bluuebunny/crossref_metadata_2025_split huggingface dataset:
Have the radiographic characteristics of total knee arthroplasty recipients in rheumatoid arthritis changed after the induction of biologic disease modifying antirheumatic drugs?
Authors: Fujimura Kenjiro , Haraguchi Akihisa , Sakurai Ryuta , Kamura Satoshi , Sakuraba Koji , Miyahara Hisaaki , Fukushi Jun-ichi 
Published: December 2021

ABSTRACTObjectivesWhether the characteristics of patients with rheumatoid arthritis (RA) undergoing total knee arthroplasty (TKA) have changed in the era of biologic disease-modifying antirheumatic drugs (bDMARDs) is unclear. We compared the radiographic findings of the knees in TKA recipients with RA before and after the introduction of bDMARDs.MethodsConsecutive patients who underwent primary TKA between 1999 and 2002 (115 knees; 79 patients, group A) and between 2013 and 2017 (117 knees; 95 patients, group B) were retrospectively evaluated. Clinical data, including disease duration, medication, C-reactive protein, erythrocyte sedimentation rate, and rheumatoid factor, were collected. The Larsen classification, joint space narrowing (JSN), bone erosion, and geode and osteophyte formation were evaluated on preoperative radiographs.ResultsOsteophyte formation was significantly increased, and bone erosion and geode formation were significantly decreased in group B. In addition, medial-dominant JSN was significantly increased, and bicompartmental JSN was significantly decreased in group B. Medial-dominant JSN was positively and bone erosion was negatively associated with osteophyte formation.ConclusionsFollowing the introduction of bDMARDs, typical radiographic findings of rheumatoid knees have decreased, and secondary osteoarthritis-like changes, characterized by osteophyte formation and medial-dominant JSN, have increased in the knees of TKA recipients.
Efficient target cleavage by Type V Cas12a effectors programmed with split CRISPR RNA
Authors: Shebanova Regina , Nikitchina Natalia , Shebanov Nikita , Mekler Vladimir , Kuznedelov Konstantin , Ulashchik Egor , Vasilev Ruslan , Sharko Olga , Shmanai Vadim , Tarassov Ivan , Severinov Konstantin , Entelis Nina , Mazunin Ilya 
Published: December 2021

Abstract
CRISPR RNAs (crRNAs) that direct target DNA cleavage by Type V Cas12a nucleases consist of constant repeat-derived 5′-scaffold moiety and variable 3′-spacer moieties. Here, we demonstrate that removal of most of the 20-nucleotide scaffold has only a slight effect on in vitro target DNA cleavage by a Cas12a ortholog from Acidaminococcus sp. (AsCas12a). In fact, residual cleavage was observed even in the presence of a 20-nucleotide crRNA spacer moiety only. crRNAs split into separate scaffold and spacer RNAs catalyzed highly specific and efficient cleavage of target DNA by AsCas12a in vitro and in lysates of human cells. In addition to dsDNA target cleavage, AsCas12a programmed with split crRNAs also catalyzed specific ssDNA target cleavage and non-specific ssDNA degradation (collateral activity). V-A effector nucleases from Francisella novicida (FnCas12a) and Lachnospiraceae bacterium (LbCas12a) were also functional with split crRNAs. Thus, the ability of V-A effectors to use split crRNAs appears to be a general property. Though higher concentrations of split crRNA components are needed to achieve efficient target cleavage, split crRNAs open new lines of inquiry into the mechanisms of target recognition and cleavage and may stimulate further development of single-tube multiplex and/or parallel diagnostic tests based on Cas12a nucleases.
Multiplex PCR Pathogen Detection in Acute Gastroenteritis Among Hospitalized US Children Compared With Healthy Controls During 2011–2016 in the Post–Rotavirus Vaccine Era
Authors: Harrison Christopher J , Hassan Ferdaus , Lee Brian , Boom Julie , Sahni Leila C , Johnson Coreen , Dunn James , Payne Daniel C , Wikswo Mary E , Parashar Umesh , Selvarangan Rangaraj 
Published: December 2021

Abstract

Background
Despite vaccine-induced decreases in US rotavirus (RV) disease, acute gastroenteritis (AGE) remains relatively common. We evaluated AGE pathogen distribution in hospitalized US children in the post–RV vaccine era.

Methods
From December 2011 to June 2016, the New Vaccine Surveillance Network (NVSN) conducted prospective, active, population-based surveillance in hospitalized children with AGE. We tested stools from 2 NVSN sites (Kansas City, Houston) with Luminex x-TAG Gastrointestinal Pathogen Panels (Luminex GPP) and analyzed selected signs and symptoms.

Results
For 660 pediatric AGE inpatients and 624 age-matched healthy controls (HCs), overall organism detection was 51.2% and 20.6%, respectively (P &lt; .001). Among AGE subjects, GPP polymerase chain reaction detected &gt;1 virus in 39% and &gt;1 bacterium in 14% of specimens. Detection frequencies for AGE subjects vs HCs were norovirus (NoV) 18.5% vs 6.6%, RV 16.1% vs 9.8%, adenovirus 7.7% vs 1.4%, Shigella 4.8% vs 1.0%, Salmonella 3.1% vs 0.1%, and Clostridioides difficile in ≥2-year-olds 4.4% vs 2.4%. More co-detections occurred among AGE patients (37/660, 5.6%) than HCs (14/624, 2.2%; P = .0024). Per logistic regression analysis, ill contacts increased risk for NoV, RV, and Shigella (P &lt; .001). More vomiting episodes occurred with NoV and RV, and more diarrheal episodes with Shigella and Salmonella. Modified Vesikari scores were highest for Shigella and lowest for C. difficile.

Conclusions
NoV detection was most frequent; however, RV remained important in hospitalized AGE in the post–RV vaccine era. Continued active surveillance is important to document ongoing vaccine effects, pathogen emergence, and baseline disease burden for new vaccines.
A cook with ‘burning in the thigh’ and a ‘hotspot’ in the groin!
Authors: Moy Wai Lun 
Published: December 2021

ABSTRACT
Meralgia paresthetica (MP) is a condition characterised by abnormal sensations on the anterolateral aspect of the thigh due to the dysfunction of the lateral femoral cutaneous nerve. Here, I present a case of a 64-year-old female cook who attended the General Medicine clinic with 2 months of persistent numbness and ‘burning’ sensation over the right anterolateral thigh. Subsequent physical examination revealed the diagnosis of meralgia paresthetica. The significance of good history taking and thorough physical examination in reaching the diagnosis of meralgia paresthetica cannot be overemphasized. In most typical presentations, advanced imaging and neurodiagnostic testing do not add value to confirm the diagnosis. If the clinical diagnosis is doubtful, nerve conduction study and magnetic resonance imaging may still be performed to exclude other mimicking pathologies. Increasing awareness of MP among doctors unfamiliar with this condition will prevent the ordering of excessive investigations.
Na+ Sensitivity of the KAT2-Like Channel Is a Common Feature of Cucurbits and Depends on the S5-P-S6 Segment
Authors: Wang Li-Min , Zhao Li-Na , Shah Iftikhar Hussain , Ramirez Dora Cano , Boeglin Martin , Véry Anne-Aliénor , Sentenac Hervé , Zhang Yi-Dong 
Published: December 2021

Abstract
Inhibition of Shaker K+ channel activity by external Na+ was previously reported in the melon (Cucumis melo L.) inwardly rectifying K+ channel MIRK and was hypothesized to contribute to salt tolerance. In this study, two inward Shaker K+ channels, CsKAT2 from cucumber (Cucumis sativus) and ClKAT2 from watermelon (Citrullus lanatus), were identified and characterized in Xenopus oocytes. Both channels were inwardly rectifying K+ channels with higher permeability to potassium than other monovalent cations and more active when external pH was acidic. Similarly to MIRK, their activity displayed an inhibition by external Na+, thus suggesting a common feature in Cucurbitaceae (Cucumis spp., Citrullus spp.). CsKAT2 and ClKAT2 are highly expressed in guard cells. After 24 h of plant treatment with 100 mM NaCl, the three KAT2-like genes were significantly downregulated in leaves and guard cells. Reciprocal chimeras were obtained between MIRK and Na+-insensitive AtKAT2 cDNAs. The chimera where the MIRK S5-P-S6 segment was replaced by that from AtKAT2 no longer showed Na+ sensitivity, while the inverse chimera gained Na+ sensitivity. These results provide evidence that the molecular basis of the channel blockage by Na+ is located in the S5-P-S6 region. Comparison of the electrostatic property in the S5-P-S6 region in AtKAT2 and MIRK revealed four key amino acid residues potentially governing Na+ sensitivity.
Nonhomologous end joining as key to CRISPR/Cas-mediated plant chromosome engineering
Authors: Gehrke Fabienne , Schindele Angelina , Puchta Holger 
Published: December 2021

Abstract
Although clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)-mediated gene editing has revolutionized biology and plant breeding, large-scale, heritable restructuring of plant chromosomes is still in its infancy. Duplications and inversions within a chromosome, and also translocations between chromosomes, can now be achieved. Subsequently, genetic linkages can be broken or can be newly created. Also, the order of genes on a chromosome can be changed. While natural chromosomal recombination occurs by homologous recombination during meiosis, CRISPR/Cas-mediated chromosomal rearrangements can be obtained best by harnessing nonhomologous end joining (NHEJ) pathways in somatic cells. NHEJ can be subdivided into the classical (cNHEJ) and alternative NHEJ (aNHEJ) pathways, which partially operate antagonistically. The cNHEJ pathway not only protects broken DNA ends from degradation but also suppresses the joining of previously unlinked broken ends. Hence, in the absence of cNHEJ, more inversions or translocations can be obtained which can be ascribed to the unrestricted use of the aNHEJ pathway for double-strand break (DSB) repair. In contrast to inversions or translocations, short tandem duplications can be produced by paired single-strand breaks via a Cas9 nickase. Interestingly, the cNHEJ pathway is essential for these kinds of duplications, whereas aNHEJ is required for patch insertions that can also be formed during DSB repair. As chromosome engineering has not only been accomplished in the model plant Arabidopsis (Arabidopsis thaliana) but also in the crop maize (Zea mays), we expect that this technology will soon transform the breeding process.
Cancer prevention, risk reduction, and control: opportunities for the next decade of health care delivery research
Authors: O’Malley Denalee M , Alfano Catherine M , Doose Michelle , Kinney Anita Y , Lee Simon J Craddock , Nekhlyudov Larissa , Duberstein Paul , Hudson Shawna V 
Published: December 2021

Abstract
In this commentary, we discuss opportunities to optimize cancer care delivery in the next decade building from evidence and advancements in the conceptualization and implementation of multi-level translational behavioral interventions. We summarize critical issues and discoveries describing new directions for translational behavioral research in the coming decade based on the promise of the accelerated application of this evidence within learning health systems. To illustrate these advances, we discuss cancer prevention, risk reduction (particularly precision prevention and early detection), and cancer treatment and survivorship (particularly risk- and need-stratified comprehensive care) and propose opportunities to equitably improve outcomes while addressing clinician shortages and cross-system coordination. We also discuss the impacts of COVID-19 and potential advances of scientific knowledge in the context of existing evidence, the need for adaptation, and potential areas of innovation to meet the needs of converging crises (e.g., fragmented care, workforce shortages, ongoing pandemic) in cancer health care delivery. Finally, we discuss new areas for exploration by applying key lessons gleaned from implementation efforts guided by advances in behavioral health.
Is tenofovir disoproxil fumarate associated with weight loss?
Authors: Shah Shahini , Pilkington Victoria , Hill Andrew 
Published: December 2021

Background:
Recent clinical trials have shown weight gain associated with newer antiretrovirals. It is unclear how the nucleoside reverse transcriptase inhibitor backbone affects weight. Recent evidence suggests greater weight gain with tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF). However, it is not fully understood whether TDF contributes to weight suppression.

Methods:
A systematic search of PubMed, Embase and clinicaltrials.gov was conducted to identify all randomized control trials comparing TDF/FTC or TDF to control in HIV-negative individuals. The primary endpoint included the number of events of 5% weight loss. Mantel–Haenszel test with random-effects modelling was used to calculate the odds ratio (OR) and 95% confidence intervals (95% CI). Further analyses of gastrointestinal (GI) adverse events were also undertaken.

Results:
Seven PrEP trials: PARTNERS, VOICE, TDF-2, Bangkok PrEP, iPrEX, FEM-PrEP and HPTN 084 were included in the analysis of weight loss, with a total sample size of 19 359. One study (HPTN 084) compared TDF/FTC to cabotegravir (CAB). HIV-negative individuals taking TDF were more likely to experience weight loss compared with control [odds ratio (OR) 1.44; 95% CI 1.12–1.85; P = 0.005). Exposure to TDF was also linked to greater odds of vomiting (OR 1.81; 95% CI 1.20–2.73; P < 0.005). There were no increased odds of nausea, diarrhoea or loss of appetite.

Conclusion:
There is evidence in HIV-negative individuals that TDF may be associated with weight loss. Further research should be carried out in HIV-positive individuals, and clinical trials of TDF/FTC should publish weight data to widen the evidence base.
Theoretical Analysis of Principal Components in an Umbrella Model of Intraspecific Evolution
Authors: Estavoyer Maxime , François Olivier 
Published: December 2021

AbstractPrincipal component analysis (PCA) is one of the most frequently-used approach to describe population structure from multilocus genotype data. Regarding geographic range expansions of modern humans, interpretations of PCA have, however, been questioned, as there is uncertainty about the wave-like patterns that have been observed in principal components. It has indeed been argued that wave-like patterns are mathematical artifacts that arise generally when PCA is applied to data in which genetic differentiation increases with geographic distance. Here, we present an alternative theory for the observation of wave-like patterns in PCA. We study a coalescent model – the umbrella model – for the diffusion of genetic variants. The model is based on genetic drift without any particular geographical structure. In the umbrella model, splits from an ancestral population occur almost continuously in time, giving birth to small daughter populations at a regular pace. Our results provide detailed mathematical descriptions of eigenvalues and eigenvectors for the PCA of sampled genomic sequences under the model. Removing variants uniquely represented in the sample, the PCA eigenvectors are defined as cosine functions of increasing periodicity, reproducing wave-like patterns observed in equilibrium isolation-by-distance models. Including rare variants in the analysis, the eigenvectors corresponding to the largest eigenvalues exhibit complex wave shapes. The accuracy of our predictions is further investigated with coalescent simulations. Our analysis supports the hypothesis that highly structured wave-like patterns could arise from genetic drift only, and may not always be artificial outcomes of spatially structured data. Genomic data related to the peopling of the Americas are reanalyzed in the light of our new theory.
Rapid multilocus adaptation of clonal cabbage leaf curl virus populations toArabidopsis thaliana
Authors: Hoyer J. Steen , Wilkins Olivia W. , Munshi Aanandi , Wiese Emma , Dubey Divya , Renard Savannah , Mortensen Karoline Rosendal Hartø , Dye Anna E. , Carbone Ignazio , Duffy Siobain , Ascencio-Ibáñez José Trinidad 
Published: December 2021

AbstractCabbage leaf curl virus (CabLCV) has a bipartite single-stranded DNA genome and infects the model plantArabidopsis thaliana. CabLCV serves as a model for the genusBegomovirus, members of which cause tremendous crop losses worldwide. We have used CabLCV as a model for within-plant virus evolution by inoculating individual plants with infectious clones of either a wild-type or mutagenized version of the CabLCV genome. Consistent with previous reports, detrimental substitutions in the Replication-associated gene (Rep) were readily compensated for by direct reversion and/or alternative mutations. A surprising number of common mutations were detected elsewhere in both viral segments (DNA-A and DNA-B) indicating convergent evolution and suggesting that CabLCV may not be as well adapted toA. thalianaas commonly presumed. Consistent with this idea, a spontaneous coat protein variant consistently rose to high allele frequency in susceptible accession Col-0, at a higher rate than in hypersusceptible accession Sei-0. Numerous high-frequency mutations were also detected in a candidate Rep binding site in DNA-B. Our results reinforce the fact that spontaneous mutation of this type of virus occurs rapidly and can change the majority consensus sequence of a within-plant virus population in weeks.
Peptide-antibody Fusions Engineered by Phage Display Exhibit Ultrapotent and Broad Neutralization of SARS-CoV-2 Variants
Authors: Labriola Jonathan M. , Miersch Shane , Chen Gang , Chen Chao , Pavlenco Alevtina , Pisanu Francesca , Caccuri Francesca , Zani Alberto , Sharma Nitin , Feng Annie , Leung Daisy W. , Caruso Arnaldo , Amarasinghe Gaya K. , Sidhu Sachdev S. 
Published: December 2021

AbstractThe COVID-19 pandemic has been exacerbated by the emergence of variants of concern (VoCs). Many VoC mutations are found in the viral spike protein (S-protein), and are thus implicated in host infection and response to therapeutics. Bivalent neutralizing antibodies (nAbs) targeting the S-protein receptor-binding domain (RBD) are promising therapeutics for COVID-19, but are limited due to low potency and vulnerability to RBD mutations found in VoCs. To address these issues, we used naïve phage-displayed peptide libraries to isolate and optimize 16-residue peptides that bind to the RBD or the N-terminal domain (NTD) of the S-protein. We fused these peptides to the N-terminus of a moderate affinity nAb to generate tetravalent peptide-IgG fusions, and showed that both classes of peptides were able to improve affinities for the S-protein trimer by >100-fold (apparent KD < 1 pM). Critically, cell-based infection assays with a panel of six SARS-CoV-2 variants demonstrate that an RBD-binding peptide was able to enhance the neutralization potency of a high-affinity nAb >100-fold. Moreover, this peptide-IgG was able to neutralize variants that were resistant to the same nAb in the bivalent IgG format. To show that this approach is general, we fused the same peptide to a clinically approved nAb drug, and showed that it rescued neutralization against a resistant variant. Taken together, these results establish minimal peptide fusions as a modular means to greatly enhance affinities, potencies, and breadth of coverage of nAbs as therapeutics for SARS-CoV-2.
GraphPrompt: Biomedical Entity Normalization Using Graph-based Prompt Templates
Authors: Zhang Jiayou , Wang Zhirui , Zhang Shizhuo , Bhalerao Megh Manoj , Liu Yucong , Zhu Dawei , Wang Sheng 
Published: December 2021

AbstractBiomedical entity normalization unifies the language across biomedical experiments and studies, and further enables us to obtain a holistic view of life sciences. Current approaches mainly study the normalization of more standardized entities such as diseases and drugs, while disregarding the more ambiguous but crucial entities such as pathways, functions and cell types, hindering their real-world applications. To achieve biomedical entity normalization on these under-explored entities, we first introduce an expert-curated dataset OBO-syn encompassing 70 different types of entities and 2 million curated entity-synonym pairs. To utilize the unique graph structure in this dataset, we propose GraphPrompt, a promptbased learning approach that creates prompt templates according to the graphs. Graph-Prompt obtained 41.0% and 29.9% improvement on zero-shot and few-shot settings respectively, indicating the effectiveness of these graph-based prompt templates. We envision that our method GraphPrompt and OBO-syn dataset can be broadly applied to graph-based NLP tasks, and serve as the basis for analyzing diverse and accumulating biomedical data.
A minimal model demonstrates the control of mouse sperm capacitation by a positive feedback loop between sNHE and SLO3
Authors: de Prelle Bertrand , Lybaert Pascale , Gall David 
Published: December 2021

ABSTRACTWhen mammalian spermatozoa are released in the female reproductive tract, they are incapable of fertilizing the oocyte. They need a prolonged exposure to the alkaline medium of the female genital tract before their flagellum gets hyperactivated and the acrosome reaction can take place, allowing the sperm to interact with the oocyte. Ionic fluxes across the sperm membrane are involved in two essential aspects of capacitation: the increase in intracellular pH and the membrane hyperpolarization. In particular, it has been shown that the SLO3 potassium channel and the sNHE sodium-proton transporter, two sperm-specific transmembrane proteins, are necessary for the capacitation process to occur. As the SLO3 channel is activated by an increase in intracellular pH and sNHE is activated by hyperpolarization, they act together as a positive feedback system. Mathematical modeling provides a unique tool to capture the essence of a molecular mechanism and can be used to derive insight from the existing data. We have therefore developed a theoretical model formalizing the positive feedback loop between SLO3 and sHNE in mouse epididymal sperm to see if this non-linear interaction can provide the core mechanism explaining the existence of uncapacited and capacitated states. We show that the proposed model can fully explain the switch between the uncapacitated and capacited states and also predicts the existence of a bistable behaviour. Furthermore, our model indicates that SLO3 inhibition, above a certain threshold, is effective to completely abolish capacitation.
RNA-guided cell targeting with CRISPR/RfxCas13d collateral activity in human cells
Authors: Shi Peiguo , Murphy Michael R. , Aparicio Alexis O. , Kesner Jordan S. , Fang Zhou , Chen Ziheng , Trehan Aditi , Wu Xuebing 
Published: December 2021

ABSTRACTWhile single-cell sequencing has allowed rapid identification of novel cell types or states and associated RNA markers, functional studies remain challenging due to the lack of tools that are able to target specific cells based on these markers. Here we show that targeting a single marker RNA with CRISPR/RfxCas13d led to collateral transcriptome destruction in human cells, which can be harnessed to inhibit cell proliferation or to suppress cell state transition.