bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of the Concept ‘Avoidable Mortality’ in Assessing the Socioeconomic Status related Inequalities in Health: A Scoping Review
Authors: Marouzi Anousheh , Plante Charles , Neudorf Cory
Published: September 2023

Introduction

Avoidable mortality is widely used by public health researchers to measure population health, and many related methodologies have been proposed for doing so. This scoping review presents a comprehensive view of global peer-reviewed and grey literature exploring the association between socioeconomic status (SES) and avoidable mortality.

Methods

We searched Ovid Medline, Scopus, and Web of Science to find articles that investigated SES inequalities in avoidable mortality. We limited our review to articles in English published between 2000 and 2020. For grey literature, we searched leading global and Canadian health information websites. We extracted data on different study characteristics, avoidable mortality definition, SES indicator, method of analysis of the association between avoidable mortality and SES, and main findings of the studies.

Results

We identified 34 articles to review, including 29 scientific papers and 5 grey literature documents. The findings of the selected articles consistently indicate a negative association between SES and avoidable mortality rates. Studies have not all used the same definitions of avoidable mortality or SES nor operationalized them in the same way.

Conclusion

Our review highlights the absence of a globally standard definition in avoidable mortality health equity research. Additional work to establish a standardized definition is crucial for supporting global comparability.
Universal digital high resolution melt analysis for the diagnosis of bacteremia
Authors: Aralar April , Goshia Tyler , Ramchandar Nanda , Lawrence Shelley M. , Karmakar Aparajita , Sharma Ankit , Sinha Mridu , Pride David T. , Kuo Peiting , Lecrone Khrissa , Chiu Megan , Mestan Karen , Sajti Eniko , Vanderpool Michelle , Lazar Sarah , Crabtree Melanie , Tesfai Yordanos , Fraley Stephanie I.
Published: September 2023

Fast and accurate diagnosis of bloodstream infection is necessary to inform treatment decisions for septic patients, who face hourly increases in mortality risk. Blood culture remains the gold standard test but typically requires ∼15 hours to detect the presence of a pathogen. Here, we assess the potential for universal digital high-resolution melt (U-dHRM) analysis to accomplish faster broad-based bacterial detection, load quantification, and species-level identification directly from whole blood. Analytical validation studies demonstrated strong agreement between U-dHRM load measurement and quantitative blood culture, indicating that U-dHRM detection is highly specific to intact organisms. In a pilot clinical study of 21 whole blood samples from pediatric patients undergoing simultaneous blood culture testing, U-dHRM achieved 100% concordance when compared with blood culture and 90.5% concordance when compared with clinical adjudication. Moreover, U-dHRM identified the causative pathogen to the species level in all cases where the organism was represented in the melt curve database. These results were achieved with a 1 mL sample input and sample-to-answer time of 6 hrs. Overall, this pilot study suggests that U-dHRM may be a promising method to address the challenges of quickly and accurately diagnosing a bloodstream infection.

Universal digital high resolution melt analysis for the diagnosis of bacteremia

April Aralar, Tyler Goshia, Nanda Ramchandar, Shelley M. Lawrence, Aparajita Karmakar, Ankit Sharma, Mridu Sinha, David Pride, Peiting Kuo, Khrissa Lecrone, Megan Chiu, Karen Mestan, Eniko Sajti, Michelle Vanderpool, Sarah Lazar, Melanie Crabtree, Yordanos Tesfai, Stephanie I. Fraley
An imputed ancestral reference genome for theMycobacterium tuberculosiscomplex better captures structural genomic diversity for reference-based alignment workflows
Authors: Harrison Luke B , Kapur Vivek , Behr Marcel A
Published: September 2023

Reference-based alignment of short-reads is a widely used technique in genomic analysis of theMycobacterium tuberculosiscomplex (MTBC) and the choice of reference sequence impacts the interpretation of analyses. The most widely used reference genomes include the ATCC type strain (H37Rv) and the putative MTBC ancestral sequence of Comaset al. both of which are based on a lineage 4 sequence. As such, these referents do not capture the complete structural variation now known to be present in the MTBC. To better represent the base of the MTBC, we generated an imputed ancestral genomic sequence, termed MTBC0from reference-free alignments of closed MTBC genomes. When used as a reference sequence in alignment workflows, MTBC0mapped more short sequencing reads and called more SNPs relative to the Comas et al. sequence while exhibiting minimal impact on the overall phylogeny of MTBC. The results also show that MTBC0provides greater fidelity in capturing genomic variation and allows for the inclusion of regions absent in H37Rv such as the TbD1 and RvD4496/RD7/RD713 regions in standard MTBC workflows without additional steps. The use of MTBC0as an ancestral reference sequence into a standard workflows modestly improved read mapping, SNP calling and intuitively facilitates the study of structural variation and evolution in MTBC.

Data Summary

The MTBC0sequence, is available in the online data supplement in FASTA format athttps://github.com/lukebharrison/MTBC0. Included with the MTBC0sequence in the data supplement are: the reference-free alignment of MTBC closed genomes in hierarchical alignment (HAL) format, control files for cactus, annotations for H37Rv and L8, a BED file of regions excluded from SNP calls lifted over onto MTBC0, as well as the scripts used to call SNPs and the phylogenetic trees generated in this article. All previously published sequence data is available at the NCBI nucleotide and SRA databases, accession number for sequences used in this manuscript are available in Supplementary Tables 1 and 2.

Impact Statement

This article describes an imputed ancestral genomic sequence (MTBC0) at the base of the MTBC for use as a reference sequence forMycobacterium tuberculosisgenomic workflows. Widely used reference sequences are limited to the structural diversity present in H37Rv, a lineage 4 isolate. MTBC0obviates this limitation by incorporating the structural variation present at the base of theMycobacterium tuberculosiscomplex (MTBC) by encompassing a wide sample of human and animal lineages including newly discovered lineages (L8,M. orygis). Use of MTBC0enables the mapping of more reads and calling of more SNPs and allows for the investigation of structural variation not present in the current used reference sequences within this important group of animal and human pathogens.
Human Brain Dynamics Dissociate Early Perceptual and Late Motor-Related Stages of Affordance Processing
Authors: Wang Sheng , Djebbara Zakaria , de Oliveira Guilherme Sanches , Gramann Klaus
Published: September 2023

Affordances, the opportunity for action offered by the environment to an agent, are vital for meaningful behavior and exist in every interaction with the environment. There is an ongoing debate in the field about whether the perception of affordances is an automated process. Some studies suggest that affordance perception is an automated process that is independent from the visual context and bodily interaction with the environment, while others argue that it is modulated by the visual and motor context in which affordances are perceived. The present paper aims to resolve this debate by examining affordance automaticity from the perspective of sensorimotor time windows. We replicated a previous study on affordance perception in which participants actively moved through doors of different width in immersive 3D virtual environments. To investigate the impact of different forms of bodily interactions with an environment, i.e., the movement context (physical vs. joystick movement), we used the identical virtual environment from Djebbara and colleagues (2019) but displayed it on a 2D screen with participants moving through different wide doors using the keys on a standard keyboard. We compared components of the event-related potential (ERP) from the continuously recorded electroencephalogram (EEG) that were previously reported to be related to affordance perception of architectural transitions (passable and impassable doors). Comparing early sensory and later motor-related ERPs, our study replicated ERPs reflecting early affordance perception but found differences in later motor-related components. These results indicate a shift from automated perception of affordances during early sensorimotor time windows to movement context dependence of affordance perception at later stages suggesting that affordance perception is a dynamic and flexible process that changes over sensorimotor stages.
Single Cell RNA-Seq Analysis of Regenerative Drug-Treated Human Pancreatic Islets Identifies A Cycling Alpha Cell Population As Key Beta Cell Progenitors
Authors: Karakose Esra , Wang Xuedi , Wang Peng , Carcamo Saul , Demircioglu Deniz , Lambertini Luca , Wood Olivia , Kang Randy , Lu Geming , Scott Donald K. , Garcia-Ocaña Adolfo , Argmann Carmen , Sebra Robert , Hasson Dan , Stewart Andrew F.
Published: September 2023

Diabetes ultimately results from an inadequate number of functional, insulin-producing human beta cells. Although current attempts to replenish the remaining beta cell pool in people with diabetes are encouraging, scalability and cost limit access for the millions of people with diabetes. The small molecule DYRK1A inhibitor class of beta cell regenerative drugs, either alone or in combination with GLP1 receptor agonists or TGFβ superfamily inhibitors, are capable of inducing beta cell replicationin vitroand increasing beta cell massin vivo. Despite these advances, the precise mechanisms of action of DYRK1A inhibitors remain incompletely understood. To address the mechanisms more deeply, we performed single cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone, or in combination with a GLP1 receptor agonist or a TGFβ superfamily inhibitor. We identify a cluster of Cycling Alpha Cells as the cells most responsive to DYRK1A inhibition. Velocity and pseudotime lineage trajectory analyses suggest that Cycling Alpha Cells serve as the primary target cell type for of DYRK1A inhibitors, and may serve as precursor cells that transdifferentiate into functional human beta cells in response to the DYRK1A inhibition. In addition to providing a novel mechanism of action for DYRK1A inhibitors, our findings suggest that efforts to target regenerative drugs to human beta cells may be mis-directed: the proper target may be Cycling Alpha Cells.
The anti-SARS-CoV-2 BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation and expression of embryo-fetal globin genes in human erythroleukemia K562 cells
Authors: Zurlo Matteo , Gasparello Jessica , Verona Marco , Papi Chiara , Cosenza Lucia Carmela , Finotti Alessia , Marzaro Giovanni , Gambari Roberto
Published: September 2023

The COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) the ongoing coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 Spike protein (S-protein) plays an important role in the early phase of SARS-CoV2 infection through efficient interaction with ACE2. The S-protein is produced by RNA-based COVID-19 vaccines, and has been hypothesized to be responsible for damaging cells of several tissues and for some important side effects of RNA-based COVID-19 vaccines. The aim of this study was to verify the effect of the BNT162b2 vaccine on erythroid differentiation of the human K562 cell line, that has been in the past intensively studied as a model system mimicking some steps of erythropoiesis. We found that the BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation of K562 cells. Reverse-transcription-PCR and Western blotting assays demonstrated that suppression of erythroid differentiation was associated with sharp inhibition of the expression of α-globin and γ-globin mRNA accumulation. Inhibition of accumulation of ζ-globin and ε-globin mRNAs was also observed. In addition, we provide in silico studies suggesting a direct interaction between SARS-CoV-2 Spike protein and Hb Portland, that is the major hemoglobin produced by K562 cells. This study thus provides information suggesting the need of great attention on possible alteration of hematopoietic parameters following SARS-CoV-2 infection and/or COVID-19 vaccination.
Loop extrusion by cohesin plays a key role in enhancer-activated gene expression during differentiation
Authors: Stolper Rosa J. , Tsang Felice H. , Georgiades Emily , Hansen Lars L.P. , Downes Damien J. , Harrold Caroline L. , Hughes Jim R. , Beagrie Robert A. , Davies Benjamin , Kassouf Mira T. , Higgs Douglas R.
Published: September 2023

Enhancers and their target promoters often come into close physical proximity when activated. This proximity may be explained by a variety of mechanisms; most recently via cohesin-mediated chromatin loop extrusion. Despite this compelling hypothesis, acute depletion of cohesin does not cause widespread changes in gene expression. We have tested the role of cohesin-mediated loop extrusion on gene expression at the mouse alpha-globin locus during erythropoiesis. Acute depletion of cohesin downregulates alpha-globin expression at early but not late stages of differentiation. When single or multiple CTCF sites are placed between the alpha-globin enhancers and promoters, alpha-gene expression is downregulated. Importantly, the orientation of the CTCF site plays a critical role, suggesting that within this activated domain, cohesin predominantly but not exclusively translocates from the enhancers to the promoters. We find that loop extrusion does play an important role in establishing enhancer-promoter proximity and consequent expression of inducible genes during differentiation.
Ecophysiological and genomic approaches to cyanobacterial hardening for soil restoration
Authors: Beatriz Roncero-Ramos , Valentina Savaglia , Benoit Durieu , Isabelle Van de Vreken , Aurore Richel , Annick Wilmotte
Published: September 2023

Cyanobacteria inhabit extreme environments, including drylands, providing multiple benefits to the ecosystem. Soil degradation in warm drylands is increasing due to land-use intensification. Restoration methods adapted to the strong stress in drylands are being developed, i.e. cyanobacterial inoculation to recover biocrusts. For success, it is crucial to optimize the survival of inoculated cyanobacterial in field. One strategy is to harden them to be re-adapted to stressful conditions after laboratory culturing. Here, we analyzed the genome and ecophysiological response to osmotic, desiccation and UVR stresses of an Antarctic cyanobacterium,Stenomitos frigidusULC029, closely related to other cyanobacteria from warm and cold dryland soils. Chlorophyllaconcentrations show that preculturing ULC029 under moderate osmotic stress improved its survival during an assay of desiccation plus rehydration under UVR. Besides, its sequential exposition to these stress factors increased the production of exopolysaccharides, carotenoids and scytonemin. Desiccation, but not osmotic stress, increased the concentrations of the osmoprotectants, trehalose and sucrose. However, osmotic stress might induce the production of other osmoprotectants, for which the complete pathways were found in the ULC029 genome. In total, 140 genes known to be involved in stress resistance were annotated and could potentially help ULC029 under stress. Here, we confirm that the sequential application of moderate osmotic stress and dehydration, could improve cyanobacterial hardening for soil restoration, by inducing several resistance mechanisms. We provide a high-quality genome of ULC029 and a description of the main resistance mechanisms found (i.e. production of exopolysaccharides, osmoprotectants, chlorophyll and carotenoids; DNA repair; oxidative stress protection).
Tardigrades dramatically upregulate DNA repair pathway genes in response to ionizing radiation
Authors: Clark-Hachtel Courtney M. , Hibshman Jonathan D. , Buysscher Tristan De , Goldstein Bob
Published: September 2023

Tardigrades can survive remarkable doses of ionizing radiation, up to about 1000 times the lethal dose for humans. How they do so is incompletely understood. We found that the tardigradeHypsibius exemplarissuffers DNA damage upon gamma irradiation, but damage is repaired. We show that tardigrades have a specific and robust response to ionizing radiation: irradiation induces a rapid, dramatic upregulation of many DNA repair genes. By expressing tardigrade genes in bacteria, we validate that increased expression of some repair genes can suffice to increase radiation tolerance. We show that at least one such gene is necessary for tardigrade radiation tolerance. Tardigrades’ ability to sense ionizing radiation and massively upregulate specific DNA repair pathway genes may represent an evolved solution for maintaining DNA integrity.

One-Sentence Summary

Tardigrades exposed to ionizing radiation survive DNA damage by massively upregulating DNA repair pathway genes.
Alfalfa vein mottling virus, a novel potyvirid infectingMedicago sativaL
Authors: Nemchinov Lev G. , Postnikova Olga A. , Wintermantel William M. , Palumbo John C. , Grinstead Sam
Published: September 2023

We have recently identified a novel virus detected in alfalfa seed material. The virus was tentatively named alfalfa-associated potyvirus 1, as its genomic fragments bore similarities with potyvirids. In this study, we obtained a complete genome sequence of the virus and classified it as a tentative species in the new genus, most closely related to the members of the genusIpomovirusin the familyPotyviridae. This assumption is based on the genome structure, phylogenetic relationships, transmission electron microscopy investigations and, in part, on serological cross-reactivity of the virus. We also demonstrated its mechanical transmission to the indicator plantNicotiana benthamianaand to the natural hostMedicago sativa, both of which developed characteristic symptoms therefore suggesting a pathogenic nature of the disease. Consistent with symptomatology, the virus was renamed to alfalfa vein mottling virus. A name Alvemovirus was proposed for the new genus in the familyPotyviridae, of which alfalfa vein mottling virus is a tentative member.
Heat Tolerance is Affected by the Gut Microbiota in a Vertebrate Ectotherm
Authors: Dallas Jason W. , Kazarina Anna , Lee Sonny T. M. , Warne Robin W.
Published: September 2023

The gut microbiota is known to influence and have regulatory effects in diverse physiological functions of host animals, but only recently has the relationship between host thermal biology and gut microbiota been explored. Here, we examined how early-life manipulations of the gut microbiota in larval amphibians influenced their critical thermal maximum (CTmax) at different acclimation temperatures. We removed the resident microbiome on the outside of wild-caught wood frog (Lithobates sylvaticus) egg masses via an antibiotic wash, and then either maintained eggs without a microbiota or inoculated eggs with pond water or the intestinal microbiota of another species, green frogs (L. clamitans), that have a wider thermal tolerance. We predicted that this cross-species transplant would improve the CTmaxof the recipient wood frog larvae relative to the other treatments. In line with this prediction, green frog-recipient larvae had the highest CTmaxwhile those with no inoculum had the lowest CTmax. Both the microbiome treatment and acclimation temperature significantly influenced the larval gut microbiota communities and alpha diversity indices. Green frog inoculated larvae were enriched in Rikenellaceae relative to the other treatments, which produce short-chain fatty acids and could contribute to greater energy availability and enhanced heat tolerance. Larvae that received no inoculation had higher relative abundances of potentially pathogenicAeromonasspp., which negatively affects host health and performance. Our results are the first to show that cross-species gut microbiota transplants alter heat tolerance in a predictive manner. This finding has repercussions for the conservation of species that are threatened by climate change and demonstrates a need to further explore the mechanisms by which the gut microbiota modulates host thermal tolerance.
Interferon induced circRNAs escape herpesvirus host shutoff and suppress lytic infection
Authors: Dremel Sarah E. , Tagawa Takanobu , Koparde Vishal N. , Arbuckle Jesse H. , Kristie Thomas M. , Krug Laurie T. , Ziegelbauer Joseph M.
Published: September 2023

A first line of defense during infection is expression of interferon (IFN)-stimulated gene products which suppress viral lytic infection. To combat this, herpesviruses express endoribonucleases to deplete host RNAs. Here we demonstrate that IFN-induced circular RNAs (circRNAs) can escape viral-mediated degradation. We performed comparative circRNA expression profiling for representative alpha- (Herpes simplex virus-1, HSV-1), beta- (human cytomegalovirus, HCMV), and gamma-herpesviruses (Kaposi sarcoma herpesvirus, KSHV; murine gamma-herpesvirus 68, MHV68). Strikingly, we found that circRNAs are, as a population, resistant to host shutoff. This observation was confirmed by ectopic expression assays of human and murine herpesvirus endoribonucleases. During primary lytic infection, ten circRNAs were commonly regulated across all subfamilies of human herpesviruses, suggesting a common mechanism of regulation. We tested one such mechanism, namely how interferon-stimulation influences circRNA expression. 67 circRNAs were upregulated by either IFN-β or -γ treatment, with half of these also upregulated during lytic infection. Using gain and loss of function studies we found an interferon-stimulated circRNA, circRELL1, inhibited lytic HSV-1 infection. We have previously reported circRELL1 inhibits lytic KSHV infection, suggesting a pan-herpesvirus antiviral activity. We propose a two-pronged model in which interferon-stimulated genes may encode both mRNA and circRNA with antiviral activity. This is critical in cases of host shutoff, such as alpha- and gamma-herpesvirus infection, where the mRNA products are degraded but circRNAs escape.
One-shot entorhinal maps enable flexible navigation in novel environments
Authors: Wen John H. , Sorscher Ben , Ganguli Surya , Giocomo Lisa M
Published: September 2023

Animals face the substantial challenge of navigating novel environments to find food, shelter, or mates. In mammals, hexagonal grid cells in the medial entorhinal cortex create a map-like population representation of the external environment1–7. However, it remains unclear how the grid map can adapt to novel environmental features on a rapid, behaviorally relevant time scale. By recording over fifteen thousand grid cells in mice navigating virtual environments, we found grid cell activity was weakly anchored to landmark inputs through afixedcircuit relationship. A computational model based on this fixed circuit assumption accurately predicted grid spatial patterns in environments with novel landmark rearrangements. Finally, a medial entorhinal cortex-dependent task revealed that while grid cell firing patterns remain anchored to landmarks, behavior can adapt to changes in landmark location via a downstream region implementing behavioral time scale synaptic plasticity8. This fixed but weak anchoring of grid cells to landmarks endows the grid map with powerful computational properties. The fixed nature allows the generation of rapid stable maps for novel environments after asingleexposure. The weak nature allows these rapidly formed maps to incur only small distortions between distances traveled in real versus neural space. Overall, such rapid low distortion mapping can then mediate accurate navigational behavior in rapidly changing environments through downstream plasticity.
KSHV Terminal Repeat Regulates Inducible Lytic Gene Promoters
Authors: Izumiya Yoshihiro , Algalil Adhraa , Espera Jonna M. , Miura Hiroki , Inagaki Tomoki , Izumiya Chie , Kumar Ashish
Published: September 2023

The Kaposi’s sarcoma-associated herpesvirus (KSHV) genome consists of an approximately 140 kb unique coding region flanked by multiple copies of 0.8 kb terminal repeat (TR) sequence. While TR’s function in plasmid maintenance is well-established, TR’s transcription regulatory roles have not been fully explored. Here, we show KSHV TR is a large transcription regulatory domain.

A series of Cleavage Under Targets & Release Using Nuclease demonstrated that TR fragments are occupied by histone modifying enzymes that are known to interact with LANA in naturally infected cells, and the TR possessed characteristic enhancer histone modifications. The H3K4me3 and H3K27Ac modifications were conserved in unique region of the KSHV genome among naturally infected cells, and the KSHV Origin of lytic replication (Ori-Lyt) showed similar protein and histone modification occupancies with TR’s. In the Ori-Lyt region, the LANA complex colocalizes with H3K27Ac-modified nucleosome along with paused RNA polymerase II, and two K-Rta recruitment sites frank the nucleosome. The isolated reporter assays demonstrated that neighboring TR fragments enhanced viral lytic gene promoter activity independent of orientation in KSHV-infected and non-infected 293FT cells. K-Rta transactivation function was drastically enhanced with TR, while LANA acquired promoter repression function with TR. KSHV TR is, therefore a regulatory domain for KSHV inducible genes. However, in contrast to cellular enhancers that are bound by multiple transcription factors, perhaps the KSHV enhancer is predominantly regulated by the LANA nuclear body with TR. KSHV evolved a clever mechanism to tightly control the latency-lytic switch with the TR/LANA complex.

Importance

Enhancers are a crucial regulator of differential gene expression programs. Enhancer is the cis-regulatory sequences that determine target genes’ spatiotemporal and quantitative expression. Here, we show that KSHV terminal repeats fulfill the enhancer definition for KSHV inducible gene promoters. KSHV enhancer is occupied by LANA and its interacting proteins, such as CHD4, and CHD4 is known to restrict enhancers to access promoters for activation. This study thus proposes a new latency-lytic switch model in which TR accessibility to the KSHV gene promoters regulates lytic gene transcription.
Children exhibit a developmental advantage in the offline processing of a learned motor sequence
Authors: Van Roy Anke , Albouy Geneviève , Burns Ryan D. , King Bradley R.
Published: September 2023

Research that examines changes in a specific behavior across the lifespan frequently reports an inverted-U trajectory. That is, young adults exhibit optimal performance, children are conceptualized as developing systems progressing towards this ideal state, and older adulthood is characterized by performance decrements. However, not all behaviors follow this trajectory, as there are instances in which children outperform young adults. This study aimed to reveal instances of childhood advantage in the domain of motor learning and memory consolidation. Using a visually cued serial reaction time task, data were acquired from 7-35 and >55-year-old participants (n=238 datasets) across two experiments that assessed initial encoding as well as memory consolidation over 5-hour and 24-hour offline periods. Results revealed comparable initial learning dynamics among age groups, but 7- to 12-year-old children exhibited smaller sequence-specific learning relative to adolescents (13-17 year-olds), young adults (18-35 year-olds) and older adults (> 55 years). Interestingly, children demonstrated the greatest performance gains in the 5-hour and 24-hour delayed retests, reflecting enhanced motor memory consolidation. These results suggest that children exhibit an advantage in the offline processing of recently learned motor sequences.
Long-read RNA sequencing redefines the clear cell renal cell carcinoma transcriptome and reveals novel genes and transcripts associated with disease recurrence and immune evasion
Authors: Lee Joshua , Snell Elizabeth A. , Brown Joanne , Banks Rosamonde E. , Turner Daniel J. , Vasudev Naveen S. , Lagos Dimitris
Published: September 2023

Background

Long-read direct RNA sequencing (DRS) and PCR cDNA sequencing (PCS) of tumour samples could lead to discovery of novel transcript isoforms, novel genes, and transcriptomic co-dependencies missed by conventional short-read sequencing. However, only a handful of reports using DRS or PCS in cancer exist with no direct comparison between the two methods. Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Following primary tumour resection approximately 30% of patients experience disease recurrence. Long-read RNA sequencing has not been applied to kidney cancer.

Methods

12 primary ccRCC archival tumours (discovery cohort), 6 from patients who went on to relapse, were analysed by Oxford Nanopore DRS and PCS. Results were validated in an independent cohort of 20 patients and compared to DRS analysis of RCC4 cells.

Results

DRS and PCS were successfully performed achieving high read length, with PCS achieving higher sequencing depth. Differentially expressed gene sets in patients who went on to relapse were determined with good overlap between DRS and PCS. Deconvolution analysis showed a loss of immune infiltrate in primary tumours of patients who relapse and revealed the CD8+T cell exhaustion markerTOXas a novel recurrence-associated gene. Notably, novel transcript analysis revealed more than 10,000 uncharacterised candidate novel transcripts detected by both methods and in a ccRCC cell linein vitro. This allowed the definition of the full exonic structure of ccRCC-associated splice variants, including variants ofMVKandHPCAL1. Remarkably, this also revealed a novel sPD-L1transcript encoding for the soluble version of the protein with a longer 3’UTR and lower stability in ccRCC cells than the annotated transcript. Levels ofsPD-L1transcripts are unchanged in primary tumours that go on to relapse, whereas membranePD-L1shows a trend towards down-regulation. Finally, both methods identified 414 novel genes, also detected in ccRCC cellsin vitro, including a novel non-coding gene over-expressed in patients who relapse.

Conclusions

PCS and DRS can be used in tumour samples to uncover substantial yet unmapped features underpinning the plasticity and instability of cancer transcriptomes which are linked to disease progression and immune evasion.
Endogenous oncogenic KRAS expression increases cell proliferation and motility in near-diploid hTERT RPE-1 cells
Authors: Hindul Naushin L. , Abbott Lauren R. , Adan Sumaya M.D. , Straatman Kornelis R. , Fry Andrew M. , Hirota Kouji , Tanaka Kayoko
Published: September 2023

About 18% of all human cancers carry a mutation in theKRASgene making it among the most sought-after anti-cancer targets. However, mutant KRas protein has proved remarkably undruggable. The recent approval of the first generation of RAS inhibitors therefore marks a seminal milestone in the history of cancer research. Inevitably though, it also raises the predictable challenges of limited drug efficacies and acquired resistance. Hence, new approaches that improve our understanding of the tumorigenic mechanisms of oncogenic RAS within more physiological settings continue to be essential. Here, we have employed the near-diploid human hTERT RPE-1 cells to generate isogenic cell lines in which one of the endogenousKRASalleles carries an oncogenicKRASmutation at glycine 12. Cells with aKRASG12V/+,KRASG12C/+, orKRASG12D/+genotype, together with wild-typeKRASG12G(WT)/+cells, reveal that oncogenicKRAS.G12Xmutations increase cell proliferation rate, while further analyses showed thatKRASG12V/+cells had increased cell motility and reduced focal adhesions. EGF-induced ERK phosphorylation was marginally increased inKRASG12V/+cells, while EGF-induced AKT phosphorylation was comparable betweenKRASG12V/+andKRASG12G(WT)/+cells. Interestingly, theKRASG12V/+cells were more sensitive to hydroxyurea and a MEK inhibitor, U0126, but more resistant to a PI3K inhibitor, PIK-90, than theKRASG12G(WT)/+cells. A combination of low doses of hydroxyurea and U0126 showed an additive inhibition on growth rate that was greater inKRASG12V/+than wild-type cells. Collectively, these cell lines will be a valuable resource for studying oncogenic RAS signalling and developing effective anti-KRAS reagents with minimum cytotoxicity on wild-type cells.
Time-of-flight spin-echo small-angle neutron scattering applied to biological cell nuclei
Authors: Iashina Ekaterina G. , Bouwman Wim G. , Duif Chris P. , Dalgliesh Robert , Varfolomeeva Elena Y. , Pantina Rimma A. , Kovalev Roman A. , Fedorova Natalia D. , Grigoriev Sergey V.
Published: September 2023

The organization of chromatin in the nuclei of rat lymphocyte was studied by time-of-flight spin-echo small-angle neutron scattering (ToF-SESANS). The procedures of the measurements in ToF and monochromatic SESANS modes were compared. It is shown that the sensitivity of the ToF method is significantly higher than that of the monochromatic mode. As a result, the SESANS correlation function can always be extracted from the ToF measurement of polarization, while this is not always the case with the monochromatic mode. The applicability of SESANS to fractal objects at the micrometre scale is demonstrated. The SESANS correlation function is well fitted by the exponential decay G(z) = exp(−z/ξ) with the correlation length ξ = 3.7 ± 0.1 µm. The exponential decay of the SESANS correlation function can be connected to the logarithmic correlation function γ(r) = ln(r/ξ) and the cubic law of the scattering intensity I(Q) = Q
−3, which is in agreement with the concept of scattering from fractal objects. This finding is interpreted as evidence of a very specific logarithmic fractal structure of the large-scale organization of chromatin. The model of the logarithmic fractal is visualized as a hierarchical object obeying the volume-conservation principle at different scales.
Synthesis, crystal structure and thermal behavior of tetrakis(3-cyanopyridine N-oxide-κO)bis(thiocyanato-κN)cobalt(II), which shows strong pseudosymmetry
Authors: Näther Christian , Jess Inke
Published: September 2023

The title compound, [Co(SCN)2(C6H4N2O)4], was prepared by the reaction of cobalt(II)thiocyanate with 3-cyanopyridine N-oxide in ethanol. In the crystal, the cobalt(II) cations are octahedrally coordinated by two terminal N-bonded thiocyanate anions and four O-bonded 3-cyanopyridine N-oxide coligands, forming discrete complexes that are located on centers of inversion, hence forming trans-CoN2O4 octahedra. The structure refinement was performed in the monoclinic space group P21/n, for which a potential lattice translation and new symmetry elements with a fit of 100% is suggested. The structure can easily be refined in the space group I2/m, where the complexes have 2/m symmetry. However, nearly all of the reflections that violate the centering are observed with significant intensity and the refinement in P21/n leads to significantly lower R(F) values (0.027 versus 0.033). Moreover, in I2/m much larger components of the anisotropic displacement parameters are observed and therefore, the crystal structure is presented in the primitive unit cell. IR investigations confirm that the anionic ligands are only terminally bonded and that the cyano group is not involved in the metal coordination. PXRD investigations show that a pure crystalline phase has been obtained and measurements using simultaneously thermogravimetry and differential thermoanalysis reveal that the compound decomposes in an exothermic reaction upon heating, without the formation of a coligand-deficient intermediate phase.
Poly[[μ-1,3-bis(pyridin-3-yl)urea]bis(μ4-succinato)dicopper(II)], a ribbon-like coordination polymer
Authors: Ezenyilimba Frederick , LaDuca Robert L.
Published: September 2023

In the title compound, [Cu2(C4H4O4)2(C11H10N4O)]
n
, mono-periodic coordination polymer ribbons are held into the crystal structure by means of N—H...O hydrogen bonding and crystal packing forces.
Poly[[(μ3-adamantane-1,3-dicarboxylato)aqua[μ-N-(pyridin-3-yl)isonicotinamide]nickel(II)] monohydrate], a layered coordination polymer with (4,4) topology
Authors: Travis Jamelah Z. , LaDuca Robert L.
Published: September 2023

The title compound, {[Ni(C12H14O4)(C11H9N3O)(H2O)]·H2O}
n
, contains octahedrally coordinated NiII ions ligated by adamantane-1,3-dicarboxylate (adc) and N-(pyridin-3-yl)isonicotinamide (3-pina) ligands forming coordination polymer layers with a (4,4) grid topology. These diperiodic layer motifs aggregate in an AAA pattern mediated by supramolecular C—H...O interactions to form the full triperiodic crystal structure of the title compound.
Modeling trade openness–unemployment nexus in sub-Saharan Africa: the role of asymmetries
Authors: Abdul-Mumuni Abdallah , Amakye Kwaku , Abukari Abdul-Lateef , Insaidoo Michael
Published: September 2023

Purpose

While several existing panel studies have focused on the linear specifications of the nexus between trade openness and unemployment, nonlinear panel studies on this subject remain less explored. This paper examines the asymmetric nexus between trade openness and unemployment in 34 selected sub-Saharan Africa (SSA) countries for the period spanning from 1991 to 2020.

Design/methodology/approach

The Pedroni and Westerlund panel cointegration tests were conducted to ascertain a long run relationship among the studied variables, while the panel nonlinear autoregressive distributed lag approach was applied to account for asymmetries.

Findings

The study revealed among other things that trade openness asymmetrically influences unemployment in the selected panel of SSA countries. In the long run, the positive shock in trade openness on unemployment is greater as compared to the negative shock.

Research limitations/implications

The implications of this study include the need to (1) ensure the effective monitoring and supervision of trade flows in the sub-region so that their full benefits are maximized in terms of job creation and (2) ensure that a positive trade balance is maintained in the selected SSA countries.

Originality/value

The positive and negative shocks in trade openness are examined to determine their asymmetric effects on unemployment.
Enhancing the employee experience: exploring a global positive climate to influence key employee outcomes
Authors: McCallum Sarah , Haar Jarrod , Myers Barbara
Published: September 2023

Purpose

Organizational climates reflect employee perceptions of the way organizational culture is actualized and most studies explore one or two climates only. The present study uses a positive organizational behavior approach and conservation of resources theory to explore a global positive climate (GPC) encompassing five climates: perceive organizational support, psychosocial safety climate, organizational mindfulness, worthy work and inclusion climate. The GPC is used to predict employee engagement and job satisfaction, with psychological capital as a mediator. Beyond this, high performance work systems (HPWS) are included as a moderator of GPC to test the potential way HR practices might interact with positive climates to achieve superior outcomes.

Design/methodology/approach

A large sample (n = 1,007) of New Zealand workers across a wide range of occupations and industries. Confirmatory factor analysis (CFA) of the data was used and moderated mediation tests were conducted.

Findings

GPC is significantly related to psychological capital, employee engagement and job satisfaction, and while psychological capital also predicts the outcomes, and has some mediation effects on GPC influence, GPC remains significant. HPWS is significantly related to psychological capital only and interacts with GPC leading to the highest psychological capital and employee engagement. Significant moderated mediation effects are found, with the indirect effect of GPC increasing as HPWS increase.

Research limitations/implications

This research is important because it provides empirical evidence around a GPC and shows how organizations and HRM managers can enhance key employee attitudes through building a strong climate and providing important HR practices.

Originality/value

Beyond unique effects from GPC, the findings provide useful theoretical insights toward conservation of resources theory.
Adapting and implementing the new normal: an Islamic university perspective
Authors: Basir Khairul Hidayatullah , Haji Sismat Muhamad Alif , Ahmad Siti Sara
Published: September 2023

Purpose

This paper explores the experiences and strategies that have emerged from an Islamic university in Brunei Darussalam in its efforts to adapt to the new normal. It aims to provide a comprehensive post COVID-19 teaching and learning strategies framework and understand how the principles of Islam can be harmonised with modern practices, offering valuable lessons for educational institutions worldwide.

Design/methodology/approach

The study employed a three-fold methodology. Initially, the authors conducted a comprehensive review of the post-COVID-19 experiences within Islamic universities. Subsequently, they administered a structured questionnaire to academic staff and students at an Islamic university in Brunei, utilising Google survey forms. Based on the insights from the data analysis, strategies were carefully formulated. Ultimately, this informed the development of a framework grounded in the established strategies.

Findings

The significant findings from this study include the adoption of “e-Talaqqi” and how this can be related to Maqasid Shariah to produce a conceptual framework of post-COVID-19 strategies adaptable for Islamic Higher Education Institutions (HEIs) and how that can be related to Maqasid Shariah in line with the values of Islamic-based universities.

Research limitations/implications

The applicability of the framework developed from data gathered at an Islamic university in Brunei might have certain limitations when extended to other Islamic HEIs. Future research should aim to cover more Islamic HEIs across various countries, thereby strengthening a broader applicability of the framework. Moreover, it is advisable that the developed framework undergoes statistical validation to fortify it.

Practical implications

The study's implications encompass theory, researchers, educators, policymakers, and all stakeholders concerned with the past, present, and future of HEIs, particularly in facilitating the adaptation of post-COVID-19 norms within Islamic HEIs.

Social implications

This paper holds the potential to significantly benefit society by providing invaluable insights to educators and various sectors, aiding them in enhancing their learning pedagogies.

Originality/value

This study has developed a conceptual framework that offers strategies tailored for Islamic HEIs in the post-COVID-19 era, harmonising with the principles of Islamic-based universities, in alignment with Maqasid Shariah. Consequently, this research serves as a significant contribution to the evolution of new theoretical paradigms because of COVID-19.
University students’ perceived service quality and attitude towards hybrid learning: ease of use and usefulness as mediators
Authors: Tan Peter Sin Howe , Seow Ai Na , Choong Yuen Onn , Tan Chi Hau , Lam Siew Yong , Choong Chee Keong
Published: September 2023

Purpose

Numerous academic institutions have embarked on the pursuit of hybrid learning as an alternative approach, catering to students who opt for replacing a fraction of their conventional in-person meeting schedule with remote teaching. However, these new remote learning patterns have brought forth new stands against students' expectations. The universities have come across immense challenges in devising efficacious strategies that encompass the delivery, effectiveness and acceptability of hybrid courses. Consequently, identifying pivotal determinants related to user acceptance of technology persists as a crucial matter. This study aims to shed light on the adoption of hybrid learning from students' perspectives.

Design/methodology/approach

Structural equation modelling (SEM) was employed to scrutinise the proposed research model and hypotheses. A total sample of 444 students responded and partook in the survey. The data were analysed using AMOS software, a powerful tool for statistical analysis in the field of social sciences.

Findings

The findings of this study show that perceived service quality positively and significantly impacts the ease of use and usefulness of a hybrid learning system among students. In addition, the results demonstrate that ease of use and usefulness of the system positively and significantly influence students' favourable attitudes toward hybrid learning. Remarkably, the statistical analysis unveils the significant mediating effect of ease of use and usefulness in the relationship between perceived service quality and students' attitudes toward hybrid learning.

Research limitations/implications

The findings suggest that the pervasive dependence on information systems and the quality of service from novel technologies continues to be a vital influence in the learning environment. The study has provided valuable insights into student perseverance learning strategies for higher education institutions.

Originality/value

This study's novelty lies in illuminating the crucial role of ease of use and usefulness as mediators, highlighting their criticality in enhancing students' attitudes towards hybrid learning. Notably, the study underscores that perceived service quality exerts a positive influence on ease of use and usefulness.
We are the dreamers, we let it happen: Morocco’s soccer team leadership story
Authors: Tahari Fadoua , Al Arkoubi Khadija
Published: September 2023

Research methodology

This case was based on secondary data that included various websites, news and academic articles, social media posts and press conferences before, during and after the World Cup. Multiple sources were examined to ensure the accuracy and credibility of the information presented in this case. The goal was to gather relevant information on the Moroccan soccer team, its performance in the FIFA World Cup and the leadership strategies used by Walid Regragui.

Case overview/synopsis

“We are the dreamers, we let it happen: Morocco’s soccer team leadership story” explores the transformative journey of Morocco’s soccer team in the 2022 World Cup, highlighting the exceptional leadership of coach Walid Regragui and the power of shared values deeply rooted in Moroccan culture. The instructional manual provides faculty with a compelling case study to inspire discussions on leadership, followership, team dynamics and cultural identity. The case emphasizes the importance of harnessing cultural roots, building trust and unity within a diverse team, strategic vision and tactical brilliance. It demonstrates that with authentic leadership, belief in shared dreams and the strength of cultural values, extraordinary achievements can be realized. The case aims to inspire and educate students, encouraging them to embrace their own cultural heritage, foster teamwork and pursue their dreams with unwavering determination.

Complexity/academic level

The academic level of this case can vary depending on the specific course or program in which it is being used. It is suitable for graduate levels in various fields such as leadership studies, sports management, organizational behavior, cultural studies, or international business. The case provides a comprehensive analysis of leadership, team dynamics and cultural identity, including faith and spirituality, making it adaptable for different academic levels and disciplines. Instructors can adjust the depth of analysis and additional readings or activities to align with the specific educational level and learning objectives of their course.