bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models
Authors: Kim Hyoung , Xu Haineng , George Erin , Hallberg Dorothy , Kumar Sushil , Jagannathan Veena , Medvedev Sergey , Kinose Yasuto , Devins Kyle , Verma Priyanka , Ly Kevin , Wang Yifan , Greenberg Roger A. , Schwartz Lauren , Johnson Neil , Scharpf Robert B. , Mills Gordon B. , Zhang Rugang , Velculescu Victor E. , Brown Eric J. , Simpkins Fiona
Published: July 2020

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum.
Phase-controllable growth of ultrathin 2D magnetic FeTe crystals
Authors: Kang Lixing , Ye Chen , Zhao Xiaoxu , Zhou Xieyu , Hu Junxiong , Li Qiao , Liu Dan , Das Chandreyee Manas , Yang Jiefu , Hu Dianyi , Chen Jieqiong , Cao Xun , Zhang Yong , Xu Manzhang , Di Jun , Tian Dan , Song Pin , Kutty Govindan , Zeng Qingsheng , Fu Qundong , Deng Ya , Zhou Jiadong , Ariando Ariando , Miao Feng , Hong Guo , Huang Yizhong , Pennycook Stephen J. , Yong Ken-Tye , Ji Wei , Renshaw Wang Xiao , Liu Zheng
Published: July 2020

Two-dimensional (2D) magnets with intrinsic ferromagnetic/antiferromagnetic (FM/AFM) ordering are highly desirable for future spintronic devices. However, the direct growth of their crystals is in its infancy. Here we report a chemical vapor deposition approach to controllably grow layered tetragonal and non-layered hexagonal FeTe nanoplates with their thicknesses down to 3.6 and 2.8 nm, respectively. Moreover, transport measurements reveal these obtained FeTe nanoflakes show a thickness-dependent magnetic transition. Antiferromagnetic tetragonal FeTe with the Néel temperature (TN) gradually decreases from 70 to 45 K as the thickness declines from 32 to 5 nm. And ferromagnetic hexagonal FeTe is accompanied by a drop of the Curie temperature (TC) from 220 K (30 nm) to 170 K (4 nm). Theoretical calculations indicate that the ferromagnetic order in hexagonal FeTe is originated from its concomitant lattice distortion and Stoner instability. This study highlights its potential applications in future spintronic devices.
Accounting for diverse evolutionary forces reveals mosaic patterns of selection on human preterm birth loci
Authors: LaBella Abigail L. , Abraham Abin , Pichkar Yakov , Fong Sarah L. , Zhang Ge , Muglia Louis J. , Abbot Patrick , Rokas Antonis , Capra John A.
Published: July 2020

Currently, there is no comprehensive framework to evaluate the evolutionary forces acting on genomic regions associated with human complex traits and contextualize the relationship between evolution and molecular function. Here, we develop an approach to test for signatures of diverse evolutionary forces on trait-associated genomic regions. We apply our method to regions associated with spontaneous preterm birth (sPTB), a complex disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary signatures including conservation, excess population differentiation, accelerated evolution, and balanced polymorphism. Furthermore, we integrate evolutionary context with molecular evidence to hypothesize how these regions contribute to sPTB risk. Finally, we observe enrichment in signatures of diverse evolutionary forces in sPTB-associated regions compared to genomic background. By quantifying multiple evolutionary forces acting on sPTB-associated regions, our approach improves understanding of both functional roles and the mosaic of evolutionary forces acting on loci. Our work provides a blueprint for investigating evolutionary pressures on complex traits.
Duplex DNA engagement and RPA oppositely regulate the DNA-unwinding rate of CMG helicase
Authors: Kose Hazal B. , Xie Sherry , Cameron George , Strycharska Melania S. , Yardimci Hasan
Published: July 2020

A ring-shaped helicase unwinds DNA during chromosome replication in all organisms. Replicative helicases generally unwind duplex DNA an order of magnitude slower compared to their in vivo replication fork rates. However, the origin of slow DNA unwinding rates by replicative helicases and the mechanism by which other replication components increase helicase speed are unclear. Here, we demonstrate that engagement of the eukaryotic CMG helicase with template DNA at the replication fork impairs its helicase activity, which is alleviated by binding of the single-stranded DNA binding protein, RPA, to the excluded DNA strand. Intriguingly, we found that, when stalled due to interaction with the parental duplex, DNA rezipping-induced helicase backtracking reestablishes productive helicase-fork engagement, underscoring the significance of plasticity in helicase action. Our work provides a mechanistic basis for relatively slow duplex unwinding by replicative helicases and explains how replisome components that interact with the excluded DNA strand stimulate fork rates.
In vivo cell biological screening identifies an endocytic capture mechanism for T-tubule formation
Authors: Hall Thomas E. , Martel Nick , Ariotti Nicholas , Xiong Zherui , Lo Harriet P. , Ferguson Charles , Rae James , Lim Ye-Wheen , Parton Robert G.
Published: July 2020

The skeletal muscle T-tubule is a specialized membrane domain essential for coordinated muscle contraction. However, in the absence of genetically tractable systems the mechanisms involved in T-tubule formation are unknown. Here, we use the optically transparent and genetically tractable zebrafish system to probe T-tubule development in vivo. By combining live imaging of transgenic markers with three-dimensional electron microscopy, we derive a four-dimensional quantitative model for T-tubule formation. To elucidate the mechanisms involved in T-tubule formation in vivo, we develop a quantitative screen for proteins that associate with and modulate early T-tubule formation, including an overexpression screen of the entire zebrafish Rab protein family. We propose an endocytic capture model involving firstly, formation of dynamic endocytic tubules at transient nucleation sites on the sarcolemma, secondly, stabilization by myofibrils/sarcoplasmic reticulum and finally, delivery of membrane from the recycling endosome and Golgi complex.
A non-invasive far-red light-induced split-Cre recombinase system for controllable genome engineering in mice
Authors: Wu Jiali , Wang Meiyan , Yang Xueping , Yi Chengwei , Jiang Jian , Yu Yuanhuan , Ye Haifeng
Published: July 2020

The Cre-loxP recombination system is a powerful tool for genetic manipulation. However, there are widely recognized limitations with chemically inducible Cre-loxP systems, and the UV and blue-light induced systems have phototoxicity and minimal capacity for deep tissue penetration. Here, we develop a far-red light-induced split Cre-loxP system (FISC system) based on a bacteriophytochrome optogenetic system and split-Cre recombinase, enabling optogenetical regulation of genome engineering in vivo solely by utilizing a far-red light (FRL). The FISC system exhibits low background and no detectable photocytotoxicity, while offering efficient FRL-induced DNA recombination. Our in vivo studies showcase the strong organ-penetration capacity of FISC system, markedly outperforming two blue-light-based Cre systems for recombination induction in the liver. Demonstrating its strong clinical relevance, we successfully deploy a FISC system using adeno-associated virus (AAV) delivery. Thus, the FISC system expands the optogenetic toolbox for DNA recombination to achieve spatiotemporally controlled, non-invasive genome engineering in living systems.
Highly compressible and anisotropic lamellar ceramic sponges with superior thermal insulation and acoustic absorption performances
Authors: Jia Chao , Li Lei , Liu Ying , Fang Ben , Ding He , Song Jianan , Liu Yibo , Xiang Kejia , Lin Sen , Li Ziwei , Si Wenjie , Li Bo , Sheng Xing , Wang Dongze , Wei Xiaoding , Wu Hui
Published: July 2020

Advanced ceramic sponge materials with temperature-invariant high compressibility are urgently needed as thermal insulators, energy absorbers, catalyst carriers, and high temperature air filters. However, the application of ceramic sponge materials is severely limited due to their complex preparation process. Here, we present a facile method for large-scale fabrication of highly compressible, temperature resistant SiO2-Al2O3 composite ceramic sponges by blow spinning and subsequent calcination. We successfully produce anisotropic lamellar ceramic sponges with numerous stacked microfiber layers and density as low as 10 mg cm−3. The anisotropic lamellar ceramic sponges exhibit high compression fatigue resistance, strain-independent zero Poisson’s ratio, robust fire resistance, temperature-invariant compression resilience from −196 to 1000 °C, and excellent thermal insulation with a thermal conductivity as low as 0.034 W m−1 K−1. In addition, the lamellar structure also endows the ceramic sponges with excellent sound absorption properties, representing a promising alternative to existing thermal insulation and acoustic absorption materials.
Differential expression of tissue-restricted antigens among mTEC is associated with distinct autoreactive T cell fates
Authors: Lebel Marie-Ève , Coutelier Marie , Galipeau Maria , Kleinman Claudia L. , Moon James J. , Melichar Heather J.
Published: July 2020

Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here, we establish bacterial artificial chromosome (BAC)-transgenic mouse lines with biased mTEClo or mTEChi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEClo supports TCRαβ+ CD8αα intraepithelial lymphocyte development; meanwhile, mTEChi-restricted expression preferentially induces Treg differentiation of antigen-specific cells in these models to impact control of infectious agents and tumor growth. In summary, our data suggest that mTEC subsets may have a function in directing distinct mechanisms of T cell tolerance.
Spinal cord injury causes chronic bone marrow failure
Authors: Carpenter Randall S. , Marbourg Jessica M. , Brennan Faith H. , Mifflin Katherine A. , Hall Jodie C. E. , Jiang Roselyn R. , Mo Xiaokui M. , Karunasiri Malith , Burke Matthew H. , Dorrance Adrienne M. , Popovich Phillip G.
Published: July 2020

Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.
Giant magneto-birefringence effect and tuneable colouration of 2D crystal suspensions
Authors: Ding Baofu , Kuang Wenjun , Pan Yikun , Grigorieva I. V. , Geim A. K. , Liu Bilu , Cheng Hui-Ming
Published: July 2020

One of the long-sought-after goals in light manipulation is tuning of transmitted interference colours. Previous approaches toward this goal include material chirality, strain and electric-field controls. Alternatively, colour control by magnetic field offers contactless, non-invasive and energy-free advantages but has remained elusive due to feeble magneto-birefringence in conventional transparent media. Here we demonstrate an anomalously large magneto-birefringence effect in transparent suspensions of magnetic two-dimensional crystals, which arises from a combination of a large Cotton-Mouton coefficient and relatively high magnetic saturation birefringence. The effect is orders of magnitude stronger than those previously demonstrated for transparent materials. The transmitted colours of the suspension can be continuously tuned over two-wavelength cycles by moderate magnetic fields below 0.8 T. The work opens a new avenue to tune transmitted colours, and can be further extended to other systems with artificially engineered magnetic birefringence.
Author Correction: Fossilized solidification fronts in the Bushveld Complex argue for liquid-dominated magmatic systems
Authors: Kruger Willem , Latypov Rais
Published: July 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Climate and atmospheric deposition effects on forest water-use efficiency and nitrogen availability across Britain
Authors: Guerrieri Rossella , Vanguelova Elena , Pitman Rona , Benham Sue , Perks Michael , Morison James I. L. , Mencuccini Maurizio
Published: July 2020

Rising atmospheric CO2 (ca) has been shown to increase forest carbon uptake. Yet, whether the ca-fertilization effect on forests is modulated by changes in sulphur (Sdep) and nitrogen (Ndep) deposition and how Ndep affects ecosystem N availability remains unclear. We explored spatial and temporal (over 30-years) changes in tree-ring δ13C-derived intrinsic water-use efficiency (iWUE), δ18O and δ15N for four species in twelve forests across climate and atmospheric deposition gradients in Britain. The increase in iWUE was not uniform across sites and species-specific underlying physiological mechanisms reflected the interactions between climate and atmospheric drivers (oak and Scots pine), but also an age effect (Sitka spruce). Most species showed no significant trends for tree-ring δ15N, suggesting no changes in N availability. Increase in iWUE was mostly associated with increase in temperature and decrease in moisture conditions across the South–North gradient and over 30-years. However, when excluding Sitka spruce (to account for age or stand development effects), variations in iWUE were significantly associated with changes in ca and Sdep. Our data suggest that overall climate had the prevailing effect on changes in iWUE across the investigated sites. Whereas, detection of Ndep, Sdep and ca signals was partially confounded by structural changes during stand development.
Structural equation modelling analysis determining causal role among methyltransferases, methylation, and apoptosis during human pregnancy and abortion
Authors: Fatima Nishat , Ahmed Syed Habeeb , Chauhan S. S. , Mohammad Owais , Rehman Syed Mohd. Fazlur
Published: July 2020

The human implantation failure during first trimester leads to spontaneous abortions. Spontaneous abortions are consecutive and occur twice or thrice (with or without prior live births) due to factors which are either maternal or fetal. However, it also constitutes of unknown etiology; known as unexplained recurrent spontaneous abortions (URSA). In this study, the medical terminated human normal early pregnancies (NEP) of the first trimester were taken as control samples, the normal decidual sample whose molecular and epigenetic changes were compared with that of decidua of human URSA subjects. Apoptosis-related genes reported in consecutive recurrent pregnancy loss became the basis for this study. So, in this study, we evaluated the hypothesis that “p53 methylation level through methyltransferases (G9aMT and DNMT1) implicates the fate of embryo towards sustenance or cessation of pregnancy”. Further, the interaction between P53, BAX, BCL-2, CASPASE-6, G9aMT, DNMT-1, and methylated p53 expression level(s) during the first trimester of both URSA and NEP are included in this study. The degree of p53 methylation during the first trimester is found to be significant and positively correlated with that of G9aMT (p < 0.05), BCL-2 (p < 0.001), and DNMT1 (p < 0.001) at both transcript and protein level. A significant and negative correlation (with p-value < 0.001) between the degree of p53 methylation during the first trimester and that of the expression level of TUNEL assay (Apoptosis), P53, BAX, and CASPASE-6 are also observed in the present study. A positive correlation between apoptosis and a higher level of p53 expression (which is possibly due to low degree of p53 methylation) is observed both at the transcript and protein level in URSA which is in line with our findings. The analysis performed using structural equation modelling (SEM) further throws light on the causal relationship between sustenance of pregnancy or URSA during the first trimester of a human pregnancy and degree of methylation of p53 which is closely correlated with the interaction between G9aMT, DNMT1, BCL-2, BAX, P53, CASPASE-6, and apoptosis.
Atypical visual processing in a mouse model of autism
Authors: Cheng Ning , Pagtalunan Eden , Abushaibah Abdulrahman , Naidu Jessica , Stell William K. , Rho Jong M. , Sauvé Yves
Published: July 2020

Human social cognition relies heavily on the processing of various visual cues, such as eye contact and facial expressions. Atypical visual perception and integration have been recognized as key phenotypes in individuals diagnosed with autism spectrum disorder (ASD), and may potentially contribute to impediments in normal social development, a hallmark of ASD. Meanwhile, increasing studies on visual function in ASD have pointed to detail-oriented perception, which has been hypothesized to result from heightened response to information of high spatial frequency. However, mixed results of human studies have led to much debate, and investigations using animal models have been limited. Here, using BTBR mice as a model of idiopathic ASD, we assessed retinal stimulus processing by full-field electroretinogram and found impaired photoreceptor function and retina-based alterations mostly in the cone pathway. Using the optokinetic reflex to evaluate visual function, we observed robustly enhanced visual response to finer spatial details and more subtle contrasts at only higher spatial frequencies in the BTBR mice, under both photopic and scotopic conditions. These behavioral results, which are similar to findings in a subset of ASD patients, indicate a bias toward processing information of high spatial frequencies. Together, these findings also suggest that, while enhancement of visual behaviors under both photopic and scotopic conditions might be due to alterations in visual processing common to both rod and cone pathways, these mechanisms are probably downstream of photoreceptor function.
Estimating the introduction time of highly pathogenic avian influenza into poultry flocks
Authors: Hobbelen Peter H. F. , Elbers Armin R. W. , Werkman Marleen , Koch Guus , Velkers Francisca C. , Stegeman Arjan , Hagenaars Thomas J.
Published: July 2020

The estimation of farm-specific time windows for the introduction of highly-pathogenic avian influenza (HPAI) virus can be used to increase the efficiency of disease control measures such as contact tracing and may help to identify risk factors for virus introduction. The aims of this research are to (1) develop and test an accurate approach for estimating farm-specific virus introduction windows and (2) evaluate this approach by applying it to 11 outbreaks of HPAI (H5N8) on Dutch commercial poultry farms during the years 2014 and 2016. We used a stochastic simulation model with susceptible, infectious and recovered/removed disease stages to generate distributions for the period from virus introduction to detection. The model was parameterized using data from the literature, except for the within-flock transmission rate, which was estimated from disease-induced mortality data using two newly developed methods that describe HPAI outbreaks using either a deterministic model (A) or a stochastic approach (B). Model testing using simulated outbreaks showed that both method A and B performed well. Application to field data showed that method A could be successfully applied to 8 out of 11 HPAI H5N8 outbreaks and is the most generally applicable one, when data on disease-induced mortality is scarce.
Universal model for the skin colouration patterns of neotropical catfishes of the genus Pseudoplatystoma
Authors: Scarabotti Pablo , Govezensky Tzipe , Bolcatto Pablo , Barrio Rafael A.
Published: July 2020

Fish skin colouration has been widely studied because it involves a variety of processes that are important to the broad field of the developmental biology. Mathematical modelling of fish skin patterning first predicted the existence of morphogens and helped to elucidate the mechanisms of pattern formation. The catfishes of the genus Pseudoplatystoma offer a good biological study model, since its species exhibit the most spectacular and amazing variations of colour patterns on the skin. They present labyrinths, closed loops (or cells), alternate spots and stripes, only spots and combinations of these. We have extended a well known mathematical model to study the skin of Pseudoplatystoma. The basic model is a two component, non-linear reaction diffusion system that presents a richness of bifurcations. The extended model assumes that there are two interacting cell/tissue layers in which morphogens diffuse and interact giving rise to the skin colouration pattern. We have found that by varying only two parameters we are able to accurately reproduce the distinct patterns found in all species of Pseudoplatystoma. The histological analysis of skin samples of two species of this genus, with different patterns, revealed differences on the disposition of the colouration cells that are consistent with our theoretical predictions.
Shape facilitates number: brain potentials and microstates reveal the interplay between shape and numerosity in human vision
Authors: Gheorghiu Elena , Dering Benjamin R.
Published: July 2020

Recognition of simple shapes and numerosity estimation for small quantities are often studied independently of each other, but we know that these processes are both rapid and accurate, suggesting that they may be mediated by common neural mechanisms. Here we address this issue by examining how spatial configuration, shape complexity, and luminance polarity of elements affect numerosity estimation. We directly compared the Event Related Potential (ERP) time-course for numerosity estimation under shape and random configurations and found a larger N2 component for shape over lateral-occipital electrodes (250–400 ms), which also increased with higher numbers. We identified a Left Mid Frontal (LMF; 400–650 ms) component over left-lateralised medial frontal sites that specifically separated low and high numbers of elements, irrespective of their spatial configuration. Different luminance-polarities increased N2 amplitude only, suggesting that shape but not numerosity is selective to polarity. Functional microstates confined numerosity to a strict topographic distribution occurring within the LMF time-window, while a microstate responding only to shape-configuration was evidenced earlier, in the N2 time-window. We conclude that shape-coding precedes numerosity estimation, which can be improved when the number of elements and shape vertices are matched. Thus, numerosity estimation around the subitizing range is facilitated by a shape-template matching process.
Covid-19 mortality is negatively associated with test number and government effectiveness
Authors: Liang Li-Lin , Tseng Ching-Hung , Ho Hsiu J. , Wu Chun-Ying
Published: July 2020

A question central to the Covid-19 pandemic is why the Covid-19 mortality rate varies so greatly across countries. This study aims to investigate factors associated with cross-country variation in Covid-19 mortality. Covid-19 mortality rate was calculated as number of deaths per 100 Covid-19 cases. To identify factors associated with Covid-19 mortality rate, linear regressions were applied to a cross-sectional dataset comprising 169 countries. We retrieved data from the Worldometer website, the Worldwide Governance Indicators, World Development Indicators, and Logistics Performance Indicators databases. Covid-19 mortality rate was negatively associated with Covid-19 test number per 100 people (RR = 0.92, P = 0.001), government effectiveness score (RR = 0.96, P = 0.017), and number of hospital beds (RR = 0.85, P < 0.001). Covid-19 mortality rate was positively associated with proportion of population aged 65 or older (RR = 1.12, P < 0.001) and transport infrastructure quality score (RR = 1.08, P = 0.002). Furthermore, the negative association between Covid-19 mortality and test number was stronger among low-income countries and countries with lower government effectiveness scores, younger populations and fewer hospital beds. Predicted mortality rates were highly associated with observed mortality rates (r = 0.77; P < 0.001). Increasing Covid-19 testing, improving government effectiveness and increasing hospital beds may have the potential to attenuate Covid-19 mortality.
Prediction of postoperative pulmonary complications using preoperative controlling nutritional status (CONUT) score in patients with resectable non-small cell lung cancer
Authors: Lee Sang Chul , Lee Jin Gu , Lee Sang Hoon , Kim Eun Young , Chang Joon , Kim Dae Joon , Paik Hyo Chae , Chung Kyung Young , Jung Ji Ye
Published: July 2020

Postoperative pulmonary complications (PPCs) significantly impact surgical outcome. We investigated the predictive ability of controlling nutritional status (CONUT) for PPC after lung resection in patients with non-small cell lung cancer (NSCLC). We retrospectively reviewed data of 922 patients with NSCLC who underwent complete resection from January 2016–December 2017. We analyzed the frequency and characteristics of PPCs and compared receiver operating characteristic (ROC) curves of various prognostic models to predict PPCs. A CONUT score higher than 1 was considered as a high CONUT score. Total incidence of PPCs was 8.6% (n = 79). The proportion of pneumonia was significantly larger in the high CONUT group (P < 0.05). The CONUT consistently had a higher area under curve (AUC) value (0.64) than other prognostic models (prognostic nutritional index (PNI): AUC = 0.61, Glasgow prognostic score (GPS): AUC = 0.57, and assessment of respiratory risk in surgical patients in Catalonia (ARISCAT): AUC = 0.54). Multivariate analysis identified underweight [Odds ratio (OR) = 4.57, P = 0.002] and high CONUT score (OR = 1.91, P = 0.009) as independent PPCs prognostic factors. One-year mortality rate for high CONUT score was significantly higher (hazard ratio = 7.97; 95% confidence interval, 1.78–35.59). Preoperative CONUT score is an independent predictor of PPCs and 1-year mortality in patients with resectable NSCLC.
Glucose counteracts wood-dependent induction of lignocellulolytic enzyme secretion in monokaryon and dikaryon submerged cultures of the white-rot basidiomycete Pleurotus ostreatus
Authors: Alfaro Manuel , Majcherczyk Andrzej , Kües Ursula , Ramírez Lucía , Pisabarro Antonio G.
Published: July 2020

The secretome complexity and lignocellulose degrading capacity of Pleurotus ostreatus monokaryons mkPC9 and mkPC15 and mated dikaryon dkN001 were studied in submerged liquid cultures containing wood, glucose, and wood plus glucose as carbon sources. The study revealed that this white-rot basidiomycete attacks all the components of the plant cell wall. P. ostreatus secretes a variety of glycoside hydrolases, carbohydrate esterases, and polysaccharide lyases, especially when wood is the only carbon source. The presence of wood increased the secretome complexity, whereas glucose diminished the secretion of enzymes involved in cellulose, hemicellulose and pectin degradation. In contrast, the presence of glucose did not influence the secretion of redox enzymes or proteases, which shows the specificity of glucose on the secretion of cellulolytic enzymes. The comparison of the secretomes of monokaryons and dikaryons reveals that secretome complexity is unrelated to the nuclear composition of the strain.
Distribution of gamma radiation dose rate related with natural radionuclides in all of Vietnam and radiological risk assessment of the built-up environment
Authors: Inoue Kazumasa , Fukushi Masahiro , Van Le Tan , Tsuruoka Hiroshi , Kasahara Shogo , Nimelan Veerasamy
Published: July 2020

A built-up environment utilizes building materials containing natural radionuclides that will change radiological risks. While radiological risks have been estimated from the activity concentrations of natural radionuclides in soil, it is important to evaluate the changes of these risks for the built-up environment using these building materials. Based on the direct measurements of absorbed dose rate in air and calculation of absorbed dose rate in air from activity concentrations in soil for all of Vietnam which has undergone significant economic growth in recent decades, the changes of absorbed dose rate in air and radiological risks before and after construction of many artificial structures were investigated. The results showed that the absorbed dose rates in air were clearly changed by the urbanization, and the difference ratio for all of Vietnam ranged from 0.5 to 2.1, meaning that the artificial structures have been acting as shielding materials to terrestrial gamma-rays or radiation sources. However, changes in annual effective dose in the built-up environment were small, and there was no new radiation risk from the built-up environment for Vietnam.
Mouse CD163 deficiency strongly enhances experimental collagen-induced arthritis
Authors: Svendsen Pia , Etzerodt Anders , Deleuran Bent W. , Moestrup Søren K.
Published: July 2020

The scavenger receptor CD163 is highly expressed in macrophages in sites of chronic inflammation where it has a not yet defined role. Here we have investigated development of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) in CD163-deficient C57BL/6 mice. Compared to wild-type mice, the CIA in CD163-deficient mice had a several-fold higher arthritis score with early onset, prolonged disease and strongly enhanced progression. Further, the serum anti-collagen antibody isotypes as well as the cytokine profiles and T cell markers in the inflamed joints revealed that CD163-deficient mice after 52 days had a predominant Th2 response in opposition to a predominant Th1 response in CD163+/+ mice. Less difference in disease severity between the CD163+/+ and CD163−/− mice was seen in the CAIA model that to a large extent induces arthritis independently of T-cell response and endogenous Th1/Th2 balance. In conclusion, the present set of data points on a novel strong anti-inflammatory role of CD163.
Topical cell-free conditioned media harvested from adipose tissue-derived stem cells promote recovery from corneal epithelial defects caused by chemical burns
Authors: Park Gae Won , Heo Jeonghoon , Kang Jung Youb , Yang Ji Won , Kim Jong Sik , Kwon Ki Dong , Yu Byung Chul , Lee Sang Joon
Published: July 2020

Corneal chemical burns can lead to blindness following serious complications. As most of these complications are caused by failure of reepithelization during the acute phase, treatment at this stage is critical. Although there have been some studies on corneal injury recovery using adipose tissue-derived stem cells (ADSCs), none has reported the effect of topical cell-free conditioned culture media (CM) derived from ADSCs on corneal epithelial regeneration. Here, the best conditions for CM were selected and used for in vitro and in vivo experiments. Corneal burn in rats was induced using 100% alcohol. The chosen CM was administered to corneal burn rats (CM-treated [CT] group) four times a day for three days and this group was compared with the normal control and corneal burn (CB) groups. Biomicroscopic fluorescence images and the actual physical corneas were taken over time and used for analysis. mRNA levels of hepatocyte growth factor and epidermal growth factor (EGF) were significantly increased, whereas those of vascular endothelial growth factor, interleukin (IL)-1β, IL-6, IL-10, and matrix metalloproteinase-9 were significantly decreased in the CT group compared with those in the CB group. The numbers of proliferating cell nuclear antigen- and zonular occludens-1-positive cells in the CT group were significantly higher than those in the CB group. The macrophage-infiltrating corneas in the CT group expressed significantly more of the M2 marker arginase than corneas in the CB group. Optimal CM (× 0.5 concentration) treatment significantly accelerated the migration of corneal epithelial cells and induced upregulation of the expression of IL-6, EGF, and C-X-C chemokine receptor type 4 mRNAs. Overall, in this study, topical administration of cell-free CM promoted regeneration of the corneal epithelium after induction of chemical burns.
A blood-based metabolomics test to distinguish relapsing–remitting and secondary progressive multiple sclerosis: addressing practical considerations for clinical application
Authors: Yeo Tianrong , Sealey Megan , Zhou Yifan , Saldana Luisa , Loveless Samantha , Claridge Timothy D. W. , Robertson Neil , DeLuca Gabriele , Palace Jacqueline , Anthony Daniel C. , Probert Fay
Published: July 2020

The transition from relapsing–remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) represents a huge clinical challenge. We previously demonstrated that serum metabolomics could distinguish RRMS from SPMS with high diagnostic accuracy. As differing sample-handling protocols can affect the blood metabolite profile, it is vital to understand which factors may influence the accuracy of this metabolomics-based test in a clinical setting. Herein, we aim to further validate the high accuracy of this metabolomics test and to determine if this is maintained in a ‘real-life’ clinical environment. Blood from 31 RRMS and 28 SPMS patients was subjected to different sample-handling protocols representing variations encountered in clinics. The effect of freeze–thaw cycles (0 or 1) and time to erythrocyte removal (30, 120, or 240 min) on the accuracy of the test was investigated. For test development, samples from the optimised protocol (30 min standing time, 0 freeze–thaw) were used, resulting in high diagnostic accuracy (mean ± SD, 91.0 ± 3.0%). This test remained able to discriminate RRMS and SPMS samples that had experienced additional freeze–thaw, and increased standing times of 120 and 240 min with accuracies ranging from 85.5 to 88.0%, because the top discriminatory metabolite biomarkers from the optimised protocol remained discriminatory between RRMS and SPMS despite these sample-handling variations. In conclusion, while strict sample-handling is essential for the development of metabolomics-based blood tests, the results confirmed that the RRMS vs. SPMS test is resistant to sample-handling variations and can distinguish these two MS stages in the clinics.
Identification of TNFAIP3 as relapse biomarker and potential therapeutic target for MOG antibody associated diseases
Authors: Saxena Shrishti , Lokhande Hrishikesh , Gombolay Grace , Raheja Radhika , Rooney Timothy , Chitnis Tanuja
Published: July 2020

MOG-antibody associated disease (MOG-AAD) is a recently recognized demyelinating disorder predominantly affecting children but also occurs in adults, with a relapsing course in approximately 50% of patients. We evaluated peripheral blood mononuclear cells from MOG-AAD patients by flow cytometry and found a strong antigen specific central memory cell (CMC) response with increased Th1 and Th17 cells at the time of a relapse. Transcriptomic analysis of CMCs by three independent sequencing platforms revealed TNFAIP3 as a relapse biomarker, whose expression was down regulated at a relapse compared to remission in MOG-AAD patients. Serum in an additional cohort of patients showed decreased TNFAIP3 levels at relapse compared to remission state in MOG-AAD patients. Our studies suggest that alterations in TNFAIP3 levels are associated with relapses in MOG-AAD patients, which may have clinical utility as a disease course biomarker and therapeutic target.
Unique cysteine-enriched, D2L5 and D4L6 extracellular loops in CaV3 T-type channels alter the passage and block of monovalent and divalent ions
Authors: Guan Wendy , Stephens Robert F. , Mourad Omar , Mehta Amrit , Fux Julia , Spafford J. David
Published: July 2020

Invertebrate LCaV3 shares the quintessential features of vertebrate CaV3 T-type channels, with a low threshold of channel activation, rapid activation and inactivation kinetics and slow deactivation kinetics compared to other known Ca2+ channels, the CaV1 and CaV2 channels. Unlike the vertebrates though, CaV3 T-type channels in non-cnidarian invertebrates possess an alternative exon 12 spanning the D2L5 extracellular loop, which alters the invertebrate LCaV3 channel into a higher Na+ and lower Ca2+ current passing channel, more resembling a classical NaV1 Na+ channel. Cnidarian CaV3 T-type channels can possess genes with alternative cysteine-rich, D4L6 extracellular loops in a manner reminiscent of the alternative cysteine-rich, D2L5 extracellular loops of non-cnidarian invertebrates. We illustrate here that the preferences for greater Na+ or Ca2+ ion current passing through CaV3 T-type channels are contributed by paired cysteines within D2L5 and D4L6 extracellular loops looming above the pore selectivity filter. Swapping of invertebrate tri- and tetra-cysteine containing extracellular loops, generates higher Na+ current passing channels in human CaV3.2 channels, while corresponding mono- and di-cysteine loop pairs in human CaV3.2 generates greater Ca2+ current passing, invertebrate LCaV3 channels. Alanine substitutions of unique D2L5 loop cysteines of LCaV3 channels increases relative monovalent ion current sizes and increases the potency of Zn2+ and Ni2+ block by ~ 50× and ~ 10× in loop cysteine mutated channels respectively, acquiring characteristics of the high affinity block of CaV3.2 channels, including the loss of the slowing of inactivation kinetics during Zn2+ block. Charge neutralization of a ubiquitous aspartate residue of calcium passing CaV1, CaV2 and CaV3 channels, in the outer pore of the selectivity filter residues in Domain II generates higher Na+ current passing channels in a manner that may resemble how the unique D2L5 extracellular loops of invertebrate CaV3 channels may confer a relatively higher peak current size for Na+ ions over Ca2+ The extracellular loops of CaV3 channels are not engaged with accessory subunit binding, as the other Na+ (NaV1) and Ca2+ (CaV1/CaV2) channels, enabling diversity and expansion of cysteine-bonded extracellular loops, which appears to serve, amongst other possibilities, to alter to the preferences for passage of Ca2+ or Na+ ions through invertebrate CaV3 channels.
Validity of dynamical analysis to characterize heart rate and oxygen consumption during effort tests
Authors: Mongin D. , Chabert C. , Uribe Caparros A. , Collado A. , Hermand E. , Hue O. , Alvero Cruz J. R. , Courvoisier D. S.
Published: July 2020

Performance is usually assessed by simple indices stemming from cardiac and respiratory data measured during graded exercise test. The goal of this study is to characterize the indices produced by a dynamical analysis of HR and VO2 for different effort test protocols, and to estimate the construct validity of these new dynamical indices by testing their links with their standard counterparts. Therefore, two groups of 32 and 14 athletes from two different cohorts performed two different graded exercise testing before and after a period of training or deconditioning. Heart rate (HR) and oxygen consumption (VO2) were measured. The new dynamical indices were the value without effort, the characteristic time and the amplitude (gain) of the HR and VO2 response to the effort. The gain of HR was moderately to strongly associated with other performance indices, while the gain for VO2 increased with training and decreased with deconditioning with an effect size slightly higher than VO2 max. Dynamical analysis performed on the first 2/3 of the effort tests showed similar patterns than the analysis of the entire effort tests, which could be useful to assess individuals who cannot perform full effort tests. In conclusion, the dynamical analysis of HR and VO2 obtained during effort test, especially through the estimation of the gain, provides a good characterization of physical performance, robust to less stringent effort test conditions.
A carbohydrate-active enzyme (CAZy) profile links successful metabolic specialization of Prevotella to its abundance in gut microbiota
Authors: Aakko Juhani , Pietilä Sami , Toivonen Raine , Rokka Anne , Mokkala Kati , Laitinen Kirsi , Elo Laura , Hänninen Arno
Published: July 2020

Gut microbiota participates in diverse metabolic and homeostatic functions related to health and well-being. Its composition varies between individuals, and depends on factors related to host and microbial communities, which need to adapt to utilize various nutrients present in gut environment. We profiled fecal microbiota in 63 healthy adult individuals using metaproteomics, and focused on microbial CAZy (carbohydrate-active) enzymes involved in glycan foraging. We identified two distinct CAZy profiles, one with many Bacteroides-derived CAZy in more than one-third of subjects (n = 25), and it associated with high abundance of Bacteroides in most subjects. In a smaller subset of donors (n = 8) with dietary parameters similar to others, microbiota showed intense expression of Prevotella-derived CAZy including exo-beta-(1,4)-xylanase, xylan-1,4-beta-xylosidase, alpha-l-arabinofuranosidase and several other CAZy belonging to glycosyl hydrolase families involved in digestion of complex plant-derived polysaccharides. This associated invariably with high abundance of Prevotella in gut microbiota, while in subjects with lower abundance of Prevotella, microbiota showed no Prevotella-derived CAZy. Identification of Bacteroides- and Prevotella-derived CAZy in microbiota proteome and their association with differences in microbiota composition are in evidence of individual variation in metabolic specialization of gut microbes affecting their colonizing competence.
Functionalisation of a heat-derived and bio-inert albumin hydrogel with extracellular matrix by air plasma treatment
Authors: Ong John , Zhao Junzhe , Levy Galit Katarivas , Macdonald James , Justin Alexander W. , Markaki Athina E.
Published: July 2020

Albumin-based hydrogels are increasingly attractive in tissue engineering because they provide a xeno-free, biocompatible and potentially patient-specific platform for tissue engineering and drug delivery. The majority of research on albumin hydrogels has focused on bovine serum albumin (BSA), leaving human serum albumin (HSA) comparatively understudied. Different gelation methods are usually employed for HSA and BSA, and variations in the amino acid sequences of HSA and BSA exist; these account for differences in the hydrogel properties. Heat-induced gelation of aqueous HSA is the easiest method of synthesizing HSA hydrogels however hydrogel opacity and poor cell attachment limit their usefulness in downstream applications. Here, a solution to this problem is presented. Stable and translucent HSA hydrogels were created by controlled thermal gelation and the addition of sodium chloride. The resulting bio-inert hydrogel was then subjected to air plasma treatment which functionalised its surface, enabling the attachment of basement membrane matrix (Geltrex). In vitro survival and proliferation studies of foetal human osteoblasts subsequently demonstrated good biocompatibility of functionalised albumin hydrogels compared to untreated samples. Thus, air plasma treatment enables functionalisation of inert heat-derived HSA hydrogels with extracellular matrix proteins and these may be used as a xeno-free platform for biomedical research or cell therapy.
Dendritic spine density is increased on nucleus accumbens D2 neurons after chronic social defeat
Authors: Fox Megan E. , Figueiredo Antonio , Menken Miriam S. , Lobo Mary Kay
Published: July 2020

Stress alters the structure and function of brain reward circuitry and is an important risk factor for developing depression. In the nucleus accumbens (NAc), structural and physiological plasticity of medium spiny neurons (MSNs) have been linked to increased stress-related and depression-like behaviors. NAc MSNs have opposing roles in driving stress-related behaviors that is dependent on their dopamine receptor expression. After chronic social defeat stress, NAc MSNs exhibit increased dendritic spine density. However, it remains unclear if the dendritic spine plasticity is MSN subtype specific. Here we use viral labeling to characterize dendritic spine morphology specifically in dopamine D2 receptor expressing MSNs (D2-MSNs). After chronic social defeat, D2-MSNs exhibit increased spine density that is correlated with enhanced social avoidance behavior. Together, our data indicate dendritic spine plasticity is MSN subtype specific, improving our understanding of structural plasticity after chronic stress.