bluuebunny/crossref_metadata_2025 huggingface dataset:
Detailed Transcriptional Landscape of Peripheral Blood Points to Increased Neutrophil Activation in Treatment-Naïve Inflammatory Bowel Disease
Authors: Juzenas Simonas , Hübenthal Matthias , Lindqvist Carl Mårten , Kruse Robert , Steiert Tim Alexander , Degenhardt Frauke , Schulte Dominik , Nikolaus Susanna , Zeissig Sebastian , Bergemalm Daniel , Almer Sven , Hjortswang Henrik , Bresso Francesca ,   SIC IBD Working Group, Strüning Nina , Kupcinskas Juozas , Keller Andreas , Lieb Wolfgang , Rosenstiel Philip , Schreiber Stefan , D’Amato Mauro , Halfvarson Jonas , Hemmrich-Stanisak Georg , Franke Andre
Published: January 2022

Background and Aims

Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn’s disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways.

Methods

Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95].

Results

Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls.

Conclusions

Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.
IL-23 Blockade in Anti-TNF Refractory IBD: From Mechanisms to Clinical Reality
Authors: Atreya Raja , Neurath Markus F
Published: January 2022

Increasing insights into the immunopathogenesis of inflammatory bowel diseases [IBD] have led to the advent of targeted therapies that inhibit crucial mediators of the inflammatory process, thereby widening our available therapeutic armamentarium. Anti-tumour necrosis factor [anti-TNF] agents are still a mainstay of our therapeutic endeavours and the introduction of corresponding biosimilars has further widened their use. Nevertheless, only a subgroup of treated patients benefit from the initiated treatment and there is secondary non-response in the course of therapy. Initiation of subsequent therapy often poses a challenge to the treating physician, as non-response to primary anti-TNF treatment generally characterizes a patient group that is more treatment-resistant, which may be due to the immunological impregnation by prior anti-TNF exposure. At present, there is currently no guidance for the most appropriate second-line therapy after anti-TNF failure. Here, we review the efficacy of secondary biological therapy in anti-TNF-treated patients. We focus on and assess available clinical trial data of the emerging substance class of IL-23p19 inhibitors, which have demonstrated remarkable efficacy not only in anti-TNF-naïve but also refractory patients. We present molecular mechanisms that drive IL-23-mediated resistance to ongoing anti-TNF therapy and discuss the dynamic fluidity of the mucosal cytokine network in the course of therapy that perpetuates the mucosal inflammatory reaction. Translation of these findings into clinical practice might finally lead to initiation of the most appropriate therapy at the right time of the individual disease course, which would have important implications for the patient’s probability of response to treatment.
Comparative Insecticide Application Techniques (Micro-Sprinkler) Against Drosophila suzukii Matsumura (Diptera: Drosophilidae) in Highbush Blueberry
Authors: Mermer Serhan , Tait Gabriella , Pfab Ferdinand , Mirandola Enrico , Bozaric Aleksandar , Thomas Canessa D , Moeller Maxwell , Oppenheimer Katherine G , Xue Lan , Wang Lu , Walton Vaughn M
Published: January 2022

Drosophila suzukii (Matsumura), spotted-wing drosophila, is a major pest in small fruit crops including highbush blueberry. Controlling D. suzukii is challenging and chemical control is the main method to manage D. suzukii populations. Growers have expressed interest in using micro-sprinklers as an alternative method to apply insecticides. The current study aimed to evaluate if insecticide applications using micro-sprinklers can be used as an alternative method to protect the fruit from D. suzukii egg-laying. Modeling was used as an additional tool to parameterize the relative insecticide efficacy on oviposition. Field measurements of different treatments were conducted over periods of eleven days on commercial-standard highbush blueberry. Cyantraniliprole and spinetoram were applied using both a micro-sprinkler and a backpack sprayer. Treatments of Chromobacterium subtsugae and zeta-cypermethrin were only applied using a backpack sprayer. Both cyantraniliprole and spinetoram treatments resulted in moderate suppression of D. suzukii egg-laying. No statistical significance was found between micro-sprinkler and backpack sprayer applications for these two insecticides. Zeta-cypermethrin treatments using a backpack sprayer resulted in the most significant suppression of D. suzukii egg-laying over eleven days, while C. subtsugae was less effective at preventing D. suzukii egg-laying. Modeling simulations estimate the impact of the control methods on D. suzukii populations dynamics and simulation outputs indicated that backpack sprayers reduced D. suzukii populations at more pronounced levels compared to micro-sprinkler applications. The present study indicates that there is an underlying value of micro-sprinkler systems as an alternative and rapid spray application technique to help suppress D. suzukii pest populations during high-pressure periods in highbush blueberry production.
SGLT-2 inhibitors and cardiovascular outcomes in patients with and without a history of heart failure: a systematic review and meta-analysis
Authors: Razuk Victor , Chiarito Mauro , Cao Davide , Nicolas Johny , Pivato Carlo A , Camaj Anton , Power David , Beerkens Frans , Jones Davis , Alter Aviv , Mathew Alvin , Spirito Alessandro , Contreras Johanna P , Dangas George D , Mehran Roxana
Published: January 2022

Aims

Sodium–glucose cotransporter 2 (SGLT-2) inhibitors have cardiovascular (CV) benefits in patients with heart failure with reduced ejection fraction (HFrEF). Whether these medications improve CV outcomes irrespective of heart failure history or left ventricular ejection fraction (LVEF) in HFrEF remains unknown.

Methods and results

All randomized, placebo-controlled trials of SGLT-2 inhibitors reporting similar CV outcomes were searched in PubMed from 1 January 2010 to 1 October 2021. The primary outcome was the composite of hospitalization for heart failure or CV death. Secondary outcomes included all-cause mortality. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used as effect estimates and calculated with a random-effects model. Data from 11 trials and a total of 66 957 patients (n = 36 758 SGLT-2 group, n = 30 199 placebo group) were included. SGLT-2 inhibitors reduced the risk of hospitalization for heart failure or CV death in patients with (HR 0.76, 95% CI 0.71–0.80) and without (HR 0.76, 95% CI 0.68–0.86; Pinteraction = 0.69) heart failure. Patients with (HR 0.87, 95% CI 0.80–0.95) and without (HR 0.84, 95% CI 0.73–0.95; Pinteraction = 0.67) heart failure treated with SGLT-2 inhibitors had a reduction in all-cause mortality. Reduction in the primary outcome was consistently observed in HFrEF patients with (HR 0.68, 95% CI 0.59–0.78) and without (HR 0.84, 95% CI 0.71–0.99; Pinteraction = 0.13) severely reduced LVEF, and in heart failure with preserved ejection fraction patients (HR 0.80, 95% CI 0.70–0.92; Pinteraction = 0.65).

Conclusion

SGLT-2 inhibitors improved CV outcomes irrespective of heart failure history or type, and severity of LVEF reduction.
Transitional Inequality Offset: Educational Expansion and Inequality of Educational Opportunity in European Countries between 2000 and 2018
Authors: Katrňák Tomáš , Hubatková Barbora
Published: January 2022

Educational expansion has been taking place in European countries since 2000. We address the relationship between this educational expansion and the inequality of educational opportunity (IEO) by educational origin. We analyse the European Social Survey data from 20 European countries over five rounds (2002, 2006, 2010, 2014, and 2018). Our analysis is restricted to the 25–34 age groups. We use a multilevel sequential logit (MLSL) model for three hierarchical educational transitions (sequences), delimited by four International Standard Classification of Education (ISCED97) categories. We apply the MLSL model to decompose IEO in completed education into the educational origin effects on passing transitions and the structural effects (weights) connected with transitions. Our results show that educational expansion slightly weakens IEO in completed education, but this is far from being a situation in which IEO does not exist. IEO is maintained in educational transitions by transitional inequality offset. The effect of the weight of each transition takes over the educational origin effect on passing transitions and vice versa over educational expansion. Both these effects are maintained in balance; educational expansion changes primarily their ratio. This holds true until one of the transitions becomes mostly universal. After that, its contribution (weighted origin effect) to IEO in completed education begins to diminish.
Tracing References: Re-dating and Interpreting Abel-Rémusat’s Chinese-French Dictionary Manuscript Dictionnaire chinois
Authors: Li Rui , Hansen Annette Skovsted
Published: January 2022

This study presents answers to the question of how one dictionary can help us understand the implications for lexicography of limited access to other dictionaries. We carefully analyzed the microstructure and macrostructure of Abel-Rémusat’s Chinese-French dictionary manuscript Dictionnaire chinois dated 1808 by systematically tracing the references noted at each entry in the dictionary. Based on his meticulous references to a large variety of Chinese language sources, this article confirms that Abel-Rémusat finished his first draft in 1808. However, tracing the references to a wide variety of sources including many references to Dictionnaire chinois, français et latin [Chinese, French, and Latin Dictionary, 1813], published in 1813 by Chrétien-Louis-Joseph de Guignes (1759–1845), we re-date the manuscript. This discovery allowed us to understand how Abel-Rémusat 1) used different types of resources when dictionaries of Chinese and various European languages were unavailable and 2) compensated initially by inventing his own macrostructure, microstructure and systems for retrieving Chinese characters until he could consult other dictionaries that offered him guidance and inspired him to make corrections in his manuscript. Our findings show how the resources available determined his approach to lexicography and lead us to conclude that he gradually developed his approach based on a combination of inspiration from and confusion caused by the limited, but very diverse resources, he located and referenced.
Islam and Suicide Terrorism: An Empirical Analysis
Authors: Choi Seung-Whan , Brown Davis
Published: January 2022

Whether Islam is responsible for increased suicide terrorist attacks is a salient but highly controversial issue. Using independently produced demographics data, we investigate whether there is a correlation between Islam and suicide attacks. We find that (1) countries with greater Muslim populations are likely to experience more suicide attacks, (2) countries with greater Sunni Muslim populations are likely to encounter more suicide attacks, and (3) countries with greater Hanafi Muslim populations, in contrast to other Sunni legal schools, face the greatest risk of experiencing suicide attacks. The overall analysis suggests that Islam is positively associated with suicide attacks, although the degree of its association is not uniform among all branches.
Weaponizing Language: Linguistic Vectors of Ethnic Oppression
Authors: Dubinsky Stanley , Starr Harvey
Published: January 2022

As part of a larger project studying language conflict, this paper documents ways in which the oppression of language use on the part of a dominant language/ethnic group is instrumentalized as a tool to inflict gratuitous societal pain and punishment upon nondominant ethnolinguistic groups and their individual members. Our arguments will be illustrated primarily by three contemporary cases: (1) the Uyghur minority in the PRC, (2) the Kurdish minority in Turkey, and (3) the Hungarian minority in Slovakia. This article also seeks to provide an example of ways in which important empirical questions in the political science/international relations literature might be more fully addressed with the help of linguistics, which is a focus of our ongoing language conflict project.
Curating the Profane: Johann Joachim Winckelmann, Neoclassical Art Historian and First Curator of a Public Profane Museum
Authors: Ruprecht Louis Arthur
Published: January 2022

Few contemporary visitors to public art museums consider the religious oddity of most such collections at their inception. From the so-called Elgin Marbles in the British Museum, to the Winged Victory of Samothrace in the Louvre, and the Apollo Belvedere and Laocoön Group in the Vatican Museums, classical statuary constituted the heart (if not the soul) of most public art museums in the first several generations of the “museum era.” In this article, I present archival evidence from the Vatican Library and the Vatican Library’s Secret Archives confirming that Johann Joachim Winckelmann (1717–1768), better known as a neoclassical evangelist and art historian, was also the semi-secret curator of the Vatican’s first “Profane Museum.” Founded in 1767, expanded and completed in 1792, looted by French Revolutionaries in 1797, and repatriated in 1818, this museum first “curated the profane,” enabling the domestication of pagan idols, first in the name of fine art and later in the name of national treasure. It thereby offered a casual flirtation with pagan form that would have a very long subsequent cultural reach and influence.
Integrating landmark modeling framework and machine learning algorithms for dynamic prediction of tuberculosis treatment outcomes
Authors: Kheirandish Maryam , Catanzaro Donald , Crudu Valeriu , Zhang Shengfan
Published: January 2022

Objective

This study aims to establish an informative dynamic prediction model of treatment outcomes using follow-up records of tuberculosis (TB) patients, which can timely detect cases when the current treatment plan may not be effective.

Materials and Methods

We used 122 267 follow-up records from 17 958 new cases of pulmonary TB in the Republic of Moldova. A dynamic prediction framework integrating landmark modeling and machine learning algorithms was designed to predict patient outcomes during the course of treatment. Sensitivity and positive predictive value (PPV) were calculated to evaluate performance of the model at critical time points. New measures were defined to determine when follow-up laboratory tests should be conducted to obtain most informative results.

Results

The random-forest algorithm performed better than support vector machine and penalized multinomial logistic regression models for predicting TB treatment outcomes. For all 3 outcome classes (ie, cured, not cured, and died after 24 months following treatment initiation), sensitivity and PPV of prediction models improved as more follow-up information was collected. Specifically, sensitivity and PPV increased from 0.55 to 0.84 and from 0.32 to 0.88, respectively, for the not cured class.

Conclusion

The dynamic prediction framework utilizes longitudinal laboratory test results to predict patient outcomes at various landmarks. Sputum culture and smear results are among the important variables for prediction; however, the most recent sputum result is not always the most informative one. This framework can potentially facilitate a more effective treatment monitoring program and provide insights for policymakers toward improved guidelines on follow-up tests.
‘C-type’ closed state and gating mechanisms of K2P channels revealed by conformational changes of the TREK-1 channel
Authors: Zhang Qiansen , Fu Jie , Zhang Shaoying , Guo Peipei , Liu Shijie , Shen Juwen , Guo Jiangtao , Yang Huaiyu , Yao Xuebiao
Published: January 2022

Two-pore domain potassium (K2P) channels gate primarily within the selectivity filter, termed ‘C-type’ gating. Due to the lack of structural insights into the nonconductive (closed) state, ‘C-type’ gating mechanisms remain elusive. Here, molecular dynamics (MD) simulations on TREK-1, a K2P channel, revealed that M4 helix movements induce filter closing in a novel ‘deeper-down’ structure that represents a ‘C-type’ closed state. The ‘down’ structure does not represent the closed state as previously proposed and instead acts as an intermediate state in gating. The study identified the allosteric ‘seesaw’ mechanism of M4 helix movements in modulating filter closing. Finally, guided by this recognition of K2P gating mechanisms, MD simulations revealed that gain-of-function mutations and small-molecule activators activate TREK-1 by perturbing state transitions from open to closed states. Together, we reveal a ‘C-type’ closed state and provide mechanical insights into gating procedures and allosteric regulations for K2P channels.
Inhibiting DHN- and DOPA-melanin biosynthesis pathway increased the therapeutic value of itraconazole in Madurella mycetomatis infected Galleria mellonella
Authors: Lim Wilson , Konings Mickey , Parel Florianne , Eadie Kimberly , Strepis Nikolaos , Fahal Ahmed , Verbon Annelies , van de Sande Wendy W J
Published: January 2022

Eumycetoma is a neglected tropical disease, and Madurella mycetomatis, the most common causative agent of this disease forms black grains in hosts. Melanin was discovered to be one of the constituents in grains. Melanins are hydrophobic, macromolecular pigments formed by oxidative polymerisation of phenolic or indolic compounds. M. mycetomatis was previously known to produce DHN-melanin and pyomelanin in vitro. These melanin was also discovered to decrease M. mycetomatis’s susceptibility to antifungals itraconazole and ketoconazole in vitro. These findings, however, have not been confirmed in vivo. To discover the melanin biosynthesis pathways used by M. mycetomatis in vivo and to determine if inhibiting melanin production would increase M. mycetomatis's susceptibility to itraconazole, inhibitors targeting DHN-, DOPA- and pyomelanin were used. Treatment with DHN-melanin inhibitors tricyclazole, carpropamid, fenoxanil and DOPA-melanin inhibitor glyphosate in M. mycetomatis infected Galleria mellonella larvae resulted in presence of non-melanized grains. Our finding suggested that M. mycetomatis is able to produce DOPA-melanin in vivo. Inhibiting DHN-melanin with carpropamid in combination with the antifungal itraconazole also significantly increased larvae survival. Our results suggested that combination treatment of antifungals and melanin inhibitors can be an alternative treatment strategy that can be further explored. Since the common black-grain eumycetoma causing agents uses similar melanin biosynthesis pathways, this strategy may be applied to them and other eumycetoma causative agents.

Lay Summary

Melanin protects fungi from environmental stress and antifungals. We have discovered that Madurella mycetomatis produces DHN-, pyomelanin and DOPA-melanin in vivo. Inhibiting M. mycetomatis DHN-melanin biosynthesis increases therapeutic value of the antifungal itraconazole in vivo.
Ultraluminous high-redshift quasars from SkyMapper – II. New quasars and the bright end of the luminosity function
Authors: Onken Christopher A , Wolf Christian , Bian Fuyan , Fan Xiaohui , Hon Wei Jeat , Raithel David , Tisserand Patrick , Lai Samuel
Published: January 2022

We search for ultraluminous Quasi-Stellar Objects (QSOs) at high redshift using photometry from the SkyMapper Southern Survey Data Release 3 (DR3), in combination with 2MASS, VHS DR6, VIKING DR5, AllWISE, and CatWISE2020, as well as parallaxes and proper motions from Gaia DR2 and eDR3. We report 142 newly discovered Southern QSOs at 3.8 < z < 5.5, of which 126 have M145 < −27 AB mag and are found in a search area of 14 486 deg2. This Southern sample, utilizing the Gaia astrometry to offset wider photometric colour criteria, achieves unprecedented completeness for an ultraluminous QSO search at high redshift. In combination with already known QSOs, we construct a sample that is >80 per cent complete for M145 < −27.33 AB mag at z = 4.7 and for M145 < −27.73 AB mag at z = 5.4. We derive the bright end of the QSO luminosity function at rest frame 145 nm for z = 4.7–5.4 and measure its slope to be β = −3.60 ± 0.37 and β = −3.38 ± 0.32 for two different estimates of the faint-end QSO density adopted from the literature. We also present the first z ∼ 5 QSO luminosity function at rest frame 300 nm.
A new photometric study of M14 (NGC 6402): an interpretation of the horizontal branch and beyond
Authors: Yepez M A , Arellano Ferro A , Deras D , Bustos Fierro I , Muneer S , Schröder K-P
Published: January 2022

We present a CCD VI photometric study of the globular cluster M14. Particular attention is given to the variable stars. This allowed new classifications and cluster membership considerations. New variables are reported: 3 RRc, 18 SR, and 1 SX Phe. The Fourier decomposition of RR Lyrae light curves lead to the mean cluster metallicity of [Fe/H]ZW = −1.3 ± 0.2. Several independent methods yield a mean distance of 9.36 ± 0.16 kpc. A colour–magnitude diagram outlined by the cluster members enabled a matching with theoretical predictions of isochrones and zero-age horizontal branches (HBs), whose fitting to the observations is in good agreement with the above distance and metallicity. The Oosterhoff type of M14 is confirmed as Oo-int, and the pulsating mode distribution of RR Lyrae stars on the HB shows that the bimodal region of the instability strip is shared by RRab and RRc stars. By modelling the mass-loss at the red giant branch after the He flash events, we were able to represent the blue tail of the HB, using a core mass of 0.48 M⊙ and total masses of 0.52–0.55 M⊙. A progenitor star on the main sequence (MS) of 0.84 M⊙ reaches the HB in about 12.5 Gyr, consonant with previous age determinations of the cluster. Type II Cepheids of M14 may be interpreted as products of post-HB evolution, driven by the complex processes involving the burning of the very thin low mass hydrogen and helium shells of these stars and their minuscule envelopes. No pieces of evidence were found in favour of M14 being of extragalactic origin.
An Improved Codon Modeling Approach for Accurate Estimation of the Mutation Bias
Authors: Latrille Thibault , Lartillot Nicolas
Published: January 2022

Phylogenetic codon models are routinely used to characterize selective regimes in coding sequences. Their parametric design, however, is still a matter of debate, in particular concerning the question of how to account for differing nucleotide frequencies and substitution rates. This problem relates to the fact that nucleotide composition in protein-coding sequences is the result of the interactions between mutation and selection. In particular, because of the structure of the genetic code, the nucleotide composition differs between the three coding positions, with the third position showing a more extreme composition. Yet, phylogenetic codon models do not correctly capture this phenomenon and instead predict that the nucleotide composition should be the same for all three positions. Alternatively, some models allow for different nucleotide rates at the three positions, an approach conflating the effects of mutation and selection on nucleotide composition. In practice, it results in inaccurate estimation of the strength of selection. Conceptually, the problem comes from the fact that phylogenetic codon models do not correctly capture the fixation bias acting against the mutational pressure at the mutation–selection equilibrium. To address this problem and to more accurately identify mutation rates and selection strength, we present an improved codon modeling approach where the fixation rate is not seen as a scalar, but as a tensor. This approach gives an accurate representation of how mutation and selection oppose each other at equilibrium and yields a reliable estimate of the mutational process, while disentangling the mean fixation probabilities prevailing in different mutational directions.
A Collaborative Classroom Investigation of the Evolution of SABATH Methyltransferase Substrate Preference Shifts over 120 My of Flowering Plant History
Authors: Dubs Nicole M , Davis Breck R , de Brito Victor , Colebrook Kate C , Tiefel Ian J , Nakayama Madison B , Huang Ruiqi , Ledvina Audrey E , Hack Samantha J , Inkelaar Brent , Martins Talline R , Aartila Sarah M , Albritton Kelli S , Almuhanna Sarah , Arnoldi Ryan J , Austin Clara K , Battle Amber C , Begeman Gregory R , Bickings Caitlin M , Bradfield Jonathon T , Branch Eric C , Conti Eric P , Cooley Breana , Dotson Nicole M , Evans Cheyone J , Fries Amber S , Gilbert Ivan G , Hillier Weston D , Huang Pornkamol , Hyde Kaitlin W , Jevtovic Filip , Johnson Mark C , Keeler Julie L , Lam Albert , Leach Kyle M , Livsey Jeremy D , Lo Jonathan T , Loney Kevin R , Martin Nich W , Mazahem Amber S , Mokris Aurora N , Nichols Destiny M , Ojha Ruchi , Okorafor Nnanna N , Paris Joshua R , Reboucas Thais Fuscaldi , Sant’Anna Pedro Beretta , Seitz Mathew R , Seymour Nathan R , Slaski Lila K , Stemaly Stephen O , Ulrich Benjamin R , Van Meter Emile N , Young Meghan L , Barkman Todd J
Published: January 2022

Next-generation sequencing has resulted in an explosion of available data, much of which remains unstudied in terms of biochemical function; yet, experimental characterization of these sequences has the potential to provide unprecedented insight into the evolution of enzyme activity. One way to make inroads into the experimental study of the voluminous data available is to engage students by integrating teaching and research in a college classroom such that eventually hundreds or thousands of enzymes may be characterized. In this study, we capitalize on this potential to focus on SABATH methyltransferase enzymes that have been shown to methylate the important plant hormone, salicylic acid (SA), to form methyl salicylate. We analyze data from 76 enzymes of flowering plant species in 23 orders and 41 families to investigate how widely conserved substrate preference is for SA methyltransferase orthologs. We find a high degree of conservation of substrate preference for SA over the structurally similar metabolite, benzoic acid, with recent switches that appear to be associated with gene duplication and at least three cases of functional compensation by paralogous enzymes. The presence of Met in active site position 150 is a useful predictor of SA methylation preference in SABATH methyltransferases but enzymes with other residues in the homologous position show the same substrate preference. Although our dense and systematic sampling of SABATH enzymes across angiosperms has revealed novel insights, this is merely the “tip of the iceberg” since thousands of sequences remain uncharacterized in this enzyme family alone.
53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone biogenesis maintains genomic integrity
Authors: Wu TingTing , Jun Semo , Choi Eun-Ji , Sun Jiao , Yang Eun-Bi , Lee Hyun-Seo , Kim Sang-Yong , Fahmi Naima Ahmed , Jiang Qibing , Zhang Wei , Yong Jeongsik , Lee Jung-Hee , You Ho Jin
Published: January 2022

p53-binding protein 1 (53BP1) regulates the DNA double-strand break (DSB) repair pathway and maintains genomic integrity. Here we found that 53BP1 functions as a molecular scaffold for the nucleoside diphosphate kinase-mediated phosphorylation of ATP-citrate lyase (ACLY) which enhances the ACLY activity. This functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication-dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation at the SLBP promoter. This chain of regulation events carried out by 53BP1, ACLY, and SLBP is crucial for both quantitative and qualitative histone biogenesis as well as for the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DNA repair-independent function in the maintenance of genomic stability through a regulatory network that includes ACLY and SLBP.
Radiation-induced neuroinflammation: a potential protective role for poly(ADP-ribose) polymerase inhibitors?
Authors: Gutierrez-Quintana Rodrigo , Walker David J , Williams Kaye J , Forster Duncan M , Chalmers Anthony J
Published: January 2022

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity.
Surrogacy Beyond Prognosis: The Importance of “Trial-Level” Surrogacy
Authors: Buyse Marc , Saad Everardo D , Burzykowski Tomasz , Regan Meredith M , Sweeney Christopher S
Published: January 2022

Many candidate surrogate endpoints are currently assessed using a 2-level statistical approach, which consists in checking whether (1) the potential surrogate is associated with the final endpoint in individual patients and (2) the effect of treatment on the surrogate can be used to reliably predict the effect of treatment on the final endpoint. In some situations, condition (1) is fulfilled but condition (2) is not. We use concepts of causal inference to explain this apparently paradoxical situation, illustrating this review with 2 contrasting examples in operable breast cancer: the example of pathological complete response (pCR) and that of disease-free survival (DFS). In a previous meta-analysis, pCR has been shown to be a strong and independent prognostic factor for event-free survival (EFS) and overall survival (OS) after neoadjuvant treatment of operable breast cancer. Yet, in randomized trials, the effects of experimental treatments on pCR have not translated into predictable effects on EFS or OS, making pCR an “individual-level” surrogate, but not a “trial-level” surrogate. In contrast, DFS has been shown to be an acceptable surrogate for OS at both the individual and trial levels in early, HER2-positive breast cancer. The distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint.
Chronic Fatigue and Postexertional Malaise in People Living With Long COVID: An Observational Study
Authors: Twomey Rosie , DeMars Jessica , Franklin Kelli , Culos-Reed S Nicole , Weatherald Jason , Wrightson James G
Published: January 2022

Objective

People living with long COVID describe a high symptom burden, and a more detailed assessment is needed to inform rehabilitation recommendations. The objectives were to use validated questionnaires to measure the severity of fatigue and compare this with normative data and thresholds for clinical relevance in other diseases; measure and describe the impact of postexertional malaise (PEM); and assess symptoms of dysfunctional breathing, self-reported physical activity, and health-related quality of life.

Methods

This was an observational study with a cross-sectional survey design (data collection from February 2021 to April 2021). Eligible participants were adults experiencing persistent symptoms due to COVID-19 that did not predate the confirmed or suspected infection. Questionnaires included the Functional Assessment of Chronic Illness Therapy–Fatigue Scale and the DePaul Symptom Questionnaire–Post-Exertional Malaise.

Results

After data cleaning, 213 participants were included in the analysis. The total Functional Assessment of Chronic Illness Therapy–Fatigue Scale score was 18 (SD = 10) (where the score can range from 0 to 52, and a lower score indicates more severe fatigue), and 71.4% were experiencing chronic fatigue. Postexertional symptom exacerbation affected most participants, and 58.7% met the PEM scoring thresholds used in people living with myalgic encephalomyelitis/chronic fatigue syndrome.

Conclusion

Long COVID is characterized by chronic fatigue that is clinically relevant and at least as severe as fatigue in several other clinical conditions. PEM is a significant challenge for this patient group. Because of the potential for setbacks and deteriorated function following overexertion, fatigue and postexertional symptom exacerbation must be monitored and reported in clinical practice and in studies involving interventions for people with long COVID.

Impact

Physical therapists working with people with long COVID should measure and validate the patient’s experience. Postexertional symptom exacerbation must be considered, and rehabilitation needs to be carefully designed based on individual presentation. Beneficial interventions might first ensure symptom stabilization via pacing, a self-management strategy for the activity that helps minimize postexertional malaise.
Evaluation of sensitivity and specificity of diagnostic criteria for Behçet’s disease in the absence of a gold standard
Authors: Zhong Zhenyu , Liao Weiting , Gao Yu , Su Guannan , Feng Xiaojie , Yang Peizeng
Published: January 2022

Objective

The performance of existing diagnostic criteria for Behçet’s disease (BD) is usually evaluated by comparison with expert opinions, which may be limited by misclassification and disagreement among experts. We aim to evaluate these criteria in the absence of a gold standard.

Methods

We obtained two datasets involving possible BD and other mimickers from a uveitis registry using case–cohort and nested case–control analyses, respectively. With a Bayesian inference approach, the sensitivity and specificity of International Study Group (ISG) and International Criteria for Behçet’s Disease (ICBD) criteria were simultaneously estimated when true BD state was unknown.

Results

A total of 2440 and 2224 participants were included in case–cohort and nested case–control analyses, respectively. In case–cohort analysis, with scores of ≥4 for BD diagnosis, ICBD criteria showed higher sensitivity (median 97.6%; 95% credible interval 96.9, 98.2) than ISG criteria (median 90.0%; 95% credible interval 88.8, 91.2) but had lower specificity (median 90.8%; 95% credible interval 89.4, 92.1) than ISG criteria (median 98.8%; 95% credible interval 98.3, 99.3). With scores of ≥5 for diagnosis, ICBD criteria demonstrated higher sensitivity (median 97.5%; 95% credible interval 96.8, 98.1) and specificity (median 99.6%; 95% credible interval 99.3, 99.8) than the sensitivity (median 92.3%; 95% credible interval 91.2, 93.3) and specificity (median 98.8%; 95% credible interval 98.2, 99.2) for ISG criteria. The highest diagnostic consistency was observed between ISG criteria and ICBD criteria with scores of ≥5 for diagnosis (Kappa = 0.999; P < 0.001). Nested case–control analysis showed similar results.

Conclusion

ICBD criteria showed optimum discriminatory properties in sensitivity and specificity with scores of ≥5 for BD diagnosis in uveitis. The diagnostic threshold of ICBD criteria could be considered adjustable according to medical specialty, disease prevalence and local practice characteristics.
Wildlife in Cameroon harbor diverse coronaviruses, including many closely related to human coronavirus 229E
Authors: Ntumvi Nkom F , Ndze Valantine Ngum , Gillis Amethyst , Le Doux Diffo Joseph , Tamoufe Ubald , Takuo Jean-Michel , Mouiche Moctar M M , Nwobegahay Julius , LeBreton Matthew , Rimoin Anne W , Schneider Bradley S , Monagin Corina , McIver David J , Roy Sanjit , Ayukekbong James A , Saylors Karen E , Joly Damien O , Wolfe Nathan D , Rubin Edward M , Lange Christian E
Published: January 2022

Zoonotic spillover of animal viruses into human populations is a continuous and increasing public health risk. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the global impact of emergence. Considering the history and diversity of coronaviruses (CoVs), especially in bats, SARS-CoV-2 will likely not be the last to spillover from animals into human populations. We sampled and tested wildlife in the Central African country Cameroon to determine which CoVs are circulating and how they relate to previously detected human and animal CoVs. We collected animal and ecological data at sampling locations and used family-level consensus PCR combined with amplicon sequencing for virus detection. Between 2003 and 2018, samples were collected from 6,580 animals of several different orders. CoV RNA was detected in 175 bats, a civet, and a shrew. The CoV RNAs detected in the bats represented 17 different genetic clusters, coinciding with alpha (n = 8) and beta (n = 9) CoVs. Sequences resembling human CoV-229E (HCoV-229E) were found in 40 Hipposideridae bats. Phylogenetic analyses place the human-derived HCoV-229E isolates closest to those from camels in terms of the S and N genes but closest to isolates from bats for the envelope, membrane, and RNA-dependent RNA polymerase genes. The CoV RNA positivity rate in bats varied significantly (P < 0.001) between the wet (8.2 per cent) and dry seasons (4.5 per cent). Most sampled species accordingly had a wet season high and dry season low, while for some the opposite was found. Eight of the suspected CoV species of which we detected RNA appear to be entirely novel CoV species, which suggests that CoV diversity in African wildlife is still rather poorly understood. The detection of multiple different variants of HCoV-229E-like viruses supports the bat reservoir hypothesis for this virus, with the phylogenetic results casting some doubt on camels as an intermediate host. The findings also support the previously proposed influence of ecological factors on CoV circulation, indicating a high level of underlying complexity to the viral ecology. These results indicate the importance of investing in surveillance activities among wild animals to detect all potential threats as well as sentinel surveillance among exposed humans to determine emerging threats.
Sleep and circadian indices for planning post-pandemic university timetables
Authors: Montagnese Sara , Zarantonello Lisa , Formentin Chiara , Giusti Gianluca , Mangini Chiara , Isherwood Cheryl M. , Ferrari Paolo , Paoli Antonio , Mapelli Daniela , Rizzuto Rosario , Toppo Stefano , Skene Debra J. , Vettor Roberto , Costa Rodolfo
Published: January 2022

The aims of the present study were to obtain sleep quality and sleep timing information in a group of university students, and to evaluate the effects of a circadian hygiene education initiative. All students of the University of Padova (approximately 64,000) were contacted by e-mail (major campaigns in October 2019 and October 2020) and directed to anad hocwebsite for collection of demographics and sleep quality/timing information. Participants (n=5740) received one of two sets of circadian hygiene advice (“A regular life”or“Bright days and dark nights”). Every month, they were then asked how easy it had been to comply, and provided with the advice again. At any even month from joining, they completed the sleep quality/timing questionnaires again. Information on academic performance was obtainedpost hoc, together with representative samples of lecture (n=5972) and exam (n=1800) timings, plus lecture attendances (n=25,302). 52% of students had poor sleep quality and 82% showed signs of sleep deprivation. Those who joined in October 2020, after several months of lockdown and distance learning, had better sleep quality, less sleep deprivation and later sleep habits. The“Bright days and dark nights”advice resulted in earlier get-up time/midsleep compared to the“A regular life”advice. Significant changes in most sleep quality and sleep timing variables were observed in both advice groups over time, also in relation to pandemic-related events characterising 2020. Early-chronotype students had better academic performances compared to their later chronotype counterparts. In a multivariate model, sleep quality, chronotype and study subject were independent predictors of academic performance. Taken together, these results underlie the importance of designing circadian-friendly university timetables.
Persistence of immunity and impact of a third (booster) dose of an inactivated SARS-CoV-2 vaccine, BBV152; a phase 2, double-blind, randomised controlled trial
Authors: Vadrevu Krishna Mohan , Ganneru Brunda , Reddy Siddharth , Jogdand Harsh , Raju Dugyala , Praturi Usha , Sapkal Gajanan , Yadav Pragya , Reddy Prabhakar , Verma Savita , Singh Chandramani , Redkar Sagar Vivek , Gillurkar Chandra Sekhar , Kushwaha Jitendra Singh , Mohapatra Satyajit , Bhate Amit , Rai Sanjay , Ella Raches , Abraham Priya , Prasad Sai , Ella Krishna
Published: January 2022

Background

Neutralising antibody responses to SARS-CoV-2 vaccines have been reported to decline within 6 months of vaccination, particularly against Variants of Concern (VOC). We assessed the immunogenicity and safety of a booster dose of BBV152 administered 6 months after the second of a two-dose primary vaccination series.

Methods

In an ongoing phase 2 trial (ClinicalTrials.gov: NCT04471519) the protocol was amended after six months to re-consent and randomise 184 previously vaccinated participants to receive a third dose of vaccine or placebo on Day 215. The primary outcome was to measure neutralising antibody titres by plaque-reduction neutralisation test (PRNT50) four weeks after the booster; safety as serious adverse events (SAE) was the key secondary outcome.

Findings

Four weeks after a second BBV152 vaccination geometric mean titres (GMTs) of neutralising antibodies were 197·0 PRNT50 (95% CI: 155·6–249·4); this level declined to 23·9 PRNT50 (14·0–40·6) six months later, with a seroconversion rate of 75·4% (95% CI: 68·4–81·6). Four weeks after booster vaccination the GMT increased on Day 243 to 746·6 PRNT50 (514·9–1081) compared with 100·7 PRNT50 (43·6–232·6) in the placebo group. Corresponding seroconversion rates were 98·7% (92·8–99·9) and 79·8% (69·6–87·8). Increased titres in the placebo group were attributed to natural infection as the study was conducted during the second wave of COVID-19 in India. PRNT50 titres against the SARS-CoV-2 variants increased—Alpha (32·6-fold), Beta (161·0-fold), Delta (264·7-fold), and Delta plus (174·2-fold)—after the booster vaccination. We found that vaccine induces both memory B and T cells with a distinct AIM+ specific CD4+T central and effector memory phenotype, including CD8+ TEMRA phenotype. Reactogenicity after vaccine and placebo was minimal and comparable, and no SAEs were reported.

Interpretation

Six months after a two-dose BBV152 vaccination series cell mediated immunity and neutralising antibodies to both homologous (D614G) and heterologous strains (Alpha, Beta, Delta and Delta plus) persisted above baseline, although the magnitude of the responses had declined. Neutralising antibodies against homologous and heterologous SARS-CoV-2 variants increased 19- to 97-fold after a third vaccination. Booster BBV152 vaccination is safe and may be necessary to ensure persistent immunity to prevent breakthrough infections.

Funding

This work was supported and funded by Bharat Biotech International Limited.
Duckweed roots are dispensable and are on a trajectory toward vestigiality
Authors: Ware Alex , Jones Dylan H , Flis Paulina , Smith Kellie , Kümpers Britta , Yant Levi , Atkinson Jonathan A , Wells Darren M , Bishopp Anthony
Published: January 2022

Duckweeds are morphologically simplified, free floating aquatic monocots comprising both rooted and rootless genera. This has led to the idea that roots in these species may be vestigial, but empirical evidence supporting this is lacking. Here we show that duckweed roots are no longer required for their ancestral role of nutrient uptake. Comparative analyses of nearly all rooted duckweed species revealed a highly reduced anatomy, with greater simplification in the more recently diverged genus Lemna. A series of root excision experiments demonstrated that roots are dispensable for normal growth in Spirodela polyrhiza and Lemna minor. Furthermore, ionomic analyses of fronds in these two species showed little difference in the elemental composition of plants in rooted versus root-excised samples. In comparison, another free-floating member of the Araceae, Pistia stratiotes, which colonized the aquatic environment independently of duckweeds, has retained a more complex root anatomy. Whilst Pistia roots were not absolutely required for growth, their removal inhibited plant growth and resulted in a broad change in the mineral profile of aerial tissues. Collectively, these observations suggest that duckweeds and Pistia may be different stages along a trajectory towards root vestigialization Given this, along with the striking diversity of root phenotypes, culminating in total loss in the most derived species, we propose that duckweed roots are a powerful system with which to understand organ loss and vestigiality.

One sentence summary

Through their adaption to the aquatic environment, duckweed roots have progressively become structurally reduced making them an ideal plant model with which to study vestigiality.