bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of S-nitrosylation of PFKM in regulation of glycolysis in ovarian cancer cells
Authors: Gao Wenwen , Huang Mengqiu , Chen Xi , Chen Jianping , Zou Zhiwei , Li Linlin , Ji Kaiyuan , Nie Zhirui , Yang Bingsheng , Wei Zibo , Xu Pengfei , Jia Junshuang , Zhang Qianbing , Shen Hongfen , Wang Qianli , Li Keyi , Zhu Lingqun , Wang Meng , Ye Shuangyan , Zeng Sisi , Lin Ying , Rong Zhili , Xu Yang , Zhu Peng , Zhang Hui , Hao Bingtao , Liu Qiuzhen
Published: April 2021

One of the malignant transformation hallmarks is metabolism reprogramming, which plays a critical role in the biosynthetic needs of unchecked proliferation, abrogating cell death programs, and immunologic escape. However, the mechanism of the metabolic switch is not fully understood. Here, we found that the S-nitrosoproteomic profile of endogenous nitrogen oxide in ovarian cancer cells targeted multiple components in metabolism processes. Phosphofructokinase (PFKM), one of the most important regulatory enzymes of glycolysis, was S-nitrosylated by nitric oxide synthase NOS1 at Cys351. S-nitrosylation at Cys351 stabilized the tetramer of PFKM, leading to resist negative feedback of downstream metabolic intermediates. The PFKM-C351S mutation decreased the proliferation rate of cultured cancer cells, and reduced tumor growth and metastasis in the mouse xenograft model. These findings indicated that S-nitrosylation at Cys351 of PFKM by NOS1 contributes to the metabolic reprogramming of ovarian cancer cells, highlighting a critical role of endogenous nitrogen oxide on metabolism regulations in tumor progression.
Alternative carbon price trajectories can avoid excessive carbon removal
Authors: Strefler Jessica , Kriegler Elmar , Bauer Nico , Luderer Gunnar , Pietzcker Robert C. , Giannousakis Anastasis , Edenhofer Ottmar
Published: April 2021

The large majority of climate change mitigation scenarios that hold warming below 2 °C show high deployment of carbon dioxide removal (CDR), resulting in a peak-and-decline behavior in global temperature. This is driven by the assumption of an exponentially increasing carbon price trajectory which is perceived to be economically optimal for meeting a carbon budget. However, this optimality relies on the assumption that a finite carbon budget associated with a temperature target is filled up steadily over time. The availability of net carbon removals invalidates this assumption and therefore a different carbon price trajectory should be chosen. We show how the optimal carbon price path for remaining well below 2 °C limits CDR demand and analyze requirements for constructing alternatives, which may be easier to implement in reality. We show that warming can be held at well below 2 °C at much lower long-term economic effort and lower CDR deployment and therefore lower risks if carbon prices are high enough in the beginning to ensure target compliance, but increase at a lower rate after carbon neutrality has been reached.
Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate
Authors: Rapino Francesca , Zhou Zhaoli , Roncero Sanchez Ana Maria , Joiret Marc , Seca Christian , El Hachem Najla , Valenti Gianluca , Latini Sara , Shostak Kateryna , Geris Liesbet , Li Ping , Huang Gang , Mazzucchelli Gabriel , Baiwir Dominique , Desmet Christophe J. , Chariot Alain , Georges Michel , Close Pierre
Published: April 2021

Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Using knockdown models of enzymes that catalyze the mcm5s2 wobble uridine tRNA modification (U34-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. While translation defects upon perturbation of U34-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U34-tRNA modification. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis.
Millennial scale feedbacks determine the shape and rapidity of glacial termination
Authors: Barker Stephen , Knorr Gregor
Published: April 2021

Within the Late Pleistocene, terminations describe the major transitions marking the end of glacial cycles. While it is established that abrupt shifts in the ocean/atmosphere system are a ubiquitous component of deglaciation, significant uncertainties remain concerning their specific role and the likelihood that terminations may be interrupted by large-amplitude abrupt oscillations. In this perspective we address these uncertainties in the light of recent developments in the understanding of glacial terminations as the ultimate interaction between millennial and orbital timescale variability. Innovations in numerical climate simulation and new geologic records allow us to highlight new avenues of research and identify key remaining uncertainties such as sea-level variability.
Global connections between El Nino and landslide impacts
Authors: Emberson Robert , Kirschbaum Dalia , Stanley Thomas
Published: April 2021

El Nino is a critical part of global inter-annual climate variability, and the intensity of El Nino has major implications for rainfall-induced natural hazards in many vulnerable countries. The impact of landslides triggered by rainfall is likely to be modulated by the strength of El Nino, but the nature of this connection and the places where it is most relevant remains unconstrained. Here we combine new satellite rainfall data with a global landslide exposure model to show that El Nino has far-reaching effects on landslide impacts to people and infrastructure. We find that the impact of El Nino on landslide exposure can be greater in parts of Southeast Asia and Latin America than that due to seasonal rainfall variability. These findings improve our understanding of hazard variability around the world and can assist disaster mitigation efforts on seasonal timescales.
Reconstitution of contractile actomyosin rings in vesicles
Authors: Litschel Thomas , Kelley Charlotte F. , Holz Danielle , Adeli Koudehi Maral , Vogel Sven K. , Burbaum Laura , Mizuno Naoko , Vavylonis Dimitrios , Schwille Petra
Published: April 2021

One of the grand challenges of bottom-up synthetic biology is the development of minimal machineries for cell division. The mechanical transformation of large-scale compartments, such as Giant Unilamellar Vesicles (GUVs), requires the geometry-specific coordination of active elements, several orders of magnitude larger than the molecular scale. Of all cytoskeletal structures, large-scale actomyosin rings appear to be the most promising cellular elements to accomplish this task. Here, we have adopted advanced encapsulation methods to study bundled actin filaments in GUVs and compare our results with theoretical modeling. By changing few key parameters, actin polymerization can be differentiated to resemble various types of networks in living cells. Importantly, we find membrane binding to be crucial for the robust condensation into a single actin ring in spherical vesicles, as predicted by theoretical considerations. Upon force generation by ATP-driven myosin motors, these ring-like actin structures contract and locally constrict the vesicle, forming furrow-like deformations. On the other hand, cortex-like actin networks are shown to induce and stabilize deformations from spherical shapes.
Real-world stress resilience is associated with the responsivity of the locus coeruleus
Authors: Grueschow Marcus , Stenz Nico , Thörn Hanna , Ehlert Ulrike , Breckwoldt Jan , Brodmann Maeder Monika , Exadaktylos Aristomenis K. , Bingisser Roland , Ruff Christian C. , Kleim Birgit
Published: April 2021

Individuals may show different responses to stressful events. Here, we investigate the neurobiological basis of stress resilience, by showing that neural responsitivity of the noradrenergic locus coeruleus (LC-NE) and associated pupil responses are related to the subsequent change in measures of anxiety and depression in response to prolonged real-life stress. We acquired fMRI and pupillometry data during an emotional-conflict task in medical residents before they underwent stressful emergency-room internships known to be a risk factor for anxiety and depression. The LC-NE conflict response and its functional coupling with the amygdala was associated with stress-related symptom changes in response to the internship. A similar relationship was found for pupil-dilation, a potential marker of LC-NE firing. Our results provide insights into the noradrenergic basis of conflict generation, adaptation and stress resilience.
Organic superstructure microwires with hierarchical spatial organisation
Authors: Zhuo Ming-Peng , He Guang-Peng , Wang Xue-Dong , Liao Liang-Sheng
Published: April 2021

Rationally designing and precisely constructing the dimensions, configurations and compositions of organic nanomaterials are key issues in material chemistry. Nevertheless, the precise synthesis of organic heterostructure nanomaterials remains challenging owing to the difficulty of manipulating the homogeneous/heterogeneous-nucleation process and the complex epitaxial relationships of combinations of dissimilar materials. Herein, we propose a hierarchical epitaxial-growth approach with the combination of longitudinal and horizontal epitaxial-growth modes for the design and synthesis of a variety of organic superstructure microwires with accurate spatial organisation by regulating the heterogeneous-nucleation crystallisation process. The lattice-matched longitudinal and horizontal epitaxial-growth modes are separately employed to construct the primary organic core/shell and segmented heterostructure microwires. Significantly, these primary organic core/shell and segmented microwires are further applied to construct the core/shell-segmented and segmented-core/shell type’s organic superstructure microwires through the implementation of multiple spatial epitaxial-growth modes. This strategy can be generalised to all organic microwires with tailored multiple substructures, which affords an avenue to manipulate their physical/chemical features for various applications.
Spin-ice physics in cadmium cyanide
Authors: Coates Chloe S. , Baise Mia , Schmutzler Adrian , Simonov Arkadiy , Makepeace Joshua W. , Seel Andrew G. , Smith Ronald I. , Playford Helen Y. , Keen David A. , Siegel Renée , Senker Jürgen , Slater Ben , Goodwin Andrew L.
Published: April 2021

Spin-ices are frustrated magnets that support a particularly rich variety of emergent physics. Typically, it is the interplay of magnetic dipole interactions, spin anisotropy, and geometric frustration on the pyrochlore lattice that drives spin-ice formation. The relevant physics occurs at temperatures commensurate with the magnetic interaction strength, which for most systems is 1–5 K. Here, we show that non-magnetic cadmium cyanide, Cd(CN)2, exhibits analogous behaviour to magnetic spin-ices, but does so on a temperature scale that is nearly two orders of magnitude greater. The electric dipole moments of cyanide ions in Cd(CN)2 assume the role of magnetic pseudospins, with the difference in energy scale reflecting the increased strength of electric vs magnetic dipolar interactions. As a result, spin-ice physics influences the structural behaviour of Cd(CN)2 even at room temperature.
Democratising deep learning for microscopy with ZeroCostDL4Mic
Authors: von Chamier Lucas , Laine Romain F. , Jukkala Johanna , Spahn Christoph , Krentzel Daniel , Nehme Elias , Lerche Martina , Hernández-Pérez Sara , Mattila Pieta K. , Karinou Eleni , Holden Séamus , Solak Ahmet Can , Krull Alexander , Buchholz Tim-Oliver , Jones Martin L. , Royer Loïc A. , Leterrier Christophe , Shechtman Yoav , Jug Florian , Heilemann Mike , Jacquemet Guillaume , Henriques Ricardo
Published: April 2021

Deep Learning (DL) methods are powerful analytical tools for microscopy and can outperform conventional image processing pipelines. Despite the enthusiasm and innovations fuelled by DL technology, the need to access powerful and compatible resources to train DL networks leads to an accessibility barrier that novice users often find difficult to overcome. Here, we present ZeroCostDL4Mic, an entry-level platform simplifying DL access by leveraging the free, cloud-based computational resources of Google Colab. ZeroCostDL4Mic allows researchers with no coding expertise to train and apply key DL networks to perform tasks including segmentation (using U-Net and StarDist), object detection (using YOLOv2), denoising (using CARE and Noise2Void), super-resolution microscopy (using Deep-STORM), and image-to-image translation (using Label-free prediction - fnet, pix2pix and CycleGAN). Importantly, we provide suitable quantitative tools for each network to evaluate model performance, allowing model optimisation. We demonstrate the application of the platform to study multiple biological processes.
Tuning local chemistry of P2 layered-oxide cathode for high energy and long cycles of sodium-ion battery
Authors: Wang Chenchen , Liu Luojia , Zhao Shuo , Liu Yanchen , Yang Yubo , Yu Haijun , Lee Suwon , Lee Gi-Hyeok , Kang Yong-Mook , Liu Rong , Li Fujun , Chen Jun
Published: April 2021

Layered transition-metal oxides have attracted intensive interest for cathode materials of sodium-ion batteries. However, they are hindered by the limited capacity and inferior phase transition due to the gliding of transition-metal layers upon Na+ extraction and insertion in the cathode materials. Here, we report that the large-sized K+ is riveted in the prismatic Na+ sites of P2-Na0.612K0.056MnO2 to enable more thermodynamically favorable Na+ vacancies. The Mn-O bonds are reinforced to reduce phase transition during charge and discharge. 0.901 Na+ per formula are reversibly extracted and inserted, in which only the two-phase transition of P2 ↔ P’2 occurs at low voltages. It exhibits the highest specific capacity of 240.5 mAh g−1 and energy density of 654 Wh kg−1 based on the redox of Mn3+/Mn4+, and a capacity retention of 98.2% after 100 cycles. This investigation will shed lights on the tuneable chemical environments of transition-metal oxides for advanced cathode materials and promote the development of sodium-ion batteries.
Primary and secondary clarithromycin resistance in Helicobacter pylori and mathematical modeling of the role of macrolides
Authors: Kocsmár Éva , Buzás György Miklós , Szirtes Ildikó , Kocsmár Ildikó , Kramer Zsófia , Szijártó Attila , Fadgyas-Freyler Petra , Szénás Kató , Rugge Massimo , Fassan Matteo , Kiss András , Schaff Zsuzsa , Röst Gergely , Lotz Gábor
Published: April 2021

Clarithromycin is a macrolide antibiotic widely used for eradication ofHelicobacter pyloriinfection, and thus resistance to this antibiotic is a major cause of treatment failure. Here, we present the results of a retrospective observational study of clarithromycin resistance (Cla-res) in 4744H. pylori-infected patients from Central Hungary. We use immunohistochemistry and fluorescence in situ hybridization on fixed gastric tissue samples to determineH. pyloriinfection and to infer Cla-res status, respectively. We correlate this information with macrolide dispensing data for the same patients (available through a prescription database) and develop a mathematical model of the population dynamics of Cla-resH. pyloriinfections. Cla-res is found in 5.5% of macrolide-naive patients (primary Cla-res), with no significant sex difference. The model predicts that this primary Cla-res originates from transmission of resistant bacteria in 98.7% of cases, and derives from spontaneous mutations in the other 1.3%. We find an age-dependent preponderance of female patients among secondary (macrolide-exposed) clarithromycin-resistant infections, predominantly associated with prior use of macrolides for non-eradication purposes. Our results shed light into the sources of primary resistant cases, and indicate that the growth rate of Cla-res prevalence would likely decrease if macrolides were no longer used for purposes other thanH. pylorieradication.
Publisher Correction: A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2
Authors: Huang Qingrui , Ji Kai , Tian Siyu , Wang Fengze , Huang Baoying , Tong Zhou , Tan Shuguang , Hao Junfeng , Wang Qihui , Tan Wenjie , Gao George F. , Yan Jinghua
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22820-x
Meta-analysis of HIV-1 vaccine elicited mucosal antibodies in humans
Authors: Seaton Kelly E. , Deal Aaron , Han Xue , Li Shuying S. , Clayton Ashley , Heptinstall Jack , Duerr Ann , Allen Mary A. , Shen Xiaoying , Sawant Sheetal , Yates Nicole L. , Spearman Paul , Churchyard Gavin , Goepfert Paul A. , Maenza Janine , Gray Glenda , Pantaleo Giuseppe , Polakowski Laura , Robinson Harriet L. , Grant Shannon , Randhawa April K. , Huang Ying , Morgan Cecilia , Grunenberg Nicole , Karuna Shelly , Gilbert Peter B. , McElrath M. Juliana , Huang Yunda , Tomaras Georgia D. ,   NIAID HIV Vaccine Trials Network (HVTN) 076, 088, 086, 096, 097, 205 Study Teams
Published: April 2021

We studied mucosal immune responses in six HIV-1 vaccine trials investigating different envelope (Env)-containing immunogens. Regimens were classified into four categories: DNA/vector, DNA/vector plus protein, protein alone, and vector alone. We measured HIV-1-specific IgG and IgA in secretions from cervical (n = 111) and rectal swabs (n = 154), saliva (n = 141), and seminal plasma (n = 124) and compared to corresponding blood levels. Protein-containing regimens had up to 100% response rates and the highest Env-specific IgG response rates. DNA/vector groups elicited mucosal Env-specific IgG response rates of up to 67% that varied across specimen types. Little to no mucosal IgA responses were observed. Overall, gp41- and gp140-specific antibodies dominated gp120 mucosal responses. In one trial, prior vaccination with a protein-containing immunogen maintained durability of cervical and rectal IgG for up to 17 years. Mucosal IgG responses were boosted after revaccination. These findings highlight a role for protein immunization in eliciting HIV-1-specific mucosal antibodies and the ability of HIV-1 vaccines to elicit durable HIV-1-specific mucosal IgG.
New results with regard to the Flora bust controversy: radiocarbon dating suggests nineteenth century origin
Authors: Reiche Ina , Beck Lucile , Caffy Ingrid
Published: April 2021

Many works of art have been attributed to Leonardo da Vinci (1452–1519), the great artist-scientist-engineer of the Italian Renaissance; however, art historians have struggled to find definitive proof to connect Leonardo to these art pieces. The Flora wax bust in the Bode Museum, Berlin, was attributed to Leonardo because her face resembles several Leonardo portraits, but this attribution has the subject of intense debate since the bust’s acquisition in 1909. Using new chemical analyses and absolute 14C dating, we are able to resolve the question of authenticity. We show that the Flora wax bust is made primarily of spermaceti which was extracted from sperm whales. Therefore, 14C dating must consider the Marine Reservoir Effect. We have generated a new calibration method and dated the bust to the 19th c. This proves that the bust was not produced during the Renaissance, and thus cannot be attributed to da Vinci, and illustrates that 14C dating can be applied to unusual materials.
Optimising assessment of dark adaptation data using time to event analysis
Authors: Higgins Bethany E. , Montesano Giovanni , Binns Alison M. , Crabb David P.
Published: April 2021

In age-related macular degeneration (AMD) research, dark adaptation has been found to be a promising functional measurement. In more severe cases of AMD, dark adaptation cannot always be recorded within a maximum allowed time for the test (~ 20–30 min). These data are recorded either as censored data-points (data capped at the maximum test time) or as an estimated recovery time based on the trend observed from the data recorded within the maximum recording time. Therefore, dark adaptation data can have unusual attributes that may not be handled by standard statistical techniques. Here we show time-to-event analysis is a more powerful method for analysis of rod-intercept time data in measuring dark adaptation. For example, at 80% power (at α = 0.05) sample sizes were estimated to be 20 and 61 with uncapped (uncensored) and capped (censored) data using a standard t-test; these values improved to 12 and 38 when using the proposed time-to-event analysis. Our method can accommodate both skewed data and censored data points and offers the advantage of significantly reducing sample sizes when planning studies where this functional test is an outcome measure. The latter is important because designing trials and studies more efficiently equates to newer treatments likely being examined more efficiently.
Soil gas probes for monitoring trace gas messengers of microbial activity
Authors: Roscioli Joseph R. , Meredith Laura K. , Shorter Joanne H. , Gil-Loaiza Juliana , Volkmann Till H. M.
Published: April 2021

Soil microbes vigorously produce and consume gases that reflect active soil biogeochemical processes. Soil gas measurements are therefore a powerful tool to monitor microbial activity. Yet, the majority of soil gases lack non-disruptive subsurface measurement methods at spatiotemporal scales relevant to microbial processes and soil structure. To address this need, we developed a soil gas sampling system that uses novel diffusive soil probes and sample transfer approaches for high-resolution sampling from discrete subsurface regions. Probe sampling requires transferring soil gas samples to above-ground gas analyzers where concentrations and isotopologues are measured. Obtaining representative soil gas samples has historically required balancing disruption to soil gas composition with measurement frequency and analyzer volume demand. These considerations have limited attempts to quantify trace gas spatial concentration gradients and heterogeneity at scales relevant to the soil microbiome. Here, we describe our new flexible diffusive probe sampling system integrated with a modified, reduced volume trace gas analyzer and demonstrate its application for subsurface monitoring of biogeochemical cycling of nitrous oxide (N2O) and its site-specific isotopologues, methane, carbon dioxide, and nitric oxide in controlled soil columns. The sampling system observed reproducible responses of soil gas concentrations to manipulations of soil nutrients and redox state, providing a new window into the microbial response to these key environmental forcings. Using site-specific N2O isotopologues as indicators of microbial processes, we constrain the dynamics of in situ microbial activity. Unlocking trace gas messengers of microbial activity will complement -omics approaches, challenge subsurface models, and improve understanding of soil heterogeneity to disentangle interactive processes in the subsurface biome.
Nanotechnology-based approaches for targeting and delivery of drugs via Hexakis (m-PE) macrocycles
Authors: Pasban Samaneh , Raissi Heidar
Published: April 2021

Hexakis (m-phenylene ethynylene) (m-PE) macrocycles, with aromatic backbones and multiple hydrogen-bonding side chains, had a very high propensity to self-assemble via H-bond and π–π stacking interactions to form nanotubular structures with defined inner pores. Such stacking of rigid macrocycles is leading to novel applications that enable the researchers to explored mass transport in the sub-nanometer scale. Herein, we performed density functional theory (DFT) calculations to examine the drug delivery performance of the hexakis dimer as a novel carrier for doxorubicin (DOX) agent in the chloroform and water solvents. Based on the DFT results, it is found that the adsorption of DOX on the carrier surface is typically physisorption with the adsorption strength values of − 115.14 and − 83.37 kJ/mol in outside and inside complexes, respectively, and so that the essence of the drug remains intact. The negative values of the binding energies for all complexes indicate the stability of the drug molecule inside and outside the carrier's cavities. The energy decomposition analysis (EDA) has also been performed and shown that the dispersion interaction has an essential role in stabilizing the drug-hexakis dimer complexes. To further explore the electronic properties of dox, the partial density of states (PDOS and TDOS) are calculated. The atom in molecules (AIM) and Becke surface (BS) methods are also analyzed to provide an inside view of the nature and strength of the H-bonding interactions in complexes. The obtained results indicate that in all studied complexes, H-bond formation is the driving force in the stabilization of these structures, and also chloroform solvent is more favorable than the water solution. Overall, our findings offer insightful information on the efficient utilization of hexakis dimer as drug delivery systems to deliver anti-cancer drugs.
Waist-to-height ratio and metabolic phenotype compared to the Matsuda index for the prediction of insulin resistance
Authors: Lechner Katharina , Lechner Benjamin , Crispin Alexander , Schwarz Peter E. H. , von Bibra Helene
Published: April 2021

Current screening algorithms for type 2 diabetes (T2D) rely on fasting plasma glucose (FPG) and/or HbA1c. This fails to identify a sizeable subgroup of individuals in early stages of metabolic dysregulation who are at high risk for developing diabetes or cardiovascular disease. The Matsuda index, a combination of parameters derived from a fasting and postprandial insulin assay, is an early biomarker for metabolic dysregulation (i.e. insulin resistance/compensatory hyperinsulinemia). The aim of this analysis was to compare four widely available anthropometric and biochemical markers indicative of this condition [waist-to-height ratio (WHtR), hypertriglyceridemic-waist phenotype (HTW), triglycerides-to-HDL-C ratio (TG/HDL-C) and FPG] to the Matsuda index. This cross-sectional analysis included 2231 individuals with normal fasting glucose (NFG, n = 1333), impaired fasting glucose (IFG, n = 599) and T2D (n = 299) from an outpatient diabetes clinic in Germany and thus extended a prior analysis from our group done on the first two subgroups. We analyzed correlations of the Matsuda index with WHtR, HTW, TG/HDL-C and FPG and their predictive accuracies by correlation and logistic regression analyses and receiver operating characteristics. In the entire group and in NFG, IFG and T2D, the best associations were observed between the Matsuda index and the WHtR (r = − 0.458), followed by HTW phenotype (r = − 0.438). As for prediction accuracy, WHtR was superior to HTW, TG/HDL-C and FPG in the entire group (AUC 0.801) and NFG, IFG and T2D. A multivariable risk score for the prediction of insulin resistance was tested and demonstrated an area under the ROC curve of 0.765 for WHtR and its interaction with sex as predictor controlled by age and sex. The predictive power increased to 0.845 when FPG and TG/HDL-C were included. Using as a comparator the Matsuda index, WHtR, compared to HTW, TG/HDL-C and FPG, showed the best predictive value for detecting metabolic dysregulation. We conclude that WHtR, a widely available anthropometric index, could refine phenotypic screening for insulin resistance/hyperinsulinemia. This may ameliorate early identification of individuals who are candidates for appropriate therapeutic interventions aimed at addressing the twin epidemic of metabolic and cardiovascular disease in settings where more extended testing such as insulin assays are not feasible.
Ultrasonic actuation of a fine-needle improves biopsy yield
Authors: Perra Emanuele , Lampsijärvi Eetu , Barreto Gonçalo , Arif Muhammad , Puranen Tuomas , Hæggström Edward , Pritzker Kenneth P. H. , Nieminen Heikki J.
Published: April 2021

Despite the ubiquitous use over the past 150 years, the functions of the current medical needle are facilitated only by mechanical shear and cutting by the needle tip, i.e. the lancet. In this study, we demonstrate how nonlinear ultrasonics (NLU) extends the functionality of the medical needle far beyond its present capability. The NLU actions were found to be localized to the proximity of the needle tip, the SonoLancet, but the effects extend to several millimeters from the physical needle boundary. The observed nonlinear phenomena, transient cavitation, fluid streams, translation of micro- and nanoparticles and atomization, were quantitatively characterized. In the fine-needle biopsy application, the SonoLancet contributed to obtaining tissue cores with an increase in tissue yield by 3–6× in different tissue types compared to conventional needle biopsy technique using the same 21G needle. In conclusion, the SonoLancet could be of interest to several other medical applications, including drug or gene delivery, cell modulation, and minimally invasive surgical procedures.
Mortality and socio-economic outcomes among patients hospitalized for stroke and diabetes in the US: a recent analysis from the National Inpatient Sample
Authors: Tabbalat Aya , Dargham Soha , Al Suwaidi Jassim , Aboulsoud Samar , Al Jerdi Salman , Abi Khalil Charbel
Published: April 2021

The prevalence and incidence of diabetes mellitus (DM) are increasing worldwide. We aim to assess mortality and socio-economic outcomes among patients hospitalized for stroke and diabetes in the US and evaluate their recent trends. We examined: in-hospital mortality, length of stay (LoS), and overall hospital charges in diabetic patients over 18 years old who were hospitalized with a stroke from 2005 to 2014, included in the National Inpatient Sample. In those patients, the mean (SD) age slightly decreased from 70 (13) years to 69 (13) years (p-trend < 0.001). Interestingly, although incident cases of stroke amongst DM patients increased from 17.4 to 20.0 /100,000 US adults (p-trend < 0.001), age-adjusted mortality for those with hemorrhagic strokes decreased from 24.3% to 19.6%, and also decreased from 3.23% to 2.48% for those with ischemic strokes (p-trend < 0.01 for both), but remained unchanged in TIAs patients. As expected, the average total charges per hospital stay almost doubled over the ten-year period, increasing from 15 970 to 31 018 USD/stay (adjusted for inflation). Nonetheless, median (IQR) LoS slightly decreased from 4 (2–6) to 3 (2–6) days (p-trend < 0.001). In total, our data show that, from 2005 to 2014, the incidence of stroke among the diabetes patient population are gradually increasing, in-hospital mortality is steadily decreasing, along with average LoS. Admission costs were up almost twofold during the same period.
Clinical utility of ANA-ELISA vs ANA-immunofluorescence in connective tissue diseases
Authors: Alsaed Omar Suhail , Alamlih Laith Ishaq , Al-Radideh Omar , Chandra Prem , Alemadi Samar , Al-Allaf Abdul-Wahab
Published: April 2021

We investigated the performance of ANA-ELISA for CTDs screening and diagnosis and comparing it to the conventional ANA-IIF. ANA-ELISA is a solid-phase immune assay includes 17 ANA-targeted recombinant antigens; dsDNA, Sm-D, Rib-P, PCNA, U1-RNP (70, A, C), SS-A/Ro (52 and 60), SS-B/La, Centromere B, Scl-70, Fibrillarin, RNA Polymerase III, Jo-1, Mi-2, and PM-Scl. During the period between March till December 2016 all requests for ANA from primary, secondary, and tertiary care centers were processed with both techniques; ANA-IIF and ANA-ELISA. The electronic medical record of these patients was reviewed looking for CTD diagnosis documented by the Senior rheumatologist. SPSS 22 is used for analysis. Between March and December 2016, a total of 12,439 ANA tests were requested. 1457 patients were assessed by the rheumatologist and included in the analysis. At a cut-off ratio ≥ 1.0 for ANA-ELISA and a dilutional titre ≥ 1:80 for ANA-IIF, the sensitivity of ANA-IIF and ANA-ELISA for all CTDs were 63.3% vs 74.8% respectively. For the SLE it was 64.3% vs 76.9%, Sjogren’s Syndrome was 50% vs 76.9% respectively. The overall specificity of ANA-ELISA was 89.05%, which was slightly better than ANA-IIF 86.72%. The clinical performance of ANA-ELISA for CTDs screening showed better sensitivity and specificity as compared to the conventional ANA-IIF in our cohort.
Exogenous enzymes and probiotics alter digestion kinetics, volatile fatty acid content and microbial interactions in the gut of Nile tilapia
Authors: Maas Roel M. , Deng Yale , Dersjant-Li Yueming , Petit Jules , Verdegem Marc C. J. , Schrama Johan W. , Kokou Fotini
Published: April 2021

Sustainable aquafeed production requires fishmeal replacement, leading to an increasing use of plant-derived ingredients. As a consequence, higher levels of antinutritional substances, such as non-starch polysaccharides and phytate, are present in aquafeeds, with negative effects on fish performance, nutrient digestibility and overall gut health. To alleviate these negative effects, providing exogenous digestive enzymes and/or probiotics can be an effective solution. In this study, we tested the effect of dietary supplementation of enzymes (phytase and xylanase) and probiotics (three strains of Bacillus amyloliquefaciens) on nutrient digestion kinetics and volatile fatty acid content along the gut, and the distal gut microbiome diversity in Nile tilapia. Chyme volatile fatty content was increased with probiotic supplementation in the proximal gut, while lactate content, measured for the first time in vivo in fish, decreased with enzymes along the gut. Enzyme supplementation enhanced crude protein, Ca and P digestibility in proximal and middle gut. Enzymes and probiotics supplementation enhanced microbial interactions as shown by network analysis, while increased the abundance of lactic acid bacteria and Bacillus species. Such results suggest that supplementation with exogenous enzymes and probiotics increases nutrient availability, while at the same time benefits gut health and contributes to a more stable microbiome environment.
Antimicrobial susceptibility, serotype distribution, virulence profile and molecular typing of piliated clinical isolates of pneumococci from east coast, Peninsular Malaysia
Authors: Dzaraly Nurul Diana , Mohd Desa Mohd Nasir , Muthanna AbdulRahman , Masri Siti Norbaya , Taib Niazlin Mohd , Suhaili Zarizal , Sulaiman Nurshahira , Baharin Nurul Hana Zainal , Shuan Cheah Yun , Ariffin Zarina , Rahman Nor Iza A. , Mohd Rani Farahiyah , Palanisamy Navindra Kumari , Soh Tuan Suhaila Tuan , Abdullah Fatimah Haslina
Published: April 2021

Pilus has been recently associated with pneumococcal pathogenesis in humans. The information regarding piliated isolates in Malaysia is scarce, especially in the less developed states on the east coast of Peninsular Malaysia. Therefore, we studied the characteristics of pneumococci, including the piliated isolates, in relation to antimicrobial susceptibility, serotypes, and genotypes at a major tertiary hospital on the east coast of Peninsular Malaysia. A total of 100 clinical isolates collected between September 2017 and December 2019 were subjected to serotyping, antimicrobial susceptibility test, and detection of pneumococcal virulence and pilus genes. Multilocus sequence typing (MLST) and phylogenetic analysis were performed only for piliated strains. The most frequent serotypes were 14 (17%), 6A/B (16%), 23F (12%), 19A (11%), and 19F (11%). The majority of isolates were resistant to erythromycin (42%), tetracycline (37%), and trimethoprim-sulfamethoxazole (24%). Piliated isolates occurred in a proportion of 19%; 47.3% of them were multidrug-resistant (MDR) and a majority had serotype 19F. This study showed ST236 was the most predominant sequence type (ST) among piliated isolates, which was related to PMEN clone Taiwan19F-14 (CC271). In the phylogenetic analysis, the piliated isolates were grouped into three major clades supported with 100% bootstrap values. Most piliated isolates belonged to internationally disseminated clones of S. pneumoniae, but pneumococcal conjugate vaccines (PCVs) have the potential to control them.
Novel application of automated machine learning with MALDI-TOF-MS for rapid high-throughput screening of COVID-19: a proof of concept
Authors: Tran Nam K. , Howard Taylor , Walsh Ryan , Pepper John , Loegering Julia , Phinney Brett , Salemi Michelle R. , Rashidi Hooman H.
Published: April 2021

The 2019 novel coronavirus infectious disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an unsustainable need for molecular diagnostic testing. Molecular approaches such as reverse transcription (RT) polymerase chain reaction (PCR) offers highly sensitive and specific means to detect SARS-CoV-2 RNA, however, despite it being the accepted “gold standard”, molecular platforms often require a tradeoff between speed versus throughput. Matrix assisted laser desorption ionization (MALDI)—time of flight (TOF)—mass spectrometry (MS) has been proposed as a potential solution for COVID-19 testing and finding a balance between analytical performance, speed, and throughput, without relying on impacted supply chains. Combined with machine learning (ML), this MALDI-TOF-MS approach could overcome logistical barriers encountered by current testing paradigms. We evaluated the analytical performance of an ML-enhanced MALDI-TOF-MS method for screening COVID-19. Residual nasal swab samples from adult volunteers were used for testing and compared against RT-PCR. Two optimized ML models were identified, exhibiting accuracy of 98.3%, positive percent agreement (PPA) of 100%, negative percent agreement (NPA) of 96%, and accuracy of 96.6%, PPA of 98.5%, and NPA of 94% respectively. Machine learning enhanced MALDI-TOF-MS for COVID-19 testing exhibited performance comparable to existing commercial SARS-CoV-2 tests.
Crop response to El Niño-Southern Oscillation related weather variation to help farmers manage their crops
Authors: Chapman Ross , Cock James , Samson Marianne , Janetski Noel , Janetski Kate , Gusyana Dadang , Dutta Sudarshan , Oberthür Thomas
Published: April 2021

Although weather is a major driver of crop yield, many farmers don’t know in advance how the weather will vary nor how their crops will respond. We hypothesized that where El Niño-Southern Oscillation (ENSO) drives weather patterns, and data on crop response to distinct management practices exists, it should be possible to map ENSO Oceanic Index (ENSO OI) patterns to crop management responses without precise weather data. Time series data on cacao farm yields in Sulawesi, Indonesia, with and without fertilizer, were used to provide proof-of-concept. A machine learning approach associated 75% of cacao yield variation with the ENSO patterns up to 8 and 24 months before harvest and predicted when fertilizer applications would be worthwhile. Thus, it’s possible to relate average cacao crop performance and management response directly to ENSO patterns without weather data provided: (1) site specific data exist on crop performance over time with distinct management practices; and (2) the weather patterns are driven by ENSO OI. We believe that the principles established here can readily be applied to other crops, particularly when there’s little data available on crop responses to management and weather. However, specific models will be required for each crop and every recommendation domain.
Reduced evoked activity and cortical oscillations are correlated with anisometric amblyopia and impairment of visual acuity
Authors: Julku Hanna , Rouhinen Santeri , Huttunen Henri J. , Lindberg Laura , Liinamaa Johanna , Saarela Ville , Karvonen Elina , Booms Sigrid , Mäkelä Jyrki P. , Uusitalo Hannu , Castrén Eero , Palva J. Matias , Palva Satu
Published: April 2021

Amblyopia is a developmental disorder associated with abnormal visual experience during early childhood commonly arising from strabismus and/or anisometropia and leading to dysfunctions in visual cortex and to various visual deficits. The different forms of neuronal activity that are attenuated in amblyopia have been only partially characterized. In electrophysiological recordings of healthy human brain, the presentation of visual stimuli is associated with event-related activity and oscillatory responses. It has remained poorly understood whether these forms of activity are reduced in amblyopia and whether possible dysfunctions would arise from lower- or higher-order visual areas. We recorded neuronal activity with magnetoencephalography (MEG) from anisometropic amblyopic patients and control participants during two visual tasks presented separately for each eye and estimated neuronal activity from source-reconstructed MEG data. We investigated whether event-related and oscillatory responses would be reduced for amblyopia and localized their cortical sources. Oscillation amplitudes and evoked responses were reduced for stimuli presented to the amblyopic eye in higher-order visual areas and in parietal and prefrontal cortices. Importantly, the reduction of oscillation amplitudes but not that of evoked responses was correlated with decreased visual acuity in amblyopia. These results show that attenuated oscillatory responses are correlated with visual deficits in anisometric amblyopia.
Sustained intrinsic WNT and BMP4 activation impairs hESC differentiation to definitive endoderm and drives the cells towards extra-embryonic mesoderm
Authors: Markouli C. , De Deckersberg E. Couvreu , Dziedzicka D. , Regin M. , Franck S. , Keller A. , Gheldof A. , Geens M. , Sermon K. , Spits C.
Published: April 2021

We identified a human embryonic stem cell subline that fails to respond to the differentiation cues needed to obtain endoderm derivatives, differentiating instead into extra-embryonic mesoderm. RNA-sequencing analysis showed that the subline has hyperactivation of the WNT and BMP4 signalling. Modulation of these pathways with small molecules confirmed them as the cause of the differentiation impairment. While activation of WNT and BMP4 in control cells resulted in a loss of endoderm differentiation and induction of extra-embryonic mesoderm markers, inhibition of these pathways in the subline restored its ability to differentiate. Karyotyping and exome sequencing analysis did not identify any changes in the genome that could account for the pathway deregulation. These findings add to the increasing evidence that different responses of stem cell lines to differentiation protocols are based on genetic and epigenetic factors, inherent to the line or acquired during cell culture.
Proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy: potential targets in calcium regulatory network
Authors: Sadeghi Leila , Rizvanov Albert Anatolyevich , Dabirmanesh Bahareh , Salafutdinov Ilnur Ildusovich , Sayyah Mohammad , Shojaei Amir , Zahiri Javad , Mirnajafi-Zadeh Javad , Khorsand Babak , Khajeh Khosro , Fathollahi Yaghoub
Published: April 2021

Herein proteomic profiling of the rat hippocampus from the kindling and pilocarpine models of epilepsy was performed to achieve new potential targets for treating epileptic seizures. A total of 144 differently expressed proteins in both left and right hippocampi by two-dimensional electrophoresis coupled to matrix-assisted laser desorption-mass spectrometry were identified across the rat models of epilepsy. Based on network analysis, the majority of differentially expressed proteins were associated with Ca2+ homeostasis. Changes in ADP-ribosyl cyclase (ADPRC), lysophosphatidic acid receptor 3 (LPAR3), calreticulin, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), synaptosomal nerve-associated protein 25 (SNAP 25) and transgelin 3 proteins were probed by Western blot analysis and validated using immunohistochemistry. Inhibition of calcium influx by 8-Bromo-cADP-Ribose (8-Br-cADPR) and 2-Aminoethyl diphenylborinate (2-APB) which act via the ADPRC and LPAR3, respectively, attenuated epileptic seizures. Considering a wide range of molecular events and effective role of calcium homeostasis in epilepsy, polypharmacy with multiple realistic targets should be further explored to reach the most effective treatments.
Tissue plasminogen activator is a ligand of cation-independent mannose 6-phosphate receptor and consists of glycoforms that contain mannose 6-phosphate
Authors: Miller James J. , Bohnsack Richard N. , Olson Linda J. , Ishihara Mayumi , Aoki Kazuhiro , Tiemeyer Michael , Dahms Nancy M.
Published: April 2021

Plasmin is the key enzyme in fibrinolysis. Upon interaction with plasminogen activators, the zymogen plasminogen is converted to active plasmin. Some studies indicate plasminogen activation is regulated by cation-independent mannose 6-phosphate receptor (CI-MPR), a protein that facilitates lysosomal enzyme trafficking and insulin-like growth factor 2 downregulation. Plasminogen regulation may be accomplished by CI-MPR binding to plasminogen or urokinase plasminogen activator receptor. We asked whether other members of the plasminogen activation system, such as tissue plasminogen activator (tPA), also interact with CI-MPR. Because tPA is a glycoprotein with three N-linked glycosylation sites, we hypothesized that tPA contains mannose 6-phosphate (M6P) and binds CI-MPR in a M6P-dependent manner. Using surface plasmon resonance, we found that two sources of tPA bound the extracellular region of human and bovine CI-MPR with low-mid nanomolar affinities. Binding was partially inhibited with phosphatase treatment or M6P. Subsequent studies revealed that the five N-terminal domains of CI-MPR were sufficient for tPA binding, and this interaction was also partially mediated by M6P. The three glycosylation sites of tPA were analyzed by mass spectrometry, and glycoforms containing M6P and M6P-N-acetylglucosamine were identified at position N448 of tPA. In summary, we found that tPA contains M6P and is a CI-MPR ligand.
Robustness of radiomic features in CT images with different slice thickness, comparing liver tumour and muscle
Authors: Escudero Sanchez Lorena , Rundo Leonardo , Gill Andrew B. , Hoare Matthew , Mendes Serrao Eva , Sala Evis
Published: April 2021

Radiomic image features are becoming a promising non-invasive method to obtain quantitative measurements for tumour classification and therapy response assessment in oncological research. However, despite its increasingly established application, there is a need for standardisation criteria and further validation of feature robustness with respect to imaging acquisition parameters. In this paper, the robustness of radiomic features extracted from computed tomography (CT) images is evaluated for liver tumour and muscle, comparing the values of the features in images reconstructed with two different slice thicknesses of 2.0 mm and 5.0 mm. Novel approaches are presented to address the intrinsic dependencies of texture radiomic features, choosing the optimal number of grey levels and correcting for the dependency on volume. With the optimal values and corrections, feature values are compared across thicknesses to identify reproducible features. Normalisation using muscle regions is also described as an alternative approach. With either method, a large fraction of features (75–90%) was found to be highly robust (< 25% difference). The analyses were performed on a homogeneous CT dataset of 43 patients with hepatocellular carcinoma, and consistent results were obtained for both tumour and muscle tissue. Finally, recommended guidelines are included for radiomic studies using variable slice thickness.