bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal alcohol consumption and risk of offspring with congenital malformation: the Japan Environment and Children’s Study
Authors: Kurita Hiroshi , Motoki Noriko , Inaba Yuji , Misawa Yuka , Ohira Satoshi , Kanai Makoto , Tsukahara Teruomi , Nomiyama Tetsuo ,   the Japan Environment and Children’s Study (JECS) Group, Kamijima Michihiro , Yamazaki Shin , Ohya Yukihiro , Kishi Reiko , Yaegashi Nobuo , Hashimoto Koichi , Mori Chisato , Ito Shuichi , Yamagata Zentaro , Inadera Hidekuni , Nakayama Takeo , Iso Hiroyasu , Shima Masayuki , Kurozawa Youichi , Suganuma Narufumi , Kusuhara Koichi , Katoh Takahiko
Published: November 2020

Background

The association between fetal exposure to alcohol and congenital structural disorders remains inconclusive. The present study searched for relationships between maternal alcohol consumption during pregnancy and the risk of congenital malformations.

Methods

We evaluated the fixed dataset of a large national birth cohort study including 73,595 mothers with a singleton live birth. Information regarding the alcohol consumption of mothers was obtained from self-reported questionnaires. Physicians assessed for 6 major congenital malformations (congenital heart defects [CHDs], male genital abnormalities, limb defects, cleft lip and/or cleft palate [orofacial clefts (OFC)], severe brain abnormalities, and gastrointestinal obstructions) up to 1 month after birth. Multiple logistic regression analysis was performed to identify associations between maternal alcohol consumption during pregnancy and each malformation.

Results

The prevalence of maternal drinking in early pregnancy and until the second/third trimester was 46.6% and 2.8%, respectively. The onset of CHD was inversely associated with mothers who quit drinking during early pregnancy (OR 0.85, 95% CI 0.74–0.98). There was no remarkable impact of maternal drinking habit status on the other congenital malformations after adjustment for covariates.

Conclusions

Maternal alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital malformations of interest.

Impact

This large-scale Japanese cohort study revealed that no teratogenic associations were found between maternal retrospective reports of periconceptional alcohol consumption and congenital malformations after adjustment for covariates.

This is the first nationwide birth cohort study in Japan to assess the effect of maternal alcohol consumption during pregnancy on major congenital malformations.

Our finding indicated that maternal low-to-moderate alcohol consumption during pregnancy, even in early pregnancy, displayed no significant adverse impact on congenital heart defects, male genital abnormalities, limb defects, orofacial clefts, severe brain abnormalities, or gastrointestinal obstructions.
Novel neuronal surface autoantibodies in plasma of patients with depression and anxiety
Authors: Zong Shenghua , Correia-Hoffmann Carolin , Mané-Damas Marina , Kappelmann Nils , Molenaar Peter C. , van Grootheest Gerard , Penninx Brenda W. J. H. , Rouhl Rob P. W. , Losen Mario , Martinez-Martinez Pilar
Published: November 2020

Neuronal surface autoantibodies (NSAbs) against various antigens cause autoimmune encephalitis. Some of these antigens are also involved in the pathology of depression and anxiety. To study whether NSAbs are more common in plasma of individuals with depression and anxiety than in controls, and to investigate if NSAbs correlate with disease status, plasma samples of 819 individuals with a current diagnosis of depression and/or anxiety, 920 in remission and 492 individuals without these disorders were included in this study. Samples were tested by a combination of immunohistochemistry (IHC), staining on live rat hippocampus neurons and cell-based assay (CBA). By IHC, 50 (2.2%) samples showed immunoreactivity to rat brain tissue, with no significant differences between the aforementioned groups (22/819 vs 18/920 vs 11/492, P > 0.99). In addition, eight IHC positive samples were positive for NSAbs on live neurons (7/819 vs 0/920 vs 1/492, P = 0.006). The IHC-staining patterns of these eight samples were atypical for autoimmune encephalitis and accordingly, they tested negative for known NSAbs by CBA. No obvious difference in the clinical characteristics between individuals with or without NSAbs was observed. In conclusion, novel NSAbs were rare but predominately found in patients with current anxiety or depression indicating they might affect mental health in a small group of patients.
Cysteine metabolic circuitries: druggable targets in cancer
Authors: Bonifácio Vasco D. B. , Pereira Sofia A. , Serpa Jacinta , Vicente João B.
Published: November 2020

To enable survival in adverse conditions, cancer cells undergo global metabolic adaptations. The amino acid cysteine actively contributes to cancer metabolic remodelling on three different levels: first, in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, a reversible post-translational modification; second, as a substrate for the production of hydrogen sulphide (H2S), which feeds the mitochondrial electron transfer chain and mediates per-sulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, finally, as a carbon source for epigenetic regulation, biomass production and energy production. This review will provide a systematic portrayal of the role of cysteine in cancer biology as a source of carbon and sulphur atoms, the pivotal role of cysteine in different metabolic pathways and the importance of H2S as an energetic substrate and signalling molecule. The different pools of cysteine in the cell and within the body, and their putative use as prognostic cancer markers will be also addressed. Finally, we will discuss the pharmacological means and potential of targeting cysteine metabolism for the treatment of cancer.
The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer
Authors: Alexander Peter G. , Roseweir Antonia K. , Pennel Kathryn A. F. , van Wyk Hester C. , Powell Arfon G. M. T. , McMillan Donald C. , Horgan Paul G. , Kelly Caroline , Hay Jennifer , Sansom Owen , Harkin Andrea , Roxburgh Campbell S. D. , Graham Janet , Church David N. , Tomlinson Ian , Saunders Mark , Iveson Tim J. , Edwards Joanne , Park James H.
Published: November 2020

Background

The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, and now requires validation and assessment of interactions with adjuvant therapy.

Methods

Two cohorts were utilised; 862 TNM I–III CRC validation cohort, and 2912 TNM II–III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.

Results

GMS independently associated with DFS (p = 0.001) and RFS (p < 0.001). GMS significantly stratified RFS for both low risk (GMS 0 v GMS 2: HR 3.24 95% CI 1.85–5.68, p < 0.001) and high-risk disease (GMS 0 v GMS 2: HR 2.18 95% CI 1.39–3.41, p = 0.001). In TransSCOT, chemotherapy type (pinteraction = 0.013), but not duration (p = 0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX (HR 2.23 95% CI 1.19–4.16, p = 0.012).

Conclusions

This study validates the GMS as a prognostic tool for patients with stage I–III colorectal cancer, independent of TNM, with the ability to stratify both low- and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.
Corticotropin-releasing hormone (CRH) alters mitochondrial morphology and function by activating the NF-kB-DRP1 axis in hippocampal neurons
Authors: Battaglia Chiara R. , Cursano Silvia , Calzia Enrico , Catanese Alberto , Boeckers Tobias M.
Published: November 2020

Neuronal stress-adaptation combines multiple molecular responses. We have previously reported that thorax trauma induces a transient loss of hippocampal excitatory synapses mediated by the local release of the stress-related hormone corticotropin-releasing hormone (CRH). Since a physiological synaptic activity relies also on mitochondrial functionality, we investigated the direct involvement of mitochondria in the (mal)-adaptive changes induced by the activation of neuronal CRH receptors 1 (CRHR1). We observed, in vivo and in vitro, a significant shift of mitochondrial dynamics towards fission, which correlated with increased swollen mitochondria and aberrant cristae. These morphological changes, which are associated with increased NF-kB activity and nitric oxide concentrations, correlated with a pronounced reduction of mitochondrial activity. However, ATP availability was unaltered, suggesting that neurons maintain a physiological energy metabolism to preserve them from apoptosis under CRH exposure. Our findings demonstrate that stress-induced CRHR1 activation leads to strong, but reversible, modifications of mitochondrial dynamics and morphology. These alterations are accompanied by bioenergetic defects and the reduction of neuronal activity, which are linked to increased intracellular oxidative stress, and to the activation of the NF-kB/c-Abl/DRP1 axis.
The regulatory function of the AAA4 ATPase domain of cytoplasmic dynein
Authors: Liu Xinglei , Rao Lu , Gennerich Arne
Published: November 2020

Cytoplasmic dynein is the primary motor for microtubule minus-end-directed transport and is indispensable to eukaryotic cells. Although each motor domain of dynein contains three active AAA+ ATPases (AAA1, 3, and 4), only the functions of AAA1 and 3 are known. Here, we use single-molecule fluorescence and optical tweezers studies to elucidate the role of AAA4 in dynein’s mechanochemical cycle. We demonstrate that AAA4 controls the priming stroke of the motion-generating linker, which connects the dimerizing tail of the motor to the AAA+ ring. Before ATP binds to AAA4, dynein remains incapable of generating motion. However, when AAA4 is bound to ATP, the gating of AAA1 by AAA3 prevails and dynein motion can occur. Thus, AAA1, 3, and 4 work together to regulate dynein function. Our work elucidates an essential role for AAA4 in dynein’s stepping cycle and underscores the complexity and crosstalk among the motor’s multiple AAA+ domains.
Structure of the respiratory MBS complex reveals iron-sulfur cluster catalyzed sulfane sulfur reduction in ancient life
Authors: Yu Hongjun , Haja Dominik K. , Schut Gerrit J. , Wu Chang-Hao , Meng Xing , Zhao Gongpu , Li Huilin , Adams Michael W. W.
Published: November 2020

Modern day aerobic respiration in mitochondria involving complex I converts redox energy into chemical energy and likely evolved from a simple anaerobic system now represented by hydrogen gas-evolving hydrogenase (MBH) where protons are the terminal electron acceptor. Here we present the cryo-EM structure of an early ancestor in the evolution of complex I, the elemental sulfur (S0)-reducing reductase MBS. Three highly conserved protein loops linking cytoplasmic and membrane domains enable scalable energy conversion in all three complexes. MBS contains two proton pumps compared to one in MBH and likely conserves twice the energy. The structure also reveals evolutionary adaptations of MBH that enabled S0 reduction by MBS catalyzed by a site-differentiated iron-sulfur cluster without participation of protons or amino acid residues. This is the simplest mechanism proposed for reduction of inorganic or organic disulfides. It is of fundamental significance in the iron and sulfur-rich volcanic environments of early earth and possibly the origin of life. MBS provides a new perspective on the evolution of modern-day respiratory complexes and of catalysis by biological iron-sulfur clusters.
STRAP regulates alternative splicing fidelity during lineage commitment of mouse embryonic stem cells
Authors: Jin Lin , Chen Yunjia , Crossman David K. , Datta Arunima , Vu Trung , Mobley James A. , Basu Malay Kumar , Scarduzio Mariangela , Wang Hengbin , Chang Chenbei , Datta Pran K.
Published: November 2020

Alternative splicing (AS) is involved in cell fate decisions and embryonic development. However, regulation of these processes is poorly understood. Here, we have identified the serine threonine kinase receptor-associated protein (STRAP) as a putative spliceosome-associated factor. Upon Strap deletion, there are numerous AS events observed in mouse embryoid bodies (EBs) undergoing a neuroectoderm-like state. Global mapping of STRAP-RNA binding in mouse embryos by enhanced-CLIP sequencing (eCLIP-seq) reveals that STRAP preferably targets transcripts for nervous system development and regulates AS through preferred binding positions, as demonstrated for two neuronal-specific genes, Nnat and Mark3. We have found that STRAP involves in the assembly of 17S U2 snRNP proteins. Moreover, in Xenopus, loss of Strap leads to impeded lineage differentiation in embryos, delayed neural tube closure, and altered exon skipping. Collectively, our findings reveal a previously unknown function of STRAP in mediating the splicing networks of lineage commitment, alteration of which may be involved in early embryonic lethality in mice.
High-performance compliant thermoelectric generators with magnetically self-assembled soft heat conductors for self-powered wearable electronics
Authors: Lee Byeongmoon , Cho Hyeon , Park Kyung Tae , Kim Jin-Sang , Park Min , Kim Heesuk , Hong Yongtaek , Chung Seungjun
Published: November 2020

Softening of thermoelectric generators facilitates conformal contact with arbitrary-shaped heat sources, which offers an opportunity to realize self-powered wearable applications. However, existing wearable thermoelectric devices inevitably exhibit reduced thermoelectric conversion efficiency due to the parasitic heat loss in high-thermal-impedance polymer substrates and poor thermal contact arising from rigid interconnects. Here, we propose compliant thermoelectric generators with intrinsically stretchable interconnects and soft heat conductors that achieve high thermoelectric performance and unprecedented conformability simultaneously. The silver-nanowire-based soft electrodes interconnect bismuth-telluride-based thermoelectric legs, effectively absorbing strain energy, which allows our thermoelectric generators to conform perfectly to curved surfaces. Metal particles magnetically self-assembled in elastomeric substrates form soft heat conductors that significantly enhance the heat transfer to the thermoelectric legs, thereby maximizing energy conversion efficiency on three-dimensional heat sources. Moreover, automated additive manufacturing paves the way for realizing self-powered wearable applications comprising hundreds of thermoelectric legs with high customizability under ambient conditions.
Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia
Authors: An Furun , Wang Huiping , Liu Zhenyun , Wu Fan , Zhang Jiakui , Tao Qianshan , Li Yingwei , Shen Yuanyuan , Ruan Yanjie , Zhang Qing , Pan Ying , Zhu Weiwei , Qin Hui , Wang Yansheng , Fu Yongling , Feng Zhenqing , Zhai Zhimin
Published: November 2020

CD19-specific chimeric antigen receptor T cell (CD19 CAR T) therapy has shown high remission rates in patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL). However, the long-term outcome and the factors that influence the efficacy need further exploration. Here we report the outcome of 51 r/r B-ALL patients from a non-randomized, Phase II clinical trial (ClinicalTrials.gov number: NCT02735291). The primary outcome shows that the overall remission rate (complete remission with or without incomplete hematologic recovery) is 80.9%. The secondary outcome reveals that the overall survival (OS) and relapse-free survival (RFS) rates at 1 year are 53.0 and 45.0%, respectively. The incidence of grade 4 adverse reactions is 6.4%. The trial meets pre-specified endpoints. Further analysis shows that patients with extramedullary diseases (EMDs) other than central nervous system (CNS) involvement have the lowest remission rate (28.6%). The OS and RFS in patients with any subtype of EMDs, higher Tregs, or high-risk genetic factors are all significantly lower than that in their corresponding control cohorts. EMDs and higher Tregs are independent high-risk factors respectively for poor OS and RFS. Thus, these patient characteristics may hinder the efficacy of CAR T therapy.
Controlling bimerons as skyrmion analogues by ferroelectric polarization in 2D van der Waals multiferroic heterostructures
Authors: Sun Wei , Wang Wenxuan , Li Hang , Zhang Guangbiao , Chen Dong , Wang Jianli , Cheng Zhenxiang
Published: November 2020

Atom-thick van der Waals heterostructures with nontrivial physical properties tunable via the magnetoelectric coupling effect are highly desirable for the future advance of multiferroic devices. In this work on LaCl/In2Se3 heterostructure consisting of a 2D ferromagnetic layer and a 2D ferroelectric layer, reversible switch of the easy axis and the Curie temperature of the magnetic LaCl layer has been enabled by switching of ferroelectric polarization in In2Se3. More importantly, magnetic skyrmions in the bimerons form have been discovered in the LaCl/In2Se3 heterostructure and can be driven by an electric current. The creation and annihilation of bimerons in LaCl magnetic nanodisks were achieved by polarization switching. It thus proves to be a feasible approach to achieve purely electric control of skyrmions in 2D van der Waals heterostructures. Such nonvolatile and tunable magnetic skyrmions are promising candidates for information carriers in future data storage and logic devices operated under small electrical currents.
TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease
Authors: Shih Yao-Hsiang , Tu Ling-Hsien , Chang Ting-Yu , Ganesan Kiruthika , Chang Wei-Wei , Chang Pao-Sheng , Fang Yu-Sheng , Lin Yeh-Tung , Jin Lee-Way , Chen Yun-Ru
Published: November 2020

TDP-43 inclusions are found in many Alzheimer’s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ’s ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.
Epidemiology and biology of a herpesvirus in rabies endemic vampire bat populations
Authors: Griffiths Megan E. , Bergner Laura M. , Broos Alice , Meza Diana K. , Filipe Ana da Silva , Davison Andrew , Tello Carlos , Becker Daniel J. , Streicker Daniel G.
Published: November 2020

Rabies is a viral zoonosis transmitted by vampire bats across Latin America. Substantial public health and agricultural burdens remain, despite decades of bats culls and livestock vaccinations. Virally vectored vaccines that spread autonomously through bat populations are a theoretically appealing solution to managing rabies in its reservoir host. We investigate the biological and epidemiological suitability of a vampire bat betaherpesvirus (DrBHV) to act as a vaccine vector. In 25 sites across Peru with serological and/or molecular evidence of rabies circulation, DrBHV infects 80–100% of bats, suggesting potential for high population-level vaccine coverage. Phylogenetic analysis reveals host specificity within neotropical bats, limiting risks to non-target species. Finally, deep sequencing illustrates DrBHV super-infections in individual bats, implying that DrBHV-vectored vaccines might invade despite the highly prevalent wild-type virus. These results indicate DrBHV as a promising candidate vector for a transmissible rabies vaccine, and provide a framework to discover and evaluate candidate viral vectors for vaccines against bat-borne zoonoses.
Aerosol jet printed capacitive strain gauge for soft structural materials
Authors: Fujimoto Kiyo T. , Watkins Jennifer K. , Phero Timothy , Litteken Doug , Tsai Kevin , Bingham Takoda , Ranganatha Kshama Lakshmi , Johnson Benjamin C. , Deng Zhangxian , Jaques Brian , Estrada David
Published: November 2020

Soft structural textiles, or softgoods, are used within the space industry for inflatable habitats, parachutes and decelerator systems. Evaluating the safety and structural integrity of these systems occurs through structural health monitoring systems (SHM), which integrate non-invasive/non-destructive testing methods to detect, diagnose, and locate damage. Strain/load monitoring of these systems is limited while utilizing traditional strain gauges as these gauges are typically stiff, operate at low temperatures, and fail when subjected to high strain that is a result of high loading classifying them as unsuitable for SHM of soft structural textiles. For this work, a capacitance based strain gauge (CSG) was fabricated via aerosol jet printing (AJP) using silver nanoparticle ink on a flexible polymer substrate. Printed strain gauges were then compared to a commercially available high elongation resistance-based strain gauge (HE-RSG) for their ability to monitor strained Kevlar straps having a 26.7 kN (6 klbf) load. Dynamic, static and cyclic loads were used to characterize both types of strain monitoring devices. Printed CSGs demonstrated superior performance for high elongation strain measurements when compared to commonly used HE-RSGs, and were observed to operate with a gauge factor of 5.2 when the electrode arrangement was perpendicular to the direction of strain.
Assessing the relationship between routine and schizophrenia symptoms with passively sensed measures of behavioral stability
Authors: He-Yueya Joy , Buck Benjamin , Campbell Andrew , Choudhury Tanzeem , Kane John M. , Ben-Zeev Dror , Althoff Tim
Published: November 2020

Increased stability in one’s daily routine is associated with well-being in the general population and often a goal of behavioral interventions for people with serious mental illnesses like schizophrenia. Assessing behavioral stability has been limited in clinical research by the use of retrospective scales, which are susceptible to reporting biases and memory inaccuracies. Mobile passive sensors, which are less susceptible to these sources of error, have emerged as tools to assess behavioral patterns in a range of populations. The present study developed and examined a metric of behavioral stability from data generated by a passive sensing system carried by 61 individuals with schizophrenia for one year. This metric—the Stability Index—appeared orthogonal from existing measures drawn from passive sensors and matched the predictive performance of state-of-the-art features. Specifically, greater stability in social activity (e.g., calls and messages) were associated with lower symptoms, and greater stability in physical activity (e.g., being still) appeared associated with elevated symptoms. This study provides additional support for the predictive value of individualized over population-level data in psychiatric populations. The Stability Index offers also a promising tool for generating insights about the impact of behavioral stability in schizophrenia-spectrum disorders.
North American historical monthly spatial climate dataset, 1901–2016
Authors: MacDonald Heather , McKenney Daniel W. , Papadopol Pia , Lawrence Kevin , Pedlar John , Hutchinson Michael F.
Published: November 2020

We present historical monthly spatial models of temperature and precipitation generated from the North American dataset version “j” from the National Oceanic and Atmospheric Administration’s (NOAA’s) National Centres for Environmental Information (NCEI). Monthly values of minimum/maximum temperature and precipitation for 1901–2016 were modelled for continental United States and Canada. Compared to similar spatial models published in 2006 by Natural Resources Canada (NRCAN), the current models show less error. The Root Generalized Cross Validation (RTGCV), a measure of the predictive error of the surfaces akin to a spatially averaged standard predictive error estimate, averaged 0.94 °C for maximum temperature models, 1.3 °C for minimum temperature and 25.2% for total precipitation. Mean prediction errors for the temperature variables were less than 0.01 °C, using all stations. In comparison, precipitation models showed a dry bias (compared to recorded values) of 0.5 mm or 0.7% of the surface mean. Mean absolute predictive errors for all stations were 0.7 °C for maximum temperature, 1.02 °C for minimum temperature, and 13.3 mm (19.3% of the surface mean) for monthly precipitation.
Structure and electrical properties of BCZT ceramics derived from microwave-assisted sol–gel-hydrothermal synthesized powders
Authors: Ji Xiang , Wang Chuanbin , Harumoto Takashi , Zhang Song , Tu Rong , Shen Qiang , Shi Ji
Published: November 2020

A novel microwave-assisted sol–gel-hydrothermal method was employed to rapidly synthesize Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) powders. The effects of reaction time on the structure, crystallinity, purity and morphology of the products were investigated. The results of XRD, FTIR, SEM and TEM indicated that BCZT powders could be obtained in even 60 min at a low synthesis temperature of 180 °C, which were well-crystallized with stoichiometric composition and uniform grain size (~ 85 nm). BCZT ceramic derived from the rapidly-synthesized powders had a dense microstructure and good electrical properties (εm = 9579, d33 = 496 pC/N, 2Pr = 25.22 µC/cm2, 2Ec = 7.52 kV/cm). The significant electrical properties were closely related to the high activity of the BCZT powders, resulting from the rapid microwave-assisted sol–gel-hydrothermal process.
Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries
Authors: Carbonnier Vincent , Leroy Bernard , Rosenberg Shai , Soussi Thierry
Published: November 2020

The diagnosis of somatic and germline TP53 mutations in human tumors or in individuals prone to various types of cancer has now reached the clinic. To increase the accuracy of the prediction of TP53 variant pathogenicity, we gathered functional data from three independent large-scale saturation mutagenesis screening studies with experimental data for more than 10,000 TP53 variants performed in different settings (yeast or mammalian) and with different readouts (transcription, growth arrest or apoptosis). Correlation analysis and multidimensional scaling showed excellent agreement between all these variables. Furthermore, we found that some missense mutations localized in TP53 exons led to impaired TP53 splicing as shown by an analysis of the TP53 expression data from the cancer genome atlas. With the increasing availability of genomic, transcriptomic and proteomic data, it is essential to employ both protein and RNA prediction to accurately define variant pathogenicity.
Bioengineering of non-pathogenic Escherichia coli to enrich for accumulation of environmental copper
Authors: Gahlot Dharmender K. , Taheri Nayyer , Mahato Dhani Ram , Francis Matthew S.
Published: November 2020

Heavy metal sequestration from industrial wastes and agricultural soils is a long-standing challenge. This is more critical for copper since copper pollution is hazardous both for the environment and for human health. In this study, we applied an integrated approach of Darwin’s theory of natural selection with bacterial genetic engineering to generate a biological system with an application for the accumulation of Cu2+ ions. A library of recombinant non-pathogenic Escherichia coli strains was engineered to express seven potential Cu2+ binding peptides encoded by a ‘synthetic degenerate’ DNA motif and fused to Maltose Binding Protein (MBP). Most of these peptide-MBP chimeras conferred tolerance to high concentrations of copper sulphate, and in certain cases in the order of 160-fold higher than the recognised EC50 toxic levels of copper in soils. UV–Vis spectroscopic analysis indicated a molar ratio of peptide-copper complexes, while a combination of bioinformatics-based structure modelling, Cu2+ ion docking, and MD simulations of peptide-MBP chimeras corroborated the extent of Cu2+ binding among the peptides. Further, in silico analysis predicted the peptides possessed binding affinity toward a broad range of divalent metal ions. Thus, we report on an efficient, cost-effective, and environment-friendly prototype biological system that is potentially capable of copper bioaccumulation, and which could easily be adapted for the removal of other hazardous heavy metals or the bio-mining of rare metals.
ClassifyCNV: a tool for clinical annotation of copy-number variants
Authors: Gurbich Tatiana A. , Ilinsky Valery Vladimirovich
Published: November 2020

Copy-number variants (CNVs) are an important part of human genetic variation. They can be benign or can play a role in human disease by creating dosage imbalances and disrupting genes and regulatory elements. Accurate identification and clinical annotation of CNVs is essential, however, manual evaluation of individual CNVs by clinicians is challenging on a large scale. Here, we present ClassifyCNV, an easy-to-use tool that implements the 2019 ACMG classification guidelines to assess CNV pathogenicity. ClassifyCNV uses genomic coordinates and CNV type as input and reports a clinical classification for each variant, a classification score breakdown, and a list of genes of potential importance for variant interpretation. We validate ClassifyCNV’s performance using a set of known clinical CNVs and a set of manually evaluated variants. ClassifyCNV matches the pathogenicity category for 81% of manually evaluated variants with the significance of the remaining pathogenic and benign variants automatically determined as uncertain, requiring a further evaluation by a clinician. ClassifyCNV facilitates the implementation of the latest ACMG guidelines in high-throughput CNV analysis, is suitable for integration into NGS analysis pipelines, and can decrease time to diagnosis. The tool is available at https://github.com/Genotek/ClassifyCNV.
Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions
Authors: Egeland Martin T. , Tarczyluk-Wells Marta M. , Asmar Melissa M. , Adintori Evan G. , Lawrence Roger , Snella Elizabeth M. , Jens Jackie K. , Crawford Brett E. , Wait Jill C. M. , McCullagh Emma , Pinkstaff Jason , Cooper Jonathan D. , Ellinwood N. Matthew
Published: November 2020

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24–30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model.
Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies
Authors: Yang Tao , Tran Kevin C. , Zeng Anne Y. , Massa Stephen M. , Longo Frank M.
Published: November 2020

Longitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.
A comparison of machine learning methods for survival analysis of high-dimensional clinical data for dementia prediction
Authors: Spooner Annette , Chen Emily , Sowmya Arcot , Sachdev Perminder , Kochan Nicole A. , Trollor Julian , Brodaty Henry
Published: November 2020

Data collected from clinical trials and cohort studies, such as dementia studies, are often high-dimensional, censored, heterogeneous and contain missing information, presenting challenges to traditional statistical analysis. There is an urgent need for methods that can overcome these challenges to model this complex data. At present there is no cure for dementia and no treatment that can successfully change the course of the disease. Machine learning models that can predict the time until a patient develops dementia are important tools in helping understand dementia risks and can give more accurate results than traditional statistical methods when modelling high-dimensional, heterogeneous, clinical data. This work compares the performance and stability of ten machine learning algorithms, combined with eight feature selection methods, capable of performing survival analysis of high-dimensional, heterogeneous, clinical data. We developed models that predict survival to dementia using baseline data from two different studies. The Sydney Memory and Ageing Study (MAS) is a longitudinal cohort study of 1037 participants, aged 70–90 years, that aims to determine the effects of ageing on cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a longitudinal study aimed at identifying biomarkers for the early detection and tracking of Alzheimer's disease. Using the concordance index as a measure of performance, our models achieve maximum performance values of 0.82 for MAS and 0.93 For ADNI.
Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells
Authors: Iosef Cristiana , Pedroza Albert J. , Cui Jason Z. , Dalal Alex R. , Arakawa Mamoru , Tashima Yasushi , Koyano Tiffany K. , Burdon Grayson , Churovich Samantha M. P. , Orrick Joshua O. , Pariani Mitchel , Fischbein Michael P.
Published: November 2020

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype–phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may be related to distinct smooth muscle cell (SMC) embryologic lineages. Thus, peripheral blood mononuclear cell (PBMC)-derived induced pluripotent stem cells (iPSC) were differentiated into lateral mesoderm (LM, aortic root) and neural crest (NC, ascending aorta/transverse arch) SMC lineages to model MFS aortic pathology. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomic analysis by tandem mass spectrometry was applied to profile LM and NC iPSC SMCs from four MFS patients and two healthy controls. Analysis revealed 45 proteins with lineage-dependent expression in MFS patients, many of which were specific to diseased samples. Single protein-level data from both iPSC SMCs and primary MFS aortic root aneurysm tissue confirmed elevated integrin αV and reduced MRC2 in clinical disease specimens, validating the iPSC iTRAQ findings. Functionally, iPSC SMCs exhibited defective adhesion to a variety of extracellular matrix proteins, especially laminin-1 and fibronectin, suggesting altered cytoskeleton dynamics. This study defines the aortic embryologic origin-specific proteome in a validated iPSC SMC model to identify novel protein markers associated with MFS aneurysm phenotype. Translating iPSC findings into clinical aortic aneurysm tissue samples highlights the potential for iPSC-based methods to model MFS disease for mechanistic studies and therapeutic discovery in vitro.
Forecasting the spread of COVID-19 under different reopening strategies
Authors: Liu Meng , Thomadsen Raphael , Yao Song
Published: November 2020

We combine COVID-19 case data with mobility data to estimate a modified susceptible-infected-recovered (SIR) model in the United States. In contrast to a standard SIR model, we find that the incidence of COVID-19 spread is concave in the number of infectious individuals, as would be expected if people have inter-related social networks. This concave shape has a significant impact on forecasted COVID-19 cases. In particular, our model forecasts that the number of COVID-19 cases would only have an exponential growth for a brief period at the beginning of the contagion event or right after a reopening, but would quickly settle into a prolonged period of time with stable, slightly declining levels of disease spread. This pattern is consistent with observed levels of COVID-19 cases in the US, but inconsistent with standard SIR modeling. We forecast rates of new cases for COVID-19 under different social distancing norms and find that if social distancing is eliminated there will be a massive increase in the cases of COVID-19.
Long-term efficacy of BCG vaccination in goat herds with a high prevalence of tuberculosis
Authors: Arrieta-Villegas Claudia , Allepuz Alberto , Grasa Miriam , Martín Maite , Cervera Zoraida , Mercader Irene , López-Soria Sergio , Domingo Mariano , Pérez de Val Bernat
Published: November 2020

Vaccination of goats against tuberculosis (TB) has been promoted as an ancillary tool for controlling the disease in infected livestock herds. A three-year trial to assess the efficacy of BCG vaccine was carried out in five goat herds. At the beginning of the trial (month 0), all animals were tested for TB using thee different diagnostic tests. Animals negative to all tests were vaccinated with BCG and all replacement goat kids were also systematically vaccinated throughout the trial. All animals were tested by Interferon-gamma release assay (IGRA) using vaccine compatible reagents at months 6, 12, 24, and 36. The risk factors for TB infection were also evaluated. At the end of the study, four out of five farms showed variable reductions of the initial prevalence (93.5%, 28.5%, 23.2%, and 14.3% respectively), and an overall incidence reduction of 50% was observed in BCG vaccinated goats, although adult vaccinated goats showed higher incidences than vaccinated goat kids. The unvaccinated positive animals remaining in herds and adult BCG vaccinated goats significantly enhanced the risk of infection in vaccinated animals. A systematic vaccination of goats with BCG, together with the removal of positive unvaccinated animals, may contribute to reducing the TB prevalence in goat herds.
Rotating edge-field driven processing of chiral spin textures in racetrack devices
Authors: Schäffer Alexander F. , Siegl Pia , Stier Martin , Posske Thore , Berakdar Jamal , Thorwart Michael , Wiesendanger Roland , Vedmedenko Elena Y.
Published: November 2020

Topologically distinct magnetic structures like skyrmions, domain walls, and the uniformly magnetized state have multiple applications in logic devices, sensors, and as bits of information. One of the most promising concepts for applying these bits is the racetrack architecture controlled by electric currents or magnetic driving fields. In state-of-the-art racetracks, these fields or currents are applied to the whole circuit. Here, we employ micromagnetic and atomistic simulations to establish a concept for racetrack memories free of global driving forces. Surprisingly, we realize that mixed sequences of topologically distinct objects can be created and propagated over far distances exclusively by local rotation of magnetization at the sample boundaries. We reveal the dependence between chirality of the rotation and the direction of propagation and define the phase space where the proposed procedure can be realized. The advantages of this approach are the exclusion of high current and field densities as well as its compatibility with an energy-efficient three-dimensional design.
Potassium application to the cover crop prior to cotton planting as a fertilization strategy in sandy soils
Authors: Echer Fábio Rafael , Peres Vinicius José Souza , Rosolem Ciro Antonio
Published: November 2020

Urochloa grasses are used as cover crops in tropical cropping systems under no-till to improve nutrient cycling. We hypothesized that potassium (K) applied to ruzigrass (Urochloa ruziziensis) grown before cotton in a sandy soil could be timely cycled and ensure nutrition, yield and quality of cotton cultivars with no need to split K application. Field experiments were performed with different K managements, applied to ruzigrass, to cotton grown after grass and without grass, or split as it is done conventionally. No yield differences were observed on K fertilized treatments. At 0 K, cotton yields were low, but they increased by 16% when ruzigrass was grown before, and short fiber content was lower when there was more K available. Ruzigrass grown before cotton increased micronaire as much as the application of 116 kg ha−1 of K without the grass. Fiber maturity was higher when K was applied to the grass or split in the grass and sidedressed in cotton. Growing ruzigrass before cotton allows for early K fertilization, i.e., application of all the fertilizer to de grass, since the nutrient is recycled, and cotton K nutrition is not harmed. Eventually K rates could be reduced as a result of higher efficiency of the systems.
Design, microwave synthesis, and molecular docking studies of catalpol crotonates as potential neuroprotective agent of diabetic encephalopathy
Authors: Liu Shuanglin , Cheng Xiaodong , Li XiaoFei , Kong Yuanfang , Jiang Shiqing , Dong Chunhong , Wang Guoqing
Published: November 2020

Catalpol has gained increasing attention for its potential contributions in controlling glycolipid metabolism and diabetic complications, which makes used as a very promising scaffold for seeking new anti-diabetic drug candidates. Acylation derivatives of catalpol crotonate (CCs) were designed as drug ligands of glutathione peroxidase (GSH-Px) based on molecular docking (MD) using Surfex-Docking method. Catalpol hexacrotonate (CC-6) was synthesized using microwave assisted method and characterized by FT-IR, NMR, HPLC and HRMS. The MD results indicate that with the increasing of esterification degree of hydroxyl, the C log P of CCs increased significantly, and the calculated total scores (Total_score) of CCs are all higher than that of catalpol. It shows that CCs maybe served as potential lead compounds for neuroprotective agents. It was found that the maximum Total_score of isomers in one group CCs is often not that the molecule with minimum energy. MD calculations show that there are five hydrogen bonds formed between CC-6 and the surrounding amino acid residues. Molecular dynamics simulation results show that the binding of CC-6 with GSH-Px is stable. CC-6 was screened for SH-SY5Y cells viability by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, the result indicates CC-6 can effectively reverse SZT induced cells apoptosis with dose-dependent manner, which can indirectly show that CC-6 is a potential neuroprotective agent.
Verminoside from Pseudolysimachion rotundum var. subintegrum sensitizes cisplatin-resistant cancer cells and suppresses metastatic growth of human breast cancer
Authors: Lee Changhu , Ryu Hyung Won , Kim Sahee , Kim Min , Oh Sei-Ryang , Ahn Kyung-Seop , Park Jiyoung
Published: November 2020

Breast cancer is one of the most common cancers in women and is associated with a high mortality rate. The majority of deaths resulting from breast cancer are attributable to metastatic growth; in addition, chemoresistance is a major concern in the treatment of patients with breast cancer. However, limited drugs are available for the treatment of metastatic breast cancer. In this study, the chemoadjuvant effects of a methanolic extract from the leaves of Pseudolysimachion rotundum var. subintegrum (NC13) and an active component isolated from the plant, verminoside (Vms), were evaluated. Furthermore, their potent anti-metastatic activities were validated in vitro and in vivo in animal models. The anti-metastatic and chemosensitizing activities of NC13 and Vms on cisplatin treatment were found to be partly mediated by suppression of the epithelial–mesenchymal transition of cancer cells. Collectively, our results implied that NC13 and its bioactive component Vms could be developed as effective chemoadjuvants in combination with conventional therapeutics.