bluuebunny/crossref_metadata_2025 huggingface dataset:
GAE-LGA: integration of multi-omics data with graph autoencoders to identify lncRNA–PCG associations
Authors: Gao Meihong , Liu Shuhui , Qi Yang , Guo Xinpeng , Shang Xuequn
Published: October 2022

Long non-coding RNAs (lncRNAs) can disrupt the biological functions of protein-coding genes (PCGs) to cause cancer. However, the relationship between lncRNAs and PCGs remains unclear and difficult to predict. Machine learning has achieved a satisfactory performance in association prediction, but to our knowledge, it is currently less used in lncRNA–PCG association prediction. Therefore, we introduce GAE-LGA, a powerful deep learning model with graph autoencoders as components, to recognize potential lncRNA–PCG associations. GAE-LGA jointly explored lncRNA–PCG learning and cross-omics correlation learning for effective lncRNA–PCG association identification. The functional similarity and multi-omics similarity of lncRNAs and PCGs were accumulated and encoded by graph autoencoders to extract feature representations of lncRNAs and PCGs, which were subsequently used for decoding to obtain candidate lncRNA–PCG pairs. Comprehensive evaluation demonstrated that GAE-LGA can successfully capture lncRNA–PCG associations with strong robustness and outperformed other machine learning-based identification methods. Furthermore, multi-omics features were shown to improve the performance of lncRNA–PCG association identification. In conclusion, GAE-LGA can act as an efficient application for lncRNA–PCG association prediction with the following advantages: It fuses multi-omics information into the similarity network, making the feature representation more accurate; it can predict lncRNA–PCG associations for new lncRNAs and identify potential lncRNA–PCG associations with high accuracy.
CysModDB: a comprehensive platform with the integration of manually curated resources and analysis tools for cysteine posttranslational modifications
Authors: Meng Yanzheng , Zhang Lin , Zhang Laizhi , Wang Ziyu , Wang Xuanwen , Li Chan , Chen Yu , Shang Shipeng , Li Lei
Published: October 2022

The unique chemical reactivity of cysteine residues results in various posttranslational modifications (PTMs), which are implicated in regulating a range of fundamental biological processes. With the advent of chemical proteomics technology, thousands of cysteine PTM (CysPTM) sites have been identified from multiple species. A few CysPTM-based databases have been developed, but they mainly focus on data collection rather than various annotations and analytical integration. Here, we present a platform-dubbed CysModDB, integrated with the comprehensive CysPTM resources and analysis tools. CysModDB contains five parts: (1) 70 536 experimentally verified CysPTM sites with annotations of sample origin and enrichment techniques, (2) 21 654 modified proteins annotated with functional regions and structure information, (3) cross-references to external databases such as the protein–protein interactions database, (4) online computational tools for predicting CysPTM sites and (5) integrated analysis tools such as gene enrichment and investigation of sequence features. These parts are integrated using a customized graphic browser and a Basket. The browser uses graphs to represent the distribution of modified sites with different CysPTM types on protein sequences and mapping these sites to the protein structures and functional regions, which assists in exploring cross-talks between the modified sites and their potential effect on protein functions. The Basket connects proteins and CysPTM sites to the analysis tools. In summary, CysModDB is an integrated platform to facilitate the CysPTM research, freely accessible via https://cysmoddb.bioinfogo.org/.
RAS oncogene signal strength regulates matrisomal gene expression and tumorigenicity of mouse keratinocytes
Authors: Cataisson Christophe , Lee Alex J , Zhang Ashley M , Mizes Alicia , Korkmaz Serena , Carofino Brandi L , Meyer Thomas J , Michalowski Aleksandra M , Li Luowei , Yuspa Stuart H
Published: October 2022

Environmental and molecular carcinogenesis are linked by the discovery that chemical carcinogen induced-mutations in the Hras or Kras genes drives tumor development in mouse skin. Importantly, enhanced expression or allele amplification of the mutant Ras gene contributes to selection of initiated cells, tumor persistence, and progression. To explore the consequences of Ras oncogene signal strength, primary keratinocytes were isolated and cultured from the LSL-HrasG12D and LSL-KrasG12D C57BL/6J mouse models and the mutant allele was activated by adeno-Cre recombinase. Keratinocytes expressing one (H) or two (HH) mutant alleles of HrasG12D, one KrasG12D allele (K), or one of each (HK) were studied. All combinations of activated Ras alleles stimulated proliferation and drove transformation marker expression, but only HH and HK formed tumors. HH, HK, and K sustained long-term keratinocyte growth in vitro, while H and WT could not. RNA-Seq yielded two distinct gene expression profiles; HH, HK, and K formed one cluster while H clustered with WT. Weak MAPK activation was seen in H keratinocytes but treatment with a BRAF inhibitor enhanced MAPK signaling and facilitated tumor formation. K keratinocytes became tumorigenic when they were isolated from mice where the LSL-KrasG12D allele was backcrossed from the C57BL/6 onto the FVB/N background. All tumorigenic keratinocytes but not the non-tumorigenic precursors shared a common remodeling of matrisomal gene expression that is associated with tumor formation. Thus, RAS oncogene signal strength determines cell-autonomous changes in initiated cells that are critical for their tumor-forming potential.
Analytical and Clinical Validation of Cell-Free Circulating Tumor DNA Assay for the Estimation of Tumor Mutational Burden
Authors: Lee Kwang Seob , Seo Jieun , Lee Choong-Kun , Shin Saeam , Choi Zisun , Min Seungki , Yang Jun Hyuek , Kwon Woo Sun , Yun Woobin , Park Mi Ri , Choi Jong Rak , Chung Hyun Cheol , Lee Seung-Tae , Rha Sun Young
Published: October 2022

Background

Ultra-deep sequencing to detect low-frequency mutations in circulating tumor-derived DNA (ctDNA) increases the diagnostic value of liquid biopsy. The demand for large ctDNA panels for comprehensive genomic profiling and tumor mutational burden (TMB) estimation is increasing; however, few ctDNA panels for TMB have been validated. Here, we designed a ctDNA panel with 531 genes, named TMB500, along with a technical and clinical validation.

Methods

Synthetic reference cell-free DNA materials with predefined allele frequencies were sequenced in a total of 92 tests in 6 batches to evaluate the precision, linearity, and limit of detection of the assay. We used clinical samples from 50 patients with various cancers, 11 healthy individuals, and paired tissue samples. Molecular barcoding and data analysis were performed using customized pipelines.

Results

The assay showed high precision and linearity (coefficient of determination, r2 =0.87) for all single nucleotide variants, with a limit of detection of 0.24%. In clinical samples, the TMB500 ctDNA assay detected most variants present and absent in tissues, showing that ctDNA could assess tumor heterogeneity in different tissues and metastasis sites. The estimated TMBs correlated well between tissue and blood, except in 4 cases with extreme heterogeneity that showed very high blood TMBs compared to tissue TMBs. A pilot evaluation showed that the TMB500 assay could be used for disease monitoring.

Conclusions

The TMB500 assay is an accurate and reliable ctDNA assay for many clinical purposes. It may be useful for guiding the treatment of cancers with diverse genomic profiles, estimating TMB in immune therapy, and disease monitoring.
Higher power short duration vs. lower power longer duration posterior wall ablation for atrial fibrillation and oesophageal injury outcomes: a prospective multi-centre randomized controlled study (Hi-Lo HEAT trial)
Authors: Chieng David , Segan Louise , Sugumar Hariharan , Al-Kaisey Ahmed , Hawson Joshua , Moore Benjamin M , Nam Michael C Y , Voskoboinik Aleksandr , Prabhu Sandeep , Ling Liang-Han , Ng Jer Fuu , Brown Gregor , Lee Geoffrey , Morton Joseph , Debinski Henry , Kalman Jonathan M , Kistler Peter M
Published: October 2022

Aims

Radiofrequency (RF) ablation for pulmonary vein isolation (PVI) in atrial fibrillation (AF) is associated with the risk of oesophageal thermal injury (ETI). Higher power short duration (HPSD) ablation results in preferential local resistive heating over distal conductive heating. Although HPSD has become increasingly common, no randomized study has compared ETI risk with conventional lower power longer duration (LPLD) ablation. This study aims to compare HPSD vs. LPLD ablation on ETI risk.

Methods and results

Eighty-eight patients were randomized 1:1 to HPSD or LPLD posterior wall (PW) ablation. Posterior wall ablation was 40 W (HPSD group) or 25 W (LPLD group), with target AI (ablation index) 400/LSI (lesion size index) 4. Anterior wall ablation was 40–50 W, with a target AI 500–550/LSI 5–5.5. Endoscopy was performed on Day 1. The primary endpoint was ETI incidence. The mean age was 61 ± 9 years (31% females). The incidence of ETI (superficial ulcers n = 4) was 4.5%, with equal occurrence in HPSD and LPLD (P = 1.0). There was no difference in the median value of maximal oesophageal temperature (HPSD 38.6°C vs. LPLD 38.7°C, P = 0.43), or the median number of lesions per patient with temperature rise above 39°C (HPSD 1.5 vs. LPLD 2, P = 0.93). Radiofrequency ablation time (23.8 vs. 29.7 min, P < 0.01), PVI duration (46.5 vs. 59 min, P = 0.01), and procedure duration (133 vs. 150 min, P = 0.05) were reduced in HPSD. After a median follow-up of 12 months, AF recurrence was lower in HPSD (15.9% vs. LPLD 34.1%; hazard ratio 0.42, log-rank P = 0.04).

Conclusion

Higher power short duration ablation was associated with similarly low rates of ETI and shorter total/PVI RF ablation times when compared with LPLD ablation. Higher power short duration ablation is a safe and efficacious approach to PVI.
Multiple solutions at the genomic level in response to selective breeding for high locomotor activity
Authors: Hillis David A , Garland Theodore
Published: October 2022

Replicate lines under uniform selection often evolve in different ways. Previously, analyses using whole-genome sequence data for individual mice (Mus musculus) from 4 replicate High Runner lines and 4 nonselected control lines demonstrated genomic regions that have responded consistently to selection for voluntary wheel-running behavior. Here, we ask whether the High Runner lines have evolved differently from each other, even though they reached selection limits at similar levels. We focus on 1 High Runner line (HR3) that became fixed for a mutation at a gene of major effect (Myh4Minimsc) that, in the homozygous condition, causes a 50% reduction in hindlimb muscle mass and many pleiotropic effects. We excluded HR3 from SNP analyses and identified 19 regions not consistently identified in analyses with all 4 lines. Repeating analyses while dropping each of the other High Runner lines identified 12, 8, and 6 such regions. (Of these 45 regions, 37 were unique.) These results suggest that each High Runner line indeed responded to selection somewhat uniquely, but also that HR3 is the most distinct. We then applied 2 additional analytical approaches when dropping HR3 only (based on haplotypes and nonstatistical tests involving fixation patterns). All 3 approaches identified 7 new regions (as compared with analyses using all 4 High Runner lines) that include genes associated with activity levels, dopamine signaling, hippocampus morphology, heart size, and body size, all of which differ between High Runner and control lines. Our results illustrate how multiple solutions and “private” alleles can obscure general signatures of selection involving “public” alleles.
Children of the Gulag, Long Road to Justice: The Challenges and Limitations of Reparations in Russia
Authors: Durdiyeva Selbi
Published: October 2022

ABSTRACT∞

The article examines the 2019 judgment of the Constitutional Court of Russia concerning the right to compensation of housing and right to return of the children of the victims deported by the Soviet state to the gulag or exile. Despite the favourable judgment of the Constitutional Court, the right to remedy for the victims was still unattainable. The article examines why this was the case by drawing on the absence of internal and external coherence of reparations programmes, the approach to reparations throughout history in the Soviet Union and Russia, the Law on Rehabilitation and other factors that rendered the reparations unobtainable. The article argues that in the absence of holistic transitional justice measures and accountability for crimes, separate laws and court judgments have been unable to deliver justice, resulting in a long, cumbersome and often humiliating and fruitless process for victims attempting to claim their rights.
Ana posteriorierror estimator for isogeometric analysis on trimmed geometries
Authors: Buffa Annalisa , Chanon Ondine , Vázquez Rafael
Published: October 2022

Trimming consists of cutting away parts of a geometric domain, without reconstructing a global parametrization (meshing). It is a widely used operation in computer-aided design, which generates meshes that are unfitted with the described physical object. This paper develops an adaptive mesh refinement strategy on trimmed geometries in the context of hierarchical B-spline-based isogeometric analysis. A residual a posteriori estimator of the energy norm of the numerical approximation error is derived, in the context of the Poisson equation. The estimator is proven to be reliable, independently of the number of hierarchical levels and of the way the trimmed boundaries cut the underlying mesh. Numerical experiments are performed to validate the presented theory, and to show that the estimator’s effectivity index is independent of the size of the active part of the trimmed mesh elements.
Backstage Mockery: Impoliteness and Asymmetry on the World Stage
Authors: Van Rythoven Eric
Published: October 2022

In recent years, episodes of diplomatic “impoliteness” have attracted growing attention among international relations (IR) scholars. Whether in the form of sharp-edged humor, insults, or other face-undermining behavior, scholars are increasingly examining episodes where the expected civility of diplomacy breaks down and impoliteness becomes weaponized as a tool of statecraft. While sympathetic to these approaches, I argue that the deployment of impoliteness cannot be understood in isolation from the powerful asymmetries that shape global politics. To show why, I advance a theory of mockery in international politics with an emphasis of a specific kind: backstage mockery. Building on the work of Goffman, I conceptualize mocking displays as acts of ridicule that undermine an actor's positive public image or “face” based on two contextual factors: (1) perceptions of transgression and (2) relative status. In hierarchical settings, lower-status members are often unable to openly criticize the transgressions of their social superiors because of the threat of retaliation. Covert or “backstage” mockery offers an outlet for weaker members to express their concerns and build solidarity with other members, while at the same time indirectly signaling those with higher status about problems. To illustrate the significance of backstage mockery, I discuss Canada–US relations and the 2019 viral video of NATO leaders appearing to privately mock US President Donald Trump.
Theorizing the Emergence of Security Regions: An Adaptation for the Regional Security Complex Theory
Authors: Amable Dennis Senam
Published: October 2022

This paper presents an analytical framework as an adaptation for the regional security complex theory (RSCT). Following the end of the Cold War, regional systems have become imperative for understanding security dynamics. Barry Buzan and Ole Wæver's expanded version of the regional security complex (RSC) concept described the regional level as the level where most of the action of security occurs. In fact, the RSCT is one of the most comprehensive frameworks that outline distinct variables necessary for regional security analysis. However, the RSCT overlooked how these RSCs (security regions) emerge and evolve into fully fledged security complexes as described by Buzan and Wæver (2003). Thus, the concept remains under-theorized on how the nascent structures of an RSC build—as it prioritizes already established RSCs. In this respect, this study develops an analytical framework with a set of criteria for identifying the nascent stages of an RSC, as an adaptation for the RSCT. The framework examines the nascent structures of an RSC and highlights the roles played by external great powers in the emergence and evolution of RSCs.
Prevalence of Multidrug-Resistant Organism in ICU Burns Patients at Tertiary Care Hospital
Authors: Buriro Fahmina , Ishaque Sadia , Saeed Aniqa , Qamar Mohammad Aadil , Batool Amna
Published: October 2022

Burns carries a high-risk of mortality and morbidity. This with increased chances of drug-resistant infections makes the management complicated. Hence this study was conducted to find out the prevalence of multidrug-resistant organisms (MDRO) in burns patients admitted to the intensive care unit at a tertiary care hospital. A 2-year retrospective study was conducted where burn patients reporting MDRO were included. Statistical analysis was performed using SPSS version 26 where a P-value < .05 was considered statistically significant. Out of 97 patients, tissue cultures of 65 patients revealed the presence of MDRO in 27 (27.8%) patients. A male predominance (17, 63.0%) was noted with a mean age of 29.0-year-old. Fire burn (15, 55.6%) was reported to be the most common cause of burn with an average of 29.9% of Total Body Surface Area (TBSA) involved. MDR Pseudomonas aeruginosa was the commonest organism reported in 12 (44%) patients. The average length of stay (LOS) was noted to be 11.3 days with a mortality rate of 48.1% (overall, in all MDRO’S infections). Patients who reported MDRO showed a tendency for longer hospitalization with a higher risk of mortality as the TBSA increased. However, in presence of other factors in burns like higher TBSA, inhalation injury and lack of advanced skin substitute these mortality figures, and their association can be debated. Lastly, the implementation of control measures, as basic as hand hygiene, should be partaken to reduce the burden of MDR infections.
Organizational dynamics: culture, design, and performance
Authors: Besley Timothy , Persson Torsten
Published: October 2022

We examine the two-way interplay between organizational cultures and organizational design, where culture is modeled as the prevailing social identities among workplace groups that can affect project choices. In a setting where cultural dynamics depend on the expected relative payoffs of holding different identities, we investigate how tribalism and charismatic leadership shape organizational dynamics and steady-state cultures. We show how a strong culture can be a virtue when it permits greater delegated authority, but a vice when the culture is poorly aligned with organizational objectives. We apply our analysis to concrete debates about the interaction of design, performance, and culture (JEL L23, M14).
Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program
Authors: Pagadala Meghana S , Lynch Julie , Karunamuni Roshan , Alba Patrick R , Lee Kyung Min , Agiri Fatai Y , Anglin Tori , Carter Hannah , Gaziano J Michael , Jasuja Guneet Kaur , Deka Rishi , Rose Brent S , Panizzon Matthew S , Hauger Richard L , Seibert Tyler M
Published: October 2022

Background

Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group.

Methods

This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer.

Results

A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer.

Conclusions

PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.
Update From the September 2022 Meeting of the Advisory Committee on Immunization Practices
Authors: Gaviria-Agudelo Claudia , Yonts Alexandra B , O’Leary Sean T , Anderson Evan J
Published: October 2022

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts that provides expert advice to the Centers for Disease Control and Prevention, normally meets three times per year to develop US vaccine recommendations. The ACIP increased its meeting frequency over the past 2.5 years to address vaccine-related issues during the severe acute respiratory syndrome coronavirus 2 pandemic. They met to discuss updating coronavirus disease-2019 (COVID-19) booster dose recommendations on September 1, 2022 recommending the use of new bivalent COVID-19 booster vaccines which include equal amounts of ancestral and Omicron BA.4/BA.5 variant mRNA that encodes the spike protein.
The new uORFdb: integrating literature, sequence, and variation data in a central hub for uORF research
Authors: Manske Felix , Ogoniak Lynn , Jürgens Lara , Grundmann Norbert , Makałowski Wojciech , Wethmar Klaus
Published: October 2022

Upstream open reading frames (uORFs) are initiated by AUG or near-cognate start codons and have been identified in the transcript leader sequences of the majority of eukaryotic transcripts. Functionally, uORFs are implicated in downstream translational regulation of the main protein coding sequence and may serve as a source of non-canonical peptides. Genetic defects in uORF sequences have been linked to the development of various diseases, including cancer. To simplify uORF-related research, the initial release of uORFdb in 2014 provided a comprehensive and manually curated collection of uORF-related literature. Here, we present an updated sequence-based version of uORFdb, accessible at https://www.bioinformatics.uni-muenster.de/tools/uorfdb. The new uORFdb enables users to directly access sequence information, graphical displays, and genetic variation data for over 2.4 million human uORFs. It also includes sequence data of >4.2 million uORFs in 12 additional species. Multiple uORFs can be displayed in transcript- and reading-frame-specific models to visualize the translational context. A variety of filters, sequence-related information, and links to external resources (UCSC Genome Browser, dbSNP, ClinVar) facilitate immediate in-depth analysis of individual uORFs. The database also contains uORF-related somatic variation data obtained from whole-genome sequencing (WGS) analyses of 677 cancer samples collected by the TCGA consortium.
SPEED: Single-cell Pan-species atlas in the light of Ecology and Evolution for Development and Diseases
Authors: Chen Yangfeng , Zhang Xingliang , Peng Xi , Jin Yicheng , Ding Peiwen , Xiao Jiedan , Li Changxiao , Wang Fei , Chang Ashley , Yue Qizhen , Pu Mingyi , Chen Peixin , Shen Jiayi , Li Mengrou , Jia Tengfei , Wang Haoyu , Huang Li , Guo Guoji , Zhang Wensheng , Liu Hebin , Wang Xiangdong , Chen Dongsheng
Published: October 2022

It is a challenge to efficiently integrate and present the tremendous amounts of single-cell data generated from multiple tissues of various species. Here, we create a new database named SPEED for single-cell pan-species atlas in the light of ecology and evolution for development and diseases (freely accessible at http://8.142.154.29 or http://speedatlas.net). SPEED is an online platform with 4 data modules, 7 function modules and 2 display modules. The ‘Pan’ module is applied for the interactive analysis of single cell sequencing datasets from 127 species, and the ‘Evo’, ‘Devo’, and ‘Diz’ modules provide comprehensive analysis of single-cell atlases on 18 evolution datasets, 28 development datasets, and 85 disease datasets. The ‘C2C’, ‘G2G’ and ‘S2S’ modules explore intercellular communications, genetic regulatory networks, and cross-species molecular evolution. The ‘sSearch’, ‘sMarker’, ‘sUp’, and ‘sDown’ modules allow users to retrieve specific data information, obtain common marker genes for cell types, freely upload, and download single-cell datasets, respectively. Two display modules (‘HOME’ and ‘HELP’) offer easier access to the SPEED database with informative statistics and detailed guidelines. All in all, SPEED is an integrated platform for single-cell RNA sequencing (scRNA-seq) and single-cell whole-genome sequencing (scWGS) datasets to assist the deep-mining and understanding of heterogeneity among cells, tissues, and species at multi-levels, angles, and orientations, as well as provide new insights into molecular mechanisms of biological development and pathogenesis.
Vitamin C enhances NF-κB-driven epigenomic reprogramming and boosts the immunogenic properties of dendritic cells
Authors: Morante-Palacios Octavio , Godoy-Tena Gerard , Calafell-Segura Josep , Ciudad Laura , Martínez-Cáceres Eva M , Sardina José Luis , Ballestar Esteban
Published: October 2022

Dendritic cells (DCs), the most potent antigen-presenting cells, are necessary for effective activation of naïve T cells. DCs’ immunological properties are modulated in response to various stimuli. Active DNA demethylation is crucial for DC differentiation and function. Vitamin C, a known cofactor of ten-eleven translocation (TET) enzymes, drives active demethylation. Vitamin C has recently emerged as a promising adjuvant for several types of cancer; however, its effects on human immune cells are poorly understood. In this study, we investigate the epigenomic and transcriptomic reprogramming orchestrated by vitamin C in monocyte-derived DC differentiation and maturation. Vitamin C triggers extensive demethylation at NF-κB/p65 binding sites, together with concordant upregulation of antigen-presentation and immune response-related genes during DC maturation. p65 interacts with TET2 and mediates the aforementioned vitamin C-mediated changes, as demonstrated by pharmacological inhibition. Moreover, vitamin C increases TNFβ production in DCs through NF-κB, in concordance with the upregulation of its coding gene and the demethylation of adjacent CpGs. Finally, vitamin C enhances DC’s ability to stimulate the proliferation of autologous antigen-specific T cells. We propose that vitamin C could potentially improve monocyte-derived DC-based cell therapies.
The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease
Authors: Groza Tudor , Gomez Federico Lopez , Mashhadi Hamed Haseli , Muñoz-Fuentes Violeta , Gunes Osman , Wilson Robert , Cacheiro Pilar , Frost Anthony , Keskivali-Bond Piia , Vardal Bora , McCoy Aaron , Cheng Tsz Kwan , Santos Luis , Wells Sara , Smedley Damian , Mallon Ann-Marie , Parkinson Helen
Published: October 2022

The International Mouse Phenotyping Consortium (IMPC; https://www.mousephenotype.org/) web portal makes available curated, integrated and analysed knockout mouse phenotyping data generated by the IMPC project consisting of 85M data points and over 95,000 statistically significant phenotype hits mapped to human diseases. The IMPC portal delivers a substantial reference dataset that supports the enrichment of various domain-specific projects and databases, as well as the wider research and clinical community, where the IMPC genotype–phenotype knowledge contributes to the molecular diagnosis of patients affected by rare disorders. Data from 9,000 mouse lines and 750 000 images provides vital resources enabling the interpretation of the ignorome, and advancing our knowledge on mammalian gene function and the mechanisms underlying phenotypes associated with human diseases. The resource is widely integrated and the lines have been used in over 4,600 publications indicating the value of the data and the materials.
‘We Can’t Afford to be a Branch Office’: The Territorial Dynamics of the British Labour Party, 2015–2019
Authors: Brown Swan Coree , Kenny Michael
Published: October 2022

Despite having delivered devolution, the British Labour Party has faced significant challenges in adapting to, and competing effectively in, a multi-level political space. This article explores this dynamic in the context of a pivotal period of change (2015–2019), in which the party was led by Jeremy Corbyn, a political outsider, and when British politics was riven by Brexit. In this article we highlight the operation of a key strategic duality underlying the territorial politics pursued by both Scottish and Welsh Labour parties: an endemic and unresolved desire to seek greater autonomy from the UK party, on the one hand: and the preference to retain or gain influence at the centre of British politics, on the other. How these goals were pursued, and tensions between them managed by the territorial parties and their leaders, are central to an understanding of how the party handled the challenges created by devolution more broadly.
BREVIPEDICELLUS/KNAT1 targets TCP15 to modulate filament elongation during Arabidopsis late stamen development
Authors: Gastaldi Victoria , Alem Antonela L , Mansilla Natanael , Ariel Federico D , Viola Ivana L , Lucero Leandro E , Gonzalez Daniel H
Published: October 2022

The Arabidopsis homeodomain protein BREVIPEDICELLUS/KNAT1 represses the expression of the gene encoding the transcription factor TCP15 to limit filament growth at late stages of stamen development.
A reverse chromatin immunoprecipitation technique based on the CRISPR–dCas9 system
Authors: Wang Zhibo , He Zihang , Liu Zhujun , Qu Ming , Gao Caiqiu , Wang Chao , Wang Yucheng
Published: October 2022

DNA–protein interaction is one of the most crucial interactions in biological processes. However, the technologies available to study DNA–protein interactions are all based on DNA hybridization; however, DNA hybridization is not highly specific and is relatively low in efficiency. RNA-guided DNA recognition is highly specific and efficient. To overcome the limitations of technologies based on DNA hybridization, we built a DNA-binding protein capture technology based on the clustered regularly interspaced palindromic repeats (CRISPR)–dead Cas9 (dCas9) system and transient genetic transformation, termed reverse chromatin immunoprecipitation based on CRISPR–dCas9 system (R-ChIP–dCas9). In this system, dCas9 was fused with Strep-Tag II to form a fusion protein for StrepTactin affinity purification. Transient transformation was performed for the expression of dCas9 and guide RNA (gRNA) to form the dCas9–gRNA complex in birch (Betula platyphylla) plants, which binds to the target genomic DNA region. The dCas9–gRNA–DNA complex was crosslinked, then the chromatin was sonicated into fragments, and purified using StrepTactin beads. The proteins binding to the target genomic DNA region were identified using mass spectrometry. Using this method, we determined the upstream regulators of a NAM, ATAF, and CUC (NAC) transcription factor (TF), BpNAC090, and 32 TFs potentially regulating BpNAC090 were identified. The reliability of R-ChIP–dCas9 was further confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assays, and yeast one-hybrid. This technology can be adapted to various plant species and does not depend on the availability of a stable transformation system; therefore, it has wide application in identifying proteins bound to genomic DNA.
S&T resource allocation considering both performance and potential: The case of Chinese research institutes
Authors: Zhao Teng-Yu , Pei Ruimin , Yang Guo-Liang
Published: October 2022

The ex-post assessment of institutional performance has been applied to allocate scientific and technological (S&T) resource to universities and public research institutes. However, over-emphasis on particular types of performance could lead to unintended results and harm the science system. This research assesses the performance of these universities and public research institutes using ‘technical efficiency’ and their potential using ‘capacity utilization’, which are obtained by data envelopment analysis methods. Moreover, a comprehensive S&T resource allocation framework is proposed, where the organizations can be classified into four groups according to their performance and potential assessment results. An empirical study is conducted using the data of 58 Chinese research institutes from 2011 to 2018. Results indicate different patterns in the distribution and evolution of the performance and potential of these research institutes. The approaches proposed by this research are expected to complement existing performance-based S&T resource allocations.
Describing the state of a research network: A mixed methods approach to network evaluation
Authors: Bowen James M , Ouimet Mathieu , Lawarée Justin , Bielecki Joanna , Rhéaume Ashley , Greenberg Caylee , Rac Valeria E
Published: October 2022

Diabetes Action Canada Strategy for Patient-Oriented Research (SPOR) Network in Chronic Disease was formed in 2016 and is funded primarily through the Canadian Institutes of Health Research (CIHR). We propose a novel mixed-methods approach to a network evaluation integrating the State of Network Evaluation framework and the Canadian Academy of Health Sciences (CAHS) preferred framework and indicators. We measure key network themes of connectivity, health and results, and impact and return on investment associated with health research networks. Our methods consist of a longitudinal cross-sectional network survey of members and social network analysis to examine Network Connectivity and assess the frequency of interactions, the topics discussed during them, and how networking effectively facilitates interactions and collaboration among members. Network Health will be evaluated through semistructured interviews, a membership survey inquiring about satisfaction and experience with the Network, and a review of documentary sources related to funding and infrastructure to evaluate Network Sustainability. Finally, we will examine Network Results and Impact using the CAHS preferred framework and indicators to measure returns on investment in health research across the five domains of the CAHS framework, which include: advancing knowledge, capacity building, informing decision making, health impact, and economic and social impact. Indicators will be assessed with various methods, including bibliometric analyses, review of relevant documentary sources (annual reports), member activities informing health and research policy, and Patient Partner involvement. The Network Evaluation will provide members and stakeholders with information for planning, improvements, and funding future Network endeavors.
Price Discrimination in the Information Age: Prices, Poaching, and Privacy with Personalized Targeted Discounts
Authors: Baik Simon Anderson, Alicia , Larson Nathan
Published: October 2022

We study list price competition when firms can individually target consumer discounts (at a cost) afterwards, and we address recent privacy regulation (like the GDPR) allowing consumers to choose whether to opt-in to targeting. Targeted consumers receive poaching and retention discount offers. Equilibrium discount offers are in mixed strategies, but only two firms vie for each contested consumer and final profits on them are Bertrand-like. When targeting is unrestricted, firm list pricing resembles monopoly. For plausible demand conditions and if targeting costs are not too low, firms and consumers are worse off with unrestricted targeting than banning it. However, targeting induces higher (lower) list prices if demand is convex (concave), and either side of the market can benefit if list prices shift enough in its favour. Given the choice, consumers opt in only when expected discounts exceed privacy costs. Under empirically plausible conditions, opt-in choice makes all consumers better off.
Reduction in Multiple Cardiometabolic Risk Factors With Combined Olanzapine/Samidorphan Compared With Olanzapine: Post Hoc Analyses From a 24-Week Phase 3 Study
Authors: Correll Christoph U , Stein Evan , Graham Christine , DiPetrillo Lauren , Akerman Sarah , Stanford Arielle D , Jiang Ying , Yagoda Sergey , McDonnell David , Hopkinson Craig
Published: October 2022

Background and Hypotheses

Weight gain and adverse cardiometabolic effects often limit the clinical utility of olanzapine. In ENLIGHTEN-2, combining olanzapine with the opioid receptor antagonist samidorphan (OLZ/SAM) mitigated olanzapine-associated weight gain. These analyses tested the hypothesis that OLZ/SAM would be associated with reduced adverse cardiometabolic effects compared with olanzapine.

Study Design

This phase 3 double-blind study randomized adults with schizophrenia to OLZ/SAM or olanzapine for 24 weeks. Post hoc analyses assessed changes from baseline to week 24 in cardiometabolic risk parameters, including body mass index (BMI), risk of developing obesity (BMI ≥30 kg/m2) or metabolic syndrome, waist circumference, along with mean and potentially clinically significant changes in blood pressure, glucose, and lipids.

Results

After 24 weeks’ treatment, compared with olanzapine, OLZ/SAM was associated with smaller least-squares mean (LSM) changes from baseline in systolic blood pressure (LSM difference, −2.63 mm Hg; 95% CI: −4.78, −0.47), diastolic blood pressure (LSM difference, −0.75 mm Hg; 95% CI: −2.31, 0.80), and BMI (LSM difference, −0.65 kg/m2; 95% CI: −1.01, −0.28). OLZ/SAM treatment was also associated with reduced risk of shifting from normal blood pressure to stage 1/2 hypertension (odds ratio [OR], 0.48; 95% CI: 0.24, 0.96), becoming obese (OR, 0.52; 95% CI: 0.32, 0.82), and developing metabolic syndrome (OR, 0.55; 95% CI: 0.31, 0.99) compared with olanzapine. No treatment group differences were noted for risk of hyperglycemia or hyperlipidemia.

Conclusions

OLZ/SAM treatment was associated with lower risk of worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome relative to olanzapine. NCT02694328, https://clinicaltrials.gov/ct2/show/NCT02694328.
Prevalence of Group B Streptococcus in pregnant women in Kerala and relation to neonatal outcomes: a prospective cross-sectional study
Authors: Gurudas Girija , Arjun Rajalakshmi , Jain Naveen , Ranganayaki Vidyalekshmy , Sasikumar Chinnu , Mohan Viji , Hussain Febeena , Pournami Femitha
Published: October 2022

Background and objectives

Early onset sepsis (EOS) in neonates is a scourge that contributes to morbidity and mortality. Prominent stakeholders recommend universal screening of antenatal women for Group B Streptococcus (GBS) and intrapartum antibiotic prophylaxis (IAP) for those who are carriers. However, there are controversies. Other guidelines allow region-specific protocols due to sociodemographic, geographical and ethnic differences. We planned to analyze the prevalence of GBS rectovaginal carriage at 36–37 weeks gestation and its effect on early neonatal status.

Methods

This prospective multidisciplinary study (Obstetrics, Perinatology, Neonatology, Microbiology and Infectious diseases) was conducted in our tertiary care center between February 2020 and May 2021.

Results

In our study group which included 966 mothers who delivered at the hospital, 4.8% of mothers who were screened by genito-rectal swabs were positive for GBS at 36–37 weeks gestation. All these mothers were given IAP as per protocol. Other organisms detected on screening mothers were Candida and Gram-negative bacteria. None of the neonates born to these mothers required any intensive care unit admission or therapy for systemic illness. There was no difference in clinically relevant outcomes between neonates who were born to GBS-positive mothers as compared to those born to negative screen result mothers.

Conclusions

GBS prevalence in our cohort was lower than most scientific reports. The neonates born to carrier mothers did not present with signs of early-onset sepsis.
Every treasured drop! Blood transfusion requirements in very preterm neonates after implementation of blood conservation strategies: an observational analytical study
Authors: Anand Vishnu , Pournami Femitha , Prithvi Ajai Kumar , Nandakumar Anand , Prabhakar Jyothi , Jain Naveen
Published: October 2022

Background

Certain morbidities are inevitable in preterm infants; the challenge lies in minimizing them. Anemia of prematurity is multifactorial. Therapy largely depends on adult red blood cell transfusions (RBCT); which inherently, are not without problems. Most literature in this respect are retrospective or evaluate individual stratagems to reduce RBCT.

Methods

This observational analytical study was planned to compare need for RBCT, before and after institution of blood conservation strategies (BCS). All those ≤30 weeks gestation at birth during two-time epochs were included (Before BCS: retrospective; After BCS: prospective). BCS constituted of delayed cord clamping (DCC), strict sampling indications, micro-sampling with point-of-care testing (MS-POCT) and adherence to RBCT thresholds.

Results

Of 45 enrolled neonates in each group, proportion of those requiring even 1 RBCT was significantly reduced after BCS [51.1% vs. 26.7%, p = 0.02, OR 0.35, 95%CI (0.14, 0.84)]. Calculated cumulative blood volume losses (35.3 ml vs. 21.9 ml) and loss per kilogram birth weight (35.3 ml/kg vs. 20.12 ml/kg) were significantly lower after BCS (p = 0.0036). Need for >1 RBCT, mean lowest Hb, mean maximum-hemoglobin drop, need for arterial lines were reduced. Adherence to RBCT thresholds were acceptably good in both time epochs. However, the compliance to DCC was low in both groups, identifying one area of focus with scope for massive improvement.

Conclusions

Need for RBCT transfusions largely attributable to reduced blood losses for lab analysis were reduced after BCS. Installation of in-house MS-POCT seemed to be the pivotal factor. Units that care for very preterm infants must make attempts to procure MS-POCT equipment.
How Health Experiences in Tanzania Foster Change in Nursing Student Perceptions of Diversity and Self
Authors: Herron Elizabeth K. , Knopp Andrea
Published: October 2022

International study abroad programs offered by American universities provide opportunities to experience global health care disparities. This qualitative phenomenological research using a hermeneutic approach was conducted to explore how clinical experience in Tanzania influenced the knowledge and attitudes of prelicensure baccalaureate nursing students toward culture, health care disparities, and health care outcomes. Two main themes emerged from the research: thinking as another and carrying it forward.
Learning Impact of Armed Forces Medical Background on Military Nursing Students in an Accelerated Bachelor of Science in Nursing Program
Authors: Wiersma Gretchen Michele , Cox Catherine Wilson , McNelis Angela M. , Tebbenhoff Billinda , Schumann Mary Jean , Maring Joyce
Published: October 2022

The study examined differences between military students enrolled in an accelerated bachelor of science in nursing (BSN) program with and without medical experience and/or a previous bachelor’s degree on graduation grade point average (GPA) and NCLEX®-RN first-time pass rates. Significant differences were found between groups with/without military medical experience on NCLEX-RN, but not graduation GPA. Significant differences were found between groups with/without prior degree on GPA, but not on NCLEX-RN. Having both medical experience and a prior degree did not make a difference on GPA or NCLEX-RN. Findings offer guidance on admission criteria to accelerated programs for this unique group of students.
Understanding COVID-19’s Impact on Nursing Students’ Education, Professional Perceptions, Stress, and Coping
Authors: Overbaugh Kristen J. , Monforto Kathleen , DiGiacomo Pat , Maloney Courtney
Published: October 2022

This descriptive mixed-methods study was conducted to understand the impact of COVID-19 on undergraduate nursing students’ education, perceptions of nursing, stress, and coping. A convenience sample (N = 150) reported high levels of stress with higher stress levels significantly associated with lower coping. The essence of nursing, emotions surrounding the transition to nursing, educational barriers, and faculty-student relationships emerged as themes. The findings can be used to revise curricula and better support nursing students in future disasters and transitions to practice during unpredictable times.
Do bacterial vaccines/adjuvants prevent wheezing episodes in children?
Authors: Nieto Antonio , Nieto María , Conejero Laura , Subiza José Luis
Published: October 2022

Purpose of review

To discuss recently discovered mechanisms of action of some bacterial vaccines that may account for their clinical benefit in the prevention of recurrent wheezing and asthma exacerbations in infants and early childhood.

Recent findings

Trained immunity has been shown to confer innate immune cells with a quite long-term nonspecific protection against a broad spectrum of pathogens. Inducers of trained immunity include some bacterial vaccines. Trained immunity-based vaccines (TIbV) of bacterial origin have the capability to induce nonspecific responses to a variety of pathogens, including respiratory viruses, in addition to their nominal bacterial antigens. Clinical data, from epidemiological surveys to well designed randomized clinical trials, indicate that TIbV formulated with bacteria prevent respiratory tract infections of viral cause, such as those associated with recurrent wheezing or asthma exacerbation, in children. Administration of these vaccines by the mucosal route may be important for their outcome in respiratory infections.

Mucosal bacterial immunotherapy, including certain TIbV, confer protection against a broad spectrum of pathogens, such as viruses, through a mechanism mediated by trained immunity. Clinical studies on the use of these preparations against recurrent wheezing reflect these mechanistic effects. These findings open a new avenue for the development of new strategies for this condition.