bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining relative mutational difficulty to understand cancer formation
Authors: Shan Lin , Yu Jiao , He Zhengjin , Chen Shishuang , Liu Mingxian , Ding Hongyu , Xu Liang , Zhao Jie , Yang Ailing , Jiang Hai
Published: July 2020

Most mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here, we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancer-promoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN, and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such a parameter, we can bring new angles to understanding cancer formation.
Wnt signaling and Loxl2 promote aggressive osteosarcoma
Authors: Matsuoka Kazuhiko , Bakiri Latifa , Wolff Lena I. , Linder Markus , Mikels-Vigdal Amanda , Patiño-García Ana , Lecanda Fernando , Hartmann Christine , Sibilia Maria , Wagner Erwin F.
Published: July 2020

Osteosarcoma (OS) is the most frequent primary malignant bone tumor in urgent need of better therapies. Using genetically modified mouse models (GEMMs), we demonstrate that Wnt signaling promotes c-Fos-induced OS formation via the actions of the collagen-modifying enzyme Loxl2. c-Fos/AP-1 directly regulates the expression of the Wnt ligands Wnt7b and Wnt9a in OS cells through promoter binding, and Wnt7b and Wnt9a in turn promote Loxl2 expression in murine and human OS cells through the transcription factors Zeb1 and Zeb2. Concordantly, inhibition of Wnt ligand secretion by inactivating the Wnt-less (Wls) gene in osteoblasts in c-Fos GEMMs either early or in a therapeutic setting reduces Loxl2 expression and progression of OS. Wls-deficient osteosarcomas proliferate less, are less mineralized and are enriched in fibroblastic cells surrounded by collagen fibers. Importantly, Loxl2 inhibition using either the pan-Lox inhibitor BAPN or a specific inducible shRNA reduces OS cell proliferation in vitro and decreases tumor growth and lung colonization in murine and human orthotopic OS transplantation models. Finally, OS development is delayed in c-Fos GEMMs treated with BAPN or with specific Loxl2 blocking antibodies. Congruently, a strong correlation between c-FOS, LOXL2 and WNT7B/WNT9A expression is observed in human OS samples, and c-FOS/LOXL2 co-expression correlates with OS aggressiveness and decreased patient survival. Therefore, therapeutic targeting of Wnt and/or Loxl2 should be considered to potentiate the inadequate current treatments for pediatric, recurrent, and metastatic OS.
Proteome activity landscapes of tumor cell lines determine drug responses
Authors: Frejno Martin , Meng Chen , Ruprecht Benjamin , Oellerich Thomas , Scheich Sebastian , Kleigrewe Karin , Drecoll Enken , Samaras Patroklos , Hogrebe Alexander , Helm Dominic , Mergner Julia , Zecha Jana , Heinzlmeir Stephanie , Wilhelm Mathias , Dorn Julia , Kvasnicka Hans-Michael , Serve Hubert , Weichert Wilko , Kuster Bernhard
Published: July 2020

Integrated analysis of genomes, transcriptomes, proteomes and drug responses of cancer cell lines (CCLs) is an emerging approach to uncover molecular mechanisms of drug action. We extend this paradigm to measuring proteome activity landscapes by acquiring and integrating quantitative data for 10,000 proteins and 55,000 phosphorylation sites (p-sites) from 125 CCLs. These data are used to contextualize proteins and p-sites and predict drug sensitivity. For example, we find that Progesterone Receptor (PGR) phosphorylation is associated with sensitivity to drugs modulating estrogen signaling such as Raloxifene. We also demonstrate that Adenylate kinase isoenzyme 1 (AK1) inactivates antimetabolites like Cytarabine. Consequently, high AK1 levels correlate with poor survival of Cytarabine-treated acute myeloid leukemia patients, qualifying AK1 as a patient stratification marker and possibly as a drug target. We provide an interactive web application termed ATLANTiC (http://atlantic.proteomics.wzw.tum.de), which enables the community to explore the thousands of novel functional associations generated by this work.
An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate
Authors: Zagozewski Jamie , Shahriary Ghazaleh M. , Morrison Ludivine Coudière , Saulnier Olivier , Stromecki Margaret , Fresnoza Agnes , Palidwor Gareth , Porter Christopher J. , Forget Antoine , Ayrault Olivier , Hawkins Cynthia , Chan Jennifer A. , Vladoiu Maria C. , Sundaresan Lakshmikirupa , Arsenio Janilyn , Taylor Michael D. , Ramaswamy Vijay , Werbowetski-Ogilvie Tamra E.
Published: July 2020

OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis.
Magnetic field boosted ferroptosis-like cell death and responsive MRI using hybrid vesicles for cancer immunotherapy
Authors: Yu Bo , Choi Bongseo , Li Weiguo , Kim Dong-Hyun
Published: July 2020

We report a strategy to boost Fenton reaction triggered by an exogenous circularly polarized magnetic field (MF) to enhance ferroptosis-like cell-death mediated immune response, as well as endow a responsive MRI capability by using a hybrid core-shell vesicles (HCSVs). HCSVs are prepared by loading ascorbic acid (AA) in the core and poly(lactic-co-glycolic acid) shell incorporating iron oxide nanocubes (IONCs). MF triggers the release of AA, resulting in the increase of ferrous ions through the redox reaction between AA and IONCs. A significant tumor suppression is achieved by Fenton reaction-mediated ferroptosis-like cell-death. The oxidative stress induced by the Fenton reaction leads to the exposure of calreticulin on tumor cells, which leads to dendritic cells maturation and the infiltration of cytotoxic T lymphocytes in tumor. Furthermore, the depletion of ferric ions during treatment enables monitoring of the Fe reaction in MRI-R2* signal change. This strategy provides a perspective on ferroptosis-based immunotherapy.
Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival
Authors: Zaidi Syed H. , Harrison Tabitha A. , Phipps Amanda I. , Steinfelder Robert , Trinh Quang M. , Qu Conghui , Banbury Barbara L. , Georgeson Peter , Grasso Catherine S. , Giannakis Marios , Adams Jeremy B. , Alwers Elizabeth , Amitay Efrat L. , Barfield Richard T. , Berndt Sonja I. , Borozan Ivan , Brenner Hermann , Brezina Stefanie , Buchanan Daniel D. , Cao Yin , Chan Andrew T. , Chang-Claude Jenny , Connolly Charles M. , Drew David A. , Farris Alton Brad , Figueiredo Jane C. , French Amy J. , Fuchs Charles S. , Garraway Levi A. , Gruber Steve , Guinter Mark A. , Hamilton Stanley R. , Harlid Sophia , Heisler Lawrence E. , Hidaka Akihisa , Hopper John L. , Huang Wen-Yi , Huyghe Jeroen R. , Jenkins Mark A. , Krzyzanowski Paul M. , Lemire Mathieu , Lin Yi , Luo Xuemei , Mardis Elaine R. , McPherson John D. , Miller Jessica K. , Moreno Victor , Mu Xinmeng Jasmine , Nishihara Reiko , Papadopoulos Nickolas , Pasternack Danielle , Quist Michael J. , Rafikova Adilya , Reid Emma E. G. , Shinbrot Eve , Shirts Brian H. , Stein Lincoln D. , Teney Cherie D. , Timms Lee , Um Caroline Y. , Van Guelpen Bethany , Van Tassel Megan , Wang Xiaolong , Wheeler David A. , Yung Christina K. , Hsu Li , Ogino Shuji , Gsur Andrea , Newcomb Polly A. , Gallinger Steven , Hoffmeister Michael , Campbell Peter T. , Thibodeau Stephen N. , Sun Wei , Hudson Thomas J. , Peters Ulrike
Published: July 2020

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21–0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21–1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.
Enantiospecific electrochemical rearrangement for the synthesis of hindered triazolopyridinone derivatives
Authors: Ye Zenghui , Wu Yanqi , Chen Na , Zhang Hong , Zhu Kai , Ding Mingruo , Liu Min , Li Yong , Zhang Fengzhi
Published: July 2020

Triazolopyridinone derivatives are of high value in both medicinal and material chemistry. However, the chiral or hindered triazolopyridinone derivatives remain an underexplored area of chemical space because they are difficult to prepare via conventional methods. Here we report an electrochemical rearrangement for the efficient synthesis of otherwise inaccessible triazolopyridinones with diverse alkyl carboxylic acids as starting materials. This enables the efficient preparation of more than 60 functionalized triazolopyridinones under mild conditions in a sustainable manner. This method is evaluated for the late stage modification of bioactive natural products, amino acids and pharmaceuticals, and it is further applied to the decagram scale preparation of enantiopure triazolopyridinones. The control experiments support a mechanism involving an oxidative cyclization and 1,2-carbon migration. This facile and scalable rearrangement demonstrates the power of electrochemical synthesis to access otherwise-inaccessible triazolopyridinones and may find wide application in organic, material and medicinal chemistry.
H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients
Authors: Schleich Kolja , Kase Julia , Dörr Jan R. , Trescher Saskia , Bhattacharya Animesh , Yu Yong , Wailes Elizabeth M. , Fan Dorothy N. Y. , Lohneis Philipp , Milanovic Maja , Lau Andrea , Lenze Dido , Hummel Michael , Chapuy Bjoern , Leser Ulf , Reimann Maurice , Lee Soyoung , Schmitt Clemens A.
Published: July 2020

Lesion-based targeting strategies underlie cancer precision medicine. However, biological principles – such as cellular senescence – remain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and cross-species validation in patient datasets might uncover clinically relevant genetics of biological response programs. Here, we show that chemotherapy-exposed primary Eµ-myc transgenic lymphomas – with and without defined genetic lesions – recapitulate molecular signatures of patients with diffuse large B-cell lymphoma (DLBCL). Importantly, we interrogate the murine lymphoma capacity to senesce and its epigenetic control via the histone H3 lysine 9 (H3K9)-methyltransferase Suv(ar)39h1 and H3K9me3-active demethylases by loss- and gain-of-function genetics, and an unbiased clinical trial-like approach. A mouse-derived senescence-indicating gene signature, termed “SUVARness”, as well as high-level H3K9me3 lymphoma expression, predict favorable DLBCL patient outcome. Our data support the use of functional genetics in transgenic mouse models to incorporate basic biology knowledge into cancer precision medicine in the clinic.
A unified catalog of 204,938 reference genomes from the human gut microbiome
Authors: Almeida Alexandre , Nayfach Stephen , Boland Miguel , Strozzi Francesco , Beracochea Martin , Shi Zhou Jason , Pollard Katherine S. , Sakharova Ekaterina , Parks Donovan H. , Hugenholtz Philip , Segata Nicola , Kyrpides Nikos C. , Finn Robert D.
Published: July 2020

Comprehensive, high-quality reference genomes are required for functional characterization and taxonomic assignment of the human gut microbiota. We present the Unified Human Gastrointestinal Genome (UHGG) collection, comprising 204,938 nonredundant genomes from 4,644 gut prokaryotes. These genomes encode >170 million protein sequences, which we collated in the Unified Human Gastrointestinal Protein (UHGP) catalog. The UHGP more than doubles the number of gut proteins in comparison to those present in the Integrated Gene Catalog. More than 70% of the UHGG species lack cultured representatives, and 40% of the UHGP lack functional annotations. Intraspecies genomic variation analyses revealed a large reservoir of accessory genes and single-nucleotide variants, many of which are specific to individual human populations. The UHGG and UHGP collections will enable studies linking genotypes to phenotypes in the human gut microbiome.
CU-BEMS, smart building electricity consumption and indoor environmental sensor datasets
Authors: Pipattanasomporn Manisa , Chitalia Gopal , Songsiri Jitkomut , Aswakul Chaodit , Pora Wanchalerm , Suwankawin Surapong , Audomvongseree Kulyos , Hoonchareon Naebboon
Published: July 2020

This paper describes the release of the detailed building operation data, including electricity consumption and indoor environmental measurements, of the seven-story 11,700-m2 office building located in Bangkok, Thailand. The electricity consumption data (kW) are that of individual air conditioning units, lighting, and plug loads in each of the 33 zones of the building. The indoor environmental sensor data comprise temperature (°C), relative humidity (%), and ambient light (lux) measurements of the same zones. The entire datasets are available at one-minute intervals for the period of 18 months from July 1, 2018, to December 31, 2019. Such datasets can be used to support a wide range of applications, such as zone-level, floor-level, and building-level load forecasting, indoor thermal model development, validation of building simulation models, development of demand response algorithms by load type, anomaly detection methods, and reinforcement learning algorithms for control of multiple AC units.
A comprehensive, multisource database for hydrometeorological modeling of 14,425 North American watersheds
Authors: Arsenault Richard , Brissette François , Martel Jean-Luc , Troin Magali , Lévesque Guillaume , Davidson-Chaput Jonathan , Gonzalez Mariana Castañeda , Ameli Ali , Poulin Annie
Published: July 2020

The Hydrometeorological Sandbox - École de technologie supérieure (HYSETS) is a rich, comprehensive and large-scale database for hydrological modelling covering 14425 watersheds in North America. The database includes data covering the period 1950–2018 depending on the type and source of data. The data include a wide array of hydrometeorological data required to perform hydrological and climate change impact studies: (1) watershed properties including boundaries, area, elevation slope, land use and other physiographic information; (2) hydrometric gauging station discharge time-series; (3) precipitation, maximum and minimum daily air temperature time-series from weather station records and from (4) the SCDNA infilled gauge meteorological dataset; (5) the NRCan and Livneh gridded interpolated products’ meteorological data; (6) ERA5 and ERA5-Land reanalysis data; and (7) the SNODAS and ERA5-Land snow water equivalent estimates. All data have been processed and averaged at the watershed scale, and provides a solid basis for hydrological modelling, climate change impact studies, model calibration assessment, regionalization method evaluation and essentially any study requiring access to large amounts of spatiotemporally varied hydrometeorological data.
Neotectonics of the Sea of Galilee (northeast Israel): implication for geodynamics and seismicity along the Dead Sea Fault system
Authors: Gasperini Luca , Lazar Michael , Mazzini Adriano , Lupi Matteo , Haddad Antoine , Hensen Christian , Schmidt Mark , Caracausi Antonio , Ligi Marco , Polonia Alina
Published: July 2020

The Sea of Galilee in northeast Israel is a freshwater lake filling a morphological depression along the Dead Sea Fault. It is located in a tectonically complex area, where a N-S main fault system intersects secondary fault patterns non-univocally interpreted by previous reconstructions. A set of multiscale geophysical, geochemical and seismological data, reprocessed or newly collected, was analysed to unravel the interplay between shallow tectonic deformations and geodynamic processes. The result is a neotectonic map highlighting major seismogenic faults in a key region at the boundary between the Africa/Sinai and Arabian plates. Most active seismogenic displacement occurs along NNW-SSE oriented transtensional faults. This results in a left-lateral bifurcation of the Dead Sea Fault forming a rhomb-shaped depression we named the Capharnaum Trough, located off-track relative to the alleged principal deformation zone. Low-magnitude (ML = 3–4) epicentres accurately located during a recent seismic sequence are aligned along this feature, whose activity, depth and regional importance is supported by geophysical and geochemical evidence. This case study, involving a multiscale/multidisciplinary approach, may serve as a reference for similar geodynamic settings in the world, where unravelling geometric and kinematic complexities is challenging but fundamental for reliable earthquake hazard assessments.
Inversion of high-amplitude magnetic total field anomaly: an application to the Mengku iron-ore deposit, northwest China
Authors: Yang Jianhua , Liu Shuang , Hu Xiangyun
Published: July 2020

In magnetic prospecting, the total field anomaly formula that represents the projection of the magnetic anomaly vector on the geomagnetic field is widely used because it simplifies the calculation of forward modelling and inversion of magnetic data. However, the projection anomaly yields errors relative to the true observed magnetic anomaly, especially for high-amplitude magnetic anomalies such as in iron orebody and unexploded ordnance prospecting. In this study, we analyse the difference between the projection anomaly and observed modulus difference anomaly with physical parameters, and propose to directly invert for the modulus difference anomaly by constructing a nonlinear matrix equation between the model corrections and data corrections. The inversion is then implemented using a preconditioned conjugate gradient algorithm. Synthetic and field magnetic data were used to test the inversion method. Comparison of the two types of total field anomalies shows that the error of the projection anomaly increased with increasing total-field magnetic anomaly. When the total-field magnetic anomaly was < 5,000 nT, the difference between the projection anomaly and modulus difference anomaly results can be ignored. For high-amplitude magnetic anomalies, the modulus difference anomaly inversion produced more accurate representations of both the shape and location of the magnetic sources.
Dynamical Casimir–Polder force on a two-level atom with superposition state in a cavity comprising a dielectric
Authors: Long Yumei , Wang Wentao , Zhang Xue , Yang Hui , Zheng Taiyu
Published: July 2020

We study the dynamical Casimir–Polder force on a two-level atom with different initial states in the one-dimensional dielectric cavity with output coupling, and obtain the analytical expression of the expectation value of dynamical Casimir–Polder force. Results show that the expectation values of dynamical Casimir–Polder force may be affected by the initial states of the atom. Moreover, the expectation value of Casimir–Polder force may vanish at some special atomic positions by properly selecting the initial state of the system. The effects of different relative dielectric constants and the cavity size on the expectation value of Casimir–Polder force are also discussed.
Increasing endogenous activity of NMDARs on GABAergic neurons increases inhibition, alters sensory processing and prevents noise-induced tinnitus
Authors: Deng Di , Masri Samer , Yao Lulu , Ma Xiaoyan , Cao Xuebing , Yang Sungchil , Bao Shaowen , Zhou Qiang
Published: July 2020

Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that selectively increasing NMDA receptor activity in inhibitory neurons using an NMDAR positive allosteric modulator (PAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. In vivo infusion of PAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. In addition, PAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. These results reveal that selectively enhancing endogenous NMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory–inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.
Mechanisms of cell damage due to mechanical impact: an in vitro investigation
Authors: Kang Wonmo , Robitaille Michael C. , Merrill Marriner , Teferra Kirubel , Kim Chunghwan , Raphael Marc P.
Published: July 2020

The dynamic response of cells when subjected to mechanical impact has become increasingly relevant for accurate assessment of potential blunt injuries and elucidating underlying injury mechanisms. When exposed to mechanical impact, a biological system such as the human skin, brain, or liver is rapidly accelerated, which could result in blunt injuries. For this reason, an acceleration of greater than > 150 g is the most commonly used criteria for head injury. To understand the main mechanism(s) of blunt injury under such extreme dynamic threats, we have developed an innovative experimental method that applies a well-characterized and -controlled mechanical impact to live cells cultured in a custom-built in vitro setup compatible with live cell microscopy. Our studies using fibroblast cells as a model indicate that input acceleration ($${a}_{in}$$ain) alone, even when it is much greater than the typical injury criteria, e.g., $${a}_{in}>1{,}000$$ain>1,000 g, does not result in cell damage. On the contrary, we have observed a material-dependent critical pressure value above which a sudden decrease in cell population and cell membrane damage have been observed. We have unambiguously shown that (1) this critical pressure is associated with the onset of cavitation bubbles in a cell culture chamber and (2) the dynamics of cavitation bubbles in the chamber induces localized compressive/tensile pressure cycles, with an amplitude that is considerably greater than the acceleration-induced pressure, to cells. More importantly, the rate of pressure change with time for cavitation-induced pressure is significantly faster (more than ten times) than acceleration-induced pressure. Our in vitro study on the dynamic response of biological systems due to mechanical impact is a crucial step towards understanding potential mechanism(s) of blunt injury and implementing novel therapeutic strategies post-trauma.
MAF1 is a chronic repressor of RNA polymerase III transcription in the mouse
Authors: Bonhoure Nicolas , Praz Viviane , Moir Robyn D. , Willemin Gilles , Mange François , Moret Catherine , Willis Ian M. , Hernandez Nouria
Published: July 2020

Maf1−/− mice are lean, obesity-resistant and metabolically inefficient. Their increased energy expenditure is thought to be driven by a futile RNA cycle that reprograms metabolism to meet an increased demand for nucleotides stemming from the deregulation of RNA polymerase (pol) III transcription. Metabolic changes consistent with this model have been reported in both fasted and refed mice, however the impact of the fasting-refeeding-cycle on pol III function has not been examined. Here we show that changes in pol III occupancy in the liver of fasted versus refed wild-type mice are largely confined to low and intermediate occupancy genes; high occupancy genes are unchanged. However, in Maf1−/− mice, pol III occupancy of the vast majority of active loci in liver and the levels of specific precursor tRNAs in this tissue and other organs are higher than wild-type in both fasted and refed conditions. Thus, MAF1 functions as a chronic repressor of active pol III loci and can modulate transcription under different conditions. Our findings support the futile RNA cycle hypothesis, elaborate the mechanism of pol III repression by MAF1 and demonstrate a modest effect of MAF1 on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins.
1.2 MV/cm pulsed electric fields promote transthyretin aggregate degradation
Authors: Urabe Gen , Sato Takashi , Nakamura Gomaru , Kobashigawa Yoshihiro , Morioka Hiroshi , Katsuki Sunao
Published: July 2020

Numerous theoretical studies have been conducted on the effects of high-voltage electric fields on proteins, but few have produced experimental evidence. To acquire experimental data for the amyloid disassemble theory, we exposed transthyretin aggregates to 1 ns 1.26 MV/cm pulsed electric fields (PEFs) to promote transthyretin degradation. The process produced no changes in pH, and the resulting temperature increases were < 1 °C. We conclude that the physical effects of PEFs, rather than thermal or chemical effects, facilitate aggregate degradation.
Albumin-derived perfluorocarbon-based artificial oxygen carriers can avoid hypoxic tissue damage in massive hemodilution
Authors: Wrobeln Anna , Jägers Johannes , Quinting Theresa , Schreiber Timm , Kirsch Michael , Fandrey Joachim , Ferenz Katja B.
Published: July 2020

Artificial blood for clinical use is not yet available therefore, we previously developed artificial oxygen carriers (capsules) and showed their functionality in vitro and biocompatibility in vivo. Herein, we assessed the functionality of the capsules in vivo in a normovolemic hemodilution rat-model. We stepwise exchanged the blood of male Wistar-rats with medium either in the presence of capsules (treatment) or in their absence (control). We investigated tissue hypoxia thoroughly through online biomonitoring, determination of enzyme activity and pancreatic hormones in plasma, histochemical and immunohistochemical staining of small intestine, heart, liver and spleen as well as in situ hybridization of kidneys. After hemodilution, treated animals show higher arterial blood pressure and have a stable body temperature. Additionally, they show a more stable pH, a higher oxygen partial pressure (pO2), and a lower carbon dioxide partial pressure (pCO2). Interestingly, blood-glucose-levels drop severely in treated animals, presumably due to glucose consumption. Creatine kinase values in these animals are increased and isoenzyme analysis indicates the spleen as origin. Moreover, the small intestine of treated animals show reduced hypoxic injury compared to controls and the kidneys have reduced expression of the hypoxia-inducible erythropoietin mRNA. In conclusion, our capsules can prevent hypoxic tissue damage. The results provide a proof of concept for capsules as adequate erythrocyte substitute.
Spin-Hall-effect-modulation skyrmion oscillator
Authors: Whang Hyun-Seok , Choe Sug-Bong
Published: July 2020

The electric-current-induced spin torque on local magnetization allows the electric control of magnetization, leading to numerous key concepts of spintronic devices. Utilizing the steady-state spin precession under spin-polarized current, a nanoscale spin-torque oscillator tunable over GHz range is one of those promising concepts. Albeit successful proof of principles to date, the spin-torque oscillators still suffer from issues regarding output power, linewidth and magnetic-field-free operation. Here we propose an entirely new concept of spin-torque oscillator, based on magnetic skyrmion dynamics subject to lateral modulation of the spin-Hall effect (SHE). In the oscillator, a skyrmion circulates around the modulation boundary between opposite SHE-torque regions, since the SHE pushes the skyrmion toward the modulation boundary in both regions. A micromagnetic simulation confirmed such oscillations with frequencies of up to 15 GHz in media composed of synthetic ferrimagnets. This fast and robust SHE-modulation-based skyrmion oscillator is expected to overcome the issues associated with conventional spin-torque oscillators.
Colorimetric and electrochemical detection of pathogens in water using silver ions as a unique probe
Authors: Kumar Virendra , Chopra Adity , Bisht Bhawana , Bhalla Vijayender
Published: July 2020

The manuscript highlights the efficacy of silver ions to act as a unique probe for the detection of bacterial contamination in water samples. The bacterial cell membrane adherence property of the silver ions was employed to develop two different bacterial detection assays employing colorimetric and electrochemical techniques. In one of the schemes, silver ion was used directly as a detector of bacteria in a colorimetric assay format, and in the other scheme surface-functionalized antibodies were used as a primary capture for specific detection of Salmonella enterica serovar Typhi. The colorimetric detection is based on silver-induced inhibition of urease activity and silver ion utilization by bacteria for the rapid screening of enteric pathogens in water. The specific detection of bacteria uses an antibody-based electrochemical method that employs silver as an electrochemical probe. The ability of silver to act as an electrochemical probe was investigated by employing Anodic Stripping Voltammetry (ASV) for targeted detection of Salmonella Typhi. For further insights into the developed assays, inductively coupled plasma mass spectrometry (ICP-MS) and transmission electron microscopy (TEM) studies were performed. The sensitivity of the developed assay was found to be 100 cfu mL−1 for colorimetric and 10 cfu mL−1 for electrochemical assay respectively.
Glyphosate and its formulation Roundup impair pig oocyte maturation
Authors: Spinaci Marcella , Nerozzi Chiara , Tamanini Car lo , Bucci Diego , Galeati Giovanna
Published: July 2020

Glyphosate, formulated as glyphosate-based herbicides (GBHs) including the best-known formulation Roundup, is the world's most widely used herbicide. During the last years, the growing and widespread use of GBHs has raised a great concern about the impact of environmental contamination on animal and human health including potential effect on reproductive systems. Using an in vitro model of pig oocyte maturation, we examined the biological impact of both glyphosate and Roundup on female gamete evaluating nuclear maturation, cytoplasmic maturation and developmental competence of oocytes, steroidogenic activity of cumulus cells as well as intracellular levels of glutathione (GSH) and ROS of oocytes. Our results indicate that although exposure to glyphosate and Roundup during in vitro maturation does not affect nuclear maturation and embryo cleavage, it does impair oocyte developmental competence in terms of blastocyst rate and cellularity. Moreover, Roundup at the same glyphosate-equivalent concentrations was shown to be more toxic than pure glyphosate, altering steroidogenesis and increasing oocyte ROS levels, thus confirming that Roundup adjuvants enhance glyphosate toxic effects and/or are biologically active in their side-effect and therefore should be considered and tested as active ingredients.
Postural change for supine position does not disturb toddlers’ nap
Authors: Ohta Hidenobu , Oishi Yoshihisa , Hirose Takako , Nakaya Sachiko , Tsuchiya Keiji , Nakagawa Machiko , Gima Hirotaka , Kusakawa Isao , Yoda Hitoshi , Sato Toshihiro , Sasaki Toru , Nishida Hiroshi , Obonai Toshimasa
Published: July 2020

This study examined whether forced postural change from prone to supine during toddlers’ nap, a preventative measure taken in Japan for sudden unexplained death in childhood (SUDC), disturbs toddlers’ sleep. When the "Back to Sleep" campaign (BSC) was introduced to Japan in 1996, its recommendations were also applied to infants aged 1 year old and over with the expectation that the BSC recommendations may also contribute to a decrease in the occurrence rate of SUDC. Since then, Japanese nurseries have routinely conducted sleeping position checks and positional adjustments of toddlers every 5–10 min during naps. A total of 52 toddlers (age 18.4 ± 3.3 months, means ± SD) were continuously monitored for 8 h during daytime at nursery schools for wake-sleep status and body position (prone, supine and lateral) with actigraphs and 3-orthogonal-axis accelerometers. Out of the 52 toddlers, 24 toddlers adopted prone positions during naps, which were adjusted by nursery staff back to supine. When nursery staff manually changed the toddlers position from prone to supine, the toddlers either did not wake or woke only briefly (3.1 ± 4.9 min) and returned to sleep soon after the positional change. Our study indicates that manual change of toddlers’ sleeping position from prone to supine, a potential SUDC prevention method, does not disturb toddlers’ sleep during their naps.
Modulation of non-bilayer lipid phases and the structure and functions of thylakoid membranes: effects on the water-soluble enzyme violaxanthin de-epoxidase
Authors: Dlouhý Ondřej , Kurasová Irena , Karlický Václav , Javornik Uroš , Šket Primož , Petrova Nia Z. , Krumova Sashka B. , Plavec Janez , Ughy Bettina , Špunda Vladimír , Garab Győző
Published: July 2020

The role of non-bilayer lipids and non-lamellar lipid phases in biological membranes is an enigmatic problem of membrane biology. Non-bilayer lipids are present in large amounts in all membranes; in energy-converting membranes they constitute about half of their total lipid content—yet their functional state is a bilayer. In vitro experiments revealed that the functioning of the water-soluble violaxanthin de-epoxidase (VDE) enzyme of plant thylakoids requires the presence of a non-bilayer lipid phase. 31P-NMR spectroscopy has provided evidence on lipid polymorphism in functional thylakoid membranes. Here we reveal reversible pH- and temperature-dependent changes of the lipid-phase behaviour, particularly the flexibility of isotropic non-lamellar phases, of isolated spinach thylakoids. These reorganizations are accompanied by changes in the permeability and thermodynamic parameters of the membranes and appear to control the activity of VDE and the photoprotective mechanism of non-photochemical quenching of chlorophyll-a fluorescence. The data demonstrate, for the first time in native membranes, the modulation of the activity of a water-soluble enzyme by a non-bilayer lipid phase.
Transgenerational transmission of behavioral phenotypes produced by exposure of male mice to saccharin and nicotine
Authors: McCarthy Deirdre M. , Lowe Sarah E. , Morgan Thomas J. , Cannon Elisa N. , Biederman Joseph , Spencer Thomas J. , Bhide Pradeep G.
Published: July 2020

The use of non-nutritive sweeteners such as saccharin is widely prevalent. Although saccharin is considered safe for human consumption, it produces behavioral changes in experimental animals. We report that saccharin’s behavioral effects are much more pervasive than currently recognized. In a mouse model, saccharin exposure produced motor impulsivity not only in the saccharin-exposed males but also in their offspring. In addition, the offspring showed locomotor hyperactivity and working memory deficit not observed in fathers. Spermatazoal DNA was hypermethylated in the saccharin-exposed fathers, especially at dopamine receptor promoter regions, suggesting that epigenetic modification of germ cell DNA may mediate transgenerational transmission of behavioral phenotypes. Dopamine’s role in hyperactivity was further highlighted by the finding that the stimulant drug methylphenidate mitigated the hyperactivity. Nicotine is another substance that is widely used. Its use via smokeless tobacco products, some of which contain saccharin, is on the rise contributing to concerns about adverse outcomes of co-exposure to saccharin and nicotine. We found that co-exposure of male mice to saccharin and nicotine produced significant behavioral impairment in their offspring. Thus, our data point to potential adverse neurobehavioral consequences of exposure to saccharin alone or saccharin and nicotine for the exposed individuals and their descendants.
Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis
Authors: Hongo Hiroki , Miyawaki Satoru , Imai Hideaki , Shimizu Masahiro , Yagi Shinichi , Mitsui Jun , Ishiura Hiroyuki , Yoshimura Jun , Doi Koichiro , Qu Wei , Teranishi Yu , Okano Atsushi , Ono Hideaki , Nakatomi Hirofumi , Shimizu Tsuneo , Morishita Shinichi , Tsuji Shoji , Saito Nobuhito
Published: July 2020

Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between ICAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P = 1.5 × 10–28, odds ratio = 29.3, 95% confidence interval 15.31–56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis.
Prediction of breeding regions for the desert locust Schistocerca gregaria in East Africa
Authors: Kimathi Emily , Tonnang Henri E. Z. , Subramanian Sevgan , Cressman Keith , Abdel-Rahman Elfatih M. , Tesfayohannes Mehari , Niassy Saliou , Torto Baldwyn , Dubois Thomas , Tanga Chrysantus M. , Kassie Menale , Ekesi Sunday , Mwangi David , Kelemu Segenet
Published: July 2020

Desert locust outbreak in East Africa is threatening livelihoods, food security, environment, and economic development in the region. The current magnitude of the desert locust invasion in East Africa is unprecedented and has not been witnessed for more than 70 years. Identifying the potential breeding sites of the pest is essential to carry out cost-effective and timely preventive measures before it inflicts significant damage. We accessed 9,134 desert locust occurrence records and applied a machine-learning algorithm to predict potential desert locust breeding sites in East Africa using key bio-climatic (temperature and rainfall) and edaphic (sand and moisture contents) factors. Ten days greenness maps from February 2020 to April 2020 were overlaid in model outputs to illustrate the temporal evolution of breeding site locations. This study demonstrated that vast areas of Kenya and Sudan, north eastern regions of Uganda, and south eastern and northern regions of South Sudan are at high risk of providing a conducive breeding environment for the desert locust. Our prediction results suggest that there is need to target these high-risk areas and strengthen ground surveillance to manage the pest in a timely, cost-effective, and environmentally friendly manner.
Unravelling the different causes of nitrate and ammonium effects on coral bleaching
Authors: Fernandes de Barros Marangoni Laura , Ferrier-Pagès Christine , Rottier Cécile , Bianchini Adalto , Grover Renaud
Published: July 2020

Mass coral bleaching represents one of the greatest threats to coral reefs and has mainly been attributed to seawater warming. However, reduced water quality can also interact with warming to increase coral bleaching, but this interaction depends on nutrient ratios and forms. In particular, nitrate (NO3−) enrichment reduces thermal tolerance while ammonium (NH4+) enrichment tends to benefit coral health. The biochemical mechanisms underpinning the different bleaching responses of corals exposed to DIN enrichment still need to be investigated. Here, we demonstrated that the coral Stylophora pistillata underwent a severe oxidative stress condition and reduced aerobic scope when exposed to NO3− enrichment combined with thermal stress. Such condition resulted in increased bleaching intensity compared to a low-nitrogen condition. On the contrary, NH4+ enrichment was able to amend the deleterious effects of thermal stress by favoring the oxidative status and energy metabolism of the coral holobiont. Overall, our results demonstrate that the opposite effects of nitrate and ammonium enrichment on coral bleaching are related to the effects on corals’ energy/redox status. As nitrate loading in coastal waters is predicted to significantly increase in the future due to agriculture and land-based pollution, there is the need for urgent management actions to prevent increases in nitrate levels in seawater. In addition, the maintenance of important fish stocks, which provide corals with recycled nitrogen such as ammonium, should be favoured.
Changes in immune parameters between pre-treatment and recurrence after (chemo) radiation therapy in patients with head and neck cancer
Authors: Ono Takeharu , Azuma Koichi , Kawahara Akihiko , Kakuma Tatsuyuki , Sato Fumihiko , Kawaguchi Toshihiko , Akiba Jun , Umeno Hirohito
Published: July 2020

Squamous cell carcinoma of the head and neck (SCCHN) has a high recurrence rate after (chemo) radiation therapy [(C)RT]. The relationship between the changing levels of immune checkpoint molecules and immune cells in pre-(C)RT tissues and locally recurrent tissues in the irradiated field, after (C)RT completion, is not known. This study aimed to assess the changes in these immune parameters between pre-(C)RT tissue and the same area after local recurrence post-(C)RT. We retrospectively reviewed 30 (C)RT-treated patients with SCCHN. We performed immunohistochemical analyses on these immune parameters using paired tissue samples obtained pre-(C)RT and at local recurrence sites post-(C)RT. No significant changes in immune parameters were found between the pre-(C)RT and locally recurrent tissues. An increased density of CD8+ tumor-infiltrating lymphocytes (TILs) showed a significantly positive correlation with PD-L expression on tumor cells (TC-PD-L1). Patients with increased TC-PD-L1 expression and CD8+TIL density showed favourable prognosis, and one of them showed a favourable response to nivolumab therapy. Our study shows a positive association between TC-PD-L1 upregulation and increased CD8+TIL density, and demonstrates that patients with these changes have a favourable survival outcome.
Endogenous neurotoxin-like protein Ly6H inhibits alpha7 nicotinic acetylcholine receptor currents at the plasma membrane
Authors: Moriwaki Yasuhiro , Kubo Natsuki , Watanabe Mizuho , Asano Shinsuke , Shinoda Tomoki , Sugino Taro , Ichikawa Daiju , Tsuji Shoutaro , Kato Fusao , Misawa Hidemi
Published: July 2020

α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and regarded as potential therapeutic targets for neurodegenerative conditions, such as Alzheimer’s disease and schizophrenia. Yet, despite the assumed pathophysiological importance of the α7 nAChR, molecular physiological characterization remains poorly advanced because α7 nAChR cannot be properly folded and sorted to the plasma membranes in most mammalian cell lines, thus preventing the analyses in heterologous expression system. Recently, ER-resident membrane protein NACHO was discovered as a strong chaperone for the functional expression of α7 nAChR in non-permissive cells. Ly6H, a brain-enriched GPI-anchored neurotoxin-like protein, was reported as a novel modulator regulating intracellular trafficking of α7 nAChR. In this study, we established cell lines that stably and robustly express surface α7 nAChR by introducing α7 nAChR, Ric-3, and NACHO cDNA into HEK293 cells (Triple α7 nAChR/RIC-3/NACHO cells; TARO cells), and re-evaluated the function of Ly6H. We report here that Ly6H binds with α7 nAChRs on the cell membrane and modulates the channel activity without affecting intracellular trafficking of α7 nAChR.
The impact of vitamin D supplementation on VDR gene expression and body composition in monozygotic twins: randomized controlled trial
Authors: Medeiros Jeane Franco Pires , de Oliveira Borges Michelle Vasconcelos , Soares Aline Alves , dos Santos Jessica Cavalcante , de Oliveira Ana Beatriz Bezerra , da Costa Conceição Horrana Belo , Cruz Marina Sampaio , Bortolin Raul Hernandes , de Freitas Renata Caroline Costa , Dantas Paulo Moreira Silva , Hirata Mario Hiroyuki , Silbiger Vivian Nogueira , Luchessi André Ducati
Published: July 2020

Vitamin D supplementation is widely used. However, there is no consensus on the use and dosage of this supplement and the existing recommendations arise from studies based on the benefits that this nutrient can facilitate in bones. In addition, individual genetics can influence the response to supplementation, therefore, research involving monozygotic twins aims to reduce these differences in phenotypic responses. The objective of this randomised controlled study is to examine the effect of vitamin D supplementation on body composition and the expression of the vitamin D receptor (VDR) mRNA. An intervention was performed through supplementation with cholecalciferol at the concentration of 2000 IU in 90 healthy adult monozygotic twins (male or female pairs) for 2 months. The findings showed that serum vitamin D concentration increased by 65% and VDR gene expression sixty times (p = 0.001). Changes in body composition parameters were observed regarding body fat and lean mass. Our results indicate that an increase in serum vitamin D concentration may have potential therapeutic implications.
Stereoselective amination via vinyl-silver intermediates derived from silver-catalyzed carboxylative cyclization of propargylamine
Authors: Sadamitsu Yuta , Saito Kodai , Yamada Tohru
Published: July 2020

The stereoselective synthesis of aminovinyloxazolidinones based on the electrophilic amination of a vinyl-silver intermediate, generated by silver-catalyzed carbon dioxide incorporation on a propargylamine, was achieved.