bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein
Authors: Manet Evelyne , Polvèche Hélène , Mure Fabrice , Mrozek-Gorska Paulina , Roisné-Hamelin Florian , Hammerschmidt Wolfgang , Auboeuf Didier , Gruffat Henri
Published: September 2021

Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides—besides transcription—an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP—together with the RBM4 splicing factor—in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.
Functional correction ofCFTRmutations in human airway epithelial cells using adenine base editors
Authors: Krishnamurthy Sateesh , Traore Soumba , Cooney Ashley L , Brommel Christian M , Kulhankova Katarina , Sinn Patrick L , Newby Gregory A , Liu David R , McCray Paul B
Published: September 2021

Mutations in the CFTR gene that lead to premature stop codons or splicing defects cause cystic fibrosis (CF) and are not amenable to treatment by small-molecule modulators. Here, we investigate the use of adenine base editor (ABE) ribonucleoproteins (RNPs) that convert A•T to G•C base pairs as a therapeutic strategy for three CF-causing mutations. Using ABE RNPs, we corrected in human airway epithelial cells premature stop codon mutations (R553X and W1282X) and a splice-site mutation (3849 + 10 kb C > T). Following ABE delivery, DNA sequencing revealed correction of these pathogenic mutations at efficiencies that reached 38–82% with minimal bystander edits or indels. This range of editing was sufficient to attain functional correction of CFTR-dependent anion channel activity in primary epithelial cells from CF patients and in a CF patient-derived cell line. These results demonstrate the utility of base editor RNPs to repair CFTR mutations that are not currently treatable with approved therapeutics.
Novel anti-repression mechanism of H-NS proteins by a phage protein
Authors: Bdira Fredj Ben , Erkelens Amanda M , Qin Liang , Volkov Alexander N , Lippa Andrew M , Bowring Nicholas , Boyle Aimee L , Ubbink Marcellus , Dove Simon L , Dame Remus T
Published: September 2021

H-NS family proteins, bacterial xenogeneic silencers, play central roles in genome organization and in the regulation of foreign genes. It is thought that gene repression is directly dependent on the DNA binding modes of H-NS family proteins. These proteins form lateral protofilaments along DNA. Under specific environmental conditions they switch to bridging two DNA duplexes. This switching is a direct effect of environmental conditions on electrostatic interactions between the oppositely charged DNA binding and N-terminal domains of H-NS proteins. The Pseudomonas lytic phage LUZ24 encodes the protein gp4, which modulates the DNA binding and function of the H-NS family protein MvaT of Pseudomonas aeruginosa. However, the mechanism by which gp4 affects MvaT activity remains elusive. In this study, we show that gp4 specifically interferes with the formation and stability of the bridged MvaT–DNA complex. Structural investigations suggest that gp4 acts as an ‘electrostatic zipper’ between the oppositely charged domains of MvaT protomers, and stabilizes a structure resembling their ‘half-open’ conformation, resulting in relief of gene silencing and adverse effects on P. aeruginosa growth. The ability to control H-NS conformation and thereby its impact on global gene regulation and growth might open new avenues to fight Pseudomonas multidrug resistance.
Family D DNA polymerase interacts with GINS to promote CMG-helicase in the archaeal replisome
Authors: Oki Keisuke , Nagata Mariko , Yamagami Takeshi , Numata Tomoyuki , Ishino Sonoko , Oyama Takuji , Ishino Yoshizumi
Published: September 2021

Genomic DNA replication requires replisome assembly. We show here the molecular mechanism by which CMG (GAN–MCM–GINS)-like helicase cooperates with the family D DNA polymerase (PolD) in Thermococcus kodakarensis. The archaeal GINS contains two Gins51 subunits, the C-terminal domain of which (Gins51C) interacts with GAN. We discovered that Gins51C also interacts with the N-terminal domain of PolD’s DP1 subunit (DP1N) to connect two PolDs in GINS. The two replicases in the replisome should be responsible for leading- and lagging-strand synthesis, respectively. Crystal structure analysis of the DP1N–Gins51C–GAN ternary complex was provided to understand the structural basis of the connection between the helicase and DNA polymerase. Site-directed mutagenesis analysis supported the interaction mode obtained from the crystal structure. Furthermore, the assembly of helicase and replicase identified in this study is also conserved in Eukarya. PolD enhances the parental strand unwinding via stimulation of ATPase activity of the CMG-complex. This is the first evidence of the functional connection between replicase and helicase in Archaea. These results suggest that the direct interaction of PolD with CMG-helicase is critical for synchronizing strand unwinding and nascent strand synthesis and possibly provide a functional machinery for the effective progression of the replication fork.
β-CASP proteins removing RNA polymerase from DNA: when a torpedo is needed to shoot a sitting duck
Authors: Wiedermannová Jana , Krásný Libor
Published: September 2021

During the first step of gene expression, RNA polymerase (RNAP) engages DNA to transcribe RNA, forming highly stable complexes. These complexes need to be dissociated at the end of transcription units or when RNAP stalls during elongation and becomes an obstacle (‘sitting duck’) to further transcription or replication. In this review, we first outline the mechanisms involved in these processes. Then, we explore in detail the torpedo mechanism whereby a 5′–3′ RNA exonuclease (torpedo) latches itself onto the 5′ end of RNA protruding from RNAP, degrades it and upon contact with RNAP, induces dissociation of the complex. This mechanism, originally described in Eukaryotes and executed by Xrn-type 5′–3′ exonucleases, was recently found in Bacteria and Archaea, mediated by β-CASP family exonucleases. We discuss the mechanistic aspects of this process across the three kingdoms of life and conclude that 5′–3′ exoribonucleases (β-CASP and Xrn families) involved in the ancient torpedo mechanism have emerged at least twice during evolution.
miRNATissueAtlas2: an update to the human miRNA tissue atlas
Authors: Keller Andreas , Gröger Laura , Tschernig Thomas , Solomon Jeffrey , Laham Omar , Schaum Nicholas , Wagner Viktoria , Kern Fabian , Schmartz Georges Pierre , Li Yongping , Borcherding Adam , Meier Carola , Wyss-Coray Tony , Meese Eckart , Fehlmann Tobias , Ludwig Nicole
Published: September 2021

Small non-coding RNAs (sncRNAs) are pervasive regulators of physiological and pathological processes. We previously developed the human miRNA Tissue Atlas, detailing the expression of miRNAs across organs in the human body. Here, we present an updated resource containing sequencing data of 188 tissue samples comprising 21 organ types retrieved from six humans. Sampling the organs from the same bodies minimizes intra-individual variability and facilitates the making of a precise high-resolution body map of the non-coding transcriptome. The data allow shedding light on the organ- and organ system-specificity of piwi-interacting RNAs (piRNAs), transfer RNAs (tRNAs), microRNAs (miRNAs) and other non-coding RNAs. As use case of our resource, we describe the identification of highly specific ncRNAs in different organs. The update also contains 58 samples from six tissues of the Tabula Muris collection, allowing to check if the tissue specificity is evolutionary conserved between Homo sapiens and Mus musculus. The updated resource of 87 252 non-coding RNAs from nine non-coding RNA classes for all organs and organ systems is available online without any restrictions (https://www.ccb.uni-saarland.de/tissueatlas2).
GPEdit: the genetic and pharmacogenomic landscape of A-to-I RNA editing in cancers
Authors: Ruan Hang , Li Qiang , Liu Yuan , Liu Yaoming , Lussier Charles , Diao Lixia , Han Leng
Published: September 2021

Altered A-to-I RNA editing has been widely observed in many human cancers and some editing sites are associated with drug sensitivity, implicating its therapeutic potential. Increasing evidence has demonstrated that a quantitative trait loci mapping approach is effective to understanding the genetic basis of RNA editing. We systematically performed RNA editing quantitative trait loci (edQTL) analysis in 33 human cancer types for >10 000 cancer samples and identified 320 029 edQTLs. We also identified 1688 ed-QTLs associated with patient overall survival and 4672 ed-QTLs associated with GWAS risk loci. Furthermore, we demonstrated the associations between RNA editing and >1000 anti-cancer drug response with ∼3.5 million significant associations. We developed GPEdit (https://hanlab.uth.edu/GPEdit/) to facilitate a global map of the genetic and pharmacogenomic landscape of RNA editing. GPEdit is a user-friendly and comprehensive database that provides an opportunity for a better understanding of the genetic impact and the effects on drug response of RNA editing in cancers.
PmiREN2.0: from data annotation to functional exploration of plant microRNAs
Authors: Guo Zhonglong , Kuang Zheng , Zhao Yongxin , Deng Yang , He Hao , Wan Miaomiao , Tao Yihan , Wang Dong , Wei Jianhua , Li Lei , Yang Xiaozeng
Published: September 2021

Nearly 200 plant genomes have been sequenced over the last two years, and new functions of plant microRNAs (miRNAs) have been revealed. Therefore, timely update of the plant miRNA databases by incorporating miRNAs from the newly sequenced species and functional information is required to provide useful resources for advancing plant miRNA research. Here we report the update of PmiREN2.0 (https://pmiren.com/) with an addition of 19 363 miRNA entries from 91 plants, doubling the amount of data in the original version. Meanwhile, abundant regulatory information centred on miRNAs was added, including predicted upstream transcription factors through binding motifs scanning and elaborate annotation of miRNA targets. As an example, a genome-wide regulatory network centred on miRNAs was constructed for Arabidopsis. Furthermore, phylogenetic trees of conserved miRNA families were built to expand the understanding of miRNA evolution across the plant lineages. These data are helpful to deduce the regulatory relationships concerning miRNA functions in diverse plants. Beside the new data, a suite of design tools was incorporated to facilitate experimental practice. Finally, a forum named ‘PmiREN Community’ was added for discussion and resource and new discovery sharing. With these upgrades, PmiREN2.0 should serve the community better and accelerate miRNA research in plants.
FACT-seq: profiling histone modifications in formalin-fixed paraffin-embedded samples with low cell numbers
Authors: Zhao Linxuan , Xing Pengwei , Polavarapu Vamsi Krishna , Zhao Miao , Valero-Martínez Blanca , Dang Yonglong , Maturi Nagaprathyusha , Mathot Lucy , Neves Inês , Yildirim Irem , Swartling Fredrik Johansson , Sjöblom Tobias , Uhrbom Lene , Chen Xingqi
Published: September 2021

The majority of biopsies in both basic research and translational cancer studies are preserved in the format of archived formalin-fixed paraffin-embedded (FFPE) samples. Profiling histone modifications in archived FFPE tissues is critically important to understand gene regulation in human disease. The required input for current genome-wide histone modification profiling studies from FFPE samples is either 10–20 tissue sections or whole tissue blocks, which prevents better resolved analyses. But it is desirable to consume a minimal amount of FFPE tissue sections in the analysis as clinical tissues of interest are limited. Here, we present FFPE tissue with antibody-guided chromatin tagmentation with sequencing (FACT-seq), the first highly sensitive method to efficiently profile histone modifications in FFPE tissues by combining a novel fusion protein of hyperactive Tn5 transposase and protein A (T7−pA−Tn5) transposition and T7 in vitro transcription. FACT-seq generates high-quality chromatin profiles from different histone modifications with low number of FFPE nuclei. We proved a very small piece of FFPE tissue section containing ∼4000 nuclei is sufficient to decode H3K27ac modifications with FACT-seq. H3K27ac FACT-seq revealed disease-specific super enhancers in the archived FFPE human colorectal and human glioblastoma cancer tissue. In summary, FACT-seq allows decoding the histone modifications in archival FFPE tissues with high sensitivity and help researchers to better understand epigenetic regulation in cancer and human disease.
Click and Cut: a click chemistry approach to developing oxidative DNA damaging agents
Authors: McStay Natasha , Slator Creina , Singh Vandana , Gibney Alex , Westerlund Fredrik , Kellett Andrew
Published: September 2021

Metallodrugs provide important first-line treatment against various forms of human cancer. To overcome chemotherapeutic resistance and widen treatment possibilities, new agents with improved or alternative modes of action are highly sought after. Here, we present a click chemistry strategy for developing DNA damaging metallodrugs. The approach involves the development of a series of polyamine ligands where three primary, secondary or tertiary alkyne-amines were selected and ‘clicked’ using the copper-catalysed azide-alkyne cycloaddition reaction to a 1,3,5-azide mesitylene core to produce a family of compounds we call the ‘Tri-Click’ (TC) series. From the isolated library, one dominant ligand (TC1) emerged as a high-affinity copper(II) binding agent with potent DNA recognition and damaging properties. Using a range of in vitro biophysical and molecular techniques—including free radical scavengers, spin trapping antioxidants and base excision repair (BER) enzymes—the oxidative DNA damaging mechanism of copper-bound TC1 was elucidated. This activity was then compared to intracellular results obtained from peripheral blood mononuclear cells exposed to Cu(II)–TC1 where use of BER enzymes and fluorescently modified dNTPs enabled the characterisation and quantification of genomic DNA lesions produced by the complex. The approach can serve as a new avenue for the design of DNA damaging agents with unique activity profiles.
A dominant-negative SOX18 mutant disrupts multiple regulatory layers essential to transcription factor activity
Authors: McCann Alex J , Lou Jieqiong , Moustaqil Mehdi , Graus Matthew S , Blum Ailisa , Fontaine Frank , Liu Hui , Luu Winnie , Rudolffi-Soto Paulina , Koopman Peter , Sierecki Emma , Gambin Yann , Meunier Frédéric A , Liu Zhe , Hinde Elizabeth , Francois Mathias
Published: September 2021

Few genetically dominant mutations involved in human disease have been fully explained at the molecular level. In cases where the mutant gene encodes a transcription factor, the dominant-negative mode of action of the mutant protein is particularly poorly understood. Here, we studied the genome-wide mechanism underlying a dominant-negative form of the SOX18 transcription factor (SOX18RaOp) responsible for both the classical mouse mutant Ragged Opossum and the human genetic disorder Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome. Combining three single-molecule imaging assays in living cells together with genomics and proteomics analysis, we found that SOX18RaOp disrupts the system through an accumulation of molecular interferences which impair several functional properties of the wild-type SOX18 protein, including its target gene selection process. The dominant-negative effect is further amplified by poisoning the interactome of its wild-type counterpart, which perturbs regulatory nodes such as SOX7 and MEF2C. Our findings explain in unprecedented detail the multi-layered process that underpins the molecular aetiology of dominant-negative transcription factor function.
Divergent degeneration ofcreAantitoxin genes from minimal CRISPRs and the convergent strategy of tRNA-sequestering CreT toxins
Authors: Cheng Feiyue , Wang Rui , Yu Haiying , Liu Chao , Yang Jun , Xiang Hua , Li Ming
Published: September 2021

Aside from providing adaptive immunity, type I CRISPR-Cas was recently unearthed to employ a noncanonical RNA guide (CreA) to transcriptionally repress an RNA toxin (CreT). Here, we report that, for most archaeal and bacterial CreTA modules, the creA gene actually carries two flanking ‘CRISPR repeats’, which are, however, highly divergent and degenerated. By deep sequencing, we show that the two repeats give rise to an 8-nt 5′ handle and a 22-nt 3′ handle, respectively, i.e., the conserved elements of a canonical CRISPR RNA, indicating they both retained critical nucleotides for Cas6 processing during divergent degeneration. We also uncovered a minimal CreT toxin that sequesters the rare transfer RNA for isoleucine, tRNAIleCAU, with a six-codon open reading frame containing two consecutive AUA codons. To fully relieve its toxicity, both tRNAIleCAU overexpression and supply of extra agmatine (modifies the wobble base of tRNAIleCAU to decipher AUA codons) are required. By replacing AUA to AGA/AGG codons, we reprogrammed this toxin to sequester rare arginine tRNAs. These data provide essential information on CreTA origin and for future CreTA prediction, and enrich the knowledge of tRNA-sequestering small RNAs that are employed by CRISPR-Cas to get addictive to the host.
SPENCER: a comprehensive database for small peptides encoded by noncoding RNAs in cancer patients
Authors: Luo Xiaotong , Huang Yuantai , Li Huiqin , Luo Yihai , Zuo Zhixiang , Ren Jian , Xie Yubin
Published: September 2021

As an increasing number of noncoding RNAs (ncRNAs) have been suggested to encode short bioactive peptides in cancer, the exploration of ncRNA-encoded small peptides (ncPEPs) is emerging as a fascinating field in cancer research. To assist in studies on the regulatory mechanisms of ncPEPs, we describe here a database called SPENCER (http://spencer.renlab.org). Currently, SPENCER has collected a total of 2806 mass spectrometry (MS) data points from 55 studies, covering 1007 tumor samples and 719 normal samples. Using an MS-based proteomics analysis pipeline, SPENCER identified 29 526 ncPEPs across 15 different cancer types. Specifically, 22 060 of these ncPEPs were experimentally validated in other studies. By comparing tumor and normal samples, the identified ncPEPs were divided into four expression groups: tumor-specific, upregulated in cancer, downregulated in cancer, and others. Additionally, since ncPEPs are potential targets for neoantigen-based cancer immunotherapy, SPENCER also predicted the immunogenicity of all the identified ncPEPs by assessing their MHC-I binding affinity, stability, and TCR recognition probability. As a result, 4497 ncPEPs curated in SPENCER were predicted to be immunogenic. Overall, SPENCER will be a useful resource for investigating cancer-associated ncPEPs and may boost further research in cancer.
RNALocate v2.0: an updated resource for RNA subcellular localization with increased coverage and annotation
Authors: Cui Tianyu , Dou Yiying , Tan Puwen , Ni Zhen , Liu Tianyuan , Wang DuoLin , Huang Yan , Cai Kaican , Zhao Xiaoyang , Xu Dong , Lin Hao , Wang Dong
Published: September 2021

Resolving the spatial distribution of the transcriptome at a subcellular level can increase our understanding of biology and diseases. To facilitate studies of biological functions and molecular mechanisms in the transcriptome, we updated RNALocate, a resource for RNA subcellular localization analysis that is freely accessible at http://www.rnalocate.org/ or http://www.rna-society.org/rnalocate/. Compared to RNALocate v1.0, the new features in version 2.0 include (i) expansion of the data sources and the coverage of species; (ii) incorporation and integration of RNA-seq datasets containing information about subcellular localization; (iii) addition and reorganization of RNA information (RNA subcellular localization conditions and descriptive figures for method, RNA homology information, RNA interaction and ncRNA disease information) and (iv) three additional prediction tools: DM3Loc, iLoc-lncRNA and iLoc-mRNA. Overall, RNALocate v2.0 provides a comprehensive RNA subcellular localization resource for researchers to deconvolute the highly complex architecture of the cell.
Higher-order topology induced by structural buckling
Authors: Huang Huaqing , Liu Feng
Published: September 2021

Higher-order topological insulator (HOTI) states, such as two-dimension (2D) HOTI featured with topologically protected corner modes at the intersection of two gapped crystalline boundaries, have attracted much recent interest. However, the physical mechanism underlying the formation of HOTI states is not fully understood, which has hindered our fundamental understanding and discovery of HOTI materials. Here we propose a mechanistic approach to induce higher-order topological phases via structural buckling of 2D topological crystalline insulators (TCIs). While in-plane mirror symmetry is broken by structural buckling, which destroys the TCI state, the combination of mirror and rotation symmetry is preserved in the buckled system, which gives rise to the HOTI state. We demonstrate that this approach is generally applicable to various 2D lattices with different symmetries and buckling patterns, opening a horizon of possible materials to realize 2D HOTIs. The HOTIs so generated are also shown to be robust against buckling height fluctuation and in-plane displacement. A concrete example is given for the buckled $\beta $-Sb monolayer from first-principles calculations. Our finding not only enriches our fundamental understanding of higher-order topology, but also opens a new route to discovering HOTI materials.
Nutrition as a modifiable factor in the onset and progression of pulmonary function impairment in COPD: a systematic review
Authors: van Iersel Lieke E J , Beijers Rosanne J H C G , Gosker Harry R , Schols Annemie M W J
Published: September 2021

Context

Chronic obstructive lung disease (COPD) is a progressive lung disease characterized by persistent airflow limitation. An increasing amount of evidence suggests an effect of dietary quality on the risk of COPD in the general population and pulmonary function decline in patients with COPD.

Objective

The association of dietary intake and nutrient status with COPD risk and onset, as well as pulmonary function decline (change in forced expiratory volume in 1 second, forced vital capacity, or the ratio of the former to the latter) in patients with COPD was investigated in this systematic review.

Data Sources

The PubMed database was searched by combining terms of pulmonary function or COPD with diet, nutrient status, or nutritional supplementation.

Data Extraction

Original studies and systematic reviews and meta-analyses were included. Articles obtained were independently screened for relevance on the bases of title and abstract by 2 researchers. Eventually, 89 articles were included in the analysis.

Results

The unhealthy Western-style diet is associated with an increased risk of COPD and an accelerated decline of pulmonary function. Intake of fruit, vegetables, dietary fibers, vitamins C and E, polyphenols, and β-carotene were individually associated with lower COPD risk, whereas consumption of processed meat was associated with higher COPD risk. Data on the effect of dietary quality on pulmonary function decline in patients with COPD are limited and inconsistent. Strong evidence for beneficial effects on pulmonary function decline was found only for vitamin D supplementation.

Conclusion

Considering the increasing burden of COPD, more attention should be given to dietary quality as a modifiable factor in disease development and progression in patients with COPD.

Systematic Review Registration

PROSPERO registration no. CRD42021240183.
The association between later eating rhythm and adiposity in children and adolescents: a systematic review and meta-analysis
Authors: Zou Mengxuan , Northstone Kate , Perry Rachel , Johnson Laura , Leary Sam
Published: September 2021

Context

Childhood adiposity, an important predictor of adult chronic disease, has been rising dramatically. Later eating rhythm, termed night eating, is increasing in adults but rarely studied in younger ages.

Objective

The objective of this study was to review the association between later eating rhythm and adiposity in children and adolescents. The aspects of later eating being considered included: energy intake (for evening main meal, evening snack, whole evening period, and around bedtime); timing (any food eaten at later timing); and meal frequency in the evening/night (evening main meal skipping, evening snack consumption).

Data Sources

Five databases (the Cochrane Library, CINAHL, Embase, MEDLINE (via OVID), and Web of Science) were searched for eligible articles published prior to and including August 2020.

Data Extraction

Data extraction and quality assessment were conducted by 2 reviewers independently.

Data Analysis

Forty-seven studies were included, all of which were observational. Meta-analysis showed positive associations between both higher energy intake around bedtime (odds ratio [OR] 1.19, 95% CI 1.06, 1.33) and evening main meal skipping (OR 1.30, 95% CI 1.14, 1.48), and adiposity. There was evidence to suggest that consuming evening snacks reduced adiposity, but it was very weak (OR 0.80, 95% CI 0.62, 1.05). No association was seen between eating later and adiposity (OR 1.04, 95% CI 0.68, 1.61). In the narrative analysis, approximately half of the studies suggested that there was no association between later eating rhythm and adiposity, either as a whole or within exposure subsets.

Conclusion

The magnitude of the relationship between later eating rhythm and adiposity is very small, and may vary depending on which aspects of later eating rhythm are under consideration; however, the evidence for this conclusion is of very low certainty . Further research with a more consistent definition of “later timing”, and longitudinal studies in different populations, may lead to different conclusions.

Systematic Review Registration

PROSPERO registration no. CRD42019134187.
Efficacy and tolerability of the ketogenic diet and its variations for preventing migraine in adolescents and adults: a systematic review
Authors: Caminha Madson C , Moreira Adriana B , Matheus Filipe C , Rieger Débora K , Moreira Júlia D , Dalmarco Eduardo M , Demarchi Izabel G , Lin Katia
Published: September 2021

Context

Migraine is a headache of variable intensity that is associated with focal and systemic symptoms. A ketogenic diet (KD), a very-low-carbohydrate diet with a proportional increase in fat, causes brain metabolic alterations, which could be beneficial for some neurologic conditions.

Objective

A systematic review was conducted to assess the efficacy and tolerability of KD in preventing migraine in adolescents and adults.

Data sources

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standard was used to review articles found in the PubMed, EMBASE, Scopus, Web of Science, LILACS, LIVIVO, Science Direct, and Cochrane Central Register of Controlled Trials databases. The Google Scholar, DOAJ, ProQuest, and OpenGrey databases were included.

Data Extraction

The population, intervention, comparison, outcome, and study design strategy included assessing the quality of the evidence using Grading of Recommendations Assessment Development and Evaluation and the risk of bias after applying the JBI critical appraisal tools.

Data Analysis

Most of the 10 selected studies reported that KD reduced the number and severity of migraine attacks in patients, with few reported adverse effects. The evidence on the effectiveness of the KD is low, so whether the final effect is due to the treatment remains inconclusive.

Conclusions

This study represents an initial effort to systematize information on the efficacy and tolerability of KD and its variations in the prevention of migraine.

Systematic Review Registration

PROSPERO registration no. CRD42020186253
How cost-effective is nutrition care delivered in primary healthcare settings? A systematic review of trial-based economic evaluations
Authors: Barnes Katelyn A , Szewczyk Zoe , Kelly Jaimon T , Campbell Katrina L , Ball Lauren E
Published: September 2021

Context

Nutrition care is an effective lifestyle intervention for the treatment and prevention of many noncommunicable diseases. Primary care is a high-value setting in which to provide nutrition care.

Objective

The objective of this review was to evaluate the cost-effectiveness of nutrition care interventions provided in primary care settings.

Data Sources

Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Central Register of Controlled Trials, EconLit, and the National Health Service Economic Evaluation Database (NHS EED) were searched from inception to May 2021.

Data Extraction

Data extraction was guided by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guidelines. Randomized trials of nutrition interventions in primary care settings were included in the analysis if incremental cost-effectiveness ratios were reported. The main outcome variable incremental cost-effectiveness ratios (ICERs) and reported interpretations were used to categorize interventions by the cost-effectiveness plane quadrant.

Results

Of 6837 articles identified, 10 were included (representing 9 studies). Eight of the 9 included studies found nutrition care in primary care settings to be more costly and more effective than usual care. High study heterogeneity limited further conclusions.

Conclusion

Nutrition care in primary care settings is effective, though it requires investment; it should, therefore, be considered in primary care planning. Further studies are needed to evaluate the long-term cost-effectiveness of providing nutrition care in primary care settings.

Systematic review registration

PROSPERO registration no. CRD42020201146.
The persistence of unhappiness: trapped into despair?
Authors:   By, Wilner Lionel
Published: September 2021

This article investigates whether self-assessed states of unhappiness are persistent. To disentangle state dependence from unobserved heterogeneity in life satisfaction, it estimates a dynamic ordered Logit with correlated random effects on longitudinal data in France, the UK, Australia, and Germany. The persistence of life satisfaction is found to be heterogeneous; people already happy with their lives tend to remain happy while unhappiness sounds more transitory. Overall, there is no empirical evidence of unhappiness traps: rather, every individual faces the risk of experiencing some temporary spell of low subjective well-being in her life course.
High Ambient Temperatures Inhibit Ghd7-Mediated Flowering Repression in Rice
Authors: Nagalla Asanga Deshappriya , Nishide Noriko , Hibara Ken-ichiro , Izawa Takeshi
Published: September 2021

The anticipation of changing seasons is crucial for reproduction in plants. Despite the broad cultivation area, the effects of ambient temperature on photoperiodic flowering are largely unknown in rice. Here, we first examined flowering time under four distinct conditions: short-day or long-day and high or low temperature, using cultivars, nearly isogenic lines, and mutants in rice. We also examined gene expression patterns of key flowering-time genes using the same lines under various conditions including temporal dynamics after light pulses. In addition to delayed flowering because of low growth rates, we found that photoperiodic flowering is clearly enhanced by both Hd1 and Ghd7 genes under low-temperature conditions in rice. We also revealed that PhyB can control Ghd7 repressor activity as a temperature sensor to inhibit Ehd1, Hd3a and RFT1 at lower temperatures, likely through a post-transcriptional regulation, despite inductive photoperiod conditions. Furthermore, we found that rapid reduction of Ghd7 messenger RNA (mRNA) under high-temperature conditions can lead to mRNA increase in a rice florigen gene, RFT1. Thus, multiple temperature-sensing mechanisms can affect photoperiodic flowering in rice. The rising of ambient temperatures in early summer likely contributes to the inhibition of Ghd7 repressor activity, resulting in the appropriate floral induction of rice in temperate climates.
Challenges Facing Counterfactual Accounts of Explanation in Mathematics
Authors: Lange Marc
Published: September 2021

Some mathematical proofs explain why the theorems they prove hold. This paper identifies several challenges for any counterfactual account of explanation in mathematics (that is, any account according to which an explanatory proof reveals how the explanandum would have been different, had facts in the explanans been different). The paper presumes that countermathematicals can be nontrivial. It argues that nevertheless, a counterfactual account portrays explanatory power as too easy to achieve, does not capture explanatory asymmetry, and fails to specify why certain proofs are explanatory and others are not. Greater informativeness about counterfactual dependence can even yield less explanatory power.
A day in the life of winter plankton: under-ice community dynamics during 24 h in a eutrophic lake
Authors: Chiapella Ariana M , Grigel Haley , Lister Hannah , Hrycik Allison , O’Malley Brian P , Stockwell Jason D
Published: September 2021

Although diel vertical migration (DVM) in aquatic systems may account for the largest daily migration of biomass globally, our understanding of this process under ice cover is limited, particularly in fresh water. The date of lake ice onset and duration of ice cover is declining globally, therefore determining the extent of plankton migrations under ice is imperative to inform our baseline understanding of seasonal differences in community structure and function, and how conditions may change over time. We investigated whether plankton exhibit DVM under ice and explored interactions between phytoplankton and zooplankton at highly resolved space–time scales across 24 h in a eutrophic system. Despite the dominance of motile taxa, phytoplankton remained vertically segregated based on morpho-functional groups throughout the sampling period. Daphnia mendotae exhibited size-structured DVM with an upward migration at sunset and sunrise, and midnight sinking, presumably to avoid the rise of predatory Chaoborus. We hypothesize that because overwintering daphnids require rich lipid stores, D. mendotae migrated to access small, lipid-rich phytoplankton that were limited to surface waters. Given our study took place during an unusually warm winter in a eutrophic system, our results may represent future under-ice dynamics under increasing eutrophication pressure and climate warming in shallow lakes.
Effect of eutrophication on the functional diversity of zooplankton in shallow ponds in Northeast Brazil
Authors: Duré Gustavo Adolfo Villalba , Simões Nadson Ressyé , Braghin Louizi de Souza Magalhães , Ribeiro Sylvia Maria Moreira Susini
Published: September 2021

Eutrophication is a process characterized by the enrichment of a given aquatic environment with nutrients, triggering a serious and growing ecological problem in continental aquatic ecosystems, including effects on the biodiversity and ecosystem functioning. For this, we predicted that eutrophication decreases zooplankton functional richness, evenness, divergence and dispersion, and changes the functional composition of zooplankton. Zooplankton and water features were sampled in sixteen shallow ponds in northeastern Brazil. Functional diversity aspects were calculated for each assembly (rotifers, cladocerans, and copepods) using multidimensional indexes and functional groups. Principal component analysis, multiple linear regression, hierarchical cluster analysis and distance-based redundancy analysis were performed to characterize the environmental variation, and to identify associations with functional zooplankton diversity. We observed that turbidity and increased nutrients influenced the functional composition and functional diversity indices of zooplankton due to aquatic pollution. Eutrophic environments favored more specialized species, with greater selectivity in food capture and greater ability to escape predators. We suggest that eutrophic conditions lead to changes in the functional composition of the assemblies decreasing differentiation and variability of functional traits. Such changes lead to a loss of ecosystem processes and make these ecosystems more vulnerable.
Dynamic changes in primexine during the tetrad stage of pollen development
Authors: Wang Rui , Owen Heather A , Dobritsa Anna A
Published: September 2021

Formation of pollen wall exine is preceded by the development of several transient layers of extracellular materials deposited on the surface of developing pollen grains. One such layer is primexine (PE), a thin, ephemeral structure that is present only for a short period of time and is difficult to visualize and study. Recent genetic studies suggested that PE is a key factor in the formation of exine, making it critical to understand its composition and the dynamics of its formation. In this study, we used high-pressure frozen/freeze-substituted samples of developing Arabidopsis (Arabidopsis thaliana) pollen for a detailed transmission electron microscopy analysis of the PE ultrastructure throughout the tetrad stage of pollen development. We also analyzed anthers from wild-type Arabidopsis and three mutants defective in PE formation by immunofluorescence, carefully tracing several carbohydrate epitopes in PE and nearby anther tissues during the tetrad and the early free-microspore stages. Our analyses revealed likely sites where these carbohydrates are produced and showed that the distribution of these carbohydrates in PE changes significantly during the tetrad stage. We also identified tools for staging tetrads and demonstrate that components of PE undergo changes resembling phase separation. Our results indicate that PE behaves like a much more dynamic structure than has been previously appreciated and clearly show that Arabidopsis PE creates a scaffolding pattern for formation of reticulate exine.
Fewer Opioids but More Benzodiazepines? Prescription Trends by Specialty in Response to the Implementation of Michigan’s Opioid Laws
Authors: Danagoulian Shooshan , King Andrew , Mangan Kyle , Tarchick John , Dolcourt Bram
Published: September 2021

Objectives

To characterize the effects of Michigan’s controlled substance legislation on acute care prescriber behavior by specialty, in a single hospital system.

Design

A retrospective study of opioid and benzodiazepine prescription records from a hospital electronic medical record system between August 1, 2016, and March 31, 2019, in Detroit, Michigan.

Setting

Discharges from inpatient and emergency department visits.

Intervention

Evaluating the impact of implementation of state controlled substance legislation, comparing prescriptions by physicians before, upon, and after June 1, 2018, using regression discontinuity analysis.

Methods

Total daily prescriptions of opioids and total daily prescriptions of benzodiazepine by physicians in the hospital system. Prescriptions were converted to morphine and lorazepam equivalents for comparability.

Results

We find 38.5% (95% confidence interval [CI] : 74.1% – 2.9%) decrease of prescription in milligrams of opioid equivalents attributable to implementation of legislation. The main catalyst of the decrease was emergency medicine which experienced 63.9% (95% CI: 109.7%–18.0%) decrease in milligrams of opioid equivalent prescriptions, while surgery increased prescriptions. Though we do not find any statistically significant changes in prescriptions of milligram equivalent of benzodiazepines, we estimate 43.1% (95% CI: 82.6%–3.7%) decrease in count of these prescriptions, implying a significant increase in average dosage of prescriptions.

Conclusions

The introduction of new regulatory requirements for the prescription of controlled substances led to a general decrease in morphine equivalent milligrams prescribed in most specialties, though it may have increased the dosage of benzodiazepine prescriptions. The change in prescription behavior could be motivated by regulatory hassle or by change in attitude towards opioid prescriptions and increased recognition of opioid use disorder.
The Effect of Scheduled Intravenous Acetaminophen in an Enhanced Recovery Protocol Pathway in Patients Undergoing Major Abdominal Procedures: A Prospective, Randomized, and Placebo-Controlled Clinical Trial
Authors: Subramaniam Kathirvel , Esper Stephen A , Mallikarjun Kushanth , Dickson Alec , Ruppert, DrPH, Kristin , Drabek Tomas , Wong Hesper , Holder-Murray Jennifer
Published: September 2021

Objective

Enhanced recovery protocols (ERPs) utilize multi-modal analgesia regimens. Individual regimen components should be evaluated for their analgesic efficacy. We evaluated the effect of scheduled intravenous (IV) acetaminophen within an ERP on analgesia and recovery after a major abdominal surgery.

Design

This study is a prospective, randomized, double-blinded clinical trial.

Setting

The study setting was a tertiary care, academic medical center.

Subjects

Adult patients scheduled for elective major abdominal surgical procedures.

Methods

Patients in group A received 1 g IV acetaminophen, while patients in group P received IV placebo every six hours for 48 hours postoperatively within an ERP. Pain scores, opioid requirements, nausea and vomiting, time to oral intake and mobilization, length of stay, and patient satisfaction scores were measured and compared.

Results

From 412 patients screened, 154 patients completed the study (Group A: 76, Group P: 78). Primary outcome was the number of patients with unsatisfactory pain relief, defined as a composite of average Numeric Rating Scale (NRS) scores above 5 and requirement of IV patient-controlled analgesia for pain relief during the first 48 hours postoperatively, and was not significantly different between the two groups (33 (43.4%) in group A versus 42 (53.8%) patients in group P, P = .20). Opioid consumption was comparable between two groups. Group A utilized significantly less postoperative rescue antiemetics compared to group P (41% vs. 58%, P = .02).

Conclusions

Scheduled administration of IV acetaminophen did not improve postoperative analgesia or characteristics of postoperative recovery in patients undergoing major abdominal surgery within an ERP pathway.
Prevalence of Dysmenorrhea and Determinants of Pain Intensity Among University-Age Women
Authors: Ullah Azmat , Fayyaz Khadijah , Javed Uswa , Usman Muhammad , Malik Rameesha , Arif Nafeesa , Kaleem Amna
Published: September 2021

Objective

The study was conducted to determine the prevalence of dysmenorrhea and investigate factors associated with dysmenorrhic pain among university students in Lahore, Pakistan.

Design and Setting

A cross-sectional study was conducted across various public and private sector universities in Lahore.

Methods

A self-administered structured questionnaire was used to collect data from 600 randomly selected female university students.

Results

The prevalence of dysmenorrhea was 91.5%. Age at menarche (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.10–3.50) was the only significant factor associated with dysmenorrhea. The mean pain severity score among dysmenorrhic students was 5.62 ± 2.28. Most of the participants (65.8%) were experiencing moderate/severe pain. Univariate analysis showed that irregular cycle (OR [95% CI] = 1.62 [1.13–2.33]), age at menarche of ≤14 years (OR [95% CI] = 1.46 [1.05–2.04]), duration of menses of more than 5 days (OR [95% CI] = 1.42 [1.02–1.99]), stress (OR [95% CI] = 2.16 [1.54–3.03]), moderate meat/protein consumption (OR [95% CI] = 1.55 [1.08–2.21]), and medical specialization (OR [95% CI] = 1.72 [1.17–2.52]) were significantly associated with pain severity among dysmenorrhic female students. Multivariate binary logistic regression analysis revealed that medical specialization (OR [95% CI] = 1.83 [1.22–2.73]), age at menarche (OR [95% CI] = 0.603 [0.42–0.86]), regularity of menses (OR [95% CI] = 1.52 [1.04–2.22]), moderate meat/protein consumption (OR [95% CI] = 1.69 [1.16–2.45]), and stress (OR [95% CI] = 1.87 [1.32–2.66]) were independent predictors of moderate/severe dysmenorrhic pain.

Conclusion

The study revealed an alarmingly high prevalence of dysmenorrhea among university students. High levels of stress and early menarche were the potent determinants of moderate/severe dysmenorrhea that disturbs quality of life.
The Polls—Trends
Authors: Hobolt Sara B , Tilley James
Published: September 2021

In 2020, the United Kingdom became the first member state to leave the European Union (EU). This followed a referendum on membership in 2016. Public opinion about EU membership has been regularly measured since the 1970s in Britain. In this Poll Trends article, we document the changes in sentiment towards the EU in a variety of different ways. We report on attitudes towards the cost and benefits; national and European identities; support for continued membership of the EU; specific policy preferences towards Britain’s involvement with the EU; vote intention in a referendum on membership pre- and post- the 2016 referendum; and the prevalence of new political identities created by the referendum.
Digital contact-tracing in France: uptake by COVID-19 risk factor and by exposure risk
Authors: Guillon M
Published: September 2021

Background

Few studies have investigated the influence of COVID-19 conspiracy theories on digital contact-tracing adoption and the differentiated uptake of digital contact-tracing by COVID-19 risk factor and by exposure risk.

Methods

Using a cross-sectional survey conducted in France in November 2020 (N = 1042), we investigate the factors associated with the use of the French ‘TousAntiCovid’ contact-tracing application. Our independent variables of interest include COVID-19 and ‘TousAntiCovid’ perceptions, trust in the government, time and risk preferences and the level of adherence to COVID-19 conspiracy theories. We conduct regression analyses by COVID-19 risk factor and exposure groups.

Results

Among the full sample, a negative association is found between the propensity to believe in COVID-19 conspiracy theories and the use of ‘TousAntiCovid’. French respondents at risk of severe COVID-19 form are more likely to use ‘TousAntiCovid’. No difference in uptake is found by exposure group. Group analyses indicate that the factors associated with the uptake of digital contact-tracing differ by COVID-19 risk factor and exposure risk.

Conclusion

Governmental communication to fight COVID-19 misinformation and to stress out the utility and data safety of ‘TousAntiCovid’ should be reinforced. Targeted communication campaigns should be conducted among low adoption groups and key groups in COVID-19 transmission.