bluuebunny/crossref_metadata_2025_split huggingface dataset:
Refining reproduction number estimates to account for unobserved generations of infection in emerging epidemics
Authors: Brizzi Andrea , O’Driscoll Megan , Dorigatti Ilaria 
Published: November 2021

AbstractBackgroundEstimating the transmissibility of infectious diseases is key to inform situational awareness and for response planning. Several methods tend to overestimate the basic (R0) and effective (Rt) reproduction numbers during the initial phases of an epidemic. The reasons driving the observed bias are unknown. In this work we explore the impact of incomplete observations and underreporting of the first generations of infections during the initial epidemic phase.MethodsWe propose a debiasing procedure which utilises a linear exponential growth model to infer unobserved initial generations of infections and apply it to EpiEstim. We assess the performance of our adjustment using simulated data, considering different levels of transmissibility and reporting rates. We also apply the proposed correction to SARS-CoV-2 incidence data reported in Italy, Sweden, the United Kingdom and the United States of America.ResultsIn all simulation scenarios, our adjustment outperforms the original EpiEstim method. The proposed correction reduces the systematic bias and the quantification of uncertainty is more precise, as better coverage of the true R0 values is achieved with tighter credible intervals. When applied to real world data, the proposed adjustment produces basic reproduction number estimates which closely match the estimates obtained in other studies while making use of a minimal amount of data.ConclusionsThe proposed adjustment refines the reproduction number estimates obtained with the current EpiEstim implementation by producing improved, more precise estimates earlier than with the original method. This has relevant public health implications.SummaryWe propose a back-imputation procedure tackling the issue of unobserved initial generations of infections to reduce the bias observed in the early R0 and Rt estimates and apply it to EpiEstim using simulated and reported COVID-19 data to evaluate it.
Regional and temporal variations affect the accuracy of variant-specific SARS-CoV-2 PCR assays
Authors: Oh Chamteut , Sashittal Palash , Zhou Aijia , Wang Leyi , El-Kebir Mohammed , Nguyen Thanh H. 
Published: November 2021

AbstractMonitoring the prevalence of SARS-CoV-2 variants is necessary to make informed public health decisions during the COVID-19 pandemic. PCR assays have received global attention, facilitating rapid understanding of variant dynamics because they are more accessible and scalable than genome sequencing. However, as PCR assays target only a few mutations, their accuracy could be compromised when these mutations are not exclusive to target variants. Here we show how to design variant-specific PCR assays with high sensitivity and specificity across different geographical regions by incorporating sequences deposited in the GISAID database. Furthermore, we demonstrate that several previously developed PCR assays have decreased accuracy outside their study areas. We introduce PRIMES, an algorithm that enables the design of reliable PCR assays, as demonstrated in our experiments to track dominant SARS-CoV-2 variants in local sewage samples. Our findings will contribute to improving PCR assays for SARS-CoV-2 variant surveillance.ImportanceMonitoring the introduction and prevalence of variants of concern (VOCs) and variants of interest (VOIs) in a community can help the local authorities make informed public health decisions. PCR assays can be designed to keep track of SARS-CoV-2 variants by measuring unique mutation markers that are exclusive to the target variants. However, the mutation markers can not be exclusive to the target variants depending on regional and temporal differences in variant dynamics. We introduce PRIMES, an algorithm that enables the design of reliable PCR assays for variant detection. Because PCR is more accessible, scalable, and robust to sewage samples over sequencing technology, our findings will contribute to improving global SARS-CoV-2 variant surveillance.
The anterior cruciate ligament in murine post-traumatic osteoarthritis: markers and mechanics
Authors: Ramos-Mucci Lorenzo , Elsheikh Ahmed , Keenan Craig , Eliasy Ashkan , D’Aout Kris , Bou-Gharios George , Comerford Eithne , Poulet Blandine 
Published: November 2021

1AbstractOsteoarthritis (OA) is a whole joint disease that affects all knee joint tissues. Ligaments, a matrix-rich connective tissue, play an important mechanical function that stabilises the knee joint and yet their role in OA is not well studied. Recent studies have shown that ligament extracellular matrix (ECM) structure is compromised in the early stages of OA, but it remains unclear how this affects ligament function and biomechanics. In this study, the aim was to investigate the structural, cellular and viscoelastic changes in the anterior cruciate ligament (ACL) in a murine non-invasive post-traumatic OA (PTOA) model. Non-invasive mechanical loading of the knee joint of C57BL/6J mice (10-week-old) was used as a PTOA model. Knee joints were analysed for joint space mineralisation and the ACLs were assessed with histology and mechanical testing. PTOA knee joints had a 33-46% increase in joint space mineralisation and PTOA knee joint ACLs exhibited ECM modifications, including collagen birefringence and COL2 and proteoglycan deposition. ECM changes were associated with cells expressing chondrogenic markers (SOX9 and RUNX2) expanding from the tibial enthesis to the ACL midbody. Viscoelastic and mechanical changes in the ACLs from PTOA knee joints included a 20-21% decrease in tangent modulus at 2MPa of stress, and a decrease strain rate sensitivity at higher strain rates and a significant increase in relaxation during stress-relaxation, but no changes to hysteresis and ultimate load to failure. These results demonstrate that ACL pathology and viscoelastic function is compromised in murine PTOA knee joints and provides further evidence of the important role of ligaments in the knee joint organ in health and disease.
Lack of Fe(II) transporters in basal Cyanobacteria complicates iron uptake in ferruginous Archean oceans
Authors: Enzingmüller-Bleyl Tristan C. , Boden Joanne S. , Herrmann Achim J. , Ebel Katharina W. , Sánchez-Baracaldo Patricia , Frankenberg-Dinkel Nicole , Gehringer Michelle M. 
Published: November 2021

Introductory paragraphCyanobacteria oxygenated Earth’s atmosphere during the Great Oxygenation Event (GOE) through oxygenic photosynthesis. Their high iron requirement was presumed met by high levels of Fe(II) in the anoxic Archean ocean. Here we show that most basal Cyanobacteria cannot synthesize the primary Fe(II) transporter, FeoB. Relaxed molecular clock analyses estimate the arrival of FeoB, as well as the Fe(III) transporters, cFTR1 and FutB, in the Cyanobacteria after the GOE. Furthermore Pseudanabaena sp. PCC7367, a basal marine, benthic strain grown under simulated Archean conditions, constitutively expressed cftr1, even after the addition of Fe(II). By utilizing gene expression studies under a simulated Archean atmosphere, as well as comparative genomics, phylogenetics and molecular clock analyses, this study identified a need to reappraise iron uptake in ancestral Cyanobacteria, as genetic profiling suggests that scavenging of siderophore bound Fe(III), rather than Fe(II), appears to have been the means of iron acquisition prior to the GOE.
Lipid nanoparticles incorporating a GalNAc ligand enable in vivo liver ANGPTL3 editing in wild-type and somatic LDLR knockout non-human primates
Authors: Kasiewicz Lisa N. , Biswas Souvik , Beach Aaron , Ren Huilan , Dutta Chaitali , Mazzola Anne Marie , Rohde Ellen , Chadwick Alexandra , Cheng Christopher , Musunuru Kiran , Kathiresan Sekar , Malyala Padma , Rajeev Kallanthottathil G. , Bellinger Andrew M. 
Published: November 2021

AbstractStandard lipid nanoparticles (LNPs) deliver gene editing cargoes to hepatocytes through receptor-mediated uptake via the low-density lipoprotein receptor (LDLR). Homozygous familial hypercholesterolemia (HoFH) is a morbid genetic disease characterized by complete or near-complete LDLR deficiency, markedly elevated blood low-density lipoprotein cholesterol (LDL-C) levels, and premature atherosclerotic cardiovascular disease. In order to enable in vivo liver gene editing in HoFH patients, we developed a novel LNP delivery technology that incorporates a targeting ligand—N-acetylgalactosamine (GalNAc)—which binds to the asialoglycoprotein receptor (ASGPR). In a cynomolgus monkey (Macaca fascicularis) non-human primate (NHP) model of HoFH created by somatic knockout of the LDLR gene via CRISPR-Cas9, treatment with GalNAc-LNPs formulated with an adenine base editor mRNA and a guide RNA (gRNA) targeting the ANGPTL3 gene yielded ~60% whole-liver editing and ~94% reduction of blood ANGPTL3 protein levels, whereas standard LNPs yielded minimal editing. Moreover, in wild-type NHPs, the editing achieved by GalNAc-LNPs compared favorably to that achieved by standard LNPs, suggesting that GalNAc-LNP delivery technology may prove useful across a range of in vivo therapeutic applications targeting the liver.
The bacterial actin-like cell division protein FtsA forms curved antiparallel double filaments upon binding of FtsN
Authors: Nierhaus Tim , McLaughlin Stephen H , Bürmann Frank , Kureisaite-Ciziene Danguole , Maslen Sarah , Skehel Mark J , Yu Conny WH , Freund Stefan MV , Funke Louise FH , Chin Jason W , Löwe Jan 
Published: November 2021

ABSTRACTCell growth and division of walled bacteria depend on the synthesis and remodelling of peptidoglycan (PG). These activities are carried out by two multiprotein complexes, the elongasome and the divisome during cell elongation and division, respectively. Filaments of tubulin-like FtsZ form the cytoplasmic scaffold for divisome assembly, the Z-ring. In E. coli, the actin homologue FtsA anchors the Z-ring to the membrane and recruits downstream divisome components, including bitopic FtsN. FtsN is recruited late and activates the periplasmic PG synthase FtsWI. To start unravelling the activation mechanism involving FtsA and FtsN, we showed that E. coli FtsA forms antiparallel double filaments on lipid monolayers when also binding FtsN’s cytoplasmic tail, and that Vibrio maritimus FtsA crystallised as an equivalent double filament. We structurally located the FtsA-FtsN interaction site in FtsA’s IA-IC interdomain cleft and confirmed FtsA double filament formation in vivo using site-specific cysteine cross-linking. FtsA-FtsN double filaments reconstituted on and in liposomes preferred negative Gaussian curvature, as was previously shown for the elongasome’s actin, MreB. MreB filaments serve as curvature-sensing “rudders”, orienting insertion of PG around the cell’s circumference. We propose that curved antiparallel FtsA double filaments function similarly in the divisome: FtsA filaments, together with dynamic FtsZ filaments orient and concentrate cell-constricting septal PG synthesis in the division plane.
Loss of function of bHLH transcription factor Nrd1 in tomato induces an arabinogalactan protein-encoding gene and enhances resistance toPseudomonas syringaepv.tomato
Authors: Zhang Ning , Hecht Chloe , Sun Xuepeng , Fei Zhangjun , Martin Gregory B. 
Published: November 2021

AbstractBasic helix-loop-helix (bHLH) transcription factors constitute a superfamily in eukaryotes but their roles in plant immunity remain largely uncharacterized. We found that the transcript abundance in tomato leaves of one bHLH transcription factor-encoding gene,Nrd1(negativeregulator of resistance toDC30001), was significantly increased after treatment with the immunity-inducing flgII-28 peptide. Plants carrying a loss-of-function mutation inNrd1(Λnrd1) showed enhanced resistance toPseudomonas syringaepv.tomato(Pst) DC3000 although early pattern-triggered immunity responses such as generation of reactive oxygen species and activation of mitogen-activated protein kinases after treatment with flagellin-derived flg22 and flgII-28 peptides were unaltered compared to wild-type plants. An RNA-Seq analysis identified a gene,Agp1, whose expression is strongly suppressed in anNrd1-dependent manner.Agp1encodes an arabinogalactan protein and overexpression of theAgp1gene inNicotiana benthamianaled to ∼10-fold lessPstgrowth compared to the control. These results suggest that the Nrd1 protein promotes tomato susceptibility toPstby suppressing the defense geneAgp1. RNA-Seq also revealed that loss of Nrd1 function has no effect on the transcript abundance of immunity-associated genes includingBti9, Core, Fls2, Fls3andWak1uponPstinoculation, suggesting that the enhanced immunity observed in the Δnrd1 mutants is due to the activation of key PRR signaling components as well as loss of Nrd1-regulated suppression ofAgp1.
INDUCED MUTATIONS INTaASN-A2REDUCE FREE ASPARAGINE CONCENTRATION IN THE WHEAT GRAIN
Authors: Alarcón-Reverte Rocío , Xie Yucong , Stromberger John , Cotter Jennifer D. , Mason Richard Esten , Pearce Stephen 
Published: November 2021

ABSTRACTAcrylamide is a neurotoxin and probable carcinogen formed as a processing contaminant during baking and production of different foodstuffs, including bread products. The amino acid asparagine is the limiting substrate in the Maillard reaction that produces acrylamide, so developing wheat varieties with low free asparagine concentrations in the grain is a promising approach to reduce dietary acrylamide exposure. A candidate gene approach was used to identify chemically-induced genetic variation inASPARAGINE SYNTHETASE 2(ASN2)genes that exhibit a grain-specific expression profile. In field trials, durum and common wheat lines carryingasn-a2null alleles exhibited reductions in free asparagine concentration in their grains of between 9 and 34% compared to wild-type sister lines. These plants showed no significant differences in spikelet number, grain size and weight, germination or baking quality traits. These non-transgenic variants can be deployed without restriction in elite wheat germplasm to reduce acrylamide-forming potential with no negative impacts on quality or agronomic performance.Core ideasThree wheatASPARAGINE SYNTHETASE 2knockout alleles were characterized in field experiments.Mutant alleles conferred significant reductions in grain free asparagine concentration.The alleles did not affect quality or agronomic traits.These non-transgenic alleles can be deployed without restriction in wheat breeding programs.
Inversely proportional myelin growth due to alteredPmp22gene dosage identifies PI3K/Akt/mTOR signaling as a novel therapeutic target in HNPP
Authors: Krauter Doris , Ewers David , Hartmann Timon J , Volkmann Stefan , Kungl Theresa , Fledrich Robert , Goebbels Sandra , Nave Klaus-Armin , Sereda Michael W 
Published: November 2021

AbstractDuplication of the gene encoding the myelin protein PMP22 causes the hereditary neuropathy Charcot-Marie-Tooth disease 1A (CMT1A), characterized by hypomyelination of medium to large caliber peripheral axons. Conversely, haplo-insufficiency ofPMP22leads to focal myelin overgrowth in hereditary neuropathy with liability to pressure palsies (HNPP). However, the molecular mechanisms of myelin growth regulation by PMP22 remain obscure. Here, we found that the major inhibitor of the myelin growth signaling pathway PI3K/Akt/mTOR, phosphatase and tensin homolog (PTEN) is increased in abundance in CMT1A and decreased in HNPP rodent models. Indeed, treatment of DRG co-cultures from HNPP mice with PI3K/Akt/mTOR pathway inhibitors reduced focal hypermyelination and, importantly, treatment of HNPP mice with the mTOR inhibitor Rapamycin improved motor behavior, increased compound muscle amplitudes (CMAP) and reduced tomacula formation in the peripheral nerve. InPmp22tgCMT1A mice, we uncovered that the differentiation defect of Schwann cells is independent from PI3K/Akt/mTOR activity, rendering the pathway insufficient as a therapy target on its own. Thus, while CMT1A pathogenesis is governed by dys-differentiation uncoupled from PI3K/Akt/mTOR signaling, targeting the pathway provides novel proof-of-principle for a therapeutic approach to HNPP.
Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition
Authors: Lee Yu-Chen , Lin Song-Chang , Yu Guoyu , Zhu Ming , Song Jian H , Rivera Keith , Pappin Darryl , Logothetis Christopher J. , Panaretakis Theocharis , Wang Guocan , Yu-Lee Li-Yuan , Lin Sue-Hwa 
Published: November 2021

AbstractMetastatic prostate cancer (PCa) in bone induces bone-forming lesions that enhance PCa progression. How tumor-induced bone formation enhances PCa progression is not known. We have previously shown that PCa-induced bone originates from endothelial cells (EC) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted BMP4. Here, we show that EC-to-OSB transition leads to changes in the tumor microenvironment that increases the metastatic potential of PCa cells. We found that conditioned medium (CM) from EC-OSB hybrid cells increases the migration, invasion and survival of PC3-mm2 and C4-2B4 PCa cells. Quantitative mass spectrometry (iTRAQ) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced osteoblasts was confirmed by immunohistochemistry of MDA-PCa118b xenograft and human bone metastasis specimens. Mechanistically, BMP4 increases TNC expression in EC-OSB cells through the Smad1-Notch/Hey1 pathway. How TNC promotes PCa metastasis was next interrogated by in vitro and in vivo studies. In vitro studies showed that a TNC neutralizing antibody inhibits EC-OSB-CM-mediated PCa cell migration and survival. TNC knockdown decreased, while addition of recombinant TNC or TNC overexpression increased migration and anchorage-independent growth of PC3 or C4-2b cells. When injected orthotopically, PC3-mm2-shTNC clones decreased metastasis to bone, while C4-2b-TNC overexpressing cells increased metastasis to lymph nodes. TNC enhances PCa cell migration through α5β1 integrin-mediated YAP/TAZ inhibition. These studies elucidate that tumor-induced stromal reprogramming generates TNC that enhances PCa metastasis and suggest that TNC may be a target for PCa therapy.
Fast and sensitive GCaMP calcium indicators for imaging neural populations
Authors: Zhang Yan , Rózsa Márton , Liang Yajie , Bushey Daniel , Wei Ziqiang , Zheng Jihong , Reep Daniel , Broussard Gerard Joey , Tsang Arthur , Tsegaye Getahun , Narayan Sujatha , Obara Christopher J. , Lim Jing-Xuan , Patel Ronak , Zhang Rongwei , Ahrens Misha B. , Turner Glenn C. , Wang Samuel S.-H. , Korff Wyatt L. , Schreiter Eric R. , Svoboda Karel , Hasseman Jeremy P. , Kolb Ilya , Looger Loren L. 
Published: November 2021

AbstractCalcium imaging with protein-based indicators is widely used to follow neural activity in intact nervous systems. The popular GCaMP indicators are based on the calcium-binding protein calmodulin and the RS20 peptide. These sensors report neural activity at timescales much slower than electrical signaling, limited by their biophysical properties and trade-offs between sensitivity and speed. We used large-scale screening and structure-guided mutagenesis to develop and optimize several fast and sensitive GCaMP-type indicators. The resulting ‘jGCaMP8’ sensors, based on calmodulin and a fragment of endothelial nitric oxide synthase, have ultra-fast kinetics (rise times, 2 ms) and still feature the highest sensitivity for neural activity reported for any protein-based sensor. jGCaMP8 sensors will allow tracking of larger populations of neurons on timescales relevant to neural computation.
Microbial signals and lymphotoxin drive TNF-independent death of A20 and ABIN-1 deficient epithelium
Authors: Rusu Iulia , Mennillo Elvira , Li Zhongmei , Bain Jared L. , Sun Xiaofei , Ly Kimberly , Rosli Yenny Y. , Naser Mohammad , Wang Zunqiu , Advincula Rommel , Achacoso Philip , Shao Ling , Razani Bahram , Klein Ophir D. , Marson Alexander , Turnbaugh Jessie A. , Turnbaugh Peter J. , Malynn Barbara A. , Ma Averil , Kattah Michael G. 
Published: November 2021

ABSTRACTAnti-TNF antibodies are effective for treating patients with inflammatory bowel disease (IBD), but many patients fail to respond to anti-TNF therapy, highlighting the importance of TNF-independent disease. We previously demonstrated that acute deletion of two IBD susceptibility genes, A20 (Tnfaip3) and Abin-1 (Tnip1), in intestinal epithelial cells (IECs) sensitizes mice to both TNF-dependent and TNF-independent death. Here we show that TNF-independent IEC death after A20 and Abin-1 deletion is rescued by germ-free derivation or deletion of MyD88, while deletion of Trif provides only partial protection. Combined deletion of Ripk3 and Casp8, which inhibits both apoptotic and necroptotic death, completely protects against death after acute deletion of A20 and Abin-1 in IECs. A20 and Abin-1-deficient IECs are sensitized to TNF-independent, TNFR-1-mediated death in response to lymphotoxin alpha (LTα) homotrimers. Blockade of LTα in vivo reduces weight loss and improves survival when combined with partial deletion of MyD88. These data show that microbial signals, MyD88, and LTα all contribute to TNF-independent intestinal injury.SUMMARYHere we show that germ-free derivation, MyD88 deletion, combined Ripk3 and Casp8 deletion, or anti-LTα, all reduce TNF-independent intestinal injury after A20 and Abin-1 deletion.
Who’s talking to whom in agribusiness? And should anyone listen? The network of intellectual influence in agribusiness research
Authors: Van Fleet David D. , McWilliams Abagail , Freeman Michael 
Published: November 2021

PurposeTo develop an understanding of communication among agribusiness journals and to examine patterns of citations that allow the measurement and description of the structure of communication flows among those journals in a network.Design/methodology/approachThe data for this study were gathered from the Journal Citation Reports (JCR) published by Thomson Scientific (Philadelphia). The authors conducted a bibliometric analysis, based on an international trade analogy to explain the network of agribusiness journals and how these journals communicate with business and economics journals.FindingsBusiness and economics journals and, particularly the traditionally major ones, surprisingly were scarcely every used. However, the British Food Journal stood out with 50 citations to marketing and strategic management journals.Research limitations/implicationsThere are predominantly four such limitations: only 33 journals were studied, only one 5-year time period was involved, that time period is a few years old and the journal characteristics were derived using data from the “Scopes” and “Information for Authors” text on the website of each journal.Practical implicationsExchanges of agribusiness knowledge and information among diverse stakeholders (consumers, suppliers and public agencies) in a complex environment require a better understanding of the network of agribusiness journals and their relation to traditional business and economics journals.Social implicationsNetworks of journals facilitate cooperation and interactions to improve developments in the field.Originality/valueExamining citations from and to the field of agribusiness is interesting and important because knowledge is transferred through networks comprise those who contribute to journals, read them and learn from them, i.e. by “talking” to each other as well as by practitioners who also read and learn from those journals.