bluuebunny/crossref_metadata_2025 huggingface dataset:
UNADON: transformer-based model to predict genome-wide chromosome spatial position
Authors: Yang Muyu , Ma Jian
Published: June 2023

Motivation

The spatial positioning of chromosomes relative to functional nuclear bodies is intertwined with genome functions such as transcription. However, the sequence patterns and epigenomic features that collectively influence chromatin spatial positioning in a genome-wide manner are not well understood.

Results

Here, we develop a new transformer-based deep learning model called UNADON, which predicts the genome-wide cytological distance to a specific type of nuclear body, as measured by TSA-seq, using both sequence features and epigenomic signals. Evaluations of UNADON in four cell lines (K562, H1, HFFc6, HCT116) show high accuracy in predicting chromatin spatial positioning to nuclear bodies when trained on a single cell line. UNADON also performed well in an unseen cell type. Importantly, we reveal potential sequence and epigenomic factors that affect large-scale chromatin compartmentalization in nuclear bodies. Together, UNADON provides new insights into the principles between sequence features and large-scale chromatin spatial localization, which has important implications for understanding nuclear structure and function.

Availability and implementation

The source code of UNADON can be found at https://github.com/ma-compbio/UNADON.
PPAD: a deep learning architecture to predict progression of Alzheimer’s disease
Authors: Al Olaimat Mohammad , Martinez Jared , Saeed Fahad , Bozdag Serdar ,   Alzheimer’s Disease Neuroimaging Initiative
Published: June 2023

Motivation

Alzheimer’s disease (AD) is a neurodegenerative disease that affects millions of people worldwide. Mild cognitive impairment (MCI) is an intermediary stage between cognitively normal state and AD. Not all people who have MCI convert to AD. The diagnosis of AD is made after significant symptoms of dementia such as short-term memory loss are already present. Since AD is currently an irreversible disease, diagnosis at the onset of the disease brings a huge burden on patients, their caregivers, and the healthcare sector. Thus, there is a crucial need to develop methods for the early prediction AD for patients who have MCI. Recurrent neural networks (RNN) have been successfully used to handle electronic health records (EHR) for predicting conversion from MCI to AD. However, RNN ignores irregular time intervals between successive events which occurs common in electronic health record data. In this study, we propose two deep learning architectures based on RNN, namely Predicting Progression of Alzheimer’s Disease (PPAD) and PPAD-Autoencoder. PPAD and PPAD-Autoencoder are designed for early predicting conversion from MCI to AD at the next visit and multiple visits ahead for patients, respectively. To minimize the effect of the irregular time intervals between visits, we propose using age in each visit as an indicator of time change between successive visits.

Results

Our experimental results conducted on Alzheimer’s Disease Neuroimaging Initiative and National Alzheimer’s Coordinating Center datasets showed that our proposed models outperformed all baseline models for most prediction scenarios in terms of F2 and sensitivity. We also observed that the age feature was one of top features and was able to address irregular time interval problem.

Availability and implementation

https://github.com/bozdaglab/PPAD.
RNA design via structure-aware multifrontier ensemble optimization
Authors: Zhou Tianshuo , Dai Ning , Li Sizhen , Ward Max , Mathews David H , Huang Liang
Published: June 2023

Motivation

RNA design is the search for a sequence or set of sequences that will fold to desired structure, also known as the inverse problem of RNA folding. However, the sequences designed by existing algorithms often suffer from low ensemble stability, which worsens for long sequence design. Additionally, for many methods only a small number of sequences satisfying the MFE criterion can be found by each run of design. These drawbacks limit their use cases.

Results

We propose an innovative optimization paradigm, SAMFEO, which optimizes ensemble objectives (equilibrium probability or ensemble defect) by iterative search and yields a very large number of successfully designed RNA sequences as byproducts. We develop a search method which leverages structure level and ensemble level information at different stages of the optimization: initialization, sampling, mutation, and updating. Our work, while being less complicated than others, is the first algorithm that is able to design thousands of RNA sequences for the puzzles from the Eterna100 benchmark. In addition, our algorithm solves the most Eterna100 puzzles among all the general optimization based methods in our study. The only baseline solving more puzzles than our work is dependent on handcrafted heuristics designed for a specific folding model. Surprisingly, our approach shows superiority on designing long sequences for structures adapted from the database of 16S Ribosomal RNAs.

Availability and implementation

Our source code and data used in this article is available at https://github.com/shanry/SAMFEO.
Higher-order genetic interaction discovery with network-based biological priors
Authors: Pellizzoni Paolo , Muzio Giulia , Borgwardt Karsten
Published: June 2023

Motivation

Complex phenotypes, such as many common diseases and morphological traits, are controlled by multiple genetic factors, namely genetic mutations and genes, and are influenced by environmental conditions. Deciphering the genetics underlying such traits requires a systemic approach, where many different genetic factors and their interactions are considered simultaneously. Many association mapping techniques available nowadays follow this reasoning, but have some severe limitations. In particular, they require binary encodings for the genetic markers, forcing the user to decide beforehand whether to use, e.g. a recessive or a dominant encoding. Moreover, most methods cannot include any biological prior or are limited to testing only lower-order interactions among genes for association with the phenotype, potentially missing a large number of marker combinations.

Results

We propose HOGImine, a novel algorithm that expands the class of discoverable genetic meta-markers by considering higher-order interactions of genes and by allowing multiple encodings for the genetic variants. Our experimental evaluation shows that the algorithm has a substantially higher statistical power compared to previous methods, allowing it to discover genetic mutations statistically associated with the phenotype at hand that could not be found before. Our method can exploit prior biological knowledge on gene interactions, such as protein–protein interaction networks, genetic pathways, and protein complexes, to restrict its search space. Since computing higher-order gene interactions poses a high computational burden, we also develop a more efficient search strategy and support computation to make our approach applicable in practice, leading to substantial runtime improvements compared to state-of-the-art methods.

Availability and implementation

Code and data are available at https://github.com/BorgwardtLab/HOGImine
O044 The risk of surgical site infection and other wound complications following surgery to the lymph nodes for staging or treatment of malignancy: a systematic review and meta-analysis of 45,415 cases
Authors: Totty JP , Nzenwa IC , Hardie CM , Iqbal HA , Sidapra M , Matteucci PL , Chetter IC , Smith GE
Published: June 2023

Introduction

For completion of staging of malignant melanoma, sentinel lymph node biopsy (SLNB) may be offered to patients with stage 1B disease or greater, and in some positive cases, completion lymphadenectomy is offered. However, there is little evidence that either procedure are beneficial to patients, and both procedures carry a risk of wound complications. The aim of this study was to assess the current prevalence of wound complications in these procedures and quantify the change over time of this risk.

Methods

This was a subgroup analysis of a larger systematic review (Prospero CRD42021239530). A systematic search was undertaken to identify all published material relating to surgery on the lymph nodes. The primary outcome was the proportion of surgical site infection and/or seroma. Studies relating to malignant melanoma were selected from the overall results, and random effects meta-analysis of proportions and meta-regression were undertaken.

Results

Seventy studies were suitable for inclusion in meta-analysis, constituting 7,585 patients. The proportion of patients developing infection following SLNB was 3.5% (95% CI 2.0–6.0%) and seroma 7.8% (4.0–14.3%). For completion lymphadenectomy, the risk of SSI was 17.4% (13.4– 22.2%) and seroma 24.7% (23.4–26.0%). Neither SSI nor seroma incidence have changed significantly in 30 years.

Conclusion

The risk of complications in these procedures remains high and has not changed in 30 years. Given a potential lack of benefit of these procedures, this data should be used as part of the decision-making process when counselling patients, and to guide future research into prevention of wound complications.

Take-home message

The risk of SSI following block dissection for melanoma is almost 20%, and the risk of seroma almost 25%. This unacceptably high risk has not improved in the last 30 years.
O055 Tenascin-C Expression and distribution following neoadjuvant chemotherapy for breast cancer
Authors: Tai JCJ , Ngai V , El Sheikh S , Ahmed M
Published: June 2023

Introduction

Tenascin-C (TNC), a matricellular glycoprotein linked to breast cancer invasion and metastasis, has never been studied exclusively in post-neoadjuvant chemotherapy (NACT) patients. This retrospective cohort analysis investigates whether TNC is expressed post-NACT and establishes potential links with patients’ clinicopathological characteristics.

Methods

Twenty-four invasive breast cancer patients who had received NACT and surgery were recruited from a single centre. The distribution and intensity of TNC expression in paraffin embedded breast specimens were analysed using a pre-determined scoring system. These scores were then correlated with the patients’ clinicopathological characteristics and ‘PREDICT’ scores.

Results

TNC was well expressed by the post-NACT cancer tissue, albeit more strongly in the tumour-associated stroma than in the tumour cells. More pronounced expression overall was seen in PR-positive patients, but greater TNC expression in the tumour invasive border was linked to ER-negativity, TNBC, and lack of lymph node involvement. A greater TNC expression in the central region of the tumour was linked to a better pathologic response to NACT. The degree of TNC expression was not statistically different between areas of response to NACT and areas with residual tumour. Patients with better post-surgical ‘PREDICT 10’ scores had greater TNC expression in the tumour.

Conclusion

This study shows that TNC remains well-expressed in the stroma of post-NACT breast cancer tissue, and may be linked to tumour phenotype, pathologic response to NACT, and prognosis. There are many potential clinical applications, including using TNC as a: (1) therapeutic target, (2) predictor of responsiveness to NACT and/or adjuvant therapies, (3) prognostic marker.

Take-home message

Tenascin-C is well-expressed in post-NACT breast cancer tissue obtained at the point of margin resection, and the degree and distribution of its expression is linked to tumour phenotype, pathologic response to NACT, and prognosis. This has potentially impactful implications for its use as a therapeutic target, predictor of responsiveness to chemotherapy, and prognostic marker.
Selective pressure on a saccharin intake phenotype and its correlates: a replication study
Authors: Dess Nancy K , Chapman Clinton D , Jacobi Paulina M
Published: June 2023

The Occidental High- and Low-Saccharin rats (respectively, HiS and LoS lines) were selectively bred for decades to examine mechanisms and correlates of a saccharin intake phenotype. Observed line differences ranged from taste and eating to drug self-administration and defensive behavior, paralleling human research on relationships between gustation, personality, and psychopathology. The original lines were terminated in 2019, and replicate lines (HiS-R and LoS-R) were selectively bred for 5 generations to test for reproducible, rapid selection for the phenotype and its correlates. The line differences chosen for replication included intake of tastants (saccharin, sugars, quinine-adulterated sucrose, sodium chloride, and ethanol) and foods (cheese, peas, Spam, and chocolate) and several noningestive behaviors (deprivation-induced hyperactivity, acoustic startle, and open field behavior). The HiS-R and LoS-R lines diverged on intake of saccharin, disaccharides, quinine-adulterated sucrose, sodium chloride, and complex foods, and open field behavior. Differences from the original lines also were observed. Reasons for and implications of the pattern of replication and lack thereof in 5 generations are discussed.
Low birthweight is associated with epigenetic age acceleration in the first 3 years of life
Authors: Quinn Edward B , Hsiao Chu J , Maisha Felicien M , Mulligan Connie J
Published: June 2023

Background and objectives

The Developmental Origins of Health and Disease hypothesis posits that early life adversity is associated with poor adult health outcomes. Epidemiological evidence has supported this framework by linking low birthweight with adult health and mortality, but the mechanisms remain unclear. Accelerated epigenetic aging may be a pathway to connect early life experiences with adult health outcomes, based on associations of accelerated epigenetic aging with increased morbidity and mortality.

Methodology

Sixty-seven mother-infant dyads were recruited in the eastern Democratic Republic of Congo. Birthweight data were collected at birth, and blood samples were collected at birth and follow-up visits up to age 3. DNA methylation data were generated with the Illumina MethylationEPIC array and used to estimate epigenetic age. A multilevel model was used to test for associations between birthweight and epigenetic age acceleration.

Results

Chronological age was highly correlated with epigenetic age from birth to age 3 (r = 0.95, p < 2.2 × 10−16). Variation in epigenetic age acceleration increased over time. Birthweight, dichotomized around 2500 g, predicted epigenetic age acceleration over the first 3 years of life (b = −0.39, p = 0.005).

Conclusions and implications

Our longitudinal analysis provides the first evidence for accelerated epigenetic aging that emerges between birth and age 3 and associates with low birthweight. These results suggest that early life experiences, such as low birthweight, may shape the trajectory of epigenetic aging in early childhood. Furthermore, accelerated epigenetic aging may be a pathway that links low birthweight and poor adult health outcomes.
Genome Comparison Reveals Inversions and Alternative Evolutionary History of Nutritional Endosymbionts in Planthoppers (Hemiptera: Fulgoromorpha)
Authors: Deng Junchen , Bennett Gordon M , Franco Diego C , Prus-Frankowska Monika , Stroiński Adam , Michalik Anna , Łukasik Piotr
Published: June 2023

The evolutionary success of sap-feeding hemipteran insects in the suborder Auchenorrhyncha was enabled by nutritional contributions from their heritable endosymbiotic bacteria. However, the symbiont diversity, functions, and evolutionary origins in this large insect group have not been broadly characterized using genomic tools. In particular, the origins and relationships among ancient betaproteobacterial symbionts Vidania (in Fulgoromorpha) and Nasuia/Zinderia (in Cicadomorpha) are uncertain. Here, we characterized the genomes of Vidania and Sulcia from three Pyrops planthoppers (family Fulgoridae) to understand their metabolic functions and evolutionary histories. We find that, like in previously characterized planthoppers, these symbionts share nutritional responsibilities, with Vidania providing seven out of ten essential amino acids. Sulcia lineages across the Auchenorrhyncha have a highly conserved genome but with multiple independent rearrangements occurring in an early ancestor of Cicadomorpha or Fulgoromorpha and in a few succeeding lineages. Genomic synteny was also observed within each of the betaproteobacterial symbiont genera Nasuia, Zinderia, and Vidania, but not across them, which challenges the expectation of a shared ancestry for these symbionts. The further comparison of other biological traits strongly suggests an independent origin of Vidania early in the planthopper evolution and possibly of Nasuia and Zinderia in their respective host lineages. This hypothesis further links the potential acquisition of novel nutritional endosymbiont lineages with the emergence of auchenorrhynchan superfamilies.
The Transcriptomic Signature of Cyclical Parthenogenesis
Authors: Huynh Trung Viet , Hall Alexander S , Xu Sen
Published: June 2023

Cyclical parthenogenesis, where females can engage in sexual or asexual reproduction depending on environmental conditions, represents a novel reproductive phenotype that emerged during eukaryotic evolution. The fact that environmental conditions can trigger cyclical parthenogens to engage in distinct reproductive modes strongly suggests that gene expression plays a key role in the origin of cyclical parthenogenesis. However, the genetic basis underlying cyclical parthenogenesis remains understudied. In this study, we characterize the female transcriptomic signature of sexual versus asexual reproduction in the cyclically parthenogenetic microcrustacean Daphnia pulex and Daphnia pulicaria. Our analyses of differentially expressed genes (DEGs), pathway enrichment, and gene ontology (GO) term enrichment clearly show that compared with sexual reproduction, the asexual reproductive stage is characterized by both the underregulation of meiosis and cell cycle genes and the upregulation of metabolic genes. The consensus set of DEGs that this study identifies within the meiotic, cell cycle, and metabolic pathways serves as candidate genes for future studies investigating how the two reproductive cycles in cyclical parthenogenesis are mediated at a molecular level. Furthermore, our analyses identify some cases of divergent expression among gene family members (e.g., doublesex and NOTCH2) associated with asexual or sexual reproductive stage, suggesting potential functional divergence among gene family members.
Impact of Obefazimod on Viral Persistence, Inflammation, and Immune Activation in People With Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy
Authors: Bernal Silvia , Puertas Maria C , Morón-López Sara , Cranston Ross D , Urrea Víctor , Dalmau Judith , Salgado María , Gálvez Cristina , Erkizia Itziar , McGowan Ian , Scherrer Didier , Revollo Boris , Sirera Guillem , Santos José Ramón , Clotet Bonaventura , Paredes Roger , Martinez-Picado Javier
Published: June 2023

Background

Persistence of viral reservoirs has been observed in people with human immunodeficiency virus (HIV), despite long-term antiretroviral therapy (ART), and likely contributes to chronic immune activation and inflammation. Obefazimod is a novel drug that inhibits human immunodeficiency virus type 1 (HIV-1) replication and reduces inflammation. Here we assess whether obefazimod is safe and might impact HIV-1 persistence, chronic immune activation, and inflammation in ART-suppressed people with HIV.

Methods

We evaluated obefazimod-related adverse events, changes in cell-associated HIV-1 DNA and RNA, residual viremia, immunophenotype, and inflammation biomarkers in blood and rectal tissue. We compared 24 ART-suppressed people with HIV who received daily doses of 50 mg obefazimod for 12 weeks (n = 13) or 150 mg for 4 weeks (n = 11) and 12 HIV-negative individuals who received 50 mg for 4 weeks.

Results

The 50- and 150-mg doses of obefazimod were safe, although the 150-mg dose showed inferior tolerability. The 150-mg dose reduced HIV-1 DNA (P = .008, median fold change = 0.6) and residual viremia in all individuals with detectable viremia at baseline. Furthermore, obefazimod upregulated miR-124 in all participants and reduced the activation markers CD38, HLA-DR, and PD-1 and several inflammation biomarkers.

Conclusions

The effect of obefazimod by reducing chronic immune activation and inflammation suggests a potential role for the drug in virus remission strategies involving other compounds that can activate immune cells, such as latency-reversing agents.
Electronic health record data quality assessment and tools: a systematic review
Authors: Lewis Abigail E , Weiskopf Nicole , Abrams Zachary B , Foraker Randi , Lai Albert M , Payne Philip R O , Gupta Aditi
Published: June 2023

Objective

We extended a 2013 literature review on electronic health record (EHR) data quality assessment approaches and tools to determine recent improvements or changes in EHR data quality assessment methodologies.

Materials and Methods

We completed a systematic review of PubMed articles from 2013 to April 2023 that discussed the quality assessment of EHR data. We screened and reviewed papers for the dimensions and methods defined in the original 2013 manuscript. We categorized papers as data quality outcomes of interest, tools, or opinion pieces. We abstracted and defined additional themes and methods though an iterative review process.

Results

We included 103 papers in the review, of which 73 were data quality outcomes of interest papers, 22 were tools, and 8 were opinion pieces. The most common dimension of data quality assessed was completeness, followed by correctness, concordance, plausibility, and currency. We abstracted conformance and bias as 2 additional dimensions of data quality and structural agreement as an additional methodology.

Discussion

There has been an increase in EHR data quality assessment publications since the original 2013 review. Consistent dimensions of EHR data quality continue to be assessed across applications. Despite consistent patterns of assessment, there still does not exist a standard approach for assessing EHR data quality.

Conclusion

Guidelines are needed for EHR data quality assessment to improve the efficiency, transparency, comparability, and interoperability of data quality assessment. These guidelines must be both scalable and flexible. Automation could be helpful in generalizing this process.
Food Security as a Predictor of Global Pediatric Postburn Mortality
Authors: Tiongco Rafael Felix P , Ali Ayman , Puthumana Joseph S , Scott Hultman Charles , Caffrey Julie A , Cooney Carisa M , Redett Richard J
Published: June 2023

Food security (FS) is defined as access to sufficient and nutritious food. Children, especially those in low- and middle- income countries (LMICs), are disproportionately affected by low FS. We hypothesized high FS would be predictive of decreased pediatric postburn mortality in LMICs. Publicly-available, deidentified datasets were obtained from the World Health Organization’s Global Burn Registry (GBR) and Economist Intelligence Unit’s Global FS Index (GFSI). The GFSI calculates FS scores annually from intergovernmental organization data reviewed by a panel of experts. FS scores are reported on a 0 to 100 scale with 100 indicating the highest FS. Patients aged 0 to 19 yr were included; after linking GBR and GFSI datasets, countries with <100 burn patients were excluded. Data were analyzed with descriptive statistics and bivariate analyses. Multiple logistic regression controlling for confounders was used to quantify associations between mortality and FS score. Significance was set at P < 0.05. From 2016 to 2020, there were 2,246 cases including 259 deaths (11.5%) over nine countries. Those who died had a higher median age (7 [IQR 2, 15] vs 3 [2, 6] years, P < 0.001), higher proportion of females (48.6% vs 42.0%, P =0.048), and lower median FS score (55.7 [IQR 45.3, 58.2] vs 59.8 [IQR 46.7, 65.7], P < 0.001). Increasing FS score was associated with decreased odds of postburn mortality [multivariable odds ratio 0.78 (95% confidence interval 0.73 to 0.83), P < 0.001]. With the association between FS and mortality, international efforts to increase FS in LMICs may help improve pediatric burn patient survival.
Galactosylation of xyloglucan is essential for the stabilization of the actin cytoskeleton and endomembrane system through the proper assembly of cell walls
Authors: Xiang Min , Yuan Shuai , Zhang Qing , Liu Xiaohui , Li Qingyao , Leng Zhengmei , Sha Jingjing , Anderson Charles T , Xiao Chaowen
Published: June 2023

Xyloglucan, a major hemicellulose, interacts with cellulose and pectin to assemble primary cell walls in plants. Loss of the xyloglucan galactosyltransferase MURUS3 (MUR3) leads to the deficiency of galactosylated xyloglucan and perturbs plant growth. However, it is unclear whether defects in xyloglucan galactosylation influence the synthesis of other wall polysaccharides, cell wall integrity, cytoskeleton behaviour, and endomembrane homeostasis. Here, we found that in mur3-7 etiolated seedlings cellulose was reduced, CELLULOSE SYNTHASE (CESA) genes were down-regulated, the density and mobility of cellulose synthase complexes (CSCs) were decreased, and cellulose microfibrils become discontinuous. Pectin, rhamnogalacturonan II (RGII), and boron contents were reduced in mur3-7 plants, and B-RGII cross-linking was abnormal. Wall porosity and thickness were significantly increased in mur3-7 seedlings. Endomembrane aggregation was also apparent in the mur3-7 mutant. Furthermore, mutant seedlings and their actin filaments were more sensitive to Latrunculin A (LatA) treatment. However, all defects in mur3-7 mutants were substantially restored by exogenous boric acid application. Our study reveals the importance of MUR3-mediated xyloglucan galactosylation for cell wall structural assembly and homeostasis, which is required for the stabilization of the actin cytoskeleton and the endomembrane system.
Type II-P supernova progenitor star initial masses and SN 2020jfo: direct detection, light-curve properties, nebular spectroscopy, and local environment
Authors: Kilpatrick Charles D , Izzo Luca , Bentley Rory O , Chambers Kenneth C , Coulter David A , Drout Maria R , de Boer Thomas , Foley Ryan J , Gall Christa , Halford Melissa R , Jones David O , Langeroodi Danial , Lin Chien-Cheng , Magnier Eugene A , McGill Peter , O’Grady Anna J G , Pan Yen-Chen , Ramirez-Ruiz Enrico , Rest Armin , Swift Jonathan J , Tinyanont Samaporn , Villar V Ashley , Wainscoat Richard J , Wasserman Amanda Rose , Yadavalli S Karthik , Yang Grace
Published: June 2023

We present optical, ultraviolet, and infrared data of the type II supernova (SN II) 2020jfo at 14.5 Mpc. This wealth of multiwavelength data allows us to compare different metrics commonly used to estimate progenitor masses of SN II for the same object. Using its early light curve, we infer SN 2020jfo had a progenitor radius of ≈700 R⊙, consistent with red supergiants of initial mass MZAMS =11–13 M⊙. The decline in its late-time light curve is best fit by a 56Ni mass of 0.018 ± 0.007 M⊙ consistent with that ejected from SN II-P with ≈13 M⊙ initial mass stars. Early spectra and photometry do not exhibit signs of interaction with circumstellar matter, implying that SN 2020jfo experienced weak mass-loss within the final years prior to explosion. Our spectra at >250 d are best fit by models from 12 M⊙ initial mass stars. We analysed integral field unit spectroscopy of the stellar population near SN 2020jfo, finding its massive star population had a zero age main sequence mass of 9.7$\substack{+2.5\\ -1.3}~{\rm M}_{\odot }$. We identify a single counterpart in pre-explosion imaging and find it has an initial mass of at most $7.2\substack{+1.2\\ -0.6}~{\rm M}_{\odot }$. We conclude that the inconsistency between this mass and indirect mass indicators from SN 2020jfo itself is most likely caused by extinction with AV = 2–3 mag due to matter around the progenitor star, which lowered its observed optical luminosity. As SN 2020jfo did not exhibit extinction at this level or evidence for interaction with circumstellar matter between 1.6 and 450 d from explosion, we conclude that this material was likely confined within ≈3000 R⊙ from the progenitor star.
Regulation of Atp7a RNA contributes to differentiation-dependent Cu redistribution in skeletal muscle cells
Authors: Whitlow Thomas J , Zhang Yu , Ferguson Nathan , Perez Alexandra M , Patel Hemchandra , Link-Kemp Josephine A , Larson Ethan M , Mezzell Allison T , Shanbhag Vinit C , Petris Michael J , Vest Katherine E
Published: June 2023

Cu (Cu) is essential for several biochemical pathways due to its role as a catalytic cofactor or allosteric regulator of enzymes. Its import and distribution are tightly controlled by transporters and metallochaperones and Cu homeostasis is maintained by balancing Cu uptake and export. Genetic diseases are caused by impaired Cu transporters CTR1, ATP7A, or ATP7B but little is known about the regulatory mechanisms by which these proteins meet the fluctuating demands of Cu in specific tissues. Cu is required for differentiation of skeletal myoblasts to myotubes. Here, we demonstrate that ATP7A is needed for myotube formation and that its increased abundance during differentiation is mediated by stabilization of Atp7a mRNA via the 3′ untranslated region. Increased ATP7A levels during differentiation resulted in increased Cu delivery to lysyl oxidase, a secreted cuproenzyme that needed for myotube formation. These studies identify a previously unknown role for Cu in regulating muscle differentiation and have broad implications for understanding Cu-dependent differentiation in other tissues.
The complement system in IgAN: mechanistic context for therapeutic opportunities
Authors: Duval Anna , Caillard Sophie , Frémeaux-Bacchi Véronique
Published: June 2023

The complement system plays a crucial role in innate immunity, providing essential defense against pathogens. However, uncontrolled or prolonged activation of the complement cascade can significantly contribute to kidney damage, especially in cases of glomerulonephritis. Immunoglobulin A nephropathy (IgAN), the most prevalent form of primary glomerulonephritis, has growing evidence supporting the involvement of complement alternative and lectin pathways. In fact, patients with IgAN experience complement activation within their kidney tissue, which may be involved in the development of glomerular damage and the progression of IgAN. Complement activation has emerged as a significant area of interest in IgAN, with numerous complement-targeting agents currently being explored within this field. Nevertheless, the exact mechanisms of complement activation and their role in IgAN progression require comprehensive elucidation. This review seeks to contextualize the proposed mechanisms of complement activation within the various stages (“hits”) of IgAN pathogenesis, while also addressing the clinical implications and anticipated outcomes of complement inhibition in IgAN.
Relational continuity in community policing: Insights from a human-centred design perspective
Authors: Signori Roberta , Heinrich Dagmar P , Wootton Andrew B , Davey Caroline L
Published: June 2023

Community policing prioritises building positive relationships between police officers and local communities. The approach focuses on working with communities to identify and address the causes of crime and disorder, rather than just reacting to calls for service. Officer’s continuity in community policing has been a concern, with calls for greater consistency in the posting of officers to local neighbourhoods. Through the Cutting Crime Impact (CCI) project, Greater Manchester Police (GMP) identified that when community police officers leave their post, knowledge and relationships they've built with the community are lost. This jeopardises citizens' trust and perceptions of the police. To preserve the important connections that community policing officers build in their neighbourhoods, GMP adopted a human-centred design approach to research and develop a novel handover protocol. This work has enabled development of a conceptual framework for 'relational continuity' in community policing, inspired by research into therapeutic relationships in health care disciplines.
The vicious circle of policy advisory systems and knowledge regimes in consolidated authoritarian regimes
Authors: Bakir Caner
Published: June 2023

So far, interest in policy and political sciences has mostly centered around the varieties of policy advisory systems (PASs) and knowledge regimes in consolidated democracies rather than in consolidated autocracies, which largely remain as black boxes. Drawing on a hybrid literature review, this article aims to fill this gap. It reviews selected articles published between 1992 and February 2023 in the Thomson Reuters Web of Knowledge Social Science Citation Index database to not only to reveal the current state of empirical and theoretical knowledge and persistent knowledge gaps but also to offer an integration of the literature that leads to a preliminary conceptual framework in this emerging topic. In doing so, it contributes to the body of knowledge on this topic in three main ways. First, it provides a comprehensive review of PASs in consolidated autocracies to identify the central features of policy knowledge production within and across autocracies. Second, it proposes “the vicious circle of authoritarian PAS and knowledge regime” as a conceptual approach. In doing so, it takes a modest step toward a holistic conceptualization and synthesis of this literature to date. Third, it establishes connections between fragmented literature studies; identifies theoretical, conceptual, empirical, and methodological gaps; and proposes suggestions concerning promising paths for future research.
Can journal reviewers dependably assess rigour, significance, and originality in theoretical papers? Evidence from physics
Authors: Thelwall Mike , Hołyst Janusz A
Published: June 2023

Peer review is a key gatekeeper for academic journals, attempting to block inadequate submissions or correcting them to a publishable standard, as well as improving those that are already satisfactory. The three key aspects of research quality are rigour, significance, and originality but no prior study has assessed whether journal reviewers are ever able to judge these effectively. In response, this article compares reviewer scores for these aspects for theoretical articles in the SciPost Physics journal. It also compares them with Italian research assessment exercise physics reviewer agreement scores. SciPost Physics theoretical articles give a nearly ideal case: a theoretical aspect of a mature science, for which suitable reviewers might comprehend the entire paper. Nevertheless, intraclass correlations between the first two reviewers for the three core quality scores were similar and moderate, 0.36 (originality), 0.39 (significance), and 0.40 (rigour), so there is no aspect that different reviewers are consistent about. Differences tended to be small, with 86% of scores agreeing or differing by 1 on a 6-point scale. Individual reviewers were most likely to give similar scores for significance and originality (Spearman 0.63), and least likely to for originality and validity (Spearman 0.38). Whilst a lack of norm referencing is probably the biggest reason for differences between reviewers, others include differing background knowledge, understanding, and beliefs about valid assumptions. The moderate agreement between reviewers on the core aspects of scientific quality, including rigour, in a nearly ideal case is concerning for the security of the wider academic record.
Schizophrenia in Print, Digital, and Audiovisual Media: Trends, Topics, and Results From an Anti-Stigma Intervention Targeting Media Professionals
Authors: Holmberg Christopher
Published: June 2023

Background

Negative portrayals of schizophrenia in media can prompt the condition’s stigmatization. However, because research on language stigmatizing schizophrenia has focused on paper-based media, its results have limited generalizability to contemporary media. Also, research on interventions to guide media professionals in accurately depicting schizophrenia has been scarce. The present study had two aims: (1) to assess how print, web, and radio/TV news media in Sweden portray schizophrenia and (2) to evaluate a campaign targeting media professionals’ responses to information about schizophrenia and the consequences of stigmatizing language.

Study Design

Using data from Retriever’s database, considering media types and topics, the terms “schizophrenia” and “schizophrenic” were examined in the past 20 years, whereas analyses of stigmatizing reporting of these terms used media from the past 10 years. Media professionals’ responses and actions in the anti-stigma information campaign StigmaWatch were also evaluated.

Study Results

Between 2002 and 2022, “schizophrenia” was mentioned 34 141 times in the dataset and “schizophrenic” 10 058 times. However, no trends were statistically significant. All media topics and most types of media contained stigmatizing reporting. Of the 230 media professionals who received informative emails from StigmaWatch, 77 (33%) responded. Most responses were supportive, and 14% of the professionals reported taking corrective measures (eg, revising erroneous descriptions of schizophrenia) following the email.

Conclusions

No media topic was free of language stigmatizing schizophrenia. The anti-stigma information campaign seemed to have been effective, for most media professionals who responded were supportive, and a sizable proportion reported taking corrective measures.
Effects of supplemental zinc on growth, carcass characteristics, and liver abscess formation in steers with experimentally induced ruminal acidosis challenge
Authors: Lundy-Woolfolk Erika L , Genther-Schroeder Olivia N , Branine Mark , Hansen Stephanie L
Published: June 2023

The study’s aim was to evaluate the effect of dietary Zn supplementation on steer performance, biomarkers of inflammation and metabolism, and liver abscess formation in response to a mild acidosis challenge. Forty-two steers (417 ± 3.99 kg; n = 6/pen) were housed in pens with bunks designed to measure individual dry matter intake (DMI) and fed one of two diets containing either 0 (CON; n = 18) or 90 mg Zn/kg from a Zn-amino acid complex (Zn-AA; n = 18; AvailaZn; Zinpro) for 109 d. Six additional steers were fed the CON diet and did not undergo the acidosis challenge (NON; n = 6). The acidosis challenge included restricting steers to 50% of the previous 7 d daily DMI on days 46 and 47, steers were individually provided 10% of DMI as cracked corn (as-fed) at 0800 h followed by ad libitum feed access 2 h post-grain consumption. Steer was the experimental unit, and two contrasts were constructed: NON vs. CON and CON vs. Zn-AA. Blood samples were collected on days 40, 48, 53, 69, 80, and 108 and analyzed as repeated measures. Final body weight and overall average daily gain (2.29, 2.30, and 2.31 ± 0.920 kg/d for CON, Zn-AA, and NON, respectively) were not different (P ≥ 0.74) between treatments. By design, DMI was greater (P < 0.01) for NON compared to CON on day 46 but was not different (P ≥ 0.41) for the rest of the experiment. While hot carcass weight (423, 428, and 424 ± 7.9 kg for CON, Zn-AA, and NON, respectively) and ribeye area were not different (P ≥ 0.53) due to treatment, marbling score tended (P = 0.06) to be greater in CON compared to Zn-AA. The 12th rib backfat thickness was greater (P = 0.05) in NON vs. CON steers. Liver abscess incidence tended to be greater (P = 0.12) in CON (24% abscesses) vs. Zn-AA (6% abscesses). NON had a greater incidence (P = 0.05; 50% abscesses) compared to CON. Overall, blood fibrinogen and leukocyte counts were not different between treatments (P ≥ 0.67); however, neutrophil-to-lymphocyte ratio tended to be greater in NON vs. CON (P = 0.08). Serum aspartate aminotransferase and gamma-glutamyl transferase concentrations were greater in NON vs. CON (P ≤ 0.02), and serum alkaline phosphatase concentration was lesser in CON vs. Zn-AA (P < 0.01). Overall, dietary Zn supplementation tended to lessen incidence of liver abscesses with limited impacts on overall cattle performance. Shifts in liver enzymes may represent opportunities to identify cattle with liver abscesses earlier in the feeding period.
Targeting the Highly Conserved 3′ Untranslated Region of Iris Severe Mosaic Virus for Sensitive Monitoring of the Disease Prevalence in Iris Production
Authors: Grunwald Derrick J. , Stroschein Sydney M. , Grinstead Sam , Mollov Dimitre , Rioux Renée A. , Rakotondrafara Aurélie M.
Published: June 2023

Iris severe mosaic virus (ISMV, Potyviridae) can threaten the sustainability of iris production and the marketability of the plants. Effective intervention and control strategies require rapid and early detection of viral infections. The wide range of viral symptoms, from asymptomatic to severe chlorosis of the leaves, renders diagnosis solely based on visual indicators ineffective. A nested PCR-based diagnostic assay was developed for the reliable detection of ISMV in iris leaves and in rhizomes. Considering the genetic variability of ISMV, two primer pairs were designed to detect the highly conserved 3′ untranslated region (UTR) of the viral genomic RNA. The specificity of the primer pairs was confirmed against four other potyviruses. The sensitivity of detection was enhanced by one order of magnitude using diluted cDNA and a nested approach. Nested PCR facilitated detecting ISMV on field-grown samples beyond the capabilities of a currently available immunological test and in iris rhizome, which would facilitate ensuring clean stock is planted. This approach dramatically improves the detection threshold of ISMV on potentially low virus titer samples. The study provides a practical, accurate, and sensitive tool for the early detection of a deleterious virus that infects a popular ornamental and landscape plant.
Higher‐temperature‐adapted dengue virus serotype 2 strain exhibits enhanced virulence in AG129 mouse model
Authors: Modak Ayan , Mishra Srishti Rajkumar , Awasthi Mansi , Sreedevi Sreeja , Sobha Archana , Aravind Arya , Kuppusamy Krithiga , Sreekumar Easwaran
Published: June 2023

The factors that drive dengue virus (DENV) evolution, and selection of virulent variants are yet not clear. Higher environmental temperature shortens DENV extrinsic incubation period in mosquitoes, increases human transmission, and plays a critical role in outbreak dynamics. In the present study, we looked at the effect of temperature in altering the virus virulence. We found that DENV cultured at a higher temperature in C6/36 mosquito cells was significantly more virulent than the virus grown at a lower temperature. In a mouse model, the virulent strain induced enhanced viremia and aggressive disease with a short course, hemorrhage, severe vascular permeability, and death. Higher inflammatory cytokine response, thrombocytopenia, and severe histopathological changes in vital organs such as heart, liver, and kidney were hallmarks of the disease. Importantly, it required only a few passages for the virus to acquire a quasi‐species population harboring virulence‐imparting mutations. Whole genome comparison with a lower temperature passaged strain identified key genomic changes in the structural protein‐coding regions as well as in the 3′UTR of the viral genome. Our results point out that virulence‐enhancing genetic changes could occur in the dengue virus genome under enhanced growth temperature conditions in mosquito cells.
Epithelial multicellular clustering enabled by polarized macrophages on soft matrices
Authors: Zmuda Hannah , Pathak Amit
Published: June 2023

Formation of epithelial structures of variegated geometries and sizes is essential for organogenesis, tumor growth, and wound repair. Although epithelial cells are predisposed with potential for multicellular clustering, it remains unclear whether immune cells and mechanical cues from their microenvironment influence this process. To explore this possibility, we cocultured human mammary epithelial cells with prepolarized macrophages on soft or stiff hydrogels. In the presence of M1 (proinflammatory) macrophages on soft matrices, epithelial cells migrated faster and subsequently formed larger multicellular clusters compared to cocultures with M0 (unpolarized) or M2 (anti‐inflammatory) macrophages. By contrast, stiff matrices disabled active clustering of epithelial cells due to their enhanced migration and cell–ECM adhesion, regardless of macrophage polarization. We found that the copresence of soft matrices and M1 macrophages reduced focal adhesions, but enhanced fibronectin deposition and nonmuscle myosin‐IIA expression, which altogether optimize conditions for epithelial clustering. Upon ROCK inhibition, epithelial clustering was abrogated, indicating a requirement for optimized cellular forces. In these cocultures, TNF‐α secretion was the highest with M1 macrophages and TGF‐β secretion was exclusively detectable in case of M2 macrophages on soft gels, which indicated potential role of macrophage secreted factors in the observed epithelial clustering. Indeed, exogenous addition of TGF‐β promoted epithelial clustering with M1 coculture on soft gels. According to our findings, optimization of both mechanical and immune factors can tune epithelial clustering responses, which could have implications in tumor growth, fibrosis, and would healing.
Hepatic Krüppel‐like factor 14 regulates lipid metabolism in nonalcoholic steatohepatitis mice
Authors: Chen Xiaoyan , Shi Wenjie , Xie Yong , Wang Yunwu , Yao Qian , Ke Huajing , Xu Xuan , Liu Hui , Liu Pi , Zhou Xiaojiang
Published: June 2023

Excessive lipid accumulation is a critical characteristic in the development of nonalcoholic steatohepatitis (NASH). The underlying molecular mechanism, however, is unclear. In this study, we explored whether and how Krüppel‐like factor 14 (KLF14) affects hepatic lipid metabolism in NASH. KLF14 expression was detected in NASH patients and mice fed a choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD). Adeno‐associated viruses and adenoviruses were used to alter hepatic KLF14 expression in vivo or in vitro to investigate how KLF14 functions in lipid regulation. The molecular mechanisms were explored using RNA‐seq, luciferase reporter, and ChIP assays. The fatty liver phenotype was analyzed histopathologically, and serum and hepatocyte biochemical parameters were measured. The NASH mouse model developed quickly in C57BL/6J mice fed a CDAHFD for 8 weeks. We found that KLF14 expression was decreased in NASH patients and CDAHFD mice. Oleic acid and palmitic acid treatment also reduced KLF14 levels in hepatocytes. KLF14 knockdown downregulated the genes involved in fatty acid oxidation, promoting the progression of hepatic steatosis. In contrast, hepatic KLF14 overexpression alleviated lipid accumulation and oxidative stress in CDAHFD mice. These effects resulted from direct activation of the PPARα signaling pathway. PPARα inhibition diminished the KLF14 overexpression‐reduced protective effects against steatosis in OA&PA‐treated MPHs and AAV‐KLF14‐infected CDAHFD mice. These data reveal that hepatic KLF14 regulates lipid accumulation and oxidative stress through the KLF14‐PPARα pathway as NASH progresses. KLF14 may be a novel therapeutic target for hepatic steatosis.