bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic inhibition differentially regulates excitability of dentate gyrus parvalbumin-expressing interneurons and granule cells
Authors: Elgueta Claudio , Bartos Marlene 
Published: December 2019

AbstractFast-spiking parvalbumin-expressing interneurons (PVIs) and granule cells (GCs) of the dentate gyrus receive layer-specific dendritic inhibition. Its impact on PVI and GC excitability is, however, unknown. By applying whole-cell recordings, GABA uncaging and single-cell-modeling, we show that proximal dendritic inhibition in PVIs is less efficient in lowering perforant path-mediated subthreshold depolarization than distal inhibition but both are highly efficient in silencing PVIs. These inhibitory effects can be explained by proximal shunting and distal strong hyperpolarizing inhibition. In contrast, GC proximal but not distal inhibition is the primary regulator of their excitability and recruitment. In GCs inhibition is hyperpolarizing along the entire somato-dendritic axis with similar strength. Thus, dendritic inhibition differentially controls input-output transformations in PVIs and GCs. Dendritic inhibition in PVIs is suited to balance PVI discharges in dependence on global network activity thereby providing strong and tuned perisomatic inhibition that contributes to the sparse representation of information in GC assemblies.
Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway
Authors: Chen Sisi , Wang Qiang , Yu Hao , Capitano Maegan L. , Vemula Sasidhar , Nabinger Sarah C. , Gao Rui , Yao Chonghua , Kobayashi Michihiro , Geng Zhuangzhuang , Fahey Aidan , Henley Danielle , Liu Stephen Z. , Barajas Sergio , Cai Wenjie , Wolf Eric R. , Ramdas Baskar , Cai Zhigang , Gao Hongyu , Luo Na , Sun Yang , Wong Terrence N. , Link Daniel C. , Liu Yunlong , Boswell H. Scott , Mayo Lindsey D. , Huang Gang , Kapur Reuben , Yoder Mervin C. , Broxmeyer Hal E. , Gao Zhonghua , Liu Yan 
Published: December 2019

AbstractClonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.
No evidence for high-pressure melting of Earth’s crust in the Archean
Authors: Smithies Robert H. , Lu Yongjun , Johnson Tim E. , Kirkland Christopher L. , Cassidy Kevin F. , Champion David C. , Mole David R. , Zibra Ivan , Gessner Klaus , Sapkota Jyotindra , De Paoli Matthew C. , Poujol Marc 
Published: December 2019

AbstractMuch of the present-day volume of Earth’s continental crust had formed by the end of the Archean Eon, 2.5 billion years ago, through the conversion of basaltic (mafic) crust into sodic granite of tonalite, trondhjemite and granodiorite (TTG) composition. Distinctive chemical signatures in a small proportion of these rocks, the so-called high-pressure TTG, are interpreted to indicate partial melting of hydrated crust at pressures above 1.5 GPa (>50 km depth), pressures typically not reached in post-Archean continental crust. These interpretations significantly influence views on early crustal evolution and the onset of plate tectonics. Here we show that high-pressure TTG did not form through melting of crust, but through fractionation of melts derived from metasomatically enriched lithospheric mantle. Although the remaining, and dominant, group of Archean TTG did form through melting of hydrated mafic crust, there is no evidence that this occurred at depths significantly greater than the ~40 km average thickness of modern continental crust.
Light-induced evaporative cooling of holes in the Hubbard model
Authors: Werner Philipp , Eckstein Martin , Müller Markus , Refael Gil 
Published: December 2019

AbstractAn elusive goal in the field of driven quantum matter is the induction of long-range order. Here, we propose a mechanism based on light-induced evaporative cooling of holes in a correlated fermionic system. Since the entropy of a filled narrow band grows rapidly with hole doping, the isentropic transfer of holes from a doped Mott insulator to such a band results in a drop of temperature. Strongly correlated Fermi liquids and symmetry-broken states could thus be produced by dipolar excitations. Using nonequilibrium dynamical mean field theory, we show that suitably designed chirped pulses may realize this cooling effect. In particular, we demonstrate the emergence of antiferromagnetic order in a system which is initially in a weakly correlated state above the maximum Néel temperature. Our work suggests a general strategy for inducing strong correlation phenomena in periodically modulated atomic gases in optical lattices or light-driven materials.
miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes
Authors: Scherm Martin G. , Serr Isabelle , Zahm Adam M. , Schug Jonathan , Bellusci Saverio , Manfredini Rossella , Salb Victoria K. , Gerlach Katharina , Weigmann Benno , Ziegler Anette-Gabriele , Kaestner Klaus H. , Daniel Carolin 
Published: December 2019

AbstractIn type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.
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

AbstractProgressive 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.
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

AbstractE-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

AbstractNegative 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

AbstractWe 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

AbstractKnowledge 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

AbstractThe 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

AbstractThe 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

AbstractWe 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

AbstractMajor 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

AbstractBEST1 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.