bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophages only sense infectious SARS-CoV-2 when they express sufficient ACE2 to permit viral entry, where rapid cytokine responses then limit viral replication
Authors: Labzin Larisa I , Chew Keng Yih , Eschke Kathrin , Wang Xiaohui , Esposito Tyron , Stocks Claudia J , Rae James , Patrick Ralph , Mostafavi Helen , Hill Brittany , Yordanov Teodor E. , Holley Caroline L , Emming Stefan , Fritzlar Svenja , Mordant Francesca L. , Steinfort Daniel P. , Subbarao Kanta , Nefzger Christian M. , Lagendijk Anne K , Gordon Emma , Parton Robert , Short Kirsty R. , Londrigan Sarah L. , Schroder Kate 
Published: March 2022

AbstractMacrophages are key cellular contributors to COVID-19 pathogenesis. Whether SARS-CoV-2 can enter macrophages, replicate and release new viral progeny remains controversial. Similarly, whether macrophages need to sense replicating virus to drive cytokine release is also unclear. Macrophages are heterogeneous cells poised to respond to their local microenvironment, and accordingly, the SARS-CoV-2 entry receptor ACE2 is only present on a subset of macrophages at sites of human infection. Here, we use in vitro approaches to investigate how SARS-CoV-2 interacts with ACE2-negative and ACE2-positive human macrophages and determine how these macrophage populations sense and respond to SARS-CoV-2. We show that SARS-CoV-2 does not replicate within ACE2-negative human macrophages and does not induce pro-inflammatory cytokine expression. By contrast, ACE2 expression in human macrophages permits SARS-CoV-2 entry, replication, and virion release. ACE2-expressing macrophages sense replicating virus to trigger pro-inflammatory and anti-viral programs that limit virus release. These combined findings resolve several controversies regarding macrophage-SARS-CoV-2 interactions and identify a signaling circuit by which macrophages sense SARS-CoV-2 cell entry and respond by restricting viral replication.One sentence summaryLack of macrophage ACE2 expression precludes SARS-CoV-2 entry and sensing, while ACE2-expressing macrophages sense intramacrophage SARS-CoV-2 replication to induce rapid anti-viral responses that limit new virion release.
A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification
Authors: Edginton-White B. , Maytum A , Kellaway S.G. , Goode D.K. , Keane P. , Pagnuco I. , Assi S.A. , Ames L. , Clarke M , Cockerill P.N. , Göttgens B. , Cazier J.B. , Bonifer C. 
Published: March 2022

AbstractDevelopmental control of gene expression critically depends on distal cis-regulatory elements including enhancers which interact with promoters to activate gene expression. To date no global experiments have been conducted that identify their cell type and cell stage-specific transcription stimulatory activity within one developmental pathway and in a chromatin context. Here, we describe a high-throughput method that identifies thousands of differentially active cis-elements able to stimulate a minimal promoter at five stages of hematopoietic progenitor development from embryonic stem cells, which can be adapted to any ES cell derived cell type. Exploring this new resource, we show that blood cell-specific gene expression is controlled by the concerted action of thousands of differentiation stage-specific sets of cis-elements which respond to cytokine signals that terminate at signalling responsive transcription factors. Our work presents a major advance in our understanding of developmental gene expression control in the hematopoietic system and beyond.
Inhalable polymer nanoparticles for versatile mRNA delivery and mucosal vaccination
Authors: Suberi Alexandra , Grun Molly K. , Mao Tianyang , Israelow Benjamin , Reschke Melanie , Grundler Julian , Akhtar Laiba , Lee Teresa , Shin Kwangsoo , Piotrowski-Daspit Alexandra S. , Homer Robert J. , Iwasaki Akiko , Suh Hee Won , Saltzman W. Mark 
Published: March 2022

AbstractAn inhalable platform for mRNA therapeutics would enable minimally invasive and lung targeted delivery for a host of pulmonary diseases. Development of lung targeted mRNA therapeutics has been limited by poor transfection efficiency and risk of vehicle-induced pathology. Here we report an inhalable polymer-based vehicle for delivery of therapeutic mRNAs to the lung. We optimized biodegradable poly(amine-co-ester) polyplexes for mRNA delivery using end group modifications and polyethylene glycol. Our polyplexes achieved high transfection of mRNA throughout the lung, particularly in epithelial and antigen-presenting cells. We applied this technology to develop a mucosal vaccine for SARS-CoV-2. Intranasal vaccination with spike protein mRNA polyplexes induced potent cellular and humoral adaptive immunity and protected K18-hACE2 mice from lethal viral challenge.One-sentence summaryInhaled polymer nanoparticles (NPs) achieve high mRNA expression in the lung and induce protective immunity against SARS-CoV-2.
Hypertension perspectives and health behaviors of African youth: The effect of health education and employment
Authors: Mhlaba M , Mpondo F , Ware LJ 
Published: March 2022

AbstractIn South Africa between 1998 and 2016, hypertension rates in young adults (15-34 years) more than doubled calling for preventive interventions. However, with many youth unemployed, young adults struggle to prioritize health or implement healthy behaviors. We conducted six focus group discussions comparing hypertension-related beliefs and behaviors between NEET youth (n=20; not in employment, education or training) and previously NEET youth on a health-focused learnership (n=20). While all youth viewed hypertension as life threatening leading to cardiovascular disease or death, especially if left untreated, only youth undertaking health education felt empowered to implement healthy behaviors for disease prevention. In contrast, NEET youth felt hypertension was inevitable and described negative experiences at clinics and fear of lifelong medication use if diagnosed as reasons not to be screened. Our results suggest that engaging NEET youth in culturally appropriate health education programs can motivate preventive health behavior for chronic diseases such as hypertension.
Calcium Channel Blockers: clinical outcome associations with reported pharmacogenetics variants in 32,000 patients
Authors: Türkmen Deniz , Masoli Jane A.H. , Delgado João , Kuo Chia-Ling , Bowden Jack , Melzer David , Pilling Luke C. 
Published: March 2022

AbstractBackgroundDihydropiridine calcium channel blockers (dCCB) (e.g. amlodipine) are widely used for treating hypertension. Pharmacogenetic variants impact treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a community-based cohort prescribed dCCB, including in high-risk subgroups.MethodsWe analysed up to 32,360 UK Biobank European-ancestry participants prescribed dCCB in primary care electronic health records (from UK General Practices, 1990 to 2017). We investigated 23 genetic variants in 16 genes reported in PharmGKB, including CYP3A5 and RYR3. Outcomes were incident diagnosis of coronary heart disease (CHD), heart failure (HF), chronic kidney disease (CKD), edema, and switching antihypertensive medication. Secondary analysis in patients with history of heart disease was also performed.ResultsParticipants were aged 40 to 79 years at first dihydropyridine prescription (treatment duration 1 month to 40 years, mean 5.9 years). Carriers of rs877087 T allele in the ryanodine receptor 3 (RYR3) had increased risk of HF (Hazard Ratio 1.13: 95% Confidence Intervals 1.02 to 1.25, p=0.02). We estimated that if rs877087 T allele carriers were prescribed an alternative treatment the incidence of HF in patients prescribed dCCB would reduce by 9.2% (95%CI 3.1 to 15.4). In patients with a history of heart disease when first prescribed dCCB (N=2,296), RYR3 rs877087 homozygotes had increased risk of new CHD or HF compared to CC variant (HR 1.25, 95%CI 1.09 to 1.44, p=0.002). Two variants increased likelihood of switching to an alternate antihypertensive medication (rs10898815 in gene NUMA1 HR 1.16: 95%CI 1.07 to 1,27, p=0.0009; rs776746 in CYP3A5 HR 1.59: 95%CI 1.09 to 2.32, p=0.02). rs776746 in CYP3A5 also increased CKD risk (HR 2.12, p=0.002). The remaining previously reported variants were not strongly or consistently associated with the studied clinical outcomes.ConclusionsIn this large primary care cohort, patients with common genetic variants in NUMA1, CYP3A5 and RYR3 had increased adverse clinical outcomes. Work is needed to establish whether outcomes of dCCB prescribing could be improved by prior knowledge of such pharmacogenetics variants supported by clinical evidence of association with adverse events.
The contribution of malaria and sickle cell disease to anaemia among children aged 6 to 59 months in Nigeria: A secondary analysis using data from the 2018 Demographic and Health Survey
Authors: Chao Dennis L. , Oron Assaf P. , Chabot-Couture Guillaume , Sopekan Alayo , Nnebe-Agumadu Uche , Bates Imelda , Piel Frédéric B. , Nnodu Obiageli E. 
Published: March 2022

AbstractIntroductionAnaemia is a major cause of morbidity and mortality among children in sub-Saharan Africa. Anaemia has many aetiologies best addressed by different treatments, so regional studies of the aetiology of anaemia may be required.MethodsWe analysed data from Nigeria’s 2018 Demographic and Health Survey (DHS) to study predictors of anaemia among children ages 6-59m. We computed the fraction of anaemia at different degrees of severity attributable to malaria and sickle cell disease (SCD) using a regression model adjusting for demographic and socioeconomic risk factors. We also estimated the contribution of the risk factors to haemoglobin concentration.ResultsWe found that 63.7% (95% CI: 58.3-69.4) of semi-severe anaemia (<80 g/L) was attributable to malaria compared to 12.4% (95% CI: 11.1-13.7) of mild-to-severe (adjusted haemoglobin concentration <110 g/L) and 29.6% (95% CI: 29.6-31.8) of moderate-to-severe (<100 g/L) anaemia and that SCD contributed 0.6% (95%CI: 0.4-0.9), 1.3% (95% CI: 1.0-1.7), and 7.3% (95%CI: 5.3-9.4) mild-to-severe, moderate-to-severe, and semi-severe anaemia, respectively. Sickle trait was protective against anaemia and was associated with higher haemoglobin concentration compared to children with normal haemoglobin (HbAA) among malaria-positive but not malaria-negative children.ConclusionThis approach used offers a new tool to estimate the contribution of malaria to anaemia in many settings using widely available DHS data. The fraction of anaemia among young children in Nigeria attributable to malaria and SCD is higher at more severe levels of anaemia. Prevention of malaria and SCD and timely treatment of affected individuals would reduce cases of severe anaemia.
The relationship between wild-type transthyretin amyloid load and ligamentum flavum thickness in lumbar stenosis patients
Authors: Wang Andy Y. , Saini Harleen , Tingen Joseph N. , Sharma Vaishnavi , Flores Alexandra , Liu Diang , Olmos Michelle , McPhail Ellen D. , Safain Mina G. , Kryzanski James , Arkun Knarik , Riesenburger Ron I. 
Published: March 2022

ABSTRACTBackgroundOne key contributor to lumbar stenosis is thickening of the ligamentum flavum (LF), a process still poorly understood. Wild-type transthyretin amyloid (ATTRwt) has been found in the LF of patients undergoing decompression surgery, suggesting that amyloid may play a role. However, it is unclear whether within patients harboring ATTRwt, the amount of amyloid is associated with LF thickness.MethodsFrom an initial cohort of 324 consecutive lumbar stenosis patients whose LF specimens from decompression surgery were sent for analysis (2018-2019), 33 patients met the following criteria: (1) Congo red-positive amyloid in the LF; (2) ATTRwt by mass spectrometry-based proteomics; and (3) an available preoperative MRI. Histological specimens were digitized, and amyloid load quantified through Trainable Weka Segmentation (TWS) machine learning. LF thicknesses were manually measured on axial T2-weighted preoperative MRI scans at each lumbar level, L1-S1. The sum of thicknesses at every lumbar LF level (L1-S1) equals “lumbar LF burden.”ResultsPatients had a mean age of 72.7 years (range 59-87), were mostly male (61%) and white (82%); and predominantly had surgery at L4-L5 levels (73%). Amyloid load was positively correlated with LF thickness (R=0.345, p=0.0492) at the levels of surgical decompression. Furthermore, amyloid load was positively correlated with lumbar LF burden (R=0.383, p=0.0279).ConclusionsAmyloid load is positively correlated with LF thickness and lumbar LF burden across all lumbar levels, in a dose-dependent manner. Further studies are needed to validate these findings, uncover the underlying pathophysiology, and pave the way towards using therapies that slow LF thickening.
Ubiquitin ligase TRAIP plays an essential role during the S-phase of unperturbed cell cycle in the resolution of DNA replication – transcription conflicts
Authors: Scaramuzza Shaun , Sadurni Martina Muste , Poovathumkadavil Divyasree , Natsume Toyoaki , Rojas Patricia , Kanemaki Masato T. , Saponaro Marco , Gambus Agnieszka 
Published: March 2022

AbstractCell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. Over the years, TRAIP E3 ubiquitin ligase has been shown to play a role in various cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability, and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, for the first time, we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells and to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We find that upon rapid TRAIP degradation, specifically in S-phase, cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. Our findings reveal that TRAIP works in S-phase to prevent DNA damage at transcription start sites, caused by replication-transcription conflicts.
Comparative analysis defines a broader FMRFamide-gated sodium channel family and determinants of neuropeptide sensitivity
Authors: Dandamudi Mowgli , Hausen Harald , Lynagh Timothy 
Published: March 2022

AbstractFMRFamide and similar neuropeptides are important physiological modulators in most invertebrates, but the molecular basis of FMRFamide activity at its receptors is unknown. We therefore sought to identify the molecular determinants of FMRFamide potency in one of its native targets, the excitatory FMRFamide-gated sodium channel (FaNaC) from gastropod mollusks. Using molecular phylogenetics and electrophysiological measurement of function, we identified a broad FaNaC family that includes mollusk and annelid channels gated by FMRFamide, FVRIamides, and/or Wamides (or myoinhibitory peptides). A comparative analysis of this broader FaNaC family and other channels from the overarching DEG/ENaC superfamily, incorporating mutagenesis and experimental dissection of function, identified a pocket of amino acid residues that determines activation of FaNaCs by neuropeptides. Although this pocket has diverged in distantly related DEG/ENaC channels that are activated by other ligands, such as mammalian acid-sensing ion channels, we show that it nonetheless contains residues that determine enhancement of those channels by similar peptides. This study thus identifies amino acid residues that determine FMRFamide activity at FaNaCs and illuminates evolution of ligand recognition in one branch of the DEG/ENaC superfamily of ion channels.
In silico analysis predicts a limited impact of SARS-CoV-2 variants on CD8 T cell recognition
Authors: Isaeva Olga I. , Ketelaars Steven L.C. , Kvistborg Pia 
Published: March 2022

AbstractSince the start of the COVID-19 pandemic, mutations have led to the emergence of new SARS-CoV-2 variants, and some of these have become prominent or dominant variants of concern. This natural course of development can have an impact on how protective the previously naturally or vaccine induced immunity is. Therefore, it is crucial to understand whether and how variant specific mutations influence host immunity. To address this, we have investigated how mutations in the recent SARS-CoV-2 variants of interest and concern influence epitope sequence similarity, predicted binding affinity to HLA, and immunogenicity of previously reported SARS-CoV-2 CD8 T cell epitopes. Our data suggests that the vast majority of SARS-CoV-2 CD8 T cell recognized epitopes are not altered by variant specific mutations. Interestingly, for the CD8 T cell epitopes that are altered due to variant specific mutations, our analyses show there is a high degree of sequence similarity between mutated and reference SARS-CoV-2 CD8 T cell epitopes. However, mutated epitopes, primarily derived from the spike protein, in SARS-CoV-2 variants Delta, AY.4.2 and Mu display reduced predicted binding affinity to their restriction element. These findings indicate that the recent SARS-CoV-2 variants of interest and concern have limited ability to escape memory CD8 T cell responses raised by vaccination or prior infection with SARS-CoV-2 early in the pandemic. The overall low impact of the mutations on CD8 T cell cross-recognition is in accordance with the notion that mutations in SARS-CoV-2 are primarily the result of receptor binding affinity and antibody selection pressures exerted on the spike protein, unrelated to T cell immunity.
A fractional-order equivalent model for characterizing the interelectrode capacitance of MOSFETs
Authors: Huang Yi , Chen Xi 
Published: March 2022

Purpose
This paper aims to characterize the relationship between the interelectrode capacitance (C) of metal-oxide-semiconductor field-effect transistors (MOSFETs) and the applied bias voltage (V) by a fractional-order equivalent model.

Design/methodology/approach
A Riemann–Liouville-type fractional-order equivalent model is proposed for the C–V characteristic of MOSFETs, which is based on the mathematical relationship between fractional calculus and the semiconductor physical model for the interelectrode capacitance of metal oxide semiconductor structure. The C–V characteristic data of an N-channel MOSFET are obtained by Silvaco TCAD simulation. A differential evolution-based offline scheme is exploited for the parameter identification of the proposed model.

Findings
According to the results of theoretical analysis, mathematical derivation, simulation and comparison, this paper illustrates that, along with the variation of bias voltage applied, the interelectrode capacitance (C) of MOSFETs performs a fractional-order characteristic.

Originality/value
This work uncovers the fractional-order characteristic of MOSFETs’ interelectrode capacitance. By the proposed model, the influence of doping concentration on the gate leakage parasitic capacitance of MOSFETs can be revealed. In the pre-defined doping concentration range, the relative error of the proposed model is less than 5% for the description of C–V characteristics of metal-oxide-semiconductor field-effect transistors (MOSFETs). Compared to some existing models, the proposed model has advantages in both model accuracy and model complexity, and the variation of model parameters can directly reflect the relationship between the characteristics of MOSFETs and the doping concentration of materials. Accordingly, the proposed model can be used for the microcosmic mechanism analysis of MOSFETs. The results of the analysis produce evidence for the widespread existence of fractional-order characteristics in the physical world.
Vibrations of complex composite double-column system by extended Laplace transform method
Authors: Zhao X.Z. , Chang Peter 
Published: March 2022

PurposeDouble-beam/column systems have drawn much attention in many engineering fields. This work aims to present the free and forced vibrations of a novel and complex double-column system with concentrated masses, axial loads and discrete viscoelastic supports subjected to the excitation of ground acceleration are solved by the extended Laplace transform method (ELTM).Design/methodology/approachIn this work, the authors proposed an extended Laplace transform method (ELTM), which is an exact and explicit analytical method. Firstly, the mathematical model simulating the vibrations of the double-column system is reformulated with Dirac's delta function. Secondly, the exact and explicit mode shape solutions are obtained, based on which the natural frequencies and dynamic responses are obtained. An illustrating example is presented to show the validity of the proposed method. A parametric study is carried out to investigate the influences of the non-dimensional column stiffness ratio and the support stiffness ratio on the peak dynamic displacement and velocity.FindingsIt is shown that the proposed method can give exact and explicit solutions of the mode shapes and natural frequencies. It is found that the asynchronous vibrations of the proposed double-column systems can be implemented to efficiently dissipate seismic energy, as shown in the time-histories of displacement and velocity.Practical implicationsThis research systematically studied the free and forced vibrations of the complex double-column system. The proposed extended ELTM is a general method. Its application to studying the energy dissipation capability implicates that the double-column system can be utilized to reduce responses in structures under earthquake attacks.Originality/valueThe proposed extended ELTM is original and powerful. Its application to study the complex double-columns system with discrete supports, concentrated masses and axial loads is novel.