bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive detection of recurring genomic abnormalities: a targeted sequencing approach for multiple myeloma
Authors: Yellapantula Venkata , Hultcrantz Malin , Rustad Even H. , Wasserman Ester , Londono Dory , Cimera Robert , Ciardiello Amanda , Landau Heather , Akhlaghi Theresia , Mailankody Sham , Patel Minal , Medina-Martinez Juan Santiago , Arango Ossa Juan Esteban , Levine Max Fine , Bolli Niccolo , Maura Francesco , Dogan Ahmet , Papaemmanuil Elli , Zhang Yanming , Landgren Ola
Published: December 2019

Recent genomic research efforts in multiple myeloma have revealed clinically relevant molecular subgroups beyond conventional cytogenetic classifications. Implementing these advances in clinical trial design and in routine patient care requires a new generation of molecular diagnostic tools. Here, we present a custom capture next-generation sequencing (NGS) panel designed to identify rearrangements involving the IGH locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay. We sequenced 154 patients with plasma cell disorders and performed a head-to-head comparison with the results from conventional clinical assays, i.e., fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarray. Our custom capture NGS panel had high sensitivity (>99%) and specificity (>99%) for detection of IGH translocations and relevant chromosomal gains and losses in multiple myeloma. In addition, the assay was able to capture novel genomic markers associated with poor outcome such as bi-allelic events involving TP53. In summary, we show that a multiple myeloma designed custom capture NGS panel can detect IGH translocations and CNAs with very high concordance in relation to FISH and SNP microarrays and importantly captures the most relevant and recurrent somatic mutations in multiple myeloma rendering this approach highly suitable for clinical application in the modern era.
The paternal and maternal genetic history of Vietnamese populations
Authors: Macholdt Enrico , Arias Leonardo , Duong Nguyen Thuy , Ton Nguyen Dang , Van Phong Nguyen , Schröder Roland , Pakendorf Brigitte , Van Hai Nong , Stoneking Mark
Published: December 2019

Vietnam exhibits great cultural and linguistic diversity, yet the genetic history of Vietnamese populations remains poorly understood. Previous studies focused mostly on the majority Kinh group, and thus the genetic diversity of the many other groups has not yet been investigated. Here we analyze complete mtDNA genome sequences and ~2.3 Mb sequences of the male-specific portion of the Y chromosome from the Kinh and 16 minority populations, encompassing all five language families present in Vietnam. We find highly variable levels of diversity within and between groups that do not correlate with either geography or language family. In particular, the Mang and Sila have undergone recent, independent bottlenecks, while the majority group, Kinh, exhibits low levels of differentiation with other groups. The two Austronesian-speaking groups, Giarai and Ede, show a potential impact of matrilocality on their patterns of variation. Overall, we find that isolation, coupled with limited contact involving some groups, has been the major factor influencing the genetic structure of Vietnamese populations, and that there is substantial genetic diversity that is not represented by the Kinh.
PINK1 phosphorylates ubiquitin predominantly in astrocytes
Authors: Barodia Sandeep K. , McMeekin Laura J. , Creed Rose B. , Quinones Elijah K. , Cowell Rita M. , Goldberg Matthew S.
Published: December 2019

Loss-of-function mutations in PINK1 are causally linked to recessively inherited Parkinson’s disease (PD), with marked loss of dopaminergic neurons in the substantia nigra that are required for normal movement. PINK1 is a nuclear-encoded mitochondrial-targeted kinase that phosphorylates a conserved serine at amino acid 65 (pS65) in ubiquitin as well as Parkin, another gene with loss-of-function mutations linked to recessive parkinsonism. The steady-state levels of PINK1 protein are very low, even in cells that express PINK1, because PINK1 is normally targeted for degradation after mitochondrial import by a process that is dependent upon mitochondrial membrane potential. Dissipation of the mitochondrial membrane potential with ionophores, such as CCCP and valinomycin, causes the accumulation of PINK1 on the outer mitochondrial membrane, a marked increase of pS65-ubiquitin and the recruitment of Parkin, which targets dysfunctional mitochondria for degradation by autophagy. While the high penetrance of PINK1 mutations establish its critical function for maintaining neurons, the activity of PINK1 in primary neurons has been difficult to detect. Mounting evidence implicates non-neuronal cells, including astrocytes and microglia, in the pathogenesis of both idiopathic and inherited PD. Herein we used both western analysis and immunofluorescence of pS65-ubiquitin to directly compare the activity of PINK1 in primary neurons, astrocytes, microglia, and oligodendrocyte progenitor cells cultured from the brains of wild-type (WT) and PINK1 knockout (KO) rat pups. Our findings that PINK1-dependent ubiquitin phosphorylation is predominantly in astrocytes supports increased priority for research on the function of PINK1 in astrocytes and the contribution of astrocyte dysfunction to PD pathogenesis.
Calculating energy derivatives for quantum chemistry on a quantum computer
Authors: O’Brien Thomas E. , Senjean Bruno , Sagastizabal Ramiro , Bonet-Monroig Xavier , Dutkiewicz Alicja , Buda Francesco , DiCarlo Leonardo , Visscher Lucas
Published: December 2019

Modeling chemical reactions and complicated molecular systems has been proposed as the “killer application” of a future quantum computer. Accurate calculations of derivatives of molecular eigenenergies are essential toward this end, allowing for geometry optimization, transition state searches, predictions of the response to an applied electric or magnetic field, and molecular dynamics simulations. In this work, we survey methods to calculate energy derivatives, and present two new methods: one based on quantum phase estimation, the other on a low-order response approximation. We calculate asymptotic error bounds and approximate computational scalings for the methods presented. Implementing these methods, we perform geometry optimization on an experimental quantum processor, estimating the equilibrium bond length of the dihydrogen molecule to within $$0.014$$0.014 Å of the full configuration interaction value. Within the same experiment, we estimate the polarizability of the H$${}_{2}$$2 molecule, finding agreement at the equilibrium bond length to within $$0.06$$0.06 a.u. ($$2 \%$$2% relative error).
Mapping dynamic QTL dissects the genetic architecture of grain size and grain filling rate at different grain-filling stages in barley
Authors: Du Binbin , Wang Qifei , Sun Genlou , Ren Xifeng , Cheng Yun , Wang Yixiang , Gao Song , Li Chengdao , Sun Dongfa
Published: December 2019

Grain filling is an important growth process in formation of yield and quality for barley final yield determination. To explore the grain development behavior during grain filling period in barley, a high-density genetic map with 1962 markers deriving from a doubled haploid (DH) population of 122 lines was used to identify dynamic quantitative trait locus (QTL) for grain filling rate (GFR) and five grain size traits: grain area (GA), grain perimeter (GP), grain length (GL), grain width (GW) and grain diameter (GD). Unconditional QTL mapping is to detect the cumulative effect of genetic factors on a phenotype from development to a certain stage. Conditional QTL mapping is to detect a net effect of genetic factors on the phenotype at adjacent time intervals. Using unconditional, conditional and covariate QTL mapping methods, we successfully detected 34 major consensus QTLs. Moreover, certain candidate genes related to grain size, plant height, yield, and starch synthesis were identified in six QTL clusters, and individual gene was specifically expressed in different grain filling stages. These findings provide useful information for understanding the genetic basis of the grain filling dynamic process and will be useful for molecular marker-assisted selection in barley breeding.
Impact of alloy fluctuations and Coulomb effects on the electronic and optical properties of c-plane GaN/AlGaN quantum wells
Authors: Roble A. A. , Patra S. K. , Massabuau F. , Frentrup M. , Leontiadou M. A. , Dawson P. , Kappers M. J. , Oliver R. A. , Graham D. M. , Schulz S.
Published: December 2019

We report on a combined theoretical and experimental study of the impact of alloy fluctuations and Coulomb effects on the electronic and optical properties of $$c$$c-plane GaN/AlGaN multi-quantum well systems. The presence of carrier localization effects in this system was demonstrated by experimental observations, such as the “S-shape” temperature dependence of the photoluminescence (PL) peak energy, and non-exponential PL decay curves that varied across the PL spectra at 10 K. A three-dimensional modified continuum model, coupled with a self-consistent Hartree scheme, was employed to gain insight into the electronic and optical properties of the experimentally studied $$c$$c-plane GaN/AlGaN quantum wells. This model confirmed the existence of strong hole localization arising from the combined effects of the built-in polarization field along the growth direction and the alloy fluctuations at the quantum well/barrier interface. However, for electrons these localization effects are less pronounced in comparison to the holes. Furthermore, our calculations show that the attractive Coulomb interaction between electron and hole results in exciton localization. This behavior is in contrast to the picture of independently localized electrons and holes, often used to explain the radiative recombination process in $$c$$c-plane InGaN/GaN quantum well systems.
miR-200 affects tamoxifen resistance in breast cancer cells through regulation of MYB
Authors: Gao Yu , Zhang Wenzhi , Liu Chengwen , Li Guanghua
Published: December 2019

Resistance to tamoxifen is a major clinical challenge. Research in recent years has identified epigenetic changes as mediated by dysregulated miRNAs that can possibly play a role in resistance to tamoxifen in breast cancer patients expressing estrogen receptor (ER). We report here elevated levels of EMT markers (vimentin and ZEB1/2) and reduced levels of EMT-regulating miR-200 (miR-200b and miR-200c) in ER-positive breast cancer cells, MCF-7, that were resistant to tamoxifen, in contrast with the naïve parental MCF-7 cells that were sensitive to tamoxifen. Further, we established regulation of c-MYB by miR-200 in our experimental model. C-MYB was up-regulated in tamoxifen resistant cells and its silencing significantly decreased resistance to tamoxifen and the EMT markers. Forced over-expression of miR-200b/c reduced c-MYB whereas reduced expression of miR-200b/c resulted in increased c-MYB We further confirmed the results in other ER-positive breast cancer cells T47D cells where forced over-expression of c-MYB resulted in induction of EMT and significantly increased resistance to tamoxifen. Thus, we identify a novel mechanism of tamoxifen resistance in breast tumor microenvironment that involves miR-200-MYB signaling.
CAIX-targeting radiotracers for hypoxia imaging in head and neck cancer models
Authors: Huizing Fokko J. , Garousi Javad , Lok Jasper , Franssen Gerben , Hoeben Bianca A. W. , Frejd Fredrik Y. , Boerman Otto C. , Bussink Johan , Tolmachev Vladimir , Heskamp Sandra
Published: December 2019

Hypoxia-induced carbonic anhydrase IX (CAIX) expression is a prognostic marker in solid tumors. In recent years many radiotracers have been developed, but a fair comparison of these compounds is not possible because of the diversity in tumor models and other experimental parameters. In this study we performed a direct in vivo comparison of three promising CAIX targeting radiotracers in xenografted head and neck cancer models. The biodistribution of [111In]In-DOTA-ZCAIX:2 was directly compared with [111In]In-DTPA-G250-F(ab′)2 and [111In] In-DTPA-G250 in female BALB/C nu/nu mice bearing two HNSCC xenografts with different levels of CAIX expression. In vivo biodistribution was quantified by means of microSPECT/CT scans and ex vivo biodistribution was determined with the use of a γ-counter. Tumors were snap frozen and sections were stained for CAIX expression, vessels, hypoxia (pimonidazole) and tumor blood perfusion. Tracer uptake was significantly higher in SSCNij153 tumors compared to SCCNij185 tumors for [111In]In-DOTA-HE3-ZCAIX:2: 0.32 ± 0.03 versus 0.18 ± 0.01%ID/g,(p = 0.003) 4 h p.i., for [111In]In-DTPA-girentuximab-F(ab′)2: 3.0 ± 0.5%ID/g and 1.2 ± 0.1%ID/g (p = 0.03), 24 h p.i. and for [111In]In-DTPA-girentuximab: 30 ± 2.1%ID/g and 7.0 ± 1.0%ID/g (p = 0.0002) 72 h p.i. SPECT imaging with both [111In]In-DTPA-girentuximab-F(ab′)2 and [111In]In-DTPA-girentuximab showed a clear difference in tracer distribution between the two tumor models. The whole IgG, i.e. [111In]In-DTPA-girentuximab, showed the highest tumor-to-muscle ratio. We showed that different CAIX-targeting radiotracers can discriminate a low CAIX-expressing tumor from a high CAIX-expressing head and neck cancer xenografts model. In these hypoxic head and neck xenograft models [111In]In-DTPA-girentuximab showed the most promising results.
A highly-selective chloride microelectrode based on a mercuracarborand anion carrier
Authors: DiFranco Marino , Quinonez Marbella , Dziedzic Rafal M. , Spokoyny Alexander M. , Cannon Stephen C.
Published: December 2019

The chloride gradient plays an important role in regulating cell volume, membrane potential, pH, secretion, and the reversal potential of inhibitory glycine and GABAA receptors. Measurement of intracellular chloride activity, $${{\boldsymbol{a}}}_{{\boldsymbol{Cl}}}^{{\boldsymbol{i}}}$$aCli, using liquid membrane ion-selective microelectrodes (ISM), however, has been limited by the physiochemical properties of Cl− ionophores which have caused poor stability, drift, sluggish response times, and interference from other biologically relevant anions. Most importantly, intracellular $${\bf{HC}}{{\bf{O}}}_{{\bf{3}}}^{-}$$HCO3− may be up to 4 times more abundant than Cl− (e.g. skeletal muscle) which places severe constraints on the required selectivity of a Cl− – sensing ISM. Previously, a sensitive and highly-selective Cl− sensor was developed in a polymeric membrane electrode using a trinuclear Hg(II) complex containing carborane-based ligands, [9]-mercuracarborand-3, or MC3 for short. Here, we have adapted the use of the MC3 anion carrier in a liquid membrane ion-selective microelectrode and show the MC3-ISM has a linear Nernstian response over a wide range of aCl (0.1 mM to 100 mM), is highly selective for Cl− over other biological anions or inhibitors of Cl− transport, and has a 10% to 90% settling  time of 3  sec. Importantly, over the physiological range of aCl (1 mM to 100 mM) the potentiometric response of the MC3-ISM is insensitive to $${\bf{HC}}{{\bf{O}}}_{{\bf{3}}}^{-}$$HCO3− or changes in pH. Finally, we demonstrate the biological application of an MC3-ISM by measuring intracellular aCl, and the response to an external Cl-free challenge, for an isolated skeletal muscle fiber.
Longitudinal structural connectomic and rich-club analysis in adolescent mTBI reveals persistent, distributed brain alterations acutely through to one year post-injury
Authors: Chung Ai Wern , Mannix Rebekah , Feldman Henry A. , Grant P. Ellen , Im Kiho
Published: December 2019

The diffuse nature of mild traumatic brain injury (mTBI) impacts brain white-matter pathways with potentially long-term consequences, even after initial symptoms have resolved. To understand post-mTBI recovery in adolescents, longitudinal studies are needed to determine the interplay between highly individualised recovery trajectories and ongoing development. To capture the distributed nature of mTBI and recovery, we employ connectomes to probe the brain’s structural organisation. We present a diffusion MRI study on adolescent mTBI subjects scanned one day, two weeks and one year after injury with controls. Longitudinal global network changes over time suggests an altered and more ‘diffuse’ network topology post-injury (specifically lower transitivity and global efficiency). Stratifying the connectome by its back-bone, known as the ‘rich-club’, these network changes were driven by the ‘peripheral’ local subnetwork by way of increased network density, fractional anisotropy and decreased diffusivities. This increased structural integrity of the local subnetwork may be to compensate for an injured network, or it may be robust to mTBI and is exhibiting a normal developmental trend. The rich-club also revealed lower diffusivities over time with controls, potentially indicative of longer-term structural ramifications. Our results show evolving, diffuse alterations in adolescent mTBI connectomes beginning acutely and continuing to one year.
Alteration autonomic control of cardiac function during hemodialysis predict cardiovascular outcomes in end stage renal disease patients
Authors: Kao Chih-Chin , Tseng Chi-Ho , Lo Men-Tzung , Lin Ying-Kuang , Hsu Chien-Yi , Wu Yueh-Lin , Chen Hsi-Hsien , Lin Feng-Yen , Lin Chen , Huang Chun-Yao
Published: December 2019

Dialysis-induced hemodynamic instability has been associated with increased risk of cardiovascular (CV) mortality. However, the control mechanisms beneath the dynamic BP changes and cardiac function during hemodialysis and subsequent CV events are not known. We hypothesize that the impaired hemodynamic control can be prognostic indicators for subsequent CV events in end stage renal diseaes (ESRD) patients. To explore the association of hemodynamic parameters and CV events in hemodialysis patients, we enrolled ESRD patients who received chronic hemodialysis without documented atherosclerotic cardiovascular disease and hemodynamic parameters were continuously obtained from the impedance cardiography during hemodialysis. A total of 35 patients were enrolled. 16 patients developed hospitalized CV events. The statistical properties [coefficient of variance (standard deviation / mean value; CoV)] of hourly beat-to-beat dynamics of hemodynamic parameters were calculated. The CoV of stroke volume (SV) and cardiac index (CI) between the 1st and 2nd hour of dialysis were significantly increased in patients without CV events compared to those with CV events. Higher CoV of SVdiff and CIdiff were significantly correlated with longer CV event-free survival, and the area under the receiver operating characteristic (ROC) curve showed fair overall discriminative power (0.783 and 0.796, respectively). The responses of hemodynamic control mechanisms can be independent predictive indexes for lower hospitalized CV events, which implies that these patients who have better autonomic control systems may have better CV outcomes.
Short-interval wildfire and drought overwhelm boreal forest resilience
Authors: Whitman Ellen , Parisien Marc-André , Thompson Dan K. , Flannigan Mike D.
Published: December 2019

The size and frequency of large wildfires in western North America have increased in recent years, a trend climate change is likely to exacerbate. Due to fuel limitations, recently burned forests resist burning for upwards of 30 years; however, extreme fire-conducive weather enables reburning at shorter fire-free intervals than expected. This research quantifies the outcomes of short-interval reburns in upland and wetland environments of northwestern Canadian boreal forests and identifies an interactive effect of post-fire drought. Despite adaptations to wildfire amongst boreal plants, post-fire forests at paired short- and long-interval sites were significantly different, with short-interval sites having lower stem densities of trees due to reduced conifer recruitment, a higher proportion of broadleaf trees, less residual organic material, and reduced herbaceous vegetation cover. Drought reinforced changes in proportions of tree species and decreases in tree recruitment, reinforcing non-resilient responses to short-interval reburning. Drier and warmer weather will increase the incidence of short-interval reburning and amplify the ecological changes such events cause, as wildfire activity and post-fire drought increase synergistically. These interacting disturbances will accelerate climate-driven changes in boreal forest structure and composition. Our findings identify processes of ongoing and future change in a climate-sensitive biome.
3D Bioprinted GelMA Based Models for the Study of Trophoblast Cell Invasion
Authors: Ding Houzhu , Illsley Nicholas P. , Chang Robert C.
Published: December 2019

Bioprinting is an emerging and promising technique for fabricating 3D cell-laden constructs for various biomedical applications. In this paper, we employed 3D bioprinted GelMA-based models to investigate the trophoblast cell invasion phenomenon, enabling studies of key placental functions. Initially, a set of optimized material and process parameters including GelMA concentration, UV crosslinking time and printing configuration were identified by systematic, parametric study. Following this, a multiple-ring model (2D multi-ring model) was tested with the HTR-8/SVneo trophoblast cell line to measure cell movement under the influence of EGF (chemoattractant) gradients. In the multi-ring model, the cell front used as a cell invasion indicator moves at a rate of 85 ± 33 µm/day with an EGF gradient of 16 µM. However, the rate was dramatically reduced to 13 ± 5 µm/day, when the multi-ring model was covered with a GelMA layer to constrain cells within the 3D environment (3D multi-ring model). Due to the geometric and the functional limitations of multi-ring model, a multi-strip model (2D multi-strip model) was developed to investigate cell movement in the presence and absence of the EGF chemoattractant. The results show that in the absence of an overlying cell-free layer of GelMA, movement of the cell front shows no significant differences between control and EGF-stimulated rates, due to the combination of migration and proliferation at high cell density (6 × 106 cells/ml) near the GelMA surface. When the model was covered by a layer of GelMA (3D multi-strip model) and migration was excluded, EGF-stimulated cells showed an invasion rate of 21 ± 3 µm/day compared to the rate for unstimulated cells, of 5 ± 4 µm/day. The novel features described in this report advance the use of the 3D bioprinted placental model as a practical tool for not only measurement of trophoblast invasion but also the interaction of invading cells with other tissue elements.
Quantitative phase contrast imaging of a shock-wave with a laser-plasma based X-ray source
Authors: Barbato F. , Atzeni S. , Batani D. , Bleiner D. , Boutoux G. , Brabetz C. , Bradford P. , Mancelli D. , Neumayer P. , Schiavi A. , Trela J. , Volpe L. , Zeraouli G. , Woolsey N. , Antonelli L.
Published: December 2019

X-ray phase contrast imaging (XPCI) is more sensitive to density variations than X-ray absorption radiography, which is a crucial advantage when imaging weakly-absorbing, low-Z materials, or steep density gradients in matter under extreme conditions. Here, we describe the application of a polychromatic X-ray laser-plasma source (duration ~0.5 ps, photon energy >1 keV) to the study of a laser-driven shock travelling in plastic material. The XPCI technique allows for a clear identification of the shock front as well as of small-scale features present during the interaction. Quantitative analysis of the compressed object is achieved using a density map reconstructed from the experimental data.
Reactive ion etching for fabrication of biofunctional titanium nanostructures
Authors: Ganjian Mahya , Modaresifar Khashayar , Zhang Hongzhi , Hagedoorn Peter-Leon , Fratila-Apachitei Lidy E. , Zadpoor Amir A.
Published: December 2019

One of the major problems with the bone implant surfaces after surgery is the competition of host and bacterial cells to adhere to the implant surfaces. To keep the implants safe against implant-associated infections, the implant surface may be decorated with bactericidal nanostructures. Therefore, fabrication of nanostructures on biomaterials is of growing interest. Here, we systematically studied the effects of different processing parameters of inductively coupled plasma reactive ion etching (ICP RIE) on the Ti nanostructures. The resultant Ti surfaces were characterized by using scanning electron microscopy and contact angle measurements. The specimens etched using different chamber pressures were chosen for measurement of the mechanical properties using nanoindentation. The etched surfaces revealed various morphologies, from flat porous structures to relatively rough surfaces consisting of nanopillars with diameters between 26.4 ± 7.0 nm and 76.0 ± 24.4 nm and lengths between 0.5 ± 0.1 μm and 5.2 ± 0.3 μm. The wettability of the surfaces widely varied in the entire range of hydrophilicity. The structures obtained at higher chamber pressure showed enhanced mechanical properties. The bactericidal behavior of selected surfaces was assessed againstStaphylococcus aureusandEscherichia colibacteria while their cytocompatibility was evaluated with murine preosteoblasts. The findings indicated the potential of such ICP RIE Ti structures to incorporate both bactericidal and osteogenic activity, and pointed out that optimization of the process conditions is essential to maximize these biofunctionalities.
Distinguishing extant elephants ivory from mammoth ivory using a short sequence of cytochrome b gene
Authors: Ngatia Jacob Njaramba , Lan Tian Ming , Ma Yue , Dinh Thi Dao , Wang Zhen , Dahmer Thomas D. , Chun Xu Yan
Published: December 2019

Trade in ivory from extant elephant species namely Asian elephant (Elephas maximus), African savanna elephant (Loxodonta africana) and African forest elephant (Loxodonta cyclotis) is regulated internationally, while the trade in ivory from extinct species of Elephantidae, including woolly mammoth, is unregulated. This distinction creates opportunity for laundering and trading elephant ivory as mammoth ivory. The existing morphological and molecular genetics methods do not reliably distinguish the source of ivory items that lack clear identification characteristics or for which the quality of extracted DNA cannot support amplification of large gene fragments. We present a PCR-sequencing method based on 116 bp target sequence of the cytochrome b gene to specifically amplify elephantid DNA while simultaneously excluding non-elephantid species and ivory substitutes, and while avoiding contamination by human DNA. The partial Cytochrome b gene sequence enabled accurate association of ivory samples with their species of origin for all three extant elephants and from mammoth. The detection limit of the PCR system was as low as 10 copy numbers of target DNA. The amplification and sequencing success reached 96.7% for woolly mammoth ivory and 100% for African savanna elephant and African forest elephant ivory. This is the first validated method for distinguishing elephant from mammoth ivory and it provides forensic support for investigation of ivory laundering cases.
Biophysics of high density nanometer regions extracted from super-resolution single particle trajectories: application to voltage-gated calcium channels and phospholipids
Authors: Parutto P. , Heck J. , Heine M. , Holcman D.
Published: December 2019

The cellular membrane is very heterogenous and enriched with high-density regions forming microdomains, as revealed by single particle tracking experiments. However the organization of these regions remain unexplained. We determine here the biophysical properties of these regions, when described as a basin of attraction. We develop two methods to recover the dynamics and local potential wells (field of force and boundary). The first method is based on the local density of points distribution of trajectories, which differs inside and outside the wells. The second method focuses on recovering the drift field that is convergent inside wells and uses the transient field to determine the boundary. Finally, we apply these two methods to the distribution of trajectories recorded from voltage gated calcium channels and phospholipid anchored GFP in the cell membrane of hippocampal neurons and obtain the size and energy of high-density regions with a nanometer precision.
Ferromagnetic excess moments and apparent exchange bias in FeF2 single crystals
Authors: Joshi D. C. , Nordblad P. , Mathieu R.
Published: December 2019

The anisotropic antiferromagnet FeF2 has been extensively used as an antiferromagnetic layer to induce exchange bias effects in ferromagnetic/antiferromagnetic bilayers and heterostructures. In this work, an apparent exchange bias occurring in the low temperature hysteresis loops of FeF2 single crystals is investigated. A detailed investigation of the hysteresis and remnant magnetization indicates that the observation of an apparent exchange bias in FeF2 stems from an intrinsic excess moment associated with a distortion of the antiferromagnetic structure of piezomagnetic origin.
The emission of γ-Ray beams with orbital angular momentum in laser-driven micro-channel plasma target
Authors: Feng B. , Qin C. Y. , Geng X. S. , Yu Q. , Wang W. Q. , Wu Y. T. , Yan X. , Ji L. L. , Shen B. F.
Published: December 2019

We investigated the emission of multi-MeV γ-Ray beams with orbital angular momentum (OAM) from the interaction of an intense circularly polarized (CP) laser with a micro-channel plasma target. The driving laser can generate high energy electrons via direct laser acceleration within the channel. By attaching a plasma foil as the reflecting mirror, the CP laser is reflected and automatically colliding with the electrons. High energy gamma-photons are emitted through inverse Compton scattering (ICS) during collision. Three-dimensional particle-in-cell simulations reveal that the spin angular momentum (SAM) of the CP laser can be transferred to the OAM of accelerated electrons and further to the emitted gamma-ray beam. These results may guide future experiments in laser-driven gamma-ray sources using micro-structures.
Unraveling Complexity about Childhood Obesity and Nutritional Interventions: Modeling Interactions Among Psychological Factors
Authors: Feldman Keith , Solymos Gisela M. B. , de Albuquerque Maria Paula , Chawla Nitesh V.
Published: December 2019

As the global prevalence of childhood obesity continues to rise, researchers and clinicians have sought to develop more effective and personalized intervention techniques. In doing so, obesity interventions have expanded beyond the traditional context of nutrition to address several facets of a child’s life, including their psychological state. While the consideration of psychological features has significantly advanced the view of obesity as a holistic condition, attempts to associate such features with outcomes of treatment have been inconclusive. We posit that such uncertainty may arise from the univariate manner in which features are evaluated, focusing on a particular aspect such as loneliness or insecurity, but failing to account for the impact of co-occurring psychological characteristics. Moreover, co-occurrence of psychological characteristics (both child and parent/guardian) have not been studied from the perspective of their relationship with nutritional intervention outcomes. To that end, this work looks to broaden the prevailing view: laying the foundation for the existence of complex interactions among psychological features. In collaboration with a non-profit nutritional clinic in Brazil, this paper demonstrates and models these interactions and their associations with the outcomes of a nutritional intervention.
Development of an in silico prediction system of human renal excretion and clearance from chemical structure information incorporating fraction unbound in plasma as a descriptor
Authors: Watanabe Reiko , Ohashi Rikiya , Esaki Tsuyoshi , Kawashima Hitoshi , Natsume-Kitatani Yayoi , Nagao Chioko , Mizuguchi Kenji
Published: December 2019

Prediction of pharmacokinetic profiles of new chemical entities is essential in drug development to minimize the risks of potential withdrawals. The excretion of unchanged compounds by the kidney constitutes a major route in drug elimination and plays an important role in pharmacokinetics. Herein, we created in silico prediction models of the fraction of drug excreted unchanged in the urine (fe) and renal clearance (CLr), with datasets of 411 and 401 compounds using freely available software; notably, all models require chemical structure information alone. The binary classification model for fe demonstrated a balanced accuracy of 0.74. The two-step prediction system for CLr was generated using a combination of the classification model to predict excretion-type compounds and regression models to predict the CLr value for each excretion type. The accuracies of the regression models increased upon adding a descriptor, which was the observed and predicted fraction unbound in plasma (fu,p); 78.6% of the samples in the higher range of renal clearance fell within 2-fold error with predicted fu,p value. Our prediction system for renal excretion is freely available to the public and can be used as a practical tool for prioritization and optimization of compound synthesis in the early stage of drug discovery.
5D Flow Tensor MRI to Efficiently Map Reynolds Stresses of Aortic Blood Flow In-Vivo
Authors: Walheim Jonas , Dillinger Hannes , Gotschy Alexander , Kozerke Sebastian
Published: December 2019

Diseased heart valves perturb normal blood flow with a range of hemodynamic and pathologic consequences. In order to better stratify patients with heart valve disease, a comprehensive characterization of blood flow including turbulent contributions is desired. In this work we present a framework to efficiently quantify velocities and Reynolds stresses in the aorta in-vivo. Using a highly undersampled 5D Flow MRI acquisition scheme with locally low-rank image reconstruction, multipoint flow tensor encoding in short and predictable scan times becomes feasible (here, 10 minutes), enabling incorporation of the protocol into clinical workflows. Based on computer simulations, a 19-point 5D Flow Tensor MRI encoding approach is proposed. It is demonstrated that, for in-vivo resolution and signal-to-noise ratios, sufficient accuracy and precision of velocity and turbulent shear stress quantification is achievable. In-vivo proof of concept is demonstrated on patients with a bio-prosthetic heart valve and healthy controls. Results demonstrate that aortic turbulent shear stresses and turbulent kinetic energy are elevated in the patients compared to the healthy subjects. Based on these data, it is concluded that 5D Flow Tensor MRI holds promise to provide comprehensive flow assessment in patients with heart valve diseases.
Crowdsourcing and the feasibility of manual gene annotation: A pilot study in the nematode Pristionchus pacificus
Authors: Rödelsperger Christian , Athanasouli Marina , Lenuzzi Maša , Theska Tobias , Sun Shuai , Dardiry Mohannad , Wighard Sara , Hu Wen , Sharma Devansh Raj , Han Ziduan
Published: December 2019

Nematodes such asCaenorhabditis elegansare powerful systems to study basically all aspects of biology. Their species richness together with tremendous genetic knowledge fromC. elegansfacilitate the evolutionary study of biological functions using reverse genetics. However, the ability to identify orthologs of candidate genes in other species can be hampered by erroneous gene annotations. To improve gene annotation in the nematode model organismPristionchus pacificus, we performed a genome-wide screen forC. elegansgenes with potentially incorrectly annotatedP. pacificusorthologs. We initiated a community-based project to manually inspect more than two thousand candidate loci and to propose new gene models based on recently generated Iso-seq and RNA-seq data. In most cases, misannotation ofC. elegansorthologs was due to artificially fused gene predictions and completely missing gene models. The community-based curation raised the gene count from 25,517 to 28,036 and increased the single copy ortholog completeness level from 86% to 97%. This pilot study demonstrates how even small-scale crowdsourcing can drastically improve gene annotations. In future, similar approaches can be used for other species, gene sets, and even larger communities thus making manual annotation of large parts of the genome feasible.
Inactivation of Interferon Regulatory Factor 1 Causes Susceptibility to Colitis-Associated Colorectal Cancer
Authors: Jeyakumar Thiviya , Fodil Nassima , Van Der Kraak Lauren , Meunier Charles , Cayrol Romain , McGregor Kevin , Langlais David , Greenwood Celia M. T. , Beauchemin Nicole , Gros Philippe
Published: December 2019

The mechanisms linking chronic inflammation of the gut (IBD) and increased colorectal cancer susceptibility are poorly understood. IBD risk is influenced by genetic factors, including the IBD5 locus (human 5q31), that harbors the IRF1 gene. A cause-to-effect relationship between chronic inflammation and colorectal cancer, and a possible role of IRF1 were studied in Irf1-/- mice in a model of colitis-associated colorectal cancer (CA-CRC) induced by azoxymethane and dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation and enhanced enterocyte proliferation in Irf1−/− mutants, prior to appearance of tumors. Considerable infiltration of leukocytes is seen in Irf1−/− colons at this early stage, and is composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells and other granulocytes, as well as CD4+ lymphoid cells. Differential susceptibility to CA-CRC of Irf1−/− vs. B6 controls is fully transferable through hematopoietic cells as observed in bone marrow chimera studies. Transcript signatures seen in Irf1−/− mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with colorectal cancer. In addition, IRF1 expression in the colon is significantly decreased in late stage colorectal cancer (stages 3, 4) and is associated with poorer prognosis. This suggests that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ during chronic inflammation, possibly via the creation of a tumor-promoting environment.
Polymorphism in the LASP1 gene promoter region alters cognitive functions of patients with schizophrenia
Authors: Lin Chieh-Hsin , Yang Sheng , Huang Yu-Jhen , Lane Hsien-Yuan
Published: December 2019

Schizophrenia’s pathogenesis remains elusive. Cognitive dysfunction is the endophenotype and outcome predictor of schizophrenia. The LIM and SH3 domain protein (LASP1) protein, a component of CNS synapses and dendritic spines, has been related to the N-methyl-D-aspartate receptor (NMDAR) dysfunction hypothesis and schizophrenia. A single-nucleotide polymorphism (rs979607) in the LASP1 gene promoter region has been also implicated in schizophrenia susceptibility. The aim of this study was to investigate the role of the LASP1 rs979607 polymorphism in the cognitive functions of patients with schizophrenia. Two hundred and ninety-one Han Taiwanese patients with schizophrenia were recruited. Ten cognitive tests and two clinical rating scales were assessed. The scores of cognitive tests were standardized to T-scores. The genotyping of the LASP1 rs979607 polymorphism was performed using TaqMan assay. Among the 291 patients, 85 were C/C homozygotes of rs979607, 141 C/T heterozygotes, and 65 T/T homozygotes, which fitted the Hardy-Weinberg equilibrium. After adjusting age, gender, and education with general linear model, the C/C homozygotes performed better than C/T heterozygotes in overall composite score (p = 0.023), Category Fluency test (representing processing speed and semantic memory) (p = 0.045), and Wechsler Memory Scale (WMS)-III backward Spatial Span test (p = 0.025), albeit without correction for multiple comparisons for the latter two individual tests. To the best of our knowledge, this is the first study suggesting that the genetic variation of LASP1 may be associated with global cognitive function, category verbal fluency, and spatial working memory of patients with schizophrenia. The finding also lends support to the NMDAR dysfunction hypothesis of schizophrenia. More studies with longitudinal designs are warranted.
NMDA attenuates the neurovascular response to hypercapnia in the neonatal cerebral cortex
Authors: Remzső Gábor , Németh János , Tóth-Szűki Valéria , Varga Viktória , Kovács Viktória , Domoki Ferenc
Published: December 2019

Cortical spreading depolarization (SD) involves activation of NMDA receptors and elicit neurovascular unit dysfunction. NMDA cannot trigger SD in newborns, thus its effect on neurovascular function is not confounded by other aspects of SD. The present study investigated if NMDA affected hypercapnia-induced microvascular and electrophysiological responses in the cerebral cortex of newborn pigs. Anesthetized piglets were fitted with cranial windows over the parietal cortex to study hemodynamic and electrophysiological responses to graded hypercapnia before/after topically applied NMDA assessed with laser-speckle contrast imaging and recording of local field potentials (LFP)/neuronal firing, respectively. NMDA increased cortical blood flow (CoBF), suppressed LFP power in most frequency bands but evoked a 2.5 Hz δ oscillation. The CoBF response to hypercapnia was abolished after NMDA and the hypercapnia-induced biphasic changes in δ and θ LFP power were also altered. MK-801 prevented NMDA-induced increases in CoBF and the attenuation of microvascular reactivity to hypercapnia. The neuronal nitric oxide synthase (nNOS) inhibitor (N-(4 S)-4-amino-5-[aminoethyl]aminopentyl-N′-nitroguanidin) also significantly preserved the CoBF response to hypercapnia after NMDA, although it didn’t reduce NMDA-induced increases in CoBF. In conclusion, excess activation of NMDA receptors alone can elicit SD-like neurovascular unit dysfunction involving nNOS activity.
Author Correction: Hyaluronic acid-CD44 interactions promote BMP4/7-dependent Id1/3 expression in melanoma cells
Authors: Wu Ruo-Lin , Sedlmeier Georg , Kyjacova Lenka , Schmaus Anja , Philipp Julia , Thiele Wilko , Garvalov Boyan K. , Sleeman Jonathan P.
Published: December 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: An upper bound for the background rate of human extinction
Authors: Snyder-Beattie Andrew E. , Ord Toby , Bonsall Michael B.
Published: December 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Open source automated insulin delivery: addressing the challenge
Authors: Oliver Nick , Reddy Monika , Marriott Claire , Walker Tomas , Heinemann Lutz
Published: December 2019

Do-it-yourself automated insulin delivery systems for people living with type 1 diabetes use commercially available continuous glucose sensors and insulin pumps linked by unregulated open source software. Uptake of these systems is increasing, with growing evidence suggesting that positive glucose outcomes may be feasible. Increasing interest from people living with, or affected by, type 1 diabetes presents challenges to healthcare professionals, device manufacturers and regulators as the legal, governance and risk frameworks for such devices are not defined. We discuss the data, education, policy, technology and medicolegal obstacles to wider implementation of DIY systems and outline the next steps required for a co-ordinated approach to reducing variation in access to a technology that has potential to enable glucose self-management closer to target.
T cell fate following Salmonella infection is determined by a STING-IRF1 signaling axis in mice
Authors: Park Sung-Moo , Omatsu Tatsushi , Zhao Yun , Yoshida Naohiro , Shah Pankaj , Zagani Rachid , Reinecker Hans-Christian
Published: December 2019

The innate immune response following infection with entero-invasive bacterial species is triggered upon release of cyclic di-guanylate monophosphate (c-di-GMP) into the host cell cytosol. Bacterial c-di-GMP activates the intracellular Sensor Stimulator of Interferon Genes (STING), encoded by Tmem173 in mice. Here we identify Interferon Regulatory Factor (IRF) 1 as a critical effector of STING-mediated microbial DNA sensing that is responsible for TH17 cell generation in the mucosal immune system. We find that STING activation induces IRF1-dependent transcriptional programs in dendritic cells (DCs) that define T cell fate determination, including induction of Gasdermin D, IL-1 family member cytokines, and enzymes for eicosanoid synthesis. Our results show that IRF1-dependent transcriptional programs in DCs are a prerequisite for antigen-specific TH17 subspecification in response to microbial c-di-GMP and Salmonella typhimurium infection. Our identification of a STING-IRF1 signaling axis for adaptive host defense control will aid further understanding of infectious disease mechanisms.
Morpho-molecular ex vivo detection and grading of non-muscle-invasive bladder cancer using forward imaging probe based multimodal optical coherence tomography and Raman spectroscopy
Authors: Placzek Fabian , Cordero Bautista Eliana , Kretschmer Simon , Wurster Lara M. , Knorr Florian , González-Cerdas Gerardo , Erkkilä Mikael T. , Stein Patrick , Ataman Çağlar , Hermann Gregers G. , Mogensen Karin , Hasselager Thomas , Andersen Peter E. , Zappe Hans , Popp Jürgen , Drexler Wolfgang , Leitgeb Rainer A. , Schie Iwan W.
Published: December 2019

Characterization of bladder biopsies, using a combined fiber optic probe-based optical coherence tomography and Raman spectroscopy imaging system that allows a large field-of-view imaging and detection and grading of cancerous bladder lesions.
Correction: Development of an ISFET-based enzyme assay for p-diphenol oxidase from locally isolated fungus Schizophyllum commune MF-O5
Authors: Faheem Muhammad , Khalid Zafar Mahmood , Shabbir Muhammad Imran , Ahmad Bashir , Jogezai Naqeeb Ullah , Shaukat Uzma , Ahmad Bilal , Ghani Abdul , Ullah Hanif , Shah Muhammad Musaddiq , Shah Waseem , Riaz Muhammad , Iqbal Anwar , Basheir Muhammad Mudassir , Mehmood Rashid , Imran Bokhari Syed Ali
Published: December 2019

Correction for ‘Development of an ISFET-based enzyme assay for p-diphenol oxidase from locally isolated fungus Schizophyllum commune MF-O5’ by Muhammad Faheem et al., Anal. Methods, 2019, 11, 5893–5900.
Angiopep-2 conjugated nanoparticles loaded with doxorubicin for the treatment of primary central nervous system lymphoma
Authors: Shi Xiao-Xiao , Miao Wei-Min , Pang Di-Wen , Wu Jia-Si , Tong Qi-Song , Li Jia-Xian , Luo Jia-Qi , Li Wen-Yu , Du Jin-Zhi , Wang Jun
Published: December 2019

APP nanoparticle was developed to deliver DOX for the treatment of PCNSL. The results indicated that APP@DOX could overcome the BBB, and significantly prolong the survival time of mice with an intracranial SU-DHL-2 lymphoma xenograft.
Exfoliation of bimetallic (Ni, Co) carbonate hydroxide nanowires by Ar plasma for enhanced oxygen evolution
Authors: Sun Hongmei , Miao Yuanling , Wu Tao , Wang Qi
Published: December 2019

Ar plasma exfoliated smooth 1D nanowires of NiCo-LDHs into thin nanosheets forming three-dimensional dendritic structure to expose electrochemical active surface area and more higher oxidation states for enhanced oxygen evolution reaction.
Atomic cobalt catalysts for the oxygen evolution reaction
Authors: Zhang Qiaoqiao , Duan Zhiyao , Li Min , Guan Jingqi
Published: December 2019

Atomically dispersed Co/N-codoped graphene electrocatalysts require an ultra-low onset overpotential of approximately 210 mV on a glassy carbon electrode in both 1.0 M KOH and 0.1 M KOH solutions.