers—LDL, HDL, total cholesterol, TG, HbA1c, Apo AI, Apo AII, Apo B, CRP, TNF-α, glucose, and fasting blood glucose among diabetic and cardiovascular disease (CVD) patients. We searched articles in six database engines, and 16 of the 696 articles reviewed met the inclusion criteria. Among these, lipid and inflammatory biomarkers investigated commonly included total cholesterol (11 studies), LDL, and TG (10 studies each). Overall, omega-3 was associated with a significant reduction in Apo AII among diabetic patients, as compared to different controls (−8.0 mg/dL 95% CI: −12.71, −3.29, p = 0.0009), triglycerides (−44.88 mg/dL 95% CI: −82.6, −7.16, p < 0.0001), HDL (−2.27 mg/dL 95% CI: −3.72, −0.83, p = 0.002), and increased fasting blood glucose (16.14 mg/dL 95% CI: 6.25, 26.04, p = 0.001). Omega-3 also was associated with increased LDL among CVD patients (2.10 mg/dL 95% CI: 1.00, 3.20, p = 0.0002). We conclude that omega-3 fatty acids may be associated with lower inflammatory biomarkers among diabetic and cardiovascular patients. Clinicians should be aware of these potential benefits; however, it is essential to recommend that patients consult with clinicians before any omega-3 intake.
Purification and biological activity of natural variants synthesized by tridecaptin M gene cluster and in vitro drug-kinetics of this antibiotic class
Authors: Jangra Manoj , Kaur Manpreet , Podia Mansi , Tambat Rushikesh , Singh Vidhu , Chandal Nishtha , Mahey Nisha , Maurya Navdezda , Nandanwar Hemraj
Published: December 2019

The flexibility of the adenylation domains of non-ribosomal peptide synthetases (NRPSs) to different substrates creates a diversity of structurally similar peptides. In the present study, we investigated the antimicrobial activity of different natural variants synthesized by tridecaptin M gene cluster and performed the in vitro drug kinetics on this class. The natural variants were isolated and characterized using MALDI-MS and tandem mass spectrometry. All the peptides were studied for their antimicrobial activity in different pathogens, including colistin-resistant bacteria, and for haemolytic activity. Furthermore, in vitro drug kinetics was performed with tridecaptin M (or M1, the major product of the gene cluster). The natural variants displayed a varying degree of bioactivity with M11 showing the most potent antibacterial activity (MIC, 1–8 µg/ml), even against A. baumannii and P. aeruginosa strains. The in vitro kinetic studies revealed that tridecaptin M at a concentration of 16 µg/ml eradicated the bacteria completely in high-density culture. The compound demonstrated desirable post-antibiotic effect after two-hour exposure at MIC concentration. We also observed the reversal of resistance to this class of antibiotics in the presence of carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Altogether, the study demonstrated that tridecaptins are an excellent drug candidate against drug-resistant Gram-negative bacteria. Future studies are required to design a superior tridecaptin by investigating the interactions of different natural variants with the target.
Three-Dimensional Skyrmions with Arbitrary Topological Number in a Ferromagnetic Spin-1 Bose-Einstein Condensate
Authors: Luo Huan-Bo , Li Lu , Liu Wu-Ming
Published: December 2019

We propose a new scheme for creating three-dimensional Skyrmions in a ferromagnetic spin-1 Bose-Einstein condensate by manipulating a multipole magnetic field and a pair of counter-propagating laser beams. The result shows that a three-dimensional Skyrmion with topological number Q = 2 can be created by a sextupole magnetic field and the laser beams. Meanwhile, the vortex ring and knot structure in the Skyrmion are found. The topological number can be calculated analytically in our model, which implies that the method can be extended to create Skyrmions with arbitrary topological number. As the examples, three-dimensional Skyrmions with Q = 3, 4 are also demonstrated and are distinguishable by the density distributions with a specific quantization axis. These topological objects have the potential to be realized in ferromagnetic spin-1 Bose-Einstein condensates experimentally.
Contribution of changing precipitation and climatic oscillations in explaining variability of water extents of large reservoirs in Pakistan
Authors: Akhtar Ibrar ul Hassan , Athar H.
Published: December 2019

Major threat that Pakistan faces today is water scarcity and any significant change in water availability from storage reservoirs coupled with below normal precipitation threatens food security of more than 207 million people. Two major reservoirs of Tarbela and Mangla on Indus and Jhelum rivers are studied. Landsat satellite’s data are used to estimate the water extents of these reservoirs during 1981–2017. A long-term significant decrease of 15–25% decade−1in water extent is found for Tarbela as compared to 37–70% decade−1for Mangla, mainly during March to June. Significant water extents reductions are observed in the range of −23.9 to −53.4 km2(1991–2017) and −63.1 to −52.3 km2(2001–2010 and 2011–2017) for Tarbela and Mangla, respectively. The precipitation amount and areas receiving this precipitation show a significant decreasing trend of −4.68 to −8.40 mm year−1and −358.1 to −309.9 km2year−1for basins of Mangla and Tarbela, respectively. The precipitation and climatic oscillations are playing roles in variability of water extents. The ensuing multiple linear regression models predict water extents with an average error of 13% and 16% for Tarbela and Mangla, respectively.
Investigation and Restoration of BEST1 Activity in Patient-derived RPEs with Dominant Mutations
Authors: Ji Changyi , Li Yao , Kittredge Alec , Hopiavuori Austin , Ward Nancy , Yao Peng , Fukuda Yohta , Zhang Yu , Tsang Stephen H. , Yang Tingting
Published: December 2019

BEST1 is a Ca2+-activated Cl− channel predominantly expressed in retinal pigment epithelium (RPE), and over 250 genetic mutations in the BEST1 gene have been identified to cause retinal degenerative disorders generally known as bestrophinopathies. As most BEST1 mutations are autosomal dominant, it is of great biomedical interest to determine their disease-causing mechanisms and the therapeutic potential of gene therapy. Here, we characterized six Best vitelliform macular dystrophy (BVMD)-associated BEST1 dominant mutations by documenting the patients’ phenotypes, examining the subcellular localization of endogenous BEST1 and surface Ca2+-dependent Cl− currents in patient-derived RPEs, and analyzing the functional influences of these mutations on BEST1 in HEK293 cells. We found that all six mutations are loss-of-function with different levels and types of deficiencies, and further demonstrated the restoration of Ca2+-dependent Cl− currents in patient-derived RPE cells by WT BEST1 gene supplementation. Importantly, BEST1 dominant and recessive mutations are both rescuable at a similar efficacy by gene augmentation via adeno-associated virus (AAV), providing a proof-of-concept for curing the vast majority of bestrophinopathies.
Diversity of P1 phage-like elements in multidrug resistant Escherichia coli
Authors: Venturini Carola , Zingali Tiziana , Wyrsch Ethan R. , Bowring Bethany , Iredell Jonathan , Partridge Sally R. , Djordjevic Steven P.
Published: December 2019

The spread of multidrug resistance via mobile genetic elements is a major clinical and veterinary concern. Pathogenic Escherichia coli harbour antibiotic resistance and virulence genes mainly on plasmids, but also bacteriophages and hybrid phage-like plasmids. In this study, the genomes of three E. coli phage-like plasmids, pJIE250-3 from a human E. coli clinical isolate, pSvP1 from a porcine ETEC O157 isolate, and pTZ20_1P from a porcine commensal E. coli, were sequenced (PacBio RSII), annotated and compared. All three elements are coliphage P1 variants, each with unique adaptations. pJIE250-3 is a P1-derivative that has lost lytic functions and contains no accessory genes. In pTZ20_1P and pSvP1, a core P1-like genome is associated with insertion sequence-mediated acquisition of plasmid modules encoding multidrug resistance and virulence, respectively. The transfer ability of pTZ20_1P, carrying antibiotic resistance markers, was also tested and, although this element was not able to transfer by conjugation, it was able to lysogenize a commensal E. coli strain with consequent transfer of resistance. The incidence of P1-like plasmids (~7%) in our E. coli collections correlated well with that in public databases. This study highlights the need to investigate the contribution of phage-like plasmids to the successful spread of antibiotic resistant pathotypes.
Two New Fucose-α (1–2)-Glycans Assigned In The Healthy Human Brain Taking The Number To Seven
Authors: Tosh Nathan , Quadrelli Scott , Galloway Graham , Mountford Carolyn
Published: December 2019

Fucosylated glycans are involved in the molecular mechanisms that underpin neuronal development, learning and memory. The capacity to study the fucose-α(1–2)-glycan residues noninvasively in the human brain, is integral to understanding their function and deregulation. Five fucose crosspeaks were assigned to fucosylated glycans using invivo two-dimensional magnetic resonance Correlated SpectroscopY (2D L-COSY) of the brain. Recent improvements encompassed on the 3T Prisma (Siemens, Erlangen) with a 64-channel head and neck coil have allowed two new assignments. These are Fuc VI (F2:4.44, F1:1.37 ppm) and Fuc VII (F2: 4.29, F1:1.36 ppm). The Fuc VI crosspeak, close to the water resonance, is resolved due to decreased T1 noise. Fuc VII crosspeak, located between Fuc I and III, is available for inspection due to increased spectral resolution. Spectra recorded from 33 healthy men and women showed a maximum variation of up to 0.02 ppm in chemical shifts for all crosspeaks.
High uptake of Intermittent Preventive Treatment of malaria in pregnancy is associated with improved birth weight among pregnant women in Ghana
Authors: Quakyi Isabella , Tornyigah Bernard , Houze Pascal , Kusi Kwadwo A. , Coleman Nathaniel , Escriou Guillaume , Laar Amos , Cot Michel , Fobil Julius , Asare Gloria Quansah , Deloron Philippe , Anang Abraham K. , Cottrell Gilles , Ofori Michael F. , Ndam Nicaise Tuikue
Published: December 2019

Despite the clinically proven advantages of intermittent preventive treatment of malaria in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP), utilisation has been low in many African countries. To increase uptake and achieve the desired effect, the World Health Organization revised the policy to a monthly administration. Assessing the coverage and impact of the revised policy on pregnancy and neonatal outcomes is, therefore, a necessity. A 2-parallel cross-sectional hospital-based study was carried out among pregnant women attending first antenatal care (ANC) and delivery. Maternal and cord blood samples were assayed for malaria parasites by quantitative PCR targeting both the 18S rDNA and the acidic terminal segment of Plasmodium falciparum var genes, and plasma SP levels were measured by liquid chromatography coupled to tandem mass spectrometry. Parasite prevalence was similar between the two study sites but decreased significantly between the first ANC (9% or 43%) and delivery (4% or 11%) based on the qPCR target. At delivery, 64.5% of women received ≥3 IPTp-SP dose, 15.5% received 2 doses and 6% had 1 dose. Taking ≥3 IPTp-SP doses was associated with an average birth weight increase of more than 0.165 kg. IPTp-SP uptake was associated with plasma SP level at delivery (OR = 32.3, p ≤ 0.005, 95% CI (13.3;78.4) for those that reported ≥3 IPTp-SP doses) while the same trend of improved birth weight was observed with high plasma SP levels. The new IPTp policy is well implemented and well utilised by women in the sites considered in this study and translates to the improved birth weight observed. This study confirms the interest and the clinical benefit expected from this policy change.
Elevated expression of miR-146a correlates with high levels of immune cell exhaustion markers and suppresses cellular immune function in chronic HIV-1-infected patients
Authors: Yu Ting , Ju Zhao , Luo Mingqi , Hu Ronghua , Teng Yan , Xie Linlin , Zhong Chaojie , Chen Lang , Hou Wei , Xiong Yong , Feng Yong
Published: December 2019

Functional exhaustion of immune cells is a defining characteristic of HIV-1 chronic infections, exhibiting dysregulation of cellular immune responses and expression of co-inhibitory receptors. Although the molecular mechanisms controlling immune-cell exhaustion retains largely unknown, immune checkpoint blockade strategy has shown inspiring potential to reinvigorate T cell functions in chronic infections. In this study, we investigated peripheral blood mononuclear cells (PBMCs) exhaustion markers from 109 chronic HIV-1-infected patients and found they correlated positively with microRNA-146a, which was inversely correlated with CD4+ T cell count. Intriguingly, ex vivo neutralization of miR-146a in PBMCs from chronic HIV-1 infection exhibited an elevated antiviral cytokines production as well as the expression of GZMB and perforin, while simultaneously, decreased the inhibitory receptors expression such as PD-1, CTLA-4, TIM-3 and LAG-3. These results highlight the importance of miR-146a to HIV-1 induced immune cell exhaustion, and uncover a novel layer of HIV/AIDS pathogenesis and provide potential targets for improved immune intervention.
Projection-to-Projection Translation for Hybrid X-ray and Magnetic Resonance Imaging
Authors: Stimpel Bernhard , Syben Christopher , Würfl Tobias , Breininger Katharina , Hoelter Philip , Dörfler Arnd , Maier Andreas
Published: December 2019

Hybrid X-ray and magnetic resonance (MR) imaging promises large potential in interventional medical imaging applications due to the broad variety of contrast of MRI combined with fast imaging of X-ray-based modalities. To fully utilize the potential of the vast amount of existing image enhancement techniques, the corresponding information from both modalities must be present in the same domain. For image-guided interventional procedures, X-ray fluoroscopy has proven to be the modality of choice. Synthesizing one modality from another in this case is an ill-posed problem due to ambiguous signal and overlapping structures in projective geometry. To take on these challenges, we present a learning-based solution to MR to X-ray projection-to-projection translation. We propose an image generator network that focuses on high representation capacity in higher resolution layers to allow for accurate synthesis of fine details in the projection images. Additionally, a weighting scheme in the loss computation that favors high-frequency structures is proposed to focus on the important details and contours in projection imaging. The proposed extensions prove valuable in generating X-ray projection images with natural appearance. Our approach achieves a deviation from the ground truth of only 6% and structural similarity measure of 0.913 ± 0.005. In particular the high frequency weighting assists in generating projection images with sharp appearance and reduces erroneously synthesized fine details.
Delineating the cognitive-neural substrates of writing: a large scale behavioral and voxel based morphometry study
Authors: Chen Haobo , Pan Xiaoping , Bickerton Wai-Ling , Lau Johnny King , Zhou Jin , Zhou Beinan , Harris Lara , Rotshtein Pia
Published: December 2019

The current study investigated the cognitive and neural substrates that underpin writing ability. We explored similarities and differences in writing numbers and words and compared these to language and manual actions in a large group of sub-acute, stroke patients (n = 740). The behavioral data showed association and dissociation in the ability to write words and numbers. Comorbidities of writing deficits with both language and motor impairments were prevalent, with less than a handful showing deficits restricted to the writing tasks. A second analysis with a subset of patients (n = 267) explored the neural networks that mediate writing abilities. Lesion to right temporal contributed to writing words, while lesions to left postcentral contributed to writing numbers. Overlapping neural mechanisms included the bilateral prefrontal cortex, right inferior parietal, left middle occipital and the right cerebellum. With the former regions associated with error pattern typical to writing based on prior knowledge (the lexical route), while lesion to left MOG was associated with errors to the phonological (non-lexical) route. Using principle components extracted from the behavioral data, we showed that right prefrontal and right parietal contributed to the ability to use pen, while lesion to bilateral prefrontal, inferior temporal and cerebellum supported unique use of pen for writing. The behavioral and imaging data suggested that writing numbers and words primarily relied on overlapping cognitive and neural functions. Incidents of pure writing deficits, in the absence of motor or language deficits were rare. Nevertheless, the PCA and neural data suggested that writing abilities were associated with some unique neuro-cognitive functions, specifically dedicated to the use of pen and the ability to transform meaning to motor command.
Modular metamaterials composed of foldable obelisk-like units with reprogrammable mechanical behaviors based on multistability
Authors: Yang Nan , Zhang Mingkai , Zhu Rui , Niu Xiao-dong
Published: December 2019

A new type of modular metamaterials with reprogrammable mechanical properties is proposed based on the multistability in decoupled units. This metamaterial consists of periodically arranged foldable obelisk-like (FO) units, and each unit has three interchangeable states: two different soft states and a stiff state. Therefore, such metamaterial can possess various mechanical properties with different state combinations of units. Both theoretical and experimental investigations are conducted to understand the multistability in one unit and the reprogrammed mechanical properties in a two-dimensional tessellation. Additionally, we investigate the inverse question that whether the identical force response can be generated with different geometrical design of the metamaterial and propose a way to build 3D metamaterials with intended architectures. This work establishes general principles for designing mechanical metamaterials with independently transformable modules, and opens new avenues for various potential applications such as: self-locking materials, impact mitigation and stiffness transformation materials.
Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase
Authors: Pollock Katie , Liu Manjuan , Zaleska Mariola , Meniconi Mirco , Pfuhl Mark , Collins Ian , Guettler Sebastian
Published: December 2019

The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A number of these are implicated in cancer-relevant processes, including Wnt/β-catenin signalling, Hippo signalling and telomere maintenance. The ARCs recognise a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase’s poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent “scaffolding” mechanisms contribute to tankyrase function. Here we report a fragment-based screening programme against tankyrase ARC domains, using a combination of biophysical assays, including differential scanning fluorimetry (DSF) and nuclear magnetic resonance (NMR) spectroscopy. We identify fragment molecules that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compounds will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.
Radiative and non-radiative transitions of excited Ti3+ cations in sapphire
Authors: Shirakov Avry , Burshtein Zeev , Shimony Yehoshua , Frumker Eugene , Ishaaya Amiel A.
Published: December 2019

We have measured the fluorescence quantum efficiency in Ti3+:sapphire single crystals between 150 K and 550 K. Using literature-given effective fluorescence lifetime temperature dependence, we show that the zero temperature radiative lifetime is (4.44 ± 0.04) μs, compared to the 3.85 μs of the fluorescence lifetime. Fluorescence lifetime thermal shortening resolves into two parallel effects: radiative lifetime shortening, and non-radiative transition rate enhancement. The first is due to thermally enhanced occupation of a ΔE = 1,700 cm−1 higher (top) electronic state of the upper multiplet, exhibiting a transition oscillator strength of f = 0.62, compared to only 0.013 of the bottom electronic state of the same multiplet. The non-radiative rate relates to multi-phonon decay transitions stimulated by the thermal phonon occupation. Thermal enhancement of the configuration potential anharmonicity is also observed. An empiric expression for the figure-of-anharmonicity temperature dependence is given as $$\hat{{\bf{H}}}$$Hˆ (T) = $$\hat{{\bf{H}}}$$Hˆ (0)(1 + β exp(−ℏωco /kBT )), where $$\hat{{\bf{H}}}$$Hˆ (0) = 0.276, β = 5.2, ℏωco = 908 cm−1, and kB is the Boltzmann constant.
Cell-based interferon gene therapy using proliferation-controllable, interferon-releasing mesenchymal stem cells
Authors: Tsujimura Mari , Kusamori Kosuke , Katsumi Hidemasa , Sakane Toshiyasu , Yamamoto Akira , Nishikawa Makiya
Published: December 2019

An important safety concern on cell-based gene therapy is that few methods have been available to control the proliferation and functioning of therapeutic protein-expressing cells after transplantation. We previously reported that the proliferation and functioning of the cells transfected with herpes simplex virus thymidine kinase (HSVtk) gene, a suicide gene, can be controlled by administration of ganciclovir. In this study, we tried to control the amount of murine interferon-γ (IFN-γ) secreted from transplanted murine mesenchymal stem cell line C3H10T1/2 cells to achieve safe cell-based IFN-γ gene therapy for cancer. C3H10T1/2 cells were transfected with HSVtk- and murine IFN-γ-expressing plasmid vectors to obtain C3H10T1/2/HSVtk/IFN-γ cells. C3H10T1/2/HSVtk/IFN-γ cells released IFN-γ and were sensitive to ganciclovir. C3H10T1/2/HSVtk/IFN-γ cells significantly suppressed the proliferation of murine adenocarcinoma cell line colon26 cells both in vitro and in vivo. Moreover, subcutaneous administration of ganciclovir to mice transplanted with NanoLuc luciferase-expressing C3H10T1/2/HSVtk cells for three consecutive days reduced the luminescence signals from the transplanted cells. These results indicate that the cell regulation system using HSVtk gene and ganciclovir can be useful for safe and efficient cell-based IFN-γ gene therapy for cancer.
The role of calcium ion release on biocompatibility and antimicrobial properties of hydraulic cements
Authors: Koutroulis Andreas , Kuehne Sarah A. , Cooper Paul R. , Camilleri Josette
Published: December 2019

Tricalcium silicate (TCS)-based materials produce calcium hydroxide as a byproduct of their hydration reaction. The present study investigated whether calcium ion release (CIR) affects their biological and antimicrobial properties when used as pulp protection materials. The effect of incorporation of micro-silica and calcium phosphate monobasic to radiopacified TCS-based materials was investigated. The commercial TCS-based Biodentine, Bio-C Pulpo, TotalFill Root Repair Material, TheraCal LC and a base/liner- ACTIVA BioACTIVE (Activa) were also evaluated. The hydration and CIR were monitored and correlated with biocompatibility and antimicrobial assessment of eluates. Overall, the additives altered the hydration and leaching profile of the prototype cements. The micro-silica inclusion resulted in a decreased long-term calcium hydroxide formation which was associated with neutralised cytotoxicity and antibacterial activity. Calcium phosphate did not alter the leaching profile, although a stronger antibacterial effect was induced. The commercial materials also had different CIR profiles. The water-based ones had higher CIR, and this was associated with stronger antimicrobial effect but not enhanced biological activity. Both TheraCal LC and Activa exhibited poor degree of conversion, low CIR, acceptable biocompatibility and moderate antibacterial activity. A positive correlation of CIR with antibacterial effectiveness was observed (0.3 < r < 0.49; p = 0.021, p = 0.011 for the two test bacterial cultures). No relation was shown between CIR and cytotoxicity (0.3 < r < 0.49; p = 0.150, p = 0.068 for the two cell cultures studied). The additives modified the CIR. The antimicrobial properties were dependent on the CIR; the cytotoxicity of the materials was unaffected.
Near ideal synaptic functionalities in Li ion synaptic transistor using Li3POxSex electrolyte with high ionic conductivity
Authors: Nikam Revannath Dnyandeo , Kwak Myonghoon , Lee Jongwon , Rajput Krishn Gopal , Banerjee Writam , Hwang Hyunsang
Published: December 2019

All solid-state lithium-ion transistors are considered as promising synaptic devices for building artificial neural networks for neuromorphic computing. However, the slow ionic conduction in existing electrolytes hinders the performance of lithium-ion-based synaptic transistors. In this study, we systematically explore the influence of ionic conductivity of electrolytes on the synaptic performance of ionic transistors. Isovalent chalcogenide substitution such as Se in Li3PO4 significantly reduces the activation energy for Li ion migration from 0.35 to 0.253 eV, leading to a fast ionic conduction. This high ionic conductivity allows linear conductance switching in the LiCoO2 channel with several discrete nonvolatile states and good retention for both potentiation and depression steps. Consequently, optimized devices demonstrate the smallest nonlinearity ratio of 0.12 and high on/off ratio of 19. However, Li3PO4 electrolyte (with lower ionic conductivity) shows asymmetric and nonlinear weight-update characteristics. Our findings show that the facilitation of Li ionic conduction in solid-state electrolyte suggests potential application in artificial synapse device development.
Effects of Exogenous Neuroglobin (Ngb) on retinal inflammatory chemokines and microglia in a rat model of transient hypoxia
Authors: Tun Sai Bo Bo , Barathi Veluchamy Amutha , Luu Chi D. , Lynn Myoe Naing , Chan Anita S. Y.
Published: December 2019

Neuroglobin is an endogenous neuroprotective protein. We determined the safety of direct delivery of Neuroglobin in the rat retina and its effects on retinal inflammatory chemokines and microglial during transient hypoxia. Exogenous Neuroglobin protein was delivered to one eye and a sham injection to the contralateral eye of six rats intravitreally. Fundus photography, Optical Coherence Topography, electroretinogram, histology and Neuroglobin, chemokines level were determined on days 7 and 30. Another 12 rats were subjected to transient hypoxia to assess the effect of Neuroglobin in hypoxia exposed retina by immunohistochemistry, retinal Neuroglobin concentration and inflammatory chemokines. Intravitreal injection of Neuroglobin did not incite morphology or functional changes in the retina. Retinal Neuroglobin protein was reduced by 30% at day 7 post hypoxia. It was restored to normoxic control levels with intravitreal exogenous Neuroglobin injections and sustained up to 30 days. IL-6, TNFα, IL-1B, RANTES, MCP-1 and VEGF were significantly decreased in Neuroglobin treated hypoxic retinae compared to non-treated hypoxic controls. This was associated with decreased microglial activation in the retina. Our findings provide proof of concept suggesting intravitreal Neuroglobin injection is non-toxic to the retina and can achieve the functional level to abrogate microglial and inflammatory chemokines responses during transient hypoxia.
Volatile scents of influenza A and S. pyogenes (co-)infected cells
Authors: Traxler Selina , Barkowsky Gina , Saß Radost , Klemenz Ann-Christin , Patenge Nadja , Kreikemeyer Bernd , Schubert Jochen K. , Miekisch Wolfram
Published: December 2019

Influenza A is a serious pathogen itself, but often leads to dangerous co-infections in combination with bacterial species such asStreptococcus pyogenes. In comparison to classical biochemical methods, analysis of volatile organic compounds (VOCs) in headspace above cultures can enable destruction free monitoring of metabolic processesin vitro. Thus, volatile biomarkers emitted from biological cell cultures and pathogens could serve for monitoring of infection processesin vitro. In this study we analysed VOCs from headspace above (co)-infected human cells by using a customized sampling system. For investigating the influenza A mono-infection and the viral-bacterial co-infectionin vitro, we analysed VOCs from Detroit cells inoculated with influenza A virus andS. pyogenesby means of needle-trap micro-extraction (NTME) and gas chromatography mass spectrometry (GC-MS). Besides the determination of microbiological data such as cell count, cytokines, virus load and bacterial load, emissions from cell medium, uninfected cells and bacteria mono-infected cells were analysed. Significant differences in emitted VOC concentrations were identified between non-infected and infected cells. After inoculation withS. pyogenes, bacterial infection was mirrored by increased emissions of acetaldehyde and propanal. N-propyl acetate was linked to viral infection. Non-destructive monitoring of infections by means of VOC analysis may open a new window for infection research and clinical applications. VOC analysis could enable early recognition of pathogen presence and in-depth understanding of their etiopathology.
Evidence for an effect of receptor density on ligand occupancy and agonist EC50
Authors: Jarvis Gavin E. , Thompson Andrew J.
Published: December 2019

Drug-receptor interaction theory predicts that proportional receptor occupancy is a function of ligand concentration as defined by a ligand-receptor affinity constant, and is independent of receptor density. However, we previously observed that the EC50 of 5-HT reduced as the density of 5-HT3 receptors increased, suggesting an effect of receptor density on occupancy. The current study was designed to maximise variability in experimentally observed currents and confirm this apparent contradiction prospectively. Xenopus oocytes were injected with RNA encoding 5-HT3A receptors under conditions designed to achieve varying receptor expression levels and 5-HT-evoked currents measured using two electrode voltage clamp. Results from 99 oocytes showed that as the maximal peak current increased from 0.05 µA to 12.1 µA there was a 3.7-fold reduction in EC50. Since occupancy and conductance are directly related in this system, this indicates that for a given concentration of 5-HT, proportional occupancy increases with increased receptor density. We conclude that normalising data masks this correlation, and can result in reduced accuracy of pharmacological measurements. We propose a mechanistic explanation for our observations.
Cranial irradiation mediated spine loss is sex-specific and complement receptor-3 dependent in male mice
Authors: Hinkle Joshua J. , Olschowka John A. , Love Tanzy M. , Williams Jacqueline P. , O’Banion M. Kerry
Published: December 2019

Cranial irradiation is the main therapeutic treatment for primary and metastatic malignancies in the brain. However, cranial radiation therapy produces long-term impairment in memory, information processing, and attention that contribute to a decline in quality of life. The hippocampal neural network is fundamental for proper storage and retrieval of episodic and spatial memories, suggesting that hippocampal signaling dysfunction could be responsible for the progressive memory deficits observed following irradiation. Previous rodent studies demonstrated that irradiation induces significant loss in dendritic spine number, alters spine morphology, and is associated with behavioral task deficits. Additionally, the literature suggests a common mechanism in which synaptic elimination via microglial-mediated phagocytosis is complement dependent and associated with cognitive impairment in aging as well as disease. We demonstrate sexual dimorphisms in irradiation-mediated alterations of microglia activation markers and dendritic spine density. Further, we find that the significant dendritic spine loss observed in male mice following irradiation is microglia complement receptor 3 (CR3)-dependent. By identifying sex-dependent cellular and molecular factors underlying irradiation-mediated spine loss, therapies can be developed to counteract irradiation-induced cognitive decline and improve patient quality of life.
Morphology of planktonic zoeal stages of Palicus caronii (Decapoda, Brachyura), identified by DNA barcoding, provides novelties to Palicoidea larval systematics
Authors: Di Muzio Giorgia , Mussat Sartor Rocco , Nurra Nicola , Battuello Marco , Pessani Daniela , Cervella Piero , Cuesta Jose A.
Published: December 2019

The zoeal development of the brachyuran crab, Palicus caronii, comprises two zoeal stages and the morphology is described and illustrated in detail. The zoeae were collected in plankton samples from the Southern Ligurian Sea (Western Mediterranean). Although the morphology of the larval stages of this species was unknown, a combination of characters allowed the zoeae to initially be assigned to the Palicidae, based on the previous unique known first zoeal description of one species of this family. Later, the identification of the larvae as Palicus caronii was confirmed through molecular analysis. The morphological features of the zoeae that characterize the Palicidae and separate them from the Crossotonotidae are confirmed. Also, the larval development comprising only two zoeal stages observed in Palicus caronii, the peculiar and uncommon carapace surface setation, and the presence of anterodorsal and posterodorsal sensory dorsal organs suggest that these characters could be common to the Palicoidea.
In situ Microfluidic Cryofixation for Cryo Focused Ion Beam Milling and Cryo Electron Tomography
Authors: Fuest Marie , Schaffer Miroslava , Nocera Giovanni Marco , Galilea-Kleinsteuber Rodrigo I. , Messling Jan-Erik , Heymann Michael , Plitzko Jürgen M. , Burg Thomas P.
Published: December 2019

We present a microfluidic platform for studying structure-function relationships at the cellular level by connecting video rate live cell imaging with in situ microfluidic cryofixation and cryo-electron tomography of near natively preserved, unstained specimens. Correlative light and electron microscopy (CLEM) has been limited by the time required to transfer live cells from the light microscope to dedicated cryofixation instruments, such as a plunge freezer or high-pressure freezer. We recently demonstrated a microfluidic based approach that enables sample cryofixation directly in the light microscope with millisecond time resolution, a speed improvement of up to three orders of magnitude. Here we show that this cryofixation method can be combined with cryo-electron tomography (cryo-ET) by using Focused Ion Beam milling at cryogenic temperatures (cryo-FIB) to prepare frozen hydrated electron transparent sections. To make cryo-FIB sectioning of rapidly frozen microfluidic channels achievable, we developed a sacrificial layer technique to fabricate microfluidic devices with a PDMS bottom wall <5 µm thick. We demonstrate the complete workflow by rapidly cryo-freezing Caenorhabditis elegans roundworms L1 larvae during live imaging in the light microscope, followed by cryo-FIB milling and lift out to produce thin, electron transparent sections for cryo-ET imaging. Cryo-ET analysis of initial results show that the structural preservation of the cryofixed C. elegans was suitable for high resolution cryo-ET work. The combination of cryofixation during live imaging enabled by microfluidic cryofixation with the molecular resolution capabilities of cryo-ET offers an exciting avenue to further advance space-time correlative light and electron microscopy (st-CLEM) for investigation of biological processes at high resolution in four dimensions.
Potential chiral fluorescent molecular probes based on an α,β-unsaturated ketone for anion detection
Authors: Li Congshu , Liu Lixia , Pan Weitong , Chen Yanmei , Shang Xuefang , Wang Yingling , Wang Tianyun , Xu Xiufang
Published: December 2019

A series of potential chiral compounds containing an α,β-unsaturated ketone was developed for anion detection. The interplay of compounds and biological momentous anions (Cl−, H2PO4−, I−, AcO−, HS−, F−, and Br−) was evaluated by UV-vis experiments, fluorescence experiments, and electrochemical tests. By comparison, compound 1 had the best selectivity and compound 5 had the strongest binding ability among the five compounds. And compound 5 had the highest sensitivity to H2PO4− among the measured anions, and it also can be applied to actual samples, the content of H2PO4− tested in the potassium dihydrogen phosphate fertilizer solution reached above 97.5% of the marked content, and the recovery rates were within the range of 98.5–99.1%, attesting that this method was reliable for the test of H2PO4− in fertilizer. Through HRMS titration, circular dichroism and optical rotation experiments, the probable interacted mechanism was proved that the interaction site was the C=C of the α,β-unsaturated ketone structure. In addition, the interacted mechanism was researched from the perspective of chirality. Furthermore, theoretical investigation analysis was introduced to reveal that the roles of molecular frontier orbitals in molecular interplay were determined. Therefore, this series of potential chiral compounds has potential application prospects in anion recognition.