bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamics of TCR repertoire and T cell function in COVID-19 convalescent individuals
Authors: Luo Lingjie , Liang Wenhua , Pang Jianfeng , Xu Gang , Chen Yingying , Guo Xinrong , Wang Xin , Zhao Yi , Lai Yangdian , Liu Yang , Li Bin , Su Bing , Zhang Shuye , Baniyash Michal , Shen Lei , Chen Lei , Ling Yun , Wang Ying , Liang Qiming , Lu Hongzhou , Zhang Zheng , Wang Feng
Published: September 2021

SARS-CoV-2 outbreak has been declared by World Health Organization as a worldwide pandemic. However, there are many unknowns about the antigen-specific T-cell-mediated immune responses to SARS-CoV-2 infection. Here, we present both single-cell TCR-seq and RNA-seq to analyze the dynamics of TCR repertoire and immune metabolic functions of blood T cells collected from recently discharged COVID-19 patients. We found that while the diversity of TCR repertoire was increased in discharged patients, it returned to basal level ~1 week after becoming virus-free. The dynamics of T cell repertoire correlated with a profound shift of gene signatures from antiviral response to metabolism adaptation. We also demonstrated that the top expanded T cell clones (~10% of total T cells) display the key anti-viral features in CD8+ T cells, confirming a critical role of antigen-specific T cells in fighting against SARS-CoV-2. Our work provides a basis for further analysis of adaptive immunity in COVID-19 patients, and also has implications in developing a T-cell-based vaccine for SARS-CoV-2.
Thiocysteine lyases as polyketide synthase domains installing hydropersulfide into natural products and a hydropersulfide methyltransferase
Authors: Meng Song , Steele Andrew D. , Yan Wei , Pan Guohui , Kalkreuter Edward , Liu Yu-Chen , Xu Zhengren , Shen Ben
Published: September 2021

Nature forms S-S bonds by oxidizing two sulfhydryl groups, and no enzyme installing an intact hydropersulfide (-SSH) group into a natural product has been identified to date. The leinamycin (LNM) family of natural products features intact S-S bonds, and previously we reported an SH domain (LnmJ-SH) within the LNM hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line as a cysteine lyase that plays a role in sulfur incorporation. Here we report the characterization of an S-adenosyl methionine (SAM)-dependent hydropersulfide methyltransferase (GnmP) for guangnanmycin (GNM) biosynthesis, discovery of hydropersulfides as the nascent products of the GNM and LNM hybrid NRPS-PKS assembly lines, and revelation of three SH domains (GnmT-SH, LnmJ-SH, and WsmR-SH) within the GNM, LNM, and weishanmycin (WSM) hybrid NRPS-PKS assembly lines as thiocysteine lyases. Based on these findings, we propose a biosynthetic model for the LNM family of natural products, featuring thiocysteine lyases as PKS domains that directly install a -SSH group into the GNM, LNM, or WSM polyketide scaffold. Genome mining reveals that SH domains are widespread in Nature, extending beyond the LNM family of natural products. The SH domains could also be leveraged as biocatalysts to install an -SSH group into other biologically relevant scaffolds.
Probabilistic tsunami forecasting for early warning
Authors: Selva J. , Lorito S. , Volpe M. , Romano F. , Tonini R. , Perfetti P. , Bernardi F. , Taroni M. , Scala A. , Babeyko A. , Løvholt F. , Gibbons S. J. , Macías J. , Castro M. J. , González-Vida J. M. , Sánchez-Linares C. , Bayraktar H. B. , Basili R. , Maesano F. E. , Tiberti M. M. , Mele F. , Piatanesi A. , Amato A.
Published: September 2021

Tsunami warning centres face the challenging task of rapidly forecasting tsunami threat immediately after an earthquake, when there is high uncertainty due to data deficiency. Here we introduce Probabilistic Tsunami Forecasting (PTF) for tsunami early warning. PTF explicitly treats data- and forecast-uncertainties, enabling alert level definitions according to any predefined level of conservatism, which is connected to the average balance of missed-vs-false-alarms. Impact forecasts and resulting recommendations become progressively less uncertain as new data become available. Here we report an implementation for near-source early warning and test it systematically by hindcasting the great 2010 M8.8 Maule (Chile) and the well-studied 2003 M6.8 Zemmouri-Boumerdes (Algeria) tsunamis, as well as all the Mediterranean earthquakes that triggered alert messages at the Italian Tsunami Warning Centre since its inception in 2015, demonstrating forecasting accuracy over a wide range of magnitudes and earthquake types.
The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
Authors: Ottema Sophie , Mulet-Lazaro Roger , Erpelinck-Verschueren Claudia , van Herk Stanley , Havermans Marije , Arricibita Varea Andrea , Vermeulen Michael , Beverloo H. Berna , Gröschel Stefan , Haferlach Torsten , Haferlach Claudia , J. Wouters Bas , Bindels Eric , Smeenk Leonie , Delwel Ruud
Published: September 2021

Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.
Measuring kinetics and metastatic propensity of CTCs by blood exchange between mice
Authors: Hamza Bashar , Miller Alex B. , Meier Lara , Stockslager Max , Ng Sheng Rong , King Emily M. , Lin Lin , DeGouveia Kelsey L. , Mulugeta Nolawit , Calistri Nicholas L. , Strouf Haley , Bray Christina , Rodriguez Felicia , Freed-Pastor William A. , Chin Christopher R. , Jaramillo Grissel C. , Burger Megan L. , Weinberg Robert A. , Shalek Alex K. , Jacks Tyler , Manalis Scott R.
Published: September 2021

Existing preclinical methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) en route to forming metastases have not been capable of providing a direct measure of CTC intravasation rate and subsequent half-life in the circulation. Here, we demonstrate an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood over several hours between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts. By tracking CTC transfer rates, we extrapolated half-life times in the circulation of between 40 and 260 s and intravasation rates between 60 and 107,000 CTCs/hour in mouse models of small-cell lung cancer (SCLC), pancreatic ductal adenocarcinoma (PDAC), and non-small cell lung cancer (NSCLC). Additionally, direct transfer of only 1−2% of daily-shed CTCs using our blood-exchange technique from late-stage, SCLC-bearing mice generated macrometastases in healthy recipient mice. We envision that our technique will help further elucidate the role of CTCs and the rate-limiting steps in metastasis.
Conserved and species-specific chromatin remodeling and regulatory dynamics during mouse and chicken limb bud development
Authors: Jhanwar Shalu , Malkmus Jonas , Stolte Jens , Romashkina Olga , Zuniga Aimée , Zeller Rolf
Published: September 2021

Chromatin remodeling and genomic alterations impact spatio-temporal regulation of gene expression, which is central to embryonic development. The analysis of mouse and chicken limb development provides important insights into the morphoregulatory mechanisms, however little is known about the regulatory differences underlying their morphological divergence. Here, we identify the underlying shared and species-specific epigenomic and genomic variations. In mouse forelimb buds, we observe striking synchrony between the temporal dynamics of chromatin accessibility and gene expression, while their divergence in chicken wing buds uncovers species-specific regulatory heterochrony. In silico mapping of transcription factor binding sites and computational footprinting establishes the developmental time-restricted transcription factor-DNA interactions. Finally, the construction of target gene networks for HAND2 and GLI3 transcriptional regulators reveals both conserved and species-specific interactions. Our analysis reveals the impact of genome evolution on the regulatory interactions orchestrating vertebrate limb bud morphogenesis and provides a molecular framework for comparative Evo-Devo studies.
Supercoiling and looping promote DNA base accessibility and coordination among distant sites
Authors: Fogg Jonathan M. , Judge Allison K. , Stricker Erik , Chan Hilda L. , Zechiedrich Lynn
Published: September 2021

DNA in cells is supercoiled and constrained into loops and this supercoiling and looping influence every aspect of DNA activity. We show here that negative supercoiling transmits mechanical stress along the DNA backbone to disrupt base pairing at specific distant sites. Cooperativity among distant sites localizes certain sequences to superhelical apices. Base pair disruption allows sharp bending at superhelical apices, which facilitates DNA writhing to relieve torsional strain. The coupling of these processes may help prevent extensive denaturation associated with genomic instability. Our results provide a model for how DNA can form short loops, which are required for many essential processes, and how cells may use DNA loops to position nicks to facilitate repair. Furthermore, our results reveal a complex interplay between site-specific disruptions to base pairing and the 3-D conformation of DNA, which influences how genomes are stored, replicated, transcribed, repaired, and many other aspects of DNA activity.
Exceptional topological insulators
Authors: Denner M. Michael , Skurativska Anastasiia , Schindler Frank , Fischer Mark H. , Thomale Ronny , Bzdušek Tomáš , Neupert Titus
Published: September 2021

We introduce the exceptional topological insulator (ETI), a non-Hermitian topological state of matter that features exotic non-Hermitian surface states which can only exist within the three-dimensional topological bulk embedding. We show how this phase can evolve from a Weyl semimetal or Hermitian three-dimensional topological insulator close to criticality when quasiparticles acquire a finite lifetime. The ETI does not require any symmetry to be stabilized. It is characterized by a bulk energy point gap, and exhibits robust surface states that cover the bulk gap as a single sheet of complex eigenvalues or with a single exceptional point. The ETI can be induced universally in gapless solid-state systems, thereby setting a paradigm for non-Hermitian topological matter.
Confronting false discoveries in single-cell differential expression
Authors: Squair Jordan W. , Gautier Matthieu , Kathe Claudia , Anderson Mark A. , James Nicholas D. , Hutson Thomas H. , Hudelle Rémi , Qaiser Taha , Matson Kaya J. E. , Barraud Quentin , Levine Ariel J. , La Manno Gioele , Skinnider Michael A. , Courtine Grégoire
Published: September 2021

Differential expression analysis in single-cell transcriptomics enables the dissection of cell-type-specific responses to perturbations such as disease, trauma, or experimental manipulations. While many statistical methods are available to identify differentially expressed genes, the principles that distinguish these methods and their performance remain unclear. Here, we show that the relative performance of these methods is contingent on their ability to account for variation between biological replicates. Methods that ignore this inevitable variation are biased and prone to false discoveries. Indeed, the most widely used methods can discover hundreds of differentially expressed genes in the absence of biological differences. To exemplify these principles, we exposed true and false discoveries of differentially expressed genes in the injured mouse spinal cord.
The identification of grain size genes by RapMap reveals directional selection during rice domestication
Authors: Zhang Juncheng , Zhang Dejian , Fan Yawei , Li Cuicui , Xu Pengkun , Li Wei , Sun Qi , Huang Xiaodong , Zhang Chunyu , Wu Linyue , Yang Huaizhou , Wang Shiyu , Su Xiaomin , Li Xingxing , Song Yingying , Wu Meng-en , Lian Xingming , Li Yibo
Published: September 2021

Cloning quantitative trait locus (QTL) is time consuming and laborious, which hinders the understanding of natural variation and genetic diversity. Here, we introduce RapMap, a method for rapid multi-QTL mapping by employing F2gradient populations (F2GPs) constructed by minor-phenotypic-difference accessions. The co-segregation standard of the single-locus genetic models ensures simultaneous integration of a three-in-one framework in RapMap i.e. detecting a real QTL, confirming its effect, and obtaining its near-isogenic line-like line (NIL-LL). We demonstrate the feasibility of RapMap by cloning eight rice grain-size genes using 15 F2GPs in three years. These genes explain a total of 75% of grain shape variation. Allele frequency analysis of these genes using a large germplasm collection reveals directional selection of the slender and long grains inindicarice domestication. In addition, major grain-size genes have been strongly selected during rice domestication. We think application of RapMap in crops will accelerate gene discovery and genomic breeding.
Self-regulated co-assembly of soft and hard nanoparticles
Authors: Cui Yan , Zhu Hongyan , Cai Jiandong , Qiu Huibin
Published: September 2021

Controlled self-assembly of colloidal particles into predetermined organization facilitates the bottom-up manufacture of artificial materials with designated hierarchies and synergistically integrated functionalities. However, it remains a major challenge to assemble individual nanoparticles with minimal building instructions in a programmable fashion due to the lack of directional interactions. Here, we develop a general paradigm for controlled co-assembly of soft block copolymer micelles and simple unvarnished hard nanoparticles through variable noncovalent interactions, including hydrogen bonding and coordination interactions. Upon association, the hairy micelle corona binds with the hard nanoparticles with a specific valence depending exactly on their relative size and feeding ratio. This permits the integration of block copolymer micelles with a diverse array of hard nanoparticles with tunable chemistry into multidimensional colloidal molecules and polymers. Secondary co-assembly of the resulting colloidal molecules further leads to the formation of more complex hierarchical colloidal superstructures. Notably, such colloidal assembly is processible on surface either through initiating the alternating co-assembly from a micelle immobilized on a substrate or directly grafting a colloidal oligomer onto the micellar anchor.
Cryo-EM structure of the sodium-driven chloride/bicarbonate exchanger NDCBE
Authors: Wang Weiguang , Tsirulnikov Kirill , Zhekova Hristina R. , Kayık Gülru , Khan Hanif Muhammad , Azimov Rustam , Abuladze Natalia , Kao Liyo , Newman Debbie , Noskov Sergei Yu. , Zhou Z. Hong , Pushkin Alexander , Kurtz Ira
Published: September 2021

SLC4 transporters play significant roles in pH regulation and cellular sodium transport. The previously solved structures of the outward facing (OF) conformation for AE1 (SLC4A1) and NBCe1 (SLC4A4) transporters revealed an identical overall fold despite their different transport modes (chloride/bicarbonate exchange versus sodium-carbonate cotransport). However, the exact mechanism determining the different transport modes in the SLC4 family remains unknown. In this work, we report the cryo-EM 3.4 Å structure of the OF conformation of NDCBE (SLC4A8), which shares transport properties with both AE1 and NBCe1 by mediating the electroneutral exchange of sodium-carbonate with chloride. This structure features a fully resolved extracellular loop 3 and well-defined densities corresponding to sodium and carbonate ions in the tentative substrate binding pocket. Further, we combine computational modeling with functional studies to unravel the molecular determinants involved in NDCBE and SLC4 transport.
In vivo structure and dynamics of the SARS-CoV-2 RNA genome
Authors: Zhang Yan , Huang Kun , Xie Dejian , Lau Jian You , Shen Wenlong , Li Ping , Wang Dong , Zou Zhong , Shi Shu , Ren Hongguang , Wang Youliang , Mao Youzhi , Jin Meilin , Kudla Grzegorz , Zhao Zhihu
Published: September 2021

The dynamics of SARS-CoV-2 RNA structure and their functional relevance are largely unknown. Here we develop a simplified SPLASH assay and comprehensively map the in vivo RNA-RNA interactome of SARS-CoV-2 genome across viral life cycle. We report canonical and alternative structures including 5′-UTR and 3′-UTR, frameshifting element (FSE) pseudoknot and genome cyclization in both cells and virions. We provide direct evidence of interactions between Transcription Regulating Sequences, which facilitate discontinuous transcription. In addition, we reveal alternative short and long distance arches around FSE. More importantly, we find that within virions, while SARS-CoV-2 genome RNA undergoes intensive compaction, genome domains remain stable but with strengthened demarcation of local domains and weakened global cyclization. Taken together, our analysis reveals the structural basis for the regulation of replication, discontinuous transcription and translational frameshifting, the alternative conformations and the maintenance of global genome organization during the whole life cycle of SARS-CoV-2, which we anticipate will help develop better antiviral strategies.
Entanglement across separate silicon dies in a modular superconducting qubit device
Authors: Gold Alysson , Paquette J. P. , Stockklauser Anna , Reagor Matthew J. , Alam M. Sohaib , Bestwick Andrew , Didier Nicolas , Nersisyan Ani , Oruc Feyza , Razavi Armin , Scharmann Ben , Sete Eyob A. , Sur Biswajit , Venturelli Davide , Winkleblack Cody James , Wudarski Filip , Harburn Mike , Rigetti Chad
Published: September 2021

Assembling future large-scale quantum computers out of smaller, specialized modules promises to simplify a number of formidable science and engineering challenges. One of the primary challenges in developing a modular architecture is in engineering high fidelity, low-latency quantum interconnects between modules. Here we demonstrate a modular solid state architecture with deterministic inter-module coupling between four physically separate, interchangeable superconducting qubit integrated circuits, achieving two-qubit gate fidelities as high as 99.1 ± 0.5% and 98.3 ± 0.3% for iSWAP and CZ entangling gates, respectively. The quality of the inter-module entanglement is further confirmed by a demonstration of Bell-inequality violation for disjoint pairs of entangled qubits across the four separate silicon dies. Having proven out the fundamental building blocks, this work provides the technological foundations for a modular quantum processor: technology which will accelerate near-term experimental efforts and open up new paths to the fault-tolerant era for solid state qubit architectures.
Specific human cytomegalovirus signature detected in NK cell metabolic changes post vaccination
Authors: Woods Elena , Zaiatz-Bittencourt Vanessa , Bannan Ciaran , Bergin Colm , Finlay David K. , Hoffmann Matthias , Brown Anthony , Turner Bethany , Makvandi-Nejad Shokouh , Vassilev Ventzi , Capone Stefania , Folgori Antonella , Hanke Tomáš , Barnes Eleanor , Dorrell Lucy , Gardiner Clair M. ,   PEACHI Consortium
Published: September 2021

Effective vaccines for human immunodeficiency virus-1 (HIV-1) and hepatitis C virus (HCV) remain a significant challenge for these infectious diseases. Given that the innate immune response is key to controlling the scale and nature of developing adaptive immune responses, targeting natural killer (NK) cells that can promote a T-helper type 1 (Th1)-type immune response through the production of interferon-γ (IFNγ) remains an untapped strategic target for improved vaccination approaches. Here, we investigate metabolic and functional responses of NK cells to simian adenovirus prime and MVA boost vaccination in a cohort of healthy volunteers receiving a dual HCV-HIV-1 vaccine. Early and late timepoints demonstrated metabolic changes that contributed to the sustained proliferation of all NK cells. However, a strong impact of human cytomegalovirus (HCMV) on some metabolic and functional responses in NK cells was observed in HCMV seropositive participants. These changes were not restricted to molecularly defined adaptive NK cells; indeed, canonical NK cells that produced most IFNγ in response to vaccination were equally impacted in individuals with latent HCMV. In summary, NK cells undergo metabolic changes in response to vaccination, and understanding these in the context of HCMV is an important step towards rational vaccine design against a range of human viral pathogens.
A doubling of stony coral cover on shallow forereefs at Carrie Bow Cay, Belize from 2014 to 2019
Authors: de Pablo Luis X. , Lefcheck Jonathan S. , Harper Leah , Paul Valerie J. , Jones Scott , Whippo Ross , Seemann Janina , Kline David I. , Duffy J. Emmett
Published: September 2021

To better understand the decline of one of earth’s most biodiverse habitats, coral reefs, many survey programs employ regular photographs of the benthos. An emerging challenge is the time required to annotate the large volume of digital imagery generated by these surveys. Here, we leverage existing machine-learning tools (CoralNet) and develop new fit-to-purpose programs to process and score benthic photoquadrats using five years of data from the Smithsonian MarineGEO Network’s biodiversity monitoring program at Carrie Bow Cay, Belize. Our analysis shows that scleractinian coral cover on forereef sites (at depths of 3–10 m) along our surveyed transects increased significantly from 6 to 13% during this period. More modest changes in macroalgae, turf algae, and sponge cover were also observed. Community-wide analysis confirmed a significant shift in benthic structure, and follow-up in situ surveys of coral demographics in 2019 revealed that the emerging coral communities are dominated by fast-recruiting and growing coral species belonging to the generaAgariciaandPorites. While the positive trajectory reported here is promising, Belizean reefs face persistent challenges related to overfishing and climate change. Open-source computational toolkits offer promise for increasing the efficiency of reef monitoring, and therefore our ability to assess the future of coral reefs in the face of rapid environmental change.
Intradiscal quantitative chemical exchange saturation transfer MRI signal correlates with discogenic pain in human patients
Authors: Pelled Gadi , Salas Margaux M. , Han Pei , Gill Howard E. , Lautenschlager Karl A. , Lai Tristan T. , Shawver Cameron M. , Hoch Matthew B. , Goff Brandon J. , Betts Aaron M. , Zhou Zhengwei , Lynch Cody , Schroeder Grant , Bez Maxim , Maya Marcel M. , Bresee Catherine , Gazit Zulma , McCallin John P. , Gazit Dan , Li Debiao
Published: September 2021

Low back pain (LBP) is often a result of a degenerative process in the intervertebral disc. The precise origin of discogenic pain is diagnosed by the invasive procedure of provocative discography (PD). Previously, we developed quantitative chemical exchange saturation transfer (qCEST) magnetic resonance imaging (MRI) to detect pH as a biomarker for discogenic pain. Based on these findings we initiated a clinical study with the goal to evaluate the correlation between qCEST values and PD results in LBP patients. Twenty five volunteers with chronic low back pain were subjected to T2-weighted (T2w) and qCEST MRI scans followed by PD. A total of 72 discs were analyzed. The average qCEST signal value of painful discs was significantly higher than non-painful discs (p = 0.012). The ratio between qCEST and normalized T2w was found to be significantly higher in painful discs compared to non-painful discs (p = 0.0022). A receiver operating characteristics (ROC) analysis indicated that qCEST/T2w ratio could be used to differentiate between painful and non-painful discs with 78% sensitivity and 81% specificity. The results of the study suggest that qCEST could be used for the diagnosis of discogenic pain, in conjunction with the commonly used T2w scan.
Protein expression reveals a molecular sexual identity of avian primordial germ cells at pre-gonadal stages
Authors: Soler Laura , Alves Sabine , Brionne Aurélien , Jacques Aurore , Guérin Vanessa , Cherif-Feildel Maeva , Combes-Soia Lucie , Fouchécourt Sophie , Thélie Aurore , Blesbois Elisabeth , McGrew Michael J. , Labas Valérie , Govoroun Marina S.
Published: September 2021

In poultry, in vitro propagated primordial germ cells (PGCs) represent an important tool for the cryopreservation of avian genetic resources. However, several studies have highlighted sexual differences exhibited by PGCs during in vitro propagation, which may compromise their reproductive capacities. To understand this phenomenon, we compared the proteome of pregonadal migratory male (ZZ) and female (ZW) chicken PGCs propagated in vitro by quantitative proteomic analysis using a GeLC-MS/MS strategy. Many proteins were found to be differentially abundant in chicken male and female PGCs indicating their early sexual identity. Many of the proteins more highly expressed in male PGCs were encoded by genes localised to the Z sex chromosome. This suggests that the known lack of dosage compensation of the transcription of Z-linked genes between sexes persists at the protein level in PGCs, and that this may be a key factor of their autonomous sex differentiation. We also found that globally, protein differences do not closely correlate with transcript differences indicating a selective translational mechanism in PGCs. Male and female PGC expressed protein sets were associated with differential biological processes and contained proteins known to be biologically relevant for male and female germ cell development, respectively. We also discovered that female PGCs have a higher capacity to uptake proteins from the cell culture medium than male PGCs. This study presents the first evidence of an early predetermined sex specific cell fate of chicken PGCs and their sexual molecular specificities which will enable the development of more precise sex-specific in vitro culture conditions for the preservation of avian genetic resources.
PaCO2-management in the neuro-critical care of patients with subarachnoid hemorrhage
Authors: Darkwah Oppong Marvin , Wrede Karsten H. , Müller Daniela , Santos Alejandro N. , Rauschenbach Laurèl , Dinger Thiemo F. , Ahmadipour Yahya , Pierscianek Daniela , Chihi Mehdi , Li Yan , Deuschl Cornelius , Sure Ulrich , Jabbarli Ramazan
Published: September 2021

The partial pressure of carbon dioxide (PaCO2) in the arterial blood is a strong vasomodulator affecting cerebral blood flow and the risk of cerebral edema and ischemia after acute brain injury. In turn, both complications are related to poor outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to analyze the effect of PaCO2 levels on the course and outcome of aSAH. All patients of a single institution treated for aSAH over 13.5 years were included (n = 633). Daily PaCO2 values from arterial blood gas measurements were recorded for up to 2 weeks after ictus. The study endpoints were: delayed cerebral ischemia (DCI), need for decompressive craniectomy due to increased intracranial pressure > 20 mmHg refractory to conservative treatment and poor outcome at 6-months follow-up (modified Rankin scale > 2). By correlations with the study endpoints, clinically relevant cutoffs for the 14-days mean values for the lowest and highest daily PaCO2 levels were defined by receiver operating characteristic curve analysis. Association with the study endpoints for the identifies subgroups was analyzed using multivariate analysis. The optimal range for PaCO2 values was identified between 30 and 38 mmHg. ASAH patients with poor initial condition (WFNS 4/5) were less likely to show PaCO2 values within the range of 30–38 mmHg (p < 0.001, OR = 0.44). In the multivariate analysis, PaCO2 values between 30 and 38 mmHg were associated with a lower risk for decompressive craniectomy (p = 0.042, aOR = 0.27), DCI occurrence (p = 0.035; aOR = 0.50), and poor patient outcome (p = 0.004; aOR = 0.42). The data from this study shows an independent positive association between low normal mean PaCO2 values during the acute phase of aSAH and patients’ outcome. This effect might be attributed to the reduction of intracranial hypertension and alterations in the cerebral blood flow.
Detection and quantification of Mycobacterium tuberculosis antigen CFP10 in serum and urine for the rapid diagnosis of active tuberculosis disease
Authors: Seifert Marva , Vargas Eva , Ruiz-Valdepeñas Montiel Victor , Wang Joseph , Rodwell Timothy C. , Catanzaro Antonino
Published: September 2021

Outside of the ongoing COVID-19 pandemic, tuberculosis is the leading cause of infectious disease mortality globally. Currently, there is no commercially available point-of-care diagnostic that is rapid, inexpensive, and highly sensitive for the diagnosis of active tuberculosis disease. Here we describe the development and optimization of a novel, highly sensitive prototype bioelectronic tuberculosis antigen (BETA) assay to detect tuberculosis-specific antigen, CFP10, in small-volume serum and urine samples. In this proof-of-concept study we evaluated the performance of the BETA assay using clinical specimens collected from presumptive tuberculosis patients from three independent cohorts. Circulating CFP10 antigen was detected in ALL serum (n = 19) and urine (n = 3) samples from bacteriologically confirmed tuberculosis patients who were untreated or had less than one week of treatment at time of serum collection, successfully identifying all culture positive tuberculosis patients. No CFP10 antigen was detected in serum (n = 7) or urine (n = 6) samples from individuals who were determined to be negative for tuberculosis disease. Additionally, antigen quantification using the BETA assay of paired serum samples collected from tuberculosis patients (n = 8) both before and after treatment initiation, indicate consistently declining within-person levels of CFP10 antigen during treatment. This novel, low-cost assay demonstrates potential as a rapid, non-sputum-based, point-of-care tool for the diagnosis of tuberculosis disease.
Genomic analysis of ionome-related QTLs in Arabidopsis thaliana
Authors: Shariatipour Nikwan , Heidari Bahram , Ravi Samathmika , Stevanato Piergiorgio
Published: September 2021

Ionome contributes to maintain cell integrity and acts as cofactors for catalyzing regulatory pathways. Identifying ionome contributing genomic regions provides a practical framework to dissect the genetic architecture of ionomic traits for use in biofortification. Meta-QTL (MQTL) analysis is a robust method to discover stable genomic regions for traits regardless of the genetic background. This study used information of 483 QTLs for ionomic traits identified from 12 populations for MQTL analysis inArabidopsis thaliana. The selected QTLs were projected onto the newly constructed genetic consensus map and 33 MQTLs distributed onA. thalianachromosomes were identified. The average confidence interval (CI) of the drafted MQTLs was 1.30 cM, reduced eight folds from a mean CI of 10.88 cM for the original QTLs. Four MQTLs were considered as stable MQTLs over different genetic backgrounds and environments. In parallel to the gene density over theA. thalianagenome, the genomic distribution of MQTLs over the genetic and physical maps indicated the highest density at non- and sub-telomeric chromosomal regions, respectively. Several candidate genes identified in the MQTLs intervals were associated with ion transportation, tolerance, and homeostasis. The genomic context of the identified MQTLs suggested nine chromosomal regions for Zn, Mn, and Fe control. The QTLs for potassium (K) and phosphorus (P) were the most frequently co-located with Zn (78.3%), Mn (76.2%), and Fe (88.2% and 70.6%) QTLs. The current MQTL analysis demonstrates that meta-QTL analysis is cheaper than, and as informative as genome-wide association study (GWAS) in refining the known QTLs.
The small-world network of global protests
Authors: Ferreira Leonardo N. , Hong Inho , Rutherford Alex , Cebrian Manuel
Published: September 2021

Protest diffusion is a cascade process that can spread over different regions of the planet. The way and the extension that this phenomenon can occur is still not properly understood. Here, we empirically investigate this question using protest data from GDELT and ICEWS, two of the most extensive and longest-running data sets freely available. We divide the globe into grid cells and construct a temporal network for each data set where nodes represent cells and links are established between nodes if their protest events co-occur. We show that the temporal networks are small-world, indicating that the cells are directly linked or separated by a few steps on average. Furthermore, the average path lengths are decreasing through the years, which suggests that the world is becoming “smaller”. The persistent temporal hubs present in both data sets indicate that protests can spread faster through the hubs. This topological feature is consistent with the hypothesis that protests can quickly diffuse from one region to any other part of the globe.
Application of improved and optimized fuzzy neural network in classification evaluation of top coal cavability
Authors: Wang Meng , Tai Caiwang , Zhang Qiaofeng , Yang Zongwei , Li Jiazheng , Shen Kejun
Published: September 2021

Longwall top coal caving technology is one of the main methods of thick coal seam mining in China, and the classification evaluation of top coal cavability in longwall top coal caving working face is of great significance for improving coal recovery. However, the empirical or numerical simulation method currently used to evaluate the top coal cavability has high cost and low-efficiency problems. Therefore, in order to improve the evaluation efficiency and reduce evaluation the cost of top coal cavability, according to the characteristics of classification evaluation of top coal cavability, this paper improved and optimized the fuzzy neural network developed by Nauck and Kruse and establishes the fuzzy neural network prediction model for classification evaluation of top coal cavability. At the same time, in order to ensure that the optimized and improved fuzzy neural network has the ability of global approximation that a neural network should have, its global approximation is verified. Then use the data in the database of published papers from CNKI as sample data to train, verify and test the established fuzzy neural network model. After that, the tested model is applied to the classification evaluation of the top coal cavability in 61,107 longwall top coal caving working face in Liuwan Coal Mine. The final evaluation result is that the top coal cavability grade of the 61,107 longwall top coal caving working face in Liuwan Coal Mine is grade II, consistent with the engineering practice.
Information flow in the rat thalamo-cortical system: spontaneous vs. stimulus-evoked activities
Authors: Ishizu Kotaro , Shiramatsu Tomoyo I. , Hitsuyu Rie , Oizumi Masafumi , Tsuchiya Naotsugu , Takahashi Hirokazu
Published: September 2021

The interaction between the thalamus and sensory cortex plays critical roles in sensory processing. Previous studies have revealed pathway-specific synaptic properties of thalamo-cortical connections. However, few studies to date have investigated how each pathway routes moment-to-moment information. Here, we simultaneously recorded neural activity in the auditory thalamus (or ventral division of the medial geniculate body; MGv) and primary auditory cortex (A1) with a laminar resolution in anesthetized rats. Transfer entropy (TE) was used as an information theoretic measure to operationalize “information flow”. Our analyses confirmed that communication between the thalamus and cortex was strengthened during presentation of auditory stimuli. In the resting state, thalamo-cortical communications almost disappeared, whereas intracortical communications were strengthened. The predominant source of information was the MGv at the onset of stimulus presentation and layer 5 during spontaneous activity. In turn, MGv was the major recipient of information from layer 6. TE suggested that a small but significant population of MGv-to-A1 pairs was “information-bearing,” whereas A1-to-MGv pairs typically exhibiting small effects played modulatory roles. These results highlight the capability of TE analyses to unlock novel avenues for bridging the gap between well-established anatomical knowledge of canonical microcircuits and physiological correlates via the concept of dynamic information flow.
Peptide-HLA-based immunotherapeutics platforms for direct modulation of antigen-specific T cells
Authors: Seidel Ronald D. , Merazga Zohra , Thapa Dharma Raj , Soriano Jonathan , Spaulding Emily , Vakkasoglu Ahmet S. , Ruthardt Paige , Bautista Wynona , Quayle Steven N. , Kiener Peter A. , Low Simon , Ross John F. , Cemerski Saso , Suri Anish , Almo Steven C. , Chaparro Rodolfo J.
Published: September 2021

Targeted pharmacologic activation of antigen-specific (AgS) T cells may bypass limitations inherent in current T cell-based cancer therapies. We describe two immunotherapeutics platforms for selective delivery of costimulatory ligands and peptide-HLA (pHLA) to AgS T cells. We engineered and deployed on these platforms an affinity-attenuated variant of interleukin-2, which selectively expands oligoclonal and polyfunctional AgS T cells in vitro and synergizes with CD80 signals for superior proliferation versus peptide stimulation.
Role of catalytic nitrile decomposition in tricopper complex mediated direct partial oxidation of methane to methanol
Authors: Moharreri Ehsan , Jafari Tahereh , Rathnayake Dinithi , Khanna Harshul , Kuo Chung-Hao , Suib Steven L. , Nandi Partha
Published: September 2021

Synthetic homogeneous system known to date performing methane to methanol conversion using O2 as terminal oxidant is unique and based on copper complex with piperazine-based ligand (Cu3L in Fig. 1) in a medium of acetonitrile. Prior work have shown that in order to achieve catalytic turnover, hydrogen peroxide is needed to regenerate the active site. We show in this paper that reaction solvent based on organic nitrile decompose concurrently with methane activation and that in the absence of either acetonitrile, Cu complex or hydrogen peroxide, the catalytic turnover does not happen. We show in this manuscript that the direct methane oxidation to methanol might have been mediated by catalytic Radziszewski oxidation between acetonitrile and H2O2. Additionally we have discovered that in the absence of methane, peroxide mediated acetonitrile decomposition also makes methanol via a background reaction which was hitherto unknown.
Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder
Authors: Jafarian Z. , Khamse S. , Afshar H. , Khorshid H.R. Khorram , Delbari A. , Ohadi M.
Published: September 2021

Expression dysregulation of the neuron-specific gene,RASGEF1C(RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N = 269), consisting of late-onset NCDs (N = 115) and controls (N = 154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency = 0.85) and NCD patients (frequency = 0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact = 0.004). A number of those genotypes were not detected in the control group (Mid-P exact = 0.007). TheRASGEF1C(GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of theRASGEF1C(GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences.
Parametric investigation of a chilled water district cooling unit using mono and hybrid nanofluids
Authors: Okonkwo Eric C. , Al-Ansari Tareq
Published: September 2021

This study presents a novel parametric investigation into the performance of a district cooling system using mono (Al2O3 and TiO2) and hybrid (Al2O3–TiO2) nanoparticles in the base fluids of water and ethylene–glycol water (EG-water) at a 20:80 ratio. The study analyses the effect of variables such as secondary fluid flow rate, evaporator and inlet temperatures, nanoparticle concentration, and air flowrate on the COP, total electrical energy consumption, and design of the district cooling unit. The analysis is performed with a thermal model developed and validated using operations data obtained from the McQuay chilled water HVAC unit operating in one of the facility plants at the Education City campus. The results of the study show that the use of nanofluids increased the overall heat transfer coefficient in the system by 6.6% when using Al2O3–TiO2/water nanofluids. The use of nanofluids in the evaporator also led to an average reduction of 23.3% in the total work input to the system and improved the COP of the system by 21.8%, 20.8% and 21.6% for Al2O3–TiO2/water, Al2O3/water, and TiO2/water nanofluids, respectively. Finally, an enhancement of 21.6% in COP was recorded for Al2O3–TiO2/EG-water nanofluids at a 5% nanoparticle volume concentration.
Chemometric approach to characterization of the selected grape seed oils based on their fatty acids composition and FTIR spectroscopy
Authors: Vladimír Mašán , Matwijczuk Arkadiusz P. , Niemczynowicz Agnieszka , Kycia Radosław A. , Karcz Dariusz , Gładyszewska Bożena , Ślusarczyk Lidia , Burg Patrik
Published: September 2021

Addressing the issues arising from the production and trade of low-quality foods necessitates developing new quality control methods. Cooking oils, especially those produced from the grape seeds, are an example of food products that often suffer from questionable quality due to various adulterations and low-quality fruits used for their production. Among many methods allowing for fast and efficient food quality control, the combination of experimental and advanced mathematical approaches seems most reliable. In this work a method for grape seed oils compositional characterization based on the infrared (FTIR) spectroscopy and fatty acids profile is reported. Also, the relevant parameters of oils are characterized using a combination of standard techniques such as the Principal Component Analysis, k-Means, and Gaussian Mixture Model (GMM) fitting parameters. Two different approaches to perform unsupervised clustering using GMM were investigated. The first approach relies on the profile of fatty acids, while the second is FT-IR spectroscopy-based. The GMM fitting parameters in both approaches were compared. The results obtained from both approaches are consistent and complementary and provide the tools to address the characterization and clustering issues in grape seed oils.
Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication
Authors: Mathew Cynthia , Tamir Sharon , Tripp Ralph A. , Ghildyal Reena
Published: September 2021

Respiratory syncytial virus (RSV) is the primary cause of serious lower respiratory tract disease in infants, young children, the elderly and immunocompromised individuals. Therapy for RSV infections is limited to high risk infants and there are no safe and efficacious vaccines. Matrix (M) protein is a major RSV structural protein with a key role in virus assembly. Interestingly, M is localised to the nucleus early in infection and its export into the cytoplasm by the nuclear exporter, exportin-1 (XPO1) is essential for RSV assembly. We have shown previously that chemical inhibition of XPO1 function results in reduced RSV replication. In this study, we have investigated the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds, KPT-335 and KPT-185. Our data shows that therapeutic administration of the SINE compounds results in reduced RSV titre in human respiratory epithelial cell culture. Within 24 h of treatment, RSV replication and XPO1 expression was reduced, M protein was partially retained in the nucleus, and cell cycle progression was delayed. Notably, the effect of SINE compounds was reversible within 24 h after their removal. Our data show that reversible inhibition of XPO1 can disrupt RSV replication by affecting downstream pathways regulated by the nuclear exporter.
Redox status of cysteines does not alter functional properties of human dUTPase but the Y54C mutation involved in monogenic diabetes decreases protein stability
Authors: Szabó Judit Eszter , Nyíri Kinga , Andrási Dániel , Matejka Judit , Ozohanics Olivér , Vértessy Beáta
Published: September 2021

Recently it was proposed that the redox status of cysteines acts as a redox switch to regulate both the oligomeric status and the activity of human dUTPase. In a separate report, a human dUTPase point mutation, resulting in a tyrosine to cysteine substitution (Y54C) was identified as the monogenic cause of a rare syndrome associated with diabetes and bone marrow failure. These issues prompt a critical investigation about the potential regulatory role of cysteines in the enzyme. Here we show on the one hand that independently of the redox status of wild-type cysteines, human dUTPase retains its characteristic trimeric assembly and its catalytic activity. On the other hand, the Y54C mutation did not compromise the substrate binding and the catalytic properties of the enzyme at room temperature. The thermal stability of the mutant protein was found to be decreased, which resulted in the loss of 67% of its activity after 90 min incubation at the physiological temperature in contrast to the wild-type enzyme. In addition, the presence or absence of reducing agents had no effect on hDUTY54C activity and stability, although it was confirmed that the introduced cysteine contains a solvent accessible thiol group.