bluuebunny/crossref_metadata_2025 huggingface dataset:
Meta-analysis of probability estimates of worldwide variation of CYP2D6 and CYP2C19
Authors: Koopmans Anne B. , Braakman Mario H. , Vinkers David J. , Hoek Hans W. , van Harten Peter N.
Published: February 2021

Extensive migration has led to the necessity of knowledge regarding the treatment of migrants with different ethnical backgrounds. This is especially relevant for pharmacological treatment, because of the significant variation between migrant groups in their capacity to metabolize drugs. For psychiatric medications, CYP2D6 and CYP2C19 enzymes are clinically relevant. The aim of this meta-analysis was to analyze studies reporting clinically useful information regarding CYP2D6 and CYP2C19 genotype frequencies, across populations and ethnic groups worldwide. To that end, we conducted a comprehensive meta-analysis using Embase, PubMed, Web of Science, and PsycINFO (>336,000 subjects, 318 reports). A non-normal metabolizer (non-NM) probability estimate was introduced as the equivalent of the sum-prevalence of predicted poor, intermediate, and ultrarapid metabolizer CYP2D6 and CYP2C19 phenotypes. The probability of having a CYP2D6 non-NM predicted phenotype was highest in Algeria (61%) and lowest in Gambia (2.7%) while the probability for CYP2C19 was highest in India (80%) and lowest in countries in the Americas, particularly Mexico (32%). The mean total probability estimates of having a non-NM predicted phenotype worldwide were 36.4% and 61.9% for CYP2D6 and CYP2C19, respectively. We provide detailed tables and world maps summarizing clinically relevant data regarding the prevalence of CYP2D6 and CYP2C19 predicted phenotypes and demonstrating large inter-ethnic differences. Based on the documented probability estimates, pre-emptive pharmacogenetic testing is encouraged for every patient who will undergo therapy with a drug(s) that is metabolized by CYP2D6 and/or CYP2C19 pathways and should be considered in case of treatment resistance or serious side effects.
RNA editing of the 5-HT2C receptor in the central nucleus of the amygdala is involved in resilience behavior
Authors: Warhaftig Gal , Sokolik Chaya Mushka , Khermesh Khen , Lichtenstein Yehuda , Barak Michal , Bareli Tzofnat , Levanon Erez Y. , Yadid Gal
Published: February 2021

Post-traumatic-stress-disorder (PTSD) is a stress-related condition that may develop after exposure to a severe trauma-event. One of the core brain areas that is considered to be a key regulatory region of PTSD is the amygdala. Specifically, the central amygdala (CeA) is involved in emotion processing and associative fear learning memory, two main circuits involved in PTSD. Long term dysregulation of trauma-related emotional processing may be caused by neuroadaptations that affect gene expression. The adenosine-(A) to-inosine (I) RNA editing machinery is a post-transcriptional process that converts a genomic encoded A to I and is critical for normal brain function and development. Such editing has the potential to increase the transcriptome diversity, and disruption of this process has been linked to various central nervous system disorders. Here, we employed a unique animal model to examine the possibility that the RNA editing machinery is involved in PTSD. Detection of RNA editing specifically in the CeA revealed changes in the editing pattern of the 5-HT2C serotonin receptor (5-HT2CR) transcript accompanied by dynamic changes in the expression levels of the ADAR family enzymes (ADARandADARb1). Deamination byADARandADARb1enzymes induces conformational changes in the 5-HT2CR that decrease the G-protein-coupling activity, agonist affinity, and thus serotonin signaling. Significantly, a single intra-CeA administration of a 5-HT2CR pharmacological antagonist produced a robust alleviation of PTSD-like behaviors (that was maintained for three weeks) as well as single systemic treatment. This work may suggest the way to a new avenue in the understanding of PTSD regulation.
Chronic mild stress-induced protein dysregulations correlated with susceptibility and resiliency to depression or anxiety revealed by quantitative proteomics of the rat prefrontal cortex
Authors: Liao Wei , Liu Yanchen , Wang Lixiang , Cai Xiao , Xie Hong , Yi Faping , Huang Rongzhong , Fang Chui , Xie Peng , Zhou Jian
Published: February 2021

Chronic stress is a significant risk factor for depression as well as anxiety disorders. Yet, the stress-induced specific and common molecular dysregulations of these disorders have not been fully understood. Previously, we constructed a chronic mild stress (CMS) rat model to separate and obtain depression-susceptible, anxiety-susceptible, and insusceptible groups. In this study, the prefrontal cortical proteomes of the three stressed groups were comparatively profiled utilizing isobaric tags for relative and absolute quantitation (iTRAQ)-coupled tandem mass spectrometry approach. A total of 212 protein dysregulations were identified, potentially correlating to susceptibility or resilience to CMS-induced depression or anxiety, and thus might serve as potential protein targets for further investigation. In addition, independent analysis by parallel reaction monitoring identified changes in Gfap, Rhog, Gnai2, Ppp1r1b, and Uqcrh; Tubb6, Urod, Cul1, Spred1, and Gpcpd1; Acadl, Ppp1r1a, Grm2, Mtor, Lsm8, Cplx2, and Tsta3 that were distinctly correlated to depression-susceptible, anxiety-susceptible, or insusceptible groups, respectively. This suggested that identical CMS had different effects on the protein regulation system of the rat prefrontal cortex. Collectively, the present proteomics study of the prefrontal cortex established a significant molecular basis and offered new insights into the specificity and commonality of pathophysiologic mechanisms underlying susceptibility and resiliency to stress-induced depression or anxiety.
Hypothermic oxygenated perfusion inhibits HECTD3-mediated TRAF3 polyubiquitination to alleviate DCD liver ischemia-reperfusion injury
Authors: Zhou Wei , Zhong Zibiao , Lin Danni , Liu Zhongzhong , Zhang Qiuyan , Xia Haoyang , Peng Sheng , Liu Anxiong , Lu Zhongshan , Wang Yanfeng , Ye Shaojun , Ye Qifa
Published: February 2021

Ischemia-reperfusion injury (IRI) is an inevitable and serious clinical problem in donations after heart death (DCD) liver transplantation. Excessive sterile inflammation plays a fateful role in liver IRI. Hypothermic oxygenated perfusion (HOPE), as an emerging organ preservation technology, has a better preservation effect than cold storage (CS) for reducing liver IRI, in which regulating inflammation is one of the main mechanisms. HECTD3, a new E3 ubiquitin ligase, and TRAF3 have an essential role in inflammation. However, little is known about HECTD3 and TRAF3 in HOPE-regulated liver IRI. Here, we aimed to investigate the effects of HOPE on liver IRI in a DCD rat model and explore the roles of HECTD3 and TRAF3 in its pathogenesis. We found that HOPE significantly improved liver damage, including hepatocyte and liver sinusoidal endothelial cell injury, and reduced DCD liver inflammation. Mechanistically, both the DOC and HECT domains of HECTD3 directly interacted with TRAF3, and the catalytic Cys (C832) in the HECT domain promoted the K63-linked polyubiquitination of TRAF3 at Lys138. Further, the ubiquitinated TRAF3 at Lys138 increased oxidative stress and activated the NF-κB inflammation pathway to induce liver IRI in BRL-3A cells under hypoxia/reoxygenation conditions. Finally, we confirmed that the expression of HECTD3 and TRAF3 was obviously increased in human DCD liver transplantation specimens. Overall, these findings demonstrated that HOPE can protect against DCD liver transplantation-induced-liver IRI by reducing inflammation via HECTD3-mediated TRAF3 K63-linked polyubiquitination. Therefore, HOPE regulating the HECTD3/TRAF3 pathway is a novel target for improving IRI in DCD liver transplantation.
Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane
Authors: Phatak Vinaya , von Grabowiecki Yannick , Janus Justyna , Officer Leah , Behan Caron , Aschauer Lydia , Pinon Lucia , Mackay Hannah , Zanivan Sara , Norman Jim C. , Kelly Michael , Le Quesne John , Muller Patricia A. J.
Published: February 2021

TP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.
Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy
Authors: Zuo Shiman , Sun Luchen , Wang Yuxin , Chen Bing , Wang Jingyue , Ge Xiangyu , Lu Yan , Yang Nanfei , Shen Pingping
Published: February 2021

Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML.
Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats
Authors: Derbis Magdalena , Kul Emre , Niewiadomska Daria , Sekrecki Michał , Piasecka Agnieszka , Taylor Katarzyna , Hukema Renate K. , Stork Oliver , Sobczak Krzysztof
Published: February 2021

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in theFMR15’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.
A simple low-latency real-time certifiable quantum random number generator
Authors: Zhang Yanbao , Lo Hsin-Pin , Mink Alan , Ikuta Takuya , Honjo Toshimori , Takesue Hiroki , Munro William J.
Published: February 2021

Quantum random numbers distinguish themselves from others by their intrinsic unpredictability arising from the principles of quantum mechanics. As such they are extremely useful in many scientific and real-world applications with considerable efforts going into their realizations. Most demonstrations focus on high asymptotic generation rates. For this goal, a large number of repeated trials are required to accumulate a significant store of certifiable randomness, resulting in a high latency between the initial request and the delivery of the requested random bits. Here we demonstrate low-latency real-time certifiable randomness generation from measurements on photonic time-bin states. For this, we develop methods to certify randomness taking into account adversarial imperfections in both the state preparation and the measurement apparatus. Every 0.12 s we generate a block of 8192 random bits which are certifiable against all quantum adversaries with an error bounded by 2−64. Our quantum random number generator is thus well suited for realizing a continuously-operating, high-security and high-speed quantum randomness beacon.
Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome
Authors: Hartlieb Sabine A. , Sieverling Lina , Nadler-Holly Michal , Ziehm Matthias , Toprak Umut H. , Herrmann Carl , Ishaque Naveed , Okonechnikov Konstantin , Gartlgruber Moritz , Park Young-Gyu , Wecht Elisa Maria , Savelyeva Larissa , Henrich Kai-Oliver , Rosswog Carolina , Fischer Matthias , Hero Barbara , Jones David T. W. , Pfaff Elke , Witt Olaf , Pfister Stefan M. , Volckmann Richard , Koster Jan , Kiesel Katharina , Rippe Karsten , Taschner-Mandl Sabine , Ambros Peter , Brors Benedikt , Selbach Matthias , Feuerbach Lars , Westermann Frank
Published: February 2021

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.
Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19
Authors: Salguero Francisco J. , White Andrew D. , Slack Gillian S. , Fotheringham Susan A. , Bewley Kevin R. , Gooch Karen E. , Longet Stephanie , Humphries Holly E. , Watson Robert J. , Hunter Laura , Ryan Kathryn A. , Hall Yper , Sibley Laura , Sarfas Charlotte , Allen Lauren , Aram Marilyn , Brunt Emily , Brown Phillip , Buttigieg Karen R. , Cavell Breeze E. , Cobb Rebecca , Coombes Naomi S. , Darby Alistair , Daykin-Pont Owen , Elmore Michael J. , Garcia-Dorival Isabel , Gkolfinos Konstantinos , Godwin Kerry J. , Gouriet Jade , Halkerston Rachel , Harris Debbie J. , Hender Thomas , Ho Catherine M. K. , Kennard Chelsea L. , Knott Daniel , Leung Stephanie , Lucas Vanessa , Mabbutt Adam , Morrison Alexandra L. , Nelson Charlotte , Ngabo Didier , Paterson Jemma , Penn Elizabeth J. , Pullan Steve , Taylor Irene , Tipton Tom , Thomas Stephen , Tree Julia A. , Turner Carrie , Vamos Edith , Wand Nadina , Wiblin Nathan R. , Charlton Sue , Dong Xiaofeng , Hallis Bassam , Pearson Geoffrey , Rayner Emma L. , Nicholson Andrew G. , Funnell Simon G. , Hiscox Julian A. , Dennis Mike J. , Gleeson Fergus V. , Sharpe Sally , Carroll Miles W.
Published: February 2021

A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.
Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer
Authors: Mizuta Hayato , Okada Koutaroh , Araki Mitsugu , Adachi Jun , Takemoto Ai , Kutkowska Justyna , Maruyama Kohei , Yanagitani Noriko , Oh-hara Tomoko , Watanabe Kana , Tamai Keiichi , Friboulet Luc , Katayama Kazuhiro , Ma Biao , Sasakura Yoko , Sagae Yukari , Kukimoto-Niino Mutsuko , Shirouzu Mikako , Takagi Satoshi , Simizu Siro , Nishio Makoto , Okuno Yasushi , Fujita Naoya , Katayama Ryohei
Published: February 2021

ALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.
Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
Authors: Colombo Alessio , Dinkel Lina , Müller Stephan A. , Sebastian Monasor Laura , Schifferer Martina , Cantuti-Castelvetri Ludovico , König Jasmin , Vidatic Lea , Bremova-Ertl Tatiana , Lieberman Andrew P. , Hecimovic Silva , Simons Mikael , Lichtenthaler Stefan F. , Strupp Michael , Schneider Susanne A. , Tahirovic Sabina
Published: February 2021

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1−/− microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.
Ensembled deep learning model outperforms human experts in diagnosing biliary atresia from sonographic gallbladder images
Authors: Zhou Wenying , Yang Yang , Yu Cheng , Liu Juxian , Duan Xingxing , Weng Zongjie , Chen Dan , Liang Qianhong , Fang Qin , Zhou Jiaojiao , Ju Hao , Luo Zhenhua , Guo Weihao , Ma Xiaoyan , Xie Xiaoyan , Wang Ruixuan , Zhou Luyao
Published: February 2021

It is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural area without relevant expertise. To help diagnose BA based on sonographic gallbladder images, an ensembled deep learning model is developed. The model yields a patient-level sensitivity 93.1% and specificity 93.9% [with areas under the receiver operating characteristic curve of 0.956 (95% confidence interval: 0.928-0.977)] on the multi-center external validation dataset, superior to that of human experts. With the help of the model, the performances of human experts with various levels are improved. Moreover, the diagnosis based on smartphone photos of sonographic gallbladder images through a smartphone app and based on video sequences by the model still yields expert-level performances. The ensembled deep learning model in this study provides a solution to help radiologists improve the diagnosis of BA in various clinical application scenarios, particularly in rural and undeveloped regions with limited expertise.
Asymmetric water transport in dense leaf cuticles and cuticle-inspired compositionally graded membranes
Authors: Kamtsikakis Aristotelis , Baales Johanna , Zeisler-Diehl Viktoria V. , Vanhecke Dimitri , Zoppe Justin O. , Schreiber Lukas , Weder Christoph
Published: February 2021

Most of the aerial organs of vascular plants are covered by a protective layer known as the cuticle, the main purpose of which is to limit transpirational water loss. Cuticles consist of an amphiphilic polyester matrix, polar polysaccharides that extend from the underlying epidermal cell wall and become less prominent towards the exterior, and hydrophobic waxes that dominate the surface. Here we report that the polarity gradient caused by this architecture renders the transport of water through astomatous olive and ivy leaf cuticles directional and that the permeation is regulated by the hydration level of the cutin-rich outer cuticular layer. We further report artificial nanocomposite membranes that are inspired by the cuticles’ compositionally graded architecture and consist of hydrophilic cellulose nanocrystals and a hydrophobic polymer. The structure and composition of these cuticle-inspired membranes can easily be varied and this enables a systematic investigation of the water transport mechanism.
Power sector investment implications of climate impacts on renewable resources in Latin America and the Caribbean
Authors: Santos da Silva Silvia R. , Hejazi Mohamad I. , Iyer Gokul , Wild Thomas B. , Binsted Matthew , Miralles-Wilhelm Fernando , Patel Pralit , Snyder Abigail C. , Vernon Chris R.
Published: February 2021

Climate change mitigation will require substantial investments in renewables. In addition, climate change will affect future renewable supply and hence, power sector investment requirements. We study the implications of climate impacts on renewables for power sector investments under deep decarbonization using a global integrated assessment model. We focus on Latin American and Caribbean, an under-studied region but of great interest due to its strong role in international climate mitigation and vulnerability to climate change. We find that accounting for climate impacts on renewables results in significant additional investments ($12–114 billion by 2100 across Latin American countries) for a region with weak financial infrastructure. We also demonstrate that accounting for climate impacts only on hydropower—a primary focus of previous studies—significantly underestimates cumulative investments, particularly in scenarios with high intermittent renewable deployment. Our study underscores the importance of comprehensive analyses of climate impacts on renewables for improved energy planning.
Ocean fronts and eddies force atmospheric rivers and heavy precipitation in western North America
Authors: Liu Xue , Ma Xiaohui , Chang Ping , Jia Yinglai , Fu Dan , Xu Guangzhi , Wu Lixin , Saravanan R. , Patricola Christina M.
Published: February 2021

Atmospheric rivers (ARs) are responsible for over 90% of poleward water vapor transport in the mid-latitudes and can produce extreme precipitation when making landfall. However, weather and climate models still have difficulty simulating and predicting landfalling ARs and associated extreme precipitation, highlighting the need to better understand AR dynamics. Here, using high-resolution climate models and observations, we demonstrate that mesoscale sea-surface temperature (SST) anomalies along the Kuroshio Extension can exert a remote influence on landfalling ARs and related heavy precipitation along the west coast of North America. Inclusion of mesoscale SST forcing in the simulations results in approximately a 40% increase in landfalling ARs and up to a 30% increase in heavy precipitation in mountainous regions and this remote impact occurs on two-week time scales. The asymmetrical response of the atmosphere to warm vs. cold mesoscale SSTs over the eddy-rich Kuroshio Extension region is proposed as a forcing mechanism that results in a net increase of moisture flux above the planetary boundary layer, prompting AR genesis via enhancing moisture transport into extratropical cyclones in the presence of mesoscale SST forcing.
The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation
Authors: Minns Danielle , Smith Katie J. , Alessandrini Virginia , Hardisty Gareth , Melrose Lauren , Jackson-Jones Lucy , MacDonald Andrew S. , Davidson Donald J. , Gwyer Findlay Emily
Published: February 2021

The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1, cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.
Accurate imputation of human leukocyte antigens with CookHLA
Authors: Cook Seungho , Choi Wanson , Lim Hyunjoon , Luo Yang , Kim Kunhee , Jia Xiaoming , Raychaudhuri Soumya , Han Buhm
Published: February 2021

The recent development of imputation methods enabled the prediction of human leukocyte antigen (HLA) alleles from intergenic SNP data, allowing studies to fine-map HLA for immune phenotypes. Here we report an accurate HLA imputation method, CookHLA, which has superior imputation accuracy compared to previous methods. CookHLA differs from other approaches in that it locally embeds prediction markers into highly polymorphic exons to account for exonic variability, and in that it adaptively learns the genetic map within MHC from the data to facilitate imputation. Our benchmarking with real datasets shows that our method achieves high imputation accuracy in a wide range of scenarios, including situations where the reference panel is small or ethnically unmatched.
Carbon prospecting in tropical forests for climate change mitigation
Authors: Koh Lian Pin , Zeng Yiwen , Sarira Tasya Vadya , Siman Kelly
Published: February 2021

Carbon finance projects that protect tropical forests could support both nature conservation and climate change mitigation goals. Global demand for nature-based carbon credits is outpacing their supply, due partly to gaps in knowledge needed to inform and prioritize investment decisions. Here, we show that at current carbon market prices the protection of tropical forests can generate investible carbon amounting to 1.8 (±1.1) GtCO2e yr−1 globally. We further show that financially viable carbon projects could generate return-on-investment amounting to $46.0b y−1 in net present value (Asia-Pacific: $24.6b y−1; Americas: $19.1b y−1; Africa: $2.4b y−1). However, we also find that ~80% (1.24 billion ha) of forest carbon sites would be financially unviable for failing to break even over the project lifetime. From a conservation perspective, unless carbon prices increase in the future, it is imperative to implement other conservation interventions, in addition to carbon finance, to safeguard carbon stocks and biodiversity in vulnerable forests.
Rare versus common diseases: a false dichotomy in precision medicine
Authors: Chung Brian Hon Yin , Chau Jeffrey Fong Ting , Wong Gane Ka-Shu
Published: February 2021

Precision medicine initiatives are being launched worldwide, each with the capacity to sequence many thousands to millions of human genomes. At the strategic planning level, all are debating the extent to which these resources will be directed towards rare diseases (and cancers) versus common diseases. However, these are not mutually exclusive choices. The organizational and governmental infrastructure created for rare diseases is extensible to common diseases. As we will explain, the underlying technology can also be used to identify drug targets for common diseases with a strategy focused on naturally occurring human knockouts. This flips on its head the prevailing modus operandi of studying people with diseases of interest, shifting the onus to defining traits worth emulating by pharmaceuticals, and searching phenotypically for people with these traits. This also shifts the question of what is rare or common from the many underlying causes to the possibility of a common final pathway.
Benefit of a single simulated hypobaric hypoxia in healthy mice performance and analysis of mitochondria-related gene changes
Authors: Wu Fei-Fei , Zhang Kun-Long , Wang Zheng-Mei , Yang Yi , Li Shao-Hua , Wang Jia-Qi , Ma Jin , Yang Yan-Ling , Zhang Hai-Feng , Wang Ya-Yun
Published: February 2021

Simulated hypobaric hypoxia (SHH) training has been used to enhance running performance. However, no studies have evaluated the effects of a single SHH exposure on healthy mice performance and analyzed the changes of mitochondria-related genes in the central nervous system. The current study used a mouse decompression chamber to simulate mild hypobaric hypoxia at the high altitude of 5000 m or severe hypobaric hypoxia at 8000 m for 16 h (SHH5000 & SHH8000, respectively). Then, the mouse behavioral tests were recorded by a modified Noldus video tracking. Third, the effects of SHH on 8 mitochondria-related genes of Drp1, Mfn1, Mfn2, Opa1, TFAM, SGK1, UCP2 and UCP4, were assessed in cerebellum, hippocampus and gastrocnemius muscles. The results have shown that a single mild or severe HH improves healthy mice performance. In cerebellum, 6 of all 8 detected genes (except Mfn2 and UCP4) did not change after SHH. In hippocampus, all detected genes did not change after SHH. In muscles, 7 of all 8 detected genes (except Opa1) did not change after SHH. The present study has indicated the benefit of a single SHH in healthy mice performance, which would due to the stabilized mitochondria against a mild stress state.
C-Glucosylation as a tool for the prevention of PAINS-induced membrane dipole potential alterations
Authors: de Matos Ana Marta , Blázquez-Sánchez Maria Teresa , Sousa Carla , Oliveira Maria Conceição , de Almeida Rodrigo F. M. , Rauter Amélia P.
Published: February 2021

The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. Based on the established relationship between altered membrane dipole potential and transmembrane protein conformation and function, we investigate here polyphenols' ability to induce changes in cell membrane dipole potential. Ultimately, we are interested in finding a tool to prevent polyphenol PAINS-type behavior and produce compounds less prone to untargeted and promiscuous interactions with the cell membrane. Di-8-ANEPPS fluorescence ratiometric measurements suggest that planar lipophilic polyphenols—phloretin, genistein and resveratrol—act by decreasing membrane dipole potential, especially in cholesterol-rich domains such as lipid rafts, which play a role in important cellular processes. These results provide a mechanism for their labelling as PAINS through their ability to disrupt cell membrane homeostasis. Aiming to explore the role ofC-glucosylation in PAINS membrane-interfering behavior, we disclose herein the first synthesis of 4-glucosylresveratrol, starting from 5-hydroxymethylbenzene-1,3-diol, viaC-glucosylation, oxidation and Horner-Wadsworth-Emmons olefination, and resynthesize phloretin and genisteinC-glucosides. We show that C-glucosylation generates compounds which are no longer able to modify membrane dipole potential. Therefore, it can be devised as a strategy to generate bioactive natural product derivatives that no longer act as membrane dipole potential modifiers. Our results offer a new technology towards rescuing bioactive polyphenols from their PAINS danger label through C–C ligation of sugars.
Development of titanium 3D mesh interlayer for enhancing the electrochemical performance of zinc–bromine flow battery
Authors: Lee Je-Nam , Do Eunbyul , Kim Youngkwon , Yu Ji-Sang , Kim Ki Jae
Published: February 2021

Zinc dendrite growth negatively affects zinc–bromine flow battery (ZBB) performance by causing membrane damage, inducing self-discharge. Herein, in a ZBB, a conventional polymer mesh was replaced with a titanium-based mesh interlayer; this provided additional abundant active sites for the Zn2+/Zn redox reaction and well-developed electrolyte flow channels, which resulted in improved reaction kinetics and suppressed Zn dendrite growth. Compared with a ZBB cell comprising a conventional polymer mesh and a carbon-based electrode, the ZBB cell using the titanium mesh interlayer and a carbon-based electrode showed significantly reduced frequency of the refreshing process, which occurs at regular cycling intervals during practical use for removing residual zinc dendrites in ZBB; also, the average energy efficiency at a current density of 40 mA cm−2 increased by 38.5%. Moreover, the modified ZBB cell exhibited higher energy efficiency at a high current density of 80 mA cm−2, which is an improvement of 14.7% than in case of the contemporary polymer mesh. Consequently, this study can provide helpful insights for new anode side structures including spacer mesh for developing high-performance ZBBs.
Predictors and complications of side branch occlusion after recanalization of chronic total occlusions complicated with bifurcation lesions
Authors: Guo Yunfei , Peng Hongyu , Zhao Yejing , Liu Jinghua
Published: February 2021

Data on risk factors and periprocedural complications associated with side branch (SB) occlusion after chronic coronary total occlusion (CTO) recanalization are limited. The aims of this study were to identify independent predictors of side branch (SB) occlusion after chronic total occlusion (CTO) recanalization and assess the relationship between SB occlusion and perioperative complications. 245 patients with CTO bifurcation lesions (BFLs) who underwent successful CTO recanalization were included in the study. In the occlusion group, most of the SB occlusions were observed after the implantation of the stents and lack of SB protection was more common. However, there was no significant between-group difference in the angles between the main vessel (MV) and SB. SB occlusion was associated with a higher risk of periprocedural myocardial infarction and a higher composite periprocedural complication rate. Identified as predictors of SB occlusion were no SB protection, use of a dissection-reentry strategy, ostial SB stenosis, and proximal MV stenosis of 50% or more.
Achieving herd immunity against COVID-19 at the country level by the exit strategy of a phased lift of control
Authors: de Vlas Sake J. , Coffeng Luc E.
Published: February 2021

The COVID-19 pandemic has affected the entire world causing substantial numbers of cases and deaths in most countries. Many have implemented nationwide stringent control to avoid overburdening the health care system. This has paralyzed economic and social activities and may continue to do so until the large-scale availability of a vaccine. We propose an alternative exit strategy to develop herd immunity in a predictable and controllable way: a phased lift of control. This means that successive parts of the country (e.g. provinces) stop stringent control, and COVID-19-related IC admissions are distributed over the country as a whole. Importantly, vulnerable individuals need to be shielded until herd immunity has developed in their area. We explore the characteristics and duration of this strategy using a novel individual-based model for geographically stratified transmission of COVID-19 in a country. The model predicts that individuals will have to experience stringent control for about 14 months on average, but this duration may be almost halved by further developments (more IC beds, better treatments). Clearly, implementation of this strategy would have a profound impact on individuals and society, and should therefore be considered carefully by various other disciplines (e.g. health systems, ethics, economics) before actual implementation.
Greenland-wide inventory of ice marginal lakes using a multi-method approach
Authors: How Penelope , Messerli Alexandra , Mätzler Eva , Santoro Maurizio , Wiesmann Andreas , Caduff Rafael , Langley Kirsty , Bojesen Mikkel Høegh , Paul Frank , Kääb Andreas , Carrivick Jonathan L.
Published: February 2021

Ice marginal lakes are a dynamic component of terrestrial meltwater storage at the margin of the Greenland Ice Sheet. Despite their significance to the sea level budget, local flood hazards and bigeochemical fluxes, there is a lack of Greenland-wide research into ice marginal lakes. Here, a detailed multi-sensor inventory of Greenland’s ice marginal lakes is presented based on three well-established detection methods to form a unified remote sensing approach. The inventory consists of 3347 ($$\pm 8$$

±
8

%) ice marginal lakes ($$>0.05\,{{\text{ km }}^{2}}$$

>
0.05

km

2

) detected for the year 2017. The greatest proportion of lakes lie around Greenland’s ice caps and mountain glaciers, and the southwest margin of the ice sheet. Through comparison to previous studies, a $$\sim 75$$

∼
75

% increase in lake frequency is evident over the west margin of the ice sheet since 1985. This suggests it is becoming increasingly important to include ice marginal lakes in future sea level projections, where these lakes will form a dynamic storage of meltwater that can influence outlet glacier dynamics. Comparison to existing global glacial lake inventories demonstrate that up to 56% of ice marginal lakes could be unaccounted for in global estimates of ice marginal lake change, likely due to the reliance on a single lake detection method.
Evaluation of different surgical approaches to remove dental implants from the maxillary sinus
Authors: Hamdoon Zaid , Mahmood Nazhat , Talaat Wael , Sattar Abier Abdul , Naeim Karrar , Qais Ahmed , Kheder Waad , Jerjes Waseem
Published: February 2021

Dental implant surgery on atrophied maxilla has many risks; in some patients, simultaneous sinus lifting with implant placement must be performed to increase the chances of successful implantation; this procedure can cause implant migration. Eleven patients were diagnosed with implant migration into the maxillary sinus in four anatomical areas: the sinus floor above the alveolar bone, near the junction of the sinus and nasal floor, near the floor of the orbit, and the most posterior aspect of the sinus. Surgical removal was performed through four different direct non-endoscopic transoral approaches depending on the location of the displaced implant. Surgical challenges, surgery duration and postoperative complications were reported. The least challenging surgical intervention was noted when removing the displaced implants from the floor of the sinus through the crestal approach. More challenges were experienced during the surgical removal of anteriorly displaced implants near the roof of the orbital floor due to surgical access and the proximity of vital anatomical structures. Bleeding from the pterygoid venous plexus was profound with the posterior lateral approach. The choice of an appropriate surgical approach to retrieve displaced dental implants from the maxillary sinus depends on the location of the implant and the surrounding vital anatomical structures.
Arm order recognition in multi-armed bandit problem with laser chaos time series
Authors: Narisawa Naoki , Chauvet Nicolas , Hasegawa Mikio , Naruse Makoto
Published: February 2021

By exploiting ultrafast and irregular time series generated by lasers with delayed feedback, we have previously demonstrated a scalable algorithm to solve multi-armed bandit (MAB) problems utilizing the time-division multiplexing of laser chaos time series. Although the algorithm detects the arm with the highest reward expectation, the correct recognition of the order of arms in terms of reward expectations is not achievable. Here, we present an algorithm where the degree of exploration is adaptively controlled based on confidence intervals that represent the estimation accuracy of reward expectations. We have demonstrated numerically that our approach did improve arm order recognition accuracy significantly, along with reduced dependence on reward environments, and the total reward is almost maintained compared with conventional MAB methods. This study applies to sectors where the order information is critical, such as efficient allocation of resources in information and communications technology.
Impact of down-stream processing on functional properties of yeasts and the implications on gut health of Atlantic salmon (Salmo salar)
Authors: Agboola Jeleel Opeyemi , Schiavone Marion , Øverland Margareth , Morales-Lange Byron , Lagos Leidy , Arntzen Magnus Øverlie , Lapeña David , Eijsink Vincent G. H. , Horn Svein Jarle , Mydland Liv Torunn , François Jean Marie , Mercado Luis , Hansen Jon Øvrum
Published: February 2021

Yeasts are becoming popular as novel ingredients in fish feeds because of their potential to support better growth and concomitantly ensure good fish health. Here, three species of yeasts (Cyberlindnera jadinii, Blastobotrys adeninivorans and Wickerhamomyces anomalus), grown on wood sugars and hydrolysates of chicken were subjected to two down-stream processes, either direct heat-inactivation or autolysis, and the feed potential of the resulting yeast preparations was assessed through a feeding trial with Atlantic salmon fry. Histological examination of distal intestine based on widening of lamina propria, showed that autolyzed W. anomalus was effective in alleviating mild intestinal enteritis, while only limited effects were observed for other yeasts. Our results showed that the functionality of yeast in counteracting intestinal enteritis in Atlantic salmon was dependent on both the type of yeast and the down-stream processing method, and demonstrated that C. jadinii and W. anomalus have promising effects on gut health of Atlantic salmon.
Population structure and genetic diversity of non-O157 Shiga toxin-producing Escherichia coli (STEC) clinical isolates from Michigan
Authors: Blankenship Heather M. , Mosci Rebekah E. , Dietrich Stephen , Burgess Elizabeth , Wholehan Jason , McWilliams Karen , Pietrzen Karen , Benko Scott , Gatesy Ted , Rudrik James. T. , Soehnlen Marty , Manning Shannon D.
Published: February 2021

Non-O157 STEC are increasingly linked to foodborne infections, yet little is known about the diversity and molecular epidemiology across locations. Herein, we used whole genome sequencing to examine genetic variation in 894 isolates collected from Michigan patients between 2001 and 2018. In all, 67 serotypes representing 69 multilocus sequence types were identified. Serotype diversity increased from an average of four (2001–2006) to 17 (2008–2018) serotypes per year. The top six serogroups reported nationally caused > 60% of infections in 16 of the 18 years; serogroups O111 and O45 were associated with hospitalization as were age ≥ 65 years, diarrhea with blood and female sex. Phylogenetic analyses of seven multilocus sequence typing (MLST) loci identified three clades as well as evidence of parallel evolution and recombination. Most (95.5%) isolates belonged to one clade, which could be further differentiated into seven subclades comprising isolates with varying virulence gene profiles and serotypes. No association was observed between specific clades and the epidemiological data, suggesting that serogroup- and serotype-specific associations are more important predictors of disease outcomes than lineages defined by MLST. Molecular epidemiological studies of non-O157 STEC are important to enhance understanding of circulating strain distributions and traits, genetic variation, and factors that may impact disease risk and severity.