bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystalline chirality and interlocked double hourglass Weyl fermion in polyhedra-intercalated transition metal dichalcogenides
Authors: Huang Pu , Chen Xinbo , Zhang Peng , Sun Hongyi , Xu Shaogang , Xiong Wen , Wang Rui , Zhang Han , Liu Qihang , Zhang Xiuwen
Published: June 2021

Introducing crystalline chirality into transition metal dichalcogenides (TMDs) has attracted much attention due to its modulation effect on optical properties and the potential to reveal new forms of electronic states. Here, we predict a number of chiral materials by intercalating polyhedra into TMD lattices, finding a type of double hourglass Weyl fermion interlocked with crystalline chirality. The best candidate RhV3S6 (P6322) possesses the largest hourglass energy window of ~380 meV, as well as strong optical circular dichroism (CD) in the infrared regime, both of which are tunable by external strains. The chirality is originally induced by the configuration of intercalated polyhedra and then reduced by the rotational atomic displacements triggered by intercalation, as indicated by CD calculations. Our study opens the way of designing chiral materials with spin-split double hourglass Weyl fermions via structural unit intercalation in achiral crystals for future chiral-functionalized optoelectronic and spintronic devices.
Intravitreal injections: past trends and future projections within a UK tertiary hospital
Authors: Chopra Reena , Preston Gabriella C. , Keenan Tiarnan D. L. , Mulholland Pádraig , Patel Praveen J. , Balaskas Konstantinos , Hamilton Robin D. , Keane Pearse A.
Published: June 2021

Aims

To describe past trends and future projections for the number of intravitreal injections being administered at a large tertiary hospital in London, United Kingdom.

Methods

Retrospective data from Moorfields Eye Hospital were collected using the electronic medical record system. Descriptive statistics were used to visualise overall trends. Time series forecasting was used to predict the number of injections that will be administered up to and including the year 2029.

Results

The number of injections has increased nearly 11-fold from 2009 to 2019, with a total of 44,924 injections delivered in 2019. The majority of injections were given for the treatment of neovascular age-related macular degeneration. Aflibercept formed 87% of injections administered in 2019. The number of injections is predicted to continue to increase every year, with nearly 83,000 injections forecasted in the year 2029.

Conclusion

The demand for intravitreal injections has increased substantially over the last decade and is predicted to further increase. Healthcare systems will need to adapt to accommodate the high demand. Other solutions may include longer-acting therapies to reduce the treatment burden.
Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Authors: Palanikumar L. , Karpauskaite Laura , Al-Sayegh Mohamed , Chehade Ibrahim , Alam Maheen , Hassan Sarah , Maity Debabrata , Ali Liaqat , Kalmouni Mona , Hunashal Yamanappa , Ahmed Jemil , Houhou Tatiana , Karapetyan Shake , Falls Zackary , Samudrala Ram , Pasricha Renu , Esposito Gennaro , Afzal Ahmed J. , Hamilton Andrew D. , Kumar Sunil , Magzoub Mazin
Published: June 2021

Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent.
Post-myocardial infarction heart failure dysregulates the bone vascular niche
Authors: Hoffmann Jedrzej , Luxán Guillermo , Abplanalp Wesley Tyler , Glaser Simone-Franziska , Rasper Tina , Fischer Ariane , Muhly-Reinholz Marion , Potente Michael , Assmus Birgit , John David , Zeiher Andreas Michael , Dimmeler Stefanie
Published: June 2021

The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the bone vascular cell composition. We demonstrate an age-independent loss of type H endothelium in heart failure after myocardial infarction in both mice and humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium, showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Endothelial-specific overexpression of MYC was sufficient to induce type H bone endothelial cells, whereas inhibition of NLRP3-dependent IL-1β production partially prevented the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of bone vascular function in ischemic heart disease.
Temporal trends of SARS-CoV-2 seroprevalence during the first wave of the COVID-19 epidemic in Kenya
Authors: Adetifa Ifedayo M. O. , Uyoga Sophie , Gitonga John N. , Mugo Daisy , Otiende Mark , Nyagwange James , Karanja Henry K. , Tuju James , Wanjiku Perpetual , Aman Rashid , Mwangangi Mercy , Amoth Patrick , Kasera Kadondi , Ng’ang’a Wangari , Rombo Charles , Yegon Christine , Kithi Khamisi , Odhiambo Elizabeth , Rotich Thomas , Orgut Irene , Kihara Sammy , Bottomley Christian , Kagucia Eunice W. , Gallagher Katherine E. , Etyang Anthony , Voller Shirine , Lambe Teresa , Wright Daniel , Barasa Edwine , Tsofa Benjamin , Bejon Philip , Ochola-Oyier Lynette I. , Agweyu Ambrose , Scott J. Anthony G. , Warimwe George M.
Published: June 2021

Observed SARS-CoV-2 infections and deaths are low in tropical Africa raising questions about the extent of transmission. We measured SARS-CoV-2 IgG by ELISA in 9,922 blood donors across Kenya and adjusted for sampling bias and test performance. By 1st September 2020, 577 COVID-19 deaths were observed nationwide and seroprevalence was 9.1% (95%CI 7.6-10.8%). Seroprevalence in Nairobi was 22.7% (18.0-27.7%). Although most people remained susceptible, SARS-CoV-2 had spread widely in Kenya with apparently low associated mortality.
Molecular determinants of response to PD-L1 blockade across tumor types
Authors: Banchereau Romain , Leng Ning , Zill Oliver , Sokol Ethan , Liu Gengbo , Pavlick Dean , Maund Sophia , Liu Li-Fen , Kadel Edward , Baldwin Nicole , Jhunjhunwala Suchit , Nickles Dorothee , Assaf Zoe June , Bower Daniel , Patil Namrata , McCleland Mark , Shames David , Molinero Luciana , Huseni Mahrukh , Sanjabi Shomyseh , Cummings Craig , Mellman Ira , Mariathasan Sanjeev , Hegde Priti , Powles Thomas
Published: June 2021

Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1+tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitorCDKN2Ais identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.
Structure and transport mechanism of P5B-ATPases
Authors: Li Ping , Wang Kaituo , Salustros Nina , Grønberg Christina , Gourdon Pontus
Published: June 2021

In human cells, P5B-ATPases execute the active export of physiologically important polyamines such as spermine from lysosomes to the cytosol, a function linked to a palette of disorders. Yet, the overall shape of P5B-ATPases and the mechanisms of polyamine recognition, uptake and transport remain elusive. Here we describe a series of cryo-electron microscopy structures of a yeast homolog of human ATP13A2-5, Ypk9, determined at resolutions reaching 3.4 Å, and depicting three separate transport cycle intermediates, including spermine-bound conformations. Surprisingly, in the absence of cargo, Ypk9 rests in a phosphorylated conformation auto-inhibited by the N-terminus. Spermine uptake is accomplished through an electronegative cleft lined by transmembrane segments 2, 4 and 6. Despite the dramatically different nature of the transported cargo, these findings pinpoint shared principles of transport and regulation among the evolutionary related P4-, P5A- and P5B-ATPases. The data also provide a framework for analysis of associated maladies, such as Parkinson’s disease.
A genetically encoded anti-CRISPR protein constrains gene drive spread and prevents population suppression
Authors: Taxiarchi Chrysanthi , Beaghton Andrea , Don Nayomi Illansinhage , Kyrou Kyros , Gribble Matthew , Shittu Dammy , Collins Scott P. , Beisel Chase L. , Galizi Roberto , Crisanti Andrea
Published: June 2021

CRISPR-based gene drives offer promising means to reduce the burden of pests and vector-borne diseases. These techniques consist of releasing genetically modified organisms carrying CRISPR-Cas nucleases designed to bias their inheritance and rapidly propagate desired modifications. Gene drives can be intended to reduce reproductive capacity of harmful insects or spread anti-pathogen effectors through wild populations, even when these confer fitness disadvantages. Technologies capable of halting the spread of gene drives may prove highly valuable in controlling, counteracting, and even reverting their effect on individual organisms as well as entire populations. Here we show engineering and testing of a genetic approach, based on the germline expression of a phage-derived anti-CRISPR protein (AcrIIA4), able to inactivate CRISPR-based gene drives and restore their inheritance to Mendelian rates in the malaria vector Anopheles gambiae. Modeling predictions and cage testing show that a single release of male mosquitoes carrying the AcrIIA4 protein can block the spread of a highly effective suppressive gene drive preventing population collapse of caged malaria mosquitoes.
Quantitative 3D real-space analysis of Laves phase supraparticles
Authors: Wang Da , van der Wee Ernest B. , Zanaga Daniele , Altantzis Thomas , Wu Yaoting , Dasgupta Tonnishtha , Dijkstra Marjolein , Murray Christopher B. , Bals Sara , van Blaaderen Alfons
Published: June 2021

Assembling binary mixtures of nanoparticles into crystals, gives rise to collective properties depending on the crystal structure and the individual properties of both species. However, quantitative 3D real-space analysis of binary colloidal crystals with a thickness of more than 10 layers of particles has rarely been performed. Here we demonstrate that an excess of one species in the binary nanoparticle mixture suppresses the formation of icosahedral order in the self-assembly in droplets, allowing the study of bulk-like binary crystal structures with a spherical morphology also called supraparticles. As example of the approach, we show single-particle level analysis of over 50 layers of Laves phase binary crystals of hard-sphere-like nanoparticles using electron tomography. We observe a crystalline lattice composed of a random mixture of the Laves phases. The number ratio of the binary species in the crystal lattice matches that of a perfect Laves crystal. Our methodology can be applied to study the structure of a broad range of binary crystals, giving insights into the structure formation mechanisms and structure-property relations of nanomaterials.
Nanoengineering of cathode layers for solid oxide fuel cells to achieve superior power densities
Authors: Develos-Bagarinao Katherine , Ishiyama Tomohiro , Kishimoto Haruo , Shimada Hiroyuki , Yamaji Katsuhiko
Published: June 2021

Solid oxide fuel cells (SOFCs) are power-generating devices with high efficiencies and considered as promising alternatives to mitigate energy and environmental issues associated with fossil fuel technologies. Nanoengineering of electrodes utilized for SOFCs has emerged as a versatile tool for significantly enhancing the electrochemical performance but needs to overcome issues for integration into practical cells suitable for widespread application. Here, we report an innovative concept for high-performance thin-film cathodes comprising nanoporous La0.6Sr0.4CoO3−δ cathodes in conjunction with highly ordered, self-assembled nanocomposite La0.6Sr0.4Co0.2Fe0.8O3−δ (lanthanum strontium cobalt ferrite) and Ce0.9Gd0.1O2−δ (gadolinia-doped ceria) cathode layers prepared using pulsed laser deposition. Integration of the nanoengineered cathode layers into conventional anode-supported cells enabled the achievement of high current densities at 0.7 V reaching ~2.2 and ~4.7 A/cm2 at 650 °C and 700 °C, respectively. This result demonstrates that tuning material properties through an effective nanoengineering approach could significantly boost the electrochemical performance of cathodes for development of next-generation SOFCs with high power output.
Light-driven decarboxylative deuteration enabled by a divergently engineered photodecarboxylase
Authors: Xu Jian , Fan Jiajie , Lou Yujiao , Xu Weihua , Wang Zhiguo , Li Danyang , Zhou Haonan , Lin Xianfu , Wu Qi
Published: June 2021

Despite the well-established chemical processes for C-D bond formation, the toolbox of enzymatic methodologies for deuterium incorporation has remained underdeveloped. Here we describe a photodecarboxylase from Chlorella variabilis NC64A (CvFAP)-catalyzed approach for the decarboxylative deuteration of various carboxylic acids by employing D2O as a cheap and readily available deuterium source. Divergent protein engineering of WT-CvFAP is implemented using Focused Rational Iterative Site-specific Mutagenesis (FRISM) as a strategy for expanding the substrate scope. Using specific mutants, several series of substrates including different chain length acids, racemic substrates as well as bulky cyclic acids are successfully converted into the deuterated products (>40 examples). In many cases WT-CvFAP fails completely. This approach also enables the enantiocomplementary kinetic resolution of racemic acids to afford chiral deuterated products, which can hardly be accomplished by existing methods. MD simulations explain the results of improved catalytic activity and stereoselectivity of WT CvFAP and mutants.
Super-resolving material microstructure image via deep learning for microstructure characterization and mechanical behavior analysis
Authors: Jung Jaimyun , Na Juwon , Park Hyung Keun , Park Jeong Min , Kim Gyuwon , Lee Seungchul , Kim Hyoung Seop
Published: June 2021

The digitized format of microstructures, or digital microstructures, plays a crucial role in modern-day materials research. Unfortunately, the acquisition of digital microstructures through experimental means can be unsuccessful in delivering sufficient resolution that is necessary to capture all relevant geometric features of the microstructures. The resolution-sensitive microstructural features overlooked due to insufficient resolution may limit one’s ability to conduct a thorough microstructure characterization and material behavior analysis such as mechanical analysis based on numerical modeling. Here, a highly efficient super-resolution imaging based on deep learning is developed using a deep super-resolution residual network to super-resolved low-resolution (LR) microstructure data for microstructure characterization and finite element (FE) mechanical analysis. Microstructure characterization and FE model based mechanical analysis using the super-resolved microstructure data not only proved to be as accurate as those based on high-resolution (HR) data but also provided insights on local microstructural features such as grain boundary normal and local stress distribution, which can be only partially considered or entirely disregarded in LR data-based analysis.
Fiber-specific white matter alterations in early-stage tremor-dominant Parkinson’s disease
Authors: Andica Christina , Kamagata Koji , Saito Yuya , Uchida Wataru , Fujita Shohei , Hagiwara Akifumi , Akashi Toshiaki , Wada Akihiko , Ogawa Takashi , Hatano Taku , Hattori Nobutaka , Aoki Shigeki
Published: June 2021

Using a fixel-based analysis (FBA), we assessed the fiber-specific white matter (WM) alterations in nonmedicated patients with early-stage Parkinson’s disease (PD) with tremor-dominant (TD; n = 53; mean age, 61.7 ± 8.7 years) and postural instability and gait disorder (PIGD; n = 27; mean age, 57.8 ± 8.1 years) motor subtypes and age- and sex-matched healthy controls (HC; n = 43; mean age, 61.6 ± 9.2 years) from Parkinson’s Progression Markers Initiative dataset. FBA revealed significantly increased macrostructural fiber cross section and a combination of fiber density and cross section metrics within the corticospinal tract in patients with TD-PD compared with HC. Nonetheless, no significant changes in FBA-derived metrics were found in patients with PIGD-PD compared with HC or patients with TD-PD. Our results may provide evidence of WM neural compensation mechanisms in patients with TD-PD marked by increases in fiber bundle size and the ability to relay information between brain regions.
Perception during use of force and the likelihood of firing upon an unarmed person
Authors: Biggs Adam T. , Hamilton Joseph A. , Jensen Andrew E. , Huffman Greg H. , Suss Joel , Dunn Timothy L. , Sherwood Sarah , Hirsch Dale A. , Rhoton Jayson , Kelly Karen R. , Markwald Rachel R.
Published: June 2021

Stress can impact perception, especially during use-of-force. Research efforts can thus advance both theory and practice by examining how perception during use-of-force might drive behavior. The current study explored the relationship between perceptual judgments and performance during novel close-combat training. Analyses included perceptual judgments from close-combat assessments conducted pre-training and post-training that required realistic use-of-force decisions in addition to an artificially construed stress-inoculation event used as a training exercise. Participants demonstrated significant reductions in situational awareness while under direct fire, which correlated to increased physiological stress. The initial likelihood of firing upon an unarmed person predicted the perceptual shortcomings of later stress-inoculation training. Subsequently, likelihood of firing upon an unarmed person was reduced following the stress-inoculation training. These preliminary findings have several implications for low or zero-cost solutions that might help trainers identify individuals who are underprepared for field responsibilities.
Coral distribution and bleaching vulnerability areas in Southwestern Atlantic under ocean warming
Authors: Bleuel Jessica , Pennino Maria Grazia , Longo Guilherme O.
Published: June 2021

Global climate change is a major threat to reefs by increasing the frequency and severity of coral bleaching events over time, reducing coral cover and diversity. Ocean warming may cause shifts in coral communities by increasing temperatures above coral’s upper thermal limits in tropical regions, and by making extratropical regions (marginal reefs) more suitable and potential refugia. We used Bayesian models to project coral occurrence, cover and bleaching probabilities in Southwestern Atlantic and predicted how these probabilities will change under a high-emission scenario (RCP8.5). By overlapping these projections, we categorized areas that combine high probabilities of coral occurrence, cover and bleaching as vulnerability-hotspots. Current coral occurrence and cover probabilities were higher in the tropics (1°S–20°S) but both will decrease and shift to new suitable extratropical reefs (20°S–27°S; tropicalization) with ocean warming. Over 90% of the area present low and mild vulnerability, while the vulnerability-hotspots represent ~ 3% under current and future scenarios, but include the most biodiverse reef complex in South Atlantic (13°S–18°S; Abrolhos Bank). As bleaching probabilities increase with warming, the least vulnerable areas that could act as potential refugia are predicted to reduce by 50%. Predicting potential refugia and highly vulnerable areas can inform conservation actions to face climate change.
Genome-wide association analyses identify genotype-by-environment interactions of growth traits in Simmental cattle
Authors: Braz Camila U. , Rowan Troy N. , Schnabel Robert D. , Decker Jared E.
Published: June 2021

Understanding genotype-by-environment interactions (G × E) is crucial to understand environmental adaptation in mammals and improve the sustainability of agricultural production. Here, we present an extensive study investigating the interaction of genome-wide SNP markers with a vast assortment of environmental variables and searching for SNPs controlling phenotypic variance (vQTL) using a large beef cattle dataset. We showed that G × E contribute 10.1%, 3.8%, and 2.8% of the phenotypic variance of birth weight, weaning weight, and yearling weight, respectively. G × E genome-wide association analysis (GWAA) detected a large number of G × E loci affecting growth traits, which the traditional GWAA did not detect, showing that functional loci may have non-additive genetic effects regardless of differences in genotypic means. Further, variance-heterogeneity GWAA detected loci enriched with G × E effects without requiring prior knowledge of the interacting environmental factors. Functional annotation and pathway analysis of G × E genes revealed biological mechanisms by which cattle respond to changes in their environment, such as neurotransmitter activity, hypoxia-induced processes, keratinization, hormone, thermogenic and immune pathways. We unraveled the relevance and complexity of the genetic basis of G × E underlying growth traits, providing new insights into how different environmental conditions interact with specific genes influencing adaptation and productivity in beef cattle and potentially across mammals.
The highly conserved FOXJ1 target CFAP161 is dispensable for motile ciliary function in mouse and Xenopus
Authors: Beckers Anja , Fuhl Franziska , Ott Tim , Boldt Karsten , Brislinger Magdalena Maria , Walentek Peter , Schuster-Gossler Karin , Hegermann Jan , Alten Leonie , Kremmer Elisabeth , Przykopanski Adina , Serth Katrin , Ueffing Marius , Blum Martin , Gossler Achim
Published: June 2021

Cilia are protrusions of the cell surface and composed of hundreds of proteins many of which are evolutionary and functionally well conserved. In cells assembling motile cilia the expression of numerous ciliary components is under the control of the transcription factor FOXJ1. Here, we analyse the evolutionary conserved FOXJ1 target CFAP161 in Xenopus and mouse. In both species Cfap161 expression correlates with the presence of motile cilia and depends on FOXJ1. Tagged CFAP161 localises to the basal bodies of multiciliated cells of the Xenopus larval epidermis, and in mice CFAP161 protein localises to the axoneme. Surprisingly, disruption of the Cfap161 gene in both species did not lead to motile cilia-related phenotypes, which contrasts with the conserved expression in cells carrying motile cilia and high sequence conservation. In mice mutation of Cfap161 stabilised the mutant mRNA making genetic compensation triggered by mRNA decay unlikely. However, genes related to microtubules and cilia, microtubule motor activity and inner dyneins were dysregulated, which might buffer the Cfap161 mutation.
The gastrin-releasing peptide/bombesin system revisited by a reverse-evolutionary study considering Xenopus
Authors: Hirooka Asuka , Hamada Mayuko , Fujiyama Daiki , Takanami Keiko , Kobayashi Yasuhisa , Oti Takumi , Katayama Yukitoshi , Sakamoto Tatsuya , Sakamoto Hirotaka
Published: June 2021

Bombesin is a putative antibacterial peptide isolated from the skin of the frog, Bombina bombina. Two related (bombesin-like) peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) have been found in mammals. The history of GRP/bombesin discovery has caused little attention to be paid to the evolutionary relationship of GRP/bombesin and their receptors in vertebrates. We have classified the peptides and their receptors from the phylogenetic viewpoint using a newly established genetic database and bioinformatics. Here we show, by using a clawed frog (Xenopus tropicalis), that GRP is not a mammalian counterpart of bombesin and also that, whereas the GRP system is widely conserved among vertebrates, the NMB/bombesin system has diversified in certain lineages, in particular in frog species. To understand the derivation of GRP system in the ancestor of mammals, we have focused on the GRP system in Xenopus. Gene expression analyses combined with immunohistochemistry and Western blotting experiments demonstrated that GRP peptides and their receptors are distributed in the brain and stomach of Xenopus. We conclude that GRP peptides and their receptors have evolved from ancestral (GRP-like peptide) homologues to play multiple roles in both the gut and the brain as one of the ‘gut-brain peptide’ systems.
Recanalization strategies in childhood stroke in Germany
Authors: Olivieri Martin , Sorg Anna-Lisa , Weinberger Raphael , Kurnik Karin , Bidlingmaier Christoph , Juranek Sabrina , Hoffmann Florian , Reiter Karl , Bonfert Michaela , Tacke Moritz , Borggraefe Ingo , Heinen Florian , Gerstl Lucia
Published: June 2021

Childhood arterial ischemic stroke (CAIS) is a rare event. Diverse etiologies, risk factors, symptoms and stroke mimics hamper obtaining a fast diagnosis and implementing immediate recanalization strategies. Over a period of 3 years (2015–2017), the data of 164 pediatric patients (> 28 days of life-18 years) with a first episode of AIS were submitted to a hospital-based nationwide surveillance system for rare disorders (ESPED). We report a subgroup analysis of patients who have undergone recanalization therapy and compare these data with those of the whole group. Twenty-eight patients (17%) with a median age of 12.2 years (range 3.3–16.9) received recanalization therapy. Hemiparesis, facial weakness and speech disturbance were the main presenting symptoms. The time from onset of symptoms to confirmation of diagnosis was significantly shorter in the intervention group (4.1 h vs. 20.4 h, p ≤ 0.0001). Only in one patient occurred a minor bleed. Cardiac disease as predisposing risk factor was more common in the recanalization group. Recanalization therapies are feasible and increasingly applied in children with AIS. High awareness, timely diagnosis and a large amount of expertise may improve time to treatment and make hyperacute therapy an option for more patients.
MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer
Authors: Hsu En-Chi , Shen Michelle , Aslan Merve , Liu Shiqin , Kumar Manoj , Garcia-Marques Fernando , Nguyen Holly M. , Nolley Rosalie , Pitteri Sharon J. , Corey Eva , Brooks James D. , Stoyanova Tanya
Published: June 2021

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.
Possibility of information encoding/decoding using the memory effect in fractional-order capacitive devices
Authors: Allagui Anis , Elwakil Ahmed S.
Published: June 2021

In this study, we show that the discharge voltage pattern of a supercapacitor exhibiting fractional-order behavior from the same initial steady-state voltage into a constant resistor is dependent on the past charging voltage profile. The charging voltage was designed to follow a power-law function, i.e. $$v_c(t)=V_{cc} \left( {t}/{t_{ss}}\right) ^p \;(0<t \leqslant t_{ss})$$

v
c

(
t
)

=

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/

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ss

p

(
0
<
t
⩽

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, in which $$t_{ss}$$

t

ss

(charging time duration between zero voltage to the terminal voltage $$V_{cc}$$

V

cc

) and p ($$0<p<1$$

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<
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1

) act as two variable parameters. We used this history-dependence of the dynamic behavior of the device to uniquely retrieve information pre-coded in the charging waveform pattern. Furthermore, we provide an analytical model based on fractional calculus that explains phenomenologically the information storage mechanism. The use of this intrinsic material memory effect may lead to new types of methods for information storage and retrieval.
The relationship between orthorexia nervosa symptomatology and body image attitudes and distortion
Authors: Pauzé Adrianne , Plouffe-Demers Marie-Pier , Fiset Daniel , Saint-Amour Dave , Cyr Caroline , Blais Caroline
Published: June 2021

Orthorexia Nervosa (ON), a condition characterized by a fixation on healthy eating, still does not conform to any consensus concerning diagnostic criteria, notably in regard to a possible body image component. This study investigated the relationship between ON symptomatology, measured with the Eating Habit Questionnaire, and body image attitudes and body image distortion in a non-clinical sample. Explicit body image attitudes and distortion were measured using the Multidimensional Body-Self Relations Questionnaire. Implicit body image attitudes and distortion were assessed using the reverse correlation technique. Correlational analyses showed that ON is associated with both explicit and implicit attitudes and distortion toward body image. More precisely, multivariate analyses combining various body image components showed that ON is mostly associated with explicit overweight preoccupation, explicit investment in physical health and leading a healthy lifestyle, and implicit muscularity distortion. These findings suggest that ON symptomatology is positively associated with body image attitudes and distortion in a non-clinical sample. However, further studies should be conducted to better understand how ON symptomatology relates to body image, especially among clinical samples.
Serum levels of inflammatory mediators as prognostic biomarker in silica exposed workers
Authors: Blanco-Pérez José Jesús , Blanco-Dorado Sara , Rodríguez-García Javier , Gonzalez-Bello Mª Elena , Salgado-Barreira Ángel , Caldera-Díaz Adriana Carolina , Pallarés-Sanmartín Abel , Fernandez-Villar Alberto , González-Barcala Francisco Javier
Published: June 2021

Silicosis is a diffuse interstitial lung disease caused by sustained inhalation of silica and silicates. Several cytokines are activated by their inhalation and can mediate the process of pulmonary fibrosis. The identification of biomarkers could allow an early diagnosis before the development of radiological alterations and help monitor the evolution of patients. The objetive of this study was to determine the clinical significance of specific biomarkers, to estimate their association with the development, severity and/or progression of silicosis, and identify determinants of this evolution. We conducted a prospective observational study in patients attending the pulmonology clinic from 2009 to 2018. Serum levels of the following inflammatory mediators were assessed: interleukin-6 (IL-6), interleukin 2 receptor subunit alpha (IL2R) interleukin 1 beta (IL1B), interleukin-8 (IL-8), tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta1 (TGF-β1), alpha-1 antitrypsin (AAT), C-reactive protein (CRP), lactate dehydrogenase (LDH) and ferritin in subjects exposed to silica, with and without silicosis. Association between those inflammatory mediators with lung function measurements and radiological severity of disease and their impact on prognosis were analysed. 337 exposed to silica (278 with silicosis) and 30 subjects in the control group were included. IL-8, α1AT, ferritin, CRP and LDH levels were higher in silicosis than in those exposed to silica without silicosis. IL-8, LDH and AAT levels were associated with progression of silicosis and IL-6, IL-8, LDH, AAT, ferritin, and CRP with vital status. The results of the ROC analysis indicated the potential of IL-8 as a biomarker in the presence of silicosis and for the prediction of mortality.
A patient-like swine model of gastrointestinal fibrotic strictures for advancing therapeutics
Authors: Li Ling , Itani Mohamad I. , Salimian Kevan J. , Li Yue , Gutierrez Olaya Brewer , Hu Haijie , Fayad George , Donet Jean A. , Joo Min Kyung , Ensign Laura M. , Kumbhari Vivek , Selaru Florin M.
Published: June 2021

Gastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans.
Quantitative assessment of intraneural vascular alterations in peripheral nerve trauma using high-resolution neurosonography: technical note
Authors: Dömer Patrick , Janssen-Bienhold Ulrike , Kewitz Bettina , Kretschmer Thomas , Heinen Christian
Published: June 2021

High-resolution neurosonography (HRNS) has become a major imaging modality in assessment of peripheral nerve trauma in the recent years. However, the vascular changes of traumatic lesions have not been quantitatively assessed in HRNS. Here, we describe the vascular-ratio, a novel HRNS-based quantitative parameter for the assessment of intraneural vascular alterations in patients with nerve lesions. N = 9 patients suffering from peripheral nerve trauma were examined clinically, electrophysiologically and with HRNS (SonoSite Exporte, Fuji). Image analyses using Fiji included determination of the established fascicular ratio (FR), the cross-section ratio (CSR), and as an extension, the calculation of a vascular ratio (VR) of the healthy versus damaged nerve and a muscle perfusion ratio (MPR) in comparison to a healthy control group. The mean VR in the healthy part of the affected nerve (14.14%) differed significantly (p < 0.0001) from the damaged part (VR of 43.26%). This coincides with significant differences in the FR and CSR calculated for the damaged part versus the healthy part and the controls. In comparison, there was no difference between VRs determined for the healthy part of the affected nerve and the healthy controls (14.14% / 17.72%). However, the MPR of denervated muscles was significantly decreased compared to the non-affected contralateral controls. VR and MPR serve as additional tools in assessing peripheral nerve trauma. Image analysis and calculation are feasible. Combined with the more morphologic FR and CSR, the VR and MPR provide a more detailed insight into alterations accompanying nerve trauma.
Viscoelastic testing reveals normalization of the coagulation profile 12 weeks after severe COVID-19
Authors: Magomedov Abakar , Zickler Daniel , Karaivanov Stoyan , Kurreck Annika , Münch Frédéric H. , Kamhieh-Milz Julian , Ferse Caroline , Kahl Andreas , Piper Sophie K. , Eckardt Kai-Uwe , Dörner Thomas , Kruse Jan Matthias
Published: June 2021

COVID 19 is associated with a hypercoagulable state and frequent thromboembolic complications. For how long this acquired abnormality lasts potentially requiring preventive measures, such as anticoagulation remains to be delineated. We used viscoelastic rotational thrombelastometry (ROTEM) in a single center cohort of 13 critical ill patients and performed follow up examinations three months after discharge from ICU. We found clear signs of a hypercoagulable state due to severe hypofibrinolysis and a high rate of thromboembolic complications during the phase of acute illness. Three month follow up revealed normalization of the initial coagulation abnormality and no evidence of venous thrombosis in all thirteen patients. In our cohort the coagulation profile was completely normalized three months after COVID-19. Based on these findings, discontinuation of anticoagulation can be discussed in patients with complete venous reperfusion.
Lung adenocarcinoma and lung squamous cell carcinoma cancer classification, biomarker identification, and gene expression analysis using overlapping feature selection methods
Authors: Chen Joe W. , Dhahbi Joseph
Published: June 2021

Lung cancer is one of the deadliest cancers in the world. Two of the most common subtypes, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), have drastically different biological signatures, yet they are often treated similarly and classified together as non-small cell lung cancer (NSCLC). LUAD and LUSC biomarkers are scarce, and their distinct biological mechanisms have yet to be elucidated. To detect biologically relevant markers, many studies have attempted to improve traditional machine learning algorithms or develop novel algorithms for biomarker discovery. However, few have used overlapping machine learning or feature selection methods for cancer classification, biomarker identification, or gene expression analysis. This study proposes to use overlapping traditional feature selection or feature reduction techniques for cancer classification and biomarker discovery. The genes selected by the overlapping method were then verified using random forest. The classification statistics of the overlapping method were compared to those of the traditional feature selection methods. The identified biomarkers were validated in an external dataset using AUC and ROC analysis. Gene expression analysis was then performed to further investigate biological differences between LUAD and LUSC. Overall, our method achieved classification results comparable to, if not better than, the traditional algorithms. It also identified multiple known biomarkers, and five potentially novel biomarkers with high discriminating values between LUAD and LUSC. Many of the biomarkers also exhibit significant prognostic potential, particularly in LUAD. Our study also unraveled distinct biological pathways between LUAD and LUSC.
Distinctive responses in anterior temporal lobe and ventrolateral prefrontal cortex during categorization of semantic information
Authors: Matsumoto Atsushi , Soshi Takahiro , Fujimaki Norio , Ihara Aya S.
Published: June 2021

Semantic categorization is a fundamental ability in language as well as in interaction with the environment. However, it is unclear what cognitive and neural basis generates this flexible and context dependent categorization of semantic information. We performed behavioral and fMRI experiments with a semantic priming paradigm to clarify this. Participants conducted semantic decision tasks in which a prime word preceded target words, using names of animals (mammals, birds, or fish). We focused on the categorization of unique marine mammals, having characteristics of both mammals and fish. Behavioral experiments indicated that marine mammals were semantically closer to fish than terrestrial mammals, inconsistent with the category membership. The fMRI results showed that the left anterior temporal lobe was sensitive to the semantic distance between prime and target words rather than category membership, while the left ventrolateral prefrontal cortex was sensitive to the consistency of category membership of word pairs. We interpreted these results as evidence of existence of dual processes for semantic categorization. The combination of bottom-up processing based on semantic characteristics in the left anterior temporal lobe and top-down processing based on task and/or context specific information in the left ventrolateral prefrontal cortex is required for the flexible categorization of semantic information.
Serum IgG4 levels at diagnosis can predict unfavorable outcomes of untreated patients with IgG4-related disease
Authors: Mizushima Ichiro , Konishi Masahiro , Sanada Hajime , Suzuki Kazuyuki , Takeji Akari , Zoshima Takeshi , Hara Satoshi , Ito Kiyoaki , Fujii Hiroshi , Yamada Kazunori , Kawano Mitsuhiro
Published: June 2021

The outcomes of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) who are not treated are unclear. This study aimed to clarify these outcomes and identify the factors related to them. We retrospectively evaluated various clinical features including laboratory data and involved organs at diagnosis in 107 patients with IgG4-RD, who were followed up for more than 6 months, at a single center in Japan. We compared the clinical features of the 27 untreated patients with those of the 80 patients treated with glucocorticoid. The patient outcomes were investigated, and logistic regression analysis was performed to identify factors related to them. The patients comprised 73 men and 34 women (median age 67 years). The untreated patients had significantly lower IgG4-RD responder index (9 vs. 12) and fewer affected organs (1 vs. 3) than did those treated with glucocorticoid. Of these 27 patients, 8 experienced deterioration of IgG4-RD after the diagnosis. In the age- and sex-adjusted logistic regression analysis, serum IgG4 elevation (per 100 mg/dL, odds ratio 1.194, 95% confidence interval 1.017–1.402) was the only significant factor related to disease deterioration in untreated patients with IgG4-RD, whereas not serum IgG4 levels (per 100 mg/dL, odds ratio 0.995, 95% confidence interval 0.921–1.075) but history of allergy (OR 3.134, 95% confidence interval 1.094–8.977, P = 0.033) related to deterioration in patients who underwent treatment. Serum IgG4 levels may be a useful predictor of unfavorable outcomes in untreated patients with IgG4-RD, who tend to have fewer affected organs and lower IgG4-RD responder index.
Characterization of micro-RNA in women with different ovarian reserve
Authors: Abu-Halima Masood , Becker Lea Simone , Ayesh Basim M. , Baus Simona Lucia , Hamza Amer , Fischer Ulrike , Hammadeh Mohamad , Keller Andreas , Meese Eckart
Published: June 2021

Women undergoing infertility treatment are routinely subjected to one or more tests of ovarian reserve. Therefore, an adequate assessment of the ovarian reserve is necessary for the treatment. In this study, we aimed to characterize the potential role of microRNAs (miRNAs) as biomarkers for women with different ovarian reserves. A total of 159 women were recruited in the study and classified according to their anti-Müllerian hormone (AMH) level into three groups: (1) low ovarian reserve (LAMH, n = 39), (2) normal ovarian reserve (NAMH, n = 80), and (3) high ovarian reserve (HAMH, n = 40). SurePrint Human miRNA array screening and reverse transcription-quantitative PCR (RT-qPCR) were respectively employed to screen and validate the miRNA abundance level in the three tested groups. Compared with NAMH, the abundance level of 34 and 98 miRNAs was found to be significantly altered in LAMH and HAMH, respectively. The abundance level of miRNAs was further validated by RT-qPCR in both, the screening samples as well as in an independent set of validation samples. The abundance levels of the validated miRNAs were significantly correlated with the AMH level. The best AUC value for the prediction of the increase and decrease in the AMH level was obtained for the miR-100-5p and miR-21-5p, respectively. The level of miRNAs abundance correlates with the level of AMH, which may serve as a tool for identifying women with a different ovarian reserve and may help to lay the ground for the development of novel diagnostic approaches.
Modulation of microglial phenotypes by dexmedetomidine through TREM2 reduces neuroinflammation in heatstroke
Authors: Li Ping , Shen Tingting , Luo Xue , Yang Ju , Luo Zhen , Tan Yulong , He Genlin , Wang Zeze , Yu Xueting , Wang Ying , Yang Xuesen
Published: June 2021

No FDA approved pharmacological therapy is available to reduce neuroinflammation following heatstroke. Previous studies have indicated that dexmedetomidine (DEX) could protect against inflammation and brain injury in various inflammation-associated diseases. However, no one has tested whether DEX has neuro-protective effects in heatstroke. In this study, we focused on microglial phenotypic modulation to investigate the mechanisms underlying the anti-inflammatory effects of DEX in vivo and in vitro. We found that DEX treatment reduced the expression of CD68, iNOS, TNF-α, and IL-1β, and increased the expression of CD206, Arg1, IL-10 and TGF-β in microglia, ameliorating heatstroke induced neuroinflammation and brain injury in mice. TREM2, whose neuro-protective function has been validated by genetic studies in Alzheimer’s disease and Nasu-Hakola disease, was significantly promoted by DEX in the microglia. TREM2 esiRNA reversed the DEX-induced activation of PI3K/Akt signalling. Overall these findings indicated that DEX may serve, as a potential therapeutic approach to ameliorate heatstroke induced neuroinflammation and brain injury via TREM2 by activating PI3K/Akt signalling.
Cl−-Induced selective fabrication of 3D AgCl microcrystals by a one-pot synthesis method
Authors: Wang Jiye , Qin Yazhou , Shi Qiaocui , Wen Luhong , Bi Lei
Published: June 2021

Cl− induces the shape evolution of AgCl crystals with different morphologies.