bluuebunny/crossref_metadata_2025 huggingface dataset:
Appropriateness of video call consultations in a Dutch primary care setting
Authors: Lindh Daniel , Luiten Eric
Published: December 2022

The pressure on healthcare is increasing worldwide. The trend toward digitalization in recent decades and the emergence of modern technologies have enabled remote treatment and offered patients new ways to interact with physicians. Despite numerous studies showing promising results in the use of video calls for primary care consultations, some survey studies report lingering doubts about the effectiveness of this method among general practitioners (GPs) and patients. Because the organization of health care varies widely across countries, we set out to investigate the appropriateness of video calling in a Dutch health care setting. Unlike many survey studies, we collected real-life data where GPs evaluated the video call directly after the consultation, allowing a more realistic assessment of perceived quality. We find that video calls are appropriate 84.2% (95% CI 80.3%-87.8%) of the time for consultations with patients of moderate to low urgency. Importantly, the appropriateness of video calls decreased with increasing urgency. These results build on previous studies and confirm the positive use cases of video calls focused on primary care in the Netherlands.
Cannabis use and the risk of primary open-angle glaucoma: a Mendelian randomization study
Authors: Katsimpris Andreas , Baumeister Sebastian-Edgar , Baurecht Hansjörg , Tatham Andrew , Nolde Michael
Published: December 2022

Background

Several observational studies have investigated the association between cannabis use and intraocular pressure, but its association with primary open-angle glaucoma (POAG) remains unclear. In this study, we leveraged human genetic data to assess through Mendelian randomization (MR) whether cannabis use affects POAG.

Methods

We used five single-nucleotide polymorphisms (SNPs) associated with lifetime cannabis use (P-value < 5×10−8) from a genome-wide association study (GWAS) (N = 184,765) by the International Cannabis Consortium, 23andMe, and UK Biobank and eleven SNPs associated with cannabis use disorder (P-value < 5×10−7) from a GWAS meta-analysis of (17,068 cases and 357,219 controls of European descent) from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative Psychiatric Research, and deCode. We associated these SNPs with the largest to date GWAS meta-analysis of POAG (16,677 cases and 199,580 controls).

Results

MR analysis suggested no evidence for a causal association of lifetime cannabis use and cannabis use disorder with POAG (odds ratio (OR) of outcome per doubling of the odds of the exposure (95% confidence interval): 1.04 (0.88; 1.23) for lifetime cannabis use and 0.97 (0.92; 1.03) for cannabis use disorder). Sensitivity analyses to address pleiotropy and weak instrument bias yielded similar estimates to the primary analysis.

Conclusions

Our results do not support a causal association between cannabis use and POAG.
Reduced Middle Cerebral Artery Blood Velocity Response during Low-Volume High-Intensity Interval Exercise in Chronic Stroke
Authors: Whitaker Alicen A. , Waghmare Saniya , Montgomery Robert N. , Aaron Stacey E. , Eickmeyer Sarah M. , Vidoni Eric D. , Billinger Sandra A.
Published: December 2022

Background

High-intensity interval exercise (HIIT) is currently being implemented in stroke rehabilitation to improve walking function. HIIT alternates between high-intensity and recovery bouts, which causes rapid increases and decreases in blood pressure, which may impact cerebrovascular function in people post-stroke. To date, there is no information on the acute cerebrovascular response in people post-stroke. To address this gap in knowledge, we tested whether the cerebrovascular response was reduced when compared to sedentary age- and sex-matched adults (CON) at the following timepoints: 1) baseline (BL), 2) during a single 10-minute bout of low-volume HIIT, 3) immediately following HIIT, and 4) 30 minutes after HIIT.

Methods

Middle cerebral artery blood velocity (MCAv), mean arterial pressure (MAP), heart rate (HR), and end tidal carbon dioxide (PETCO2) were recorded at all timepoints. A submaximal exercise test was used to determine the estimated maximal workload. The low-volume HIIT bout was performed on a recumbent stepper and consisted of 1-minute high-intensity bouts (70% estimated maximal watts) separated by 1-minute active recovery (10% estimated maximal watts). Statistical analysis used linear mixed models and ANCOVA.

Results

Individuals post-stroke demonstrated a reduced MCAv response during HIIT compared to CON (p = 0.03) and MCAv remained lower immediately following HIIT and 30-minutes after HIIT. MCAv decreased below BL immediately following HIIT in both groups (p ≤ 0.04) and returned to BL at 30-minutes after HIIT. No between differences were found for MAP, HR, and PETCO2.

Conclusions

The key finding from this study suggests a reduced MCAv response during low-volume HIIT in individuals post-stroke compared to age and sex-matched sedentary adults and these differences remained up to 30 minutes following HIIT. Future work is needed to better understand the reduced MCAv response during HIIT despite increased metabolic demand.Clinicaltrials.gov#NCT04673994.
Protein biomarkers for response to XPO1 inhibition in hematologic malignancies
Authors: Totiger Tulasigeri M. , Chaudhry Sana , Musi Elgilda , Afaghani Jumana , Montoya Skye , Owusu-Ansah Frank , Lee Stanley , Schwartz Gary , Klimek Virginia , Taylor Justin
Published: December 2022

XPO1 (Exportin-1) is the nuclear export protein responsible for the normal shuttling of several proteins and RNA species between the nucleocytoplasmic compartment of eukaryotic cells. XPO1 recognizes the nuclear export signal (NES) of its cargo proteins to facilitate its export. Alterations of nuclear export have been shown to play a role in oncogenesis in several types of solid tumor and hematologic cancers. Over more than a decade, there has been substantial progress in targeting nuclear export in cancer using selective XPO1 inhibitors. This has resulted in recent approval for the first-in-class drug selinexor for use in relapsed, refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Despite these successes not all patients respond effectively to XPO1 inhibition and there has been lack of biomarkers for response to XPO1 inhibitors in the clinic. Using hematologic malignancy cell lines and samples from patients with myelodysplastic neoplasms treated with selinexor, we have identified XPO1, NF-κB(p65), MCL-1 and p53 protein levels as protein markers of response to XPO1 inhibitor therapy. These markers could lead to the identification of response upon XPO1 inhibition for more accurate decision making in the personalized treatment of cancer patients undergoing treatment with selinexor.
Local-Scale phylodynamics reveal differential community impact of SARS-CoV-2 in metropolitan US county
Authors: Paredes Miguel I. , Perofsky Amanda C. , Frisbie Lauren , Moncla Louise H. , Roychoudhury Pavitra , Xie Hong , Mohamed Bakhash Shah A. , Kong Kevin , Arnould Isabel , Nguyen Tien V. , Wendm Seffir T. , Hajian Pooneh , Ellis Sean , Mathias Patrick C. , Greninger Alexander L. , Starita Lea M. , Frazar Chris D. , Ryke Erica , Zhong Weizhi , Gamboa Luis , Threlkeld Machiko , Lee Jover , Stone Jeremy , McDermot Evan , Truong Melissa , Shendure Jay , Oltean Hanna N. , Viboud Cécile , Chu Helen , Müller Nicola F. , Bedford Trevor
Published: December 2022

SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.

One Sentence Summary

Analysis of SARS-CoV-2 genomes in King County, Washington show that diverse areas in the same metropolitan region can have different epidemic dynamics.
Oral aspirin for preventing colorectal adenoma recurrence: a systematic review and network meta-analysis of randomized controlled trials
Authors: Hoang Khanh Dinh , Chen Jin-Hua , Huang Tsai-Wei , Kang Yi-No , Chen Chiehfeng
Published: December 2022

Colorectal adenomas have the potential of malignant transformation if left untreated. Multiple randomized controlled trials have been performed to evaluate the efficacy of aspirin in preventing colorectal adenoma recurrence in a population with a history of colorectal adenoma but not colorectal cancer, however, the relationship between aspirin dose and colorectal adenoma recurrence remains unclear. We conducted pairwise meta-analysis, meta-regression, trial sequential analysis, and network meta-analysis of all eligible studies. The ROB 2.0 tool was used to assess the risk of bias in the studies. The confidence in network meta-analysis (CINeMA) approach was used to evaluate the confidence of the network meta-analysis results. The network meta-analysis included eight RCTs (nine reports), comprising four on aspirin (low or high dose) alone and four on aspirin combined with another medication, all compared with placebo. In the network meta-analysis, low-dose aspirin (LDA <300 mg per day) was more effective than high-dose aspirin (HDA ≥300 mg per day) and placebo, with risk ratios of 0.76 (95% CI: 0.58 to 0.99) and 0.7 (95% CI: 0.54 to 0.91), respectively. LDA was the optimal treatment relative to HDA and placebo (P-score = 0.99). In the trial sequential analysis, LDA was only more effective than placebo when the number of included participants exceeded the optimal information size; this was not the case for HDA. LDA has statistically significant efficacy for colorectal adenoma prevention, but compared with HDA, its efficacy remains uncertain. Further trials are therefore required.
Multi-omics on truncatingASXL1mutations in Bohring Opitz syndrome identify dysregulation of canonical and non-canonical Wnt signaling
Authors: Lin Isabella , Wei Angela , Awamleh Zain , Singh Meghna , Ning Aileen , Herrera Analeyla , Russell Bianca , Weksberg Rosanna , Arboleda Valerie A.
Published: December 2022

ASXL1(Additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression.De novotruncating mutations inASXL1cause Bohring-Opitz syndrome (BOS, OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, characteristic facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies including heart defects and severe skeletal defects giving rise to a typical ‘BOS posture’. These BOS-causingASXL1variants are also high-prevalence somatic driver mutations in acute myeloid leukemia (AML). We use primary cells from BOS individuals (n = 18) and controls (n = 49) to dissect gene regulatory changes caused byASXL1mutations using comprehensive multi-omics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data shows that regardless of cell type,ASXL1mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation ofVANGL2, a planar cell polarity pathway protein that acts through non-canonical Wnt signaling to direct tissue patterning and cell migration. This multi-omics approach identifies the core impact ofASXL1mutations and therapeutic targets for BOS and myeloid leukemias.

Brief summary

GermlineASXL1mutations that cause Bohring Optiz syndrome disrupt the epigenome and dysregulate gene expression resulting in activation of canonical and non-canonical Wnt signaling pathways.
The Kelch13 compartment is a hub of highly divergent vesicle trafficking proteins in malaria parasites
Authors: Schmidt Sabine , Wichers-Misterek Jan Stephan , Behrens Hannah Michaela , Birnbaum Jakob , Henshall Isabelle G. , Dröge Jana , Jonscher Ernst , Flemming Sven , Castro-Peña Carolina , Mesén-Ramírez Paolo , Spielmann Tobias
Published: December 2022

Single amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility ofP. falciparumparasites to artemisinin and its derivatives (ART). Recent work indicated that K13 and other proteins co-localising with K13 (K13 compartment proteins) are involved in the endocytic uptake of host cell cytosol (HCCU) and that a reduction in HCCU results in ART resistance. HCCU is critical for parasite survival but is poorly understood, with the K13 compartment proteins among the few proteins so far functionally linked to this process. Here we further defined the composition of the K13 compartment by analysing more hits from a previous BioID, showing that MyoF and MCA2 as well as Kelch13 interaction candidate (KIC) 11 and 12 are found at this site. Functional analyses, tests for ART susceptibility as well as comparisons of structural similarities using AlphaFold2 predictions of these and previously identified proteins showed that canonical vesicle trafficking and endocytosis domains were frequent in proteins involved in resistance or endocytosis (or both), comprising one group of K13 compartment proteins. While this strengthened the link of the K13 compartment to endocytosis, many proteins of this group showed unusual domain combinations and large parasite-specific regions, indicating a high level of taxon-specific adaptation of this process. Another group of K13 compartment proteins did not influence endocytosis or ART susceptibility and lacked detectable vesicle trafficking domains. We here identified the first protein of this group that is important for asexual blood stage development and showed that it likely is involved in invasion. Overall, this work identified novel proteins functioning in endocytosis and at the K13 compartment. Together with comparisons of structural predictions it provides a repertoire of functional domains at the K13 compartment that indicate a high level of adaption of endocytosis in malaria parasites.
Cytidine deaminase regulates mitochondrial biogenesis in pancreatic cancer cells
Authors: Frances Audrey , Lumeau Audrey , Stuani Lucille , Gayral Marion , Saland Estelle , Bery Nicolas , Pagan Delphine , Hanoun Naima , Torrisani Jérôme , Lemarié Anthony , Portais Jean-Charles , Buscail Louis , Dusetti Nelson , Sarry Jean-Emmanuel , Cordelier Pierre
Published: December 2022

Despite tremendous efforts from the scientific community, pancreatic ductal adenocarcinoma (PDAC) is still a deadly disease and will soon become the second cause of death by cancer worldwide1. When surgery is not possible, therapeutic options are few and ineffective2. Patients are most often treated with Folfirinox or gemcitabine chemotherapy, that extends survival in weeks to months. Cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine to fuel RNA and DNA synthesis3. CDA also deaminates and neutralizes deoxycytidine-based therapies, and as such, has been identified as a major contributor of tumor chemoresistance, especially to gemcitabine in PDAC3. We previously identified that CDA is elevated in PDAC tumors at diagnosis and that CDA exerts an unexpected role on DNA replication that can be exploited for therapeutic intervention4. Very recently, CDA was associated with cellular metabolism5. Here, we show that CDA promotes mitochondrial biogenesis and oxidative phosphorylation independently of its deaminase activity. This uncloaks novel therapeutic vulnerabilities in primary cancer cells that overexpress this protein. This study shines a new light on the tumoral potential of CDA in PDAC.
Discovery and remodeling ofVibrio natriegensas a microbial platform for efficient formic acid biorefinery
Authors: Tian Jinzhong , Deng Wangshuying , Zhang Ziwen , Xu Jiaqi , Zhao Guoping , Yang Sheng , Jiang Weihong , Gu Yang
Published: December 2022

Formic acid (FA), an organic one-carbon source that is easily produced from CO2, has emerged as a promising CO2-equivalent feedstock for one-carbon biorefinery. However, developing efficient formatotrophs for an economically competitive FA utilization system remains a grand challenge. Here, we discovered that the gram-negative bacteriumVibrio natriegenshas exceptional FA tolerance and metabolic capacity natively. This strain was then remodeled by rewiring the serine cycle and the TCA cycle which resulted in a non-native closed loop (S-TCA) for enhancing FA assimilation. The rational design generated a powerful metabolic sink that enabled rapid emergence of the evolved strains with further significantly improved performance in using FA as the major or sole carbon source. Furthermore, the introduction of a foreign indigoidine-forming pathway into the best-performingV. natriegensstrain (S-TCA-2.0) led to production of 29.0 g·L-1indigoidine and consumption of 233.7 g·L-1formate within 72 h, achieving an order of magnitude higher formate consumption rate (3.2 g·L-1·h-1) than the reported highest level in microorganisms. This work represents a significant step towards the development of industrially viable microorganisms for FA biorefinery.
Encoding social preference by interhemispheric neurons in the Insula
Authors: Glangetas Christelle , Ladevèze Elodie , Guillaumin Adriane , Gauthier Manon , Doudnikoff Evelyne , Bézard Erwan , Taupignon Anne , Baufreton Jérôme , Georges François
Published: December 2022

The Insula is a multisensory relay that participates in socio-emotional processing through multiple projections to sensory, cognitive, emotional, and motivational regions. Interestingly, the Insula interhemispheric projection to the contralateral Insula is a strong but understudied projection. Using cutting-edge neuroanatomy,ex vivoandin vivoelectrophysiology associated with specific circuit manipulation, we unraveled the nature and role of Insula interhemispheric communication in social and anxiety processing in mice. In this study, we 1) characterized the anatomical and molecular profile of the interhemispheric neurons of the Insula, 2) highlighted that stimulation of this neuronal subpopulation triggers excitation in the Insula interhemispheric circuit 3) uncovered their engagement in social processing. In conclusion, this study demonstrates that interhemispheric neurons of the Insula constitute a unique class of Insula neurons and proposes new meaningful insights into the neuronal mechanisms underlying social behavior.
Heterologous expression ofPtAAS1reveals the metabolic potential of the common plant metabolite phenylacetaldehyde for auxin synthesisin planta
Authors: Günther Jan , Halitschke Rayko , Gershenzon Jonathan , Burow Meike
Published: December 2022

Aromatic aldehydes and amines are common plant metabolites involved in several specialized metabolite biosynthesis pathways. Recently, we showed that the aromatic aldehyde synthase PtAAS1 and the aromatic amino acid decarboxylase PtAADC1 contribute to the herbivory-induced formation of volatile 2-phenylethanol and its glucoside 2-phenylethyl-β-D-glucopyranoside inPopulus trichocarpa. To gain insights into alternative metabolic fates of phenylacetaldehyde and 2-phenylethylamine beyond alcohol and alcohol glucoside formation, we expressedPtAAS1andPtAADC1heterologously inNicotiana benthamianaand analyzed plant extracts using untargeted LC-qTOF-MS analysis. While the metabolomes ofPtAADC1-expressing plants did not significantly differ from those of control plants, expression ofPtAAS1resulted in the accumulation of phenylacetic acid (PAA) and PAA-amino acid conjugates, identified as PAA-aspartate and PAA-glutamate. Moreover, targeted LC-MS/MS analysis showed thatPtAAS1-expressing plants accumulated significant amounts of free PAA. The measurement of PAA and PAA-Asp in undamaged and herbivory-damaged poplar leaves revealed significantly induced accumulation of PAA-Asp while levels of free PAA remained unaltered by herbivore treatment. Sequence comparisons and transcriptome analysis showed that members of a small gene family comprising five putative auxin-amido synthetaseGH3genes potentially involved in the conjugation of auxins like PAA with amino acids were significantly upregulated upon herbivory inP. trichocarpaleaves. Overall, our data indicates that phenylacetaldehyde generated by poplar PtAAS1 serves as a hub metabolite linking the biosynthesis of volatile, non-volatile herbivory-induced specialized metabolites, and phytohormones, suggesting that growth and defense are balanced on a metabolic level.
Restriction-modification systems have shaped the evolution and distribution of plasmids across bacteria
Authors: Shaw Liam P. , Rocha Eduardo P. C. , MacLean R. Craig
Published: December 2022

Many novel traits such as antibiotic resistance are spread by plasmids between species. Yet plasmids have different host ranges. Restriction-modification systems (R-M systems) are by far the most abundant bacterial defense system and therefore represent one of the key barriers to plasmid spread. However, their effect on plasmid evolution and host range has been neglected. Here we analyse the avoidance of targets of the most abundant R-M systems (Type II) for complete genomes and plasmids across bacterial diversity. For the most common target length (6 bp) we show that target avoidance is strongly correlated with the taxonomic distribution of R-M systems and is greater in plasmid genes than core genes. We find stronger avoidance of R-M targets in plasmids which are smaller and have a broader host range. Our results suggest two different evolutionary strategies for plasmids: small plasmids primarily adapt to R-M systems by tuning their sequence composition, and large plasmids primarily adapt through the carriage of additional genes protecting from restriction. Our work provides systematic evidence that R-M systems are important barriers to plasmid transfer and have left their mark on plasmids over long evolutionary time.
Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS
Authors: Mora Santiago , von Huth Friis Rasmus , Stuckert Anna , Noes-Holt Gith , Montañana-Rosell Roser , Sørensen Andreas Toft , Selvan Raghavendra , Allodi Ilary
Published: December 2022

Loss of connectivity between spinal V1 inhibitory inter-neurons and motor neurons is found early in disease in the SOD1G93AALS mice. Such changes in premotor inputs can contribute to homeostatic imbalance of vulnerable motor neurons. Here, we show, for the first time, that stabilization of V1 synapses by overexpression of the Extended Synap-totagmin 1 presynaptic organizer increases motor neuron survival and ameliorates motor phenotypes, demonstrating that interneurons can be a potential target to attenuate ALS symptoms.
Single-step genome-wide association study for susceptibility toTeratosphaeria nubilosaand precocity of vegetative phase change inEucalyptus globulus
Authors: Quezada Marianella , Giorello Facundo , Da Silva Cecilia , Aguilar Ignacio , Balmelli Gustavo
Published: December 2022

Mycosphaerella leaf disease (MLD) is one of the most prevalent foliar diseases ofE. globulusplantations around the world. Since resistance management strategies have not been effective in commercial plantations, breeding to develop more resistant genotypes is the most promising strategy. Available genomic information can be used to detect genomic regions associated with resistance to MLD, which could significantly speed up the process of genetic improvement. In this study, we investigated the genetic basis of MLD resistance in a breeding population ofE. globuluswhich was genotyped with the EUChip60K SNP array. Resistance to MLD was evaluated for resistance of the juvenile foliage, as defoliation and leaf spot severity, and for precocity of change to resistant adult foliage. Genome-wide association studies (GWAS) were carried out applying four Single-SNP models, a Genomic Best Linear Unbiased Prediction (GBLUP-GWAS) approach, and a Single-step genome-wide association study (ssGWAS). The Single-SNP and GBLUP-GWAS models detected 13 and 16 SNP-trait associations in chromosomes 2, 3 y 11; whereas the ssGWAS detected 66 SNP-trait associations in the same chromosomes, and additional significant SNP-trait associations in chromosomes 5 to 9 for the precocity of phase change (proportion of adult foliage). For this trait, the two main regions in chromosomes 3 and 11 were identified for the three approaches. The SNPs identified in these regions were positioned near the key miRNA genes,miR156.5andmiR157.4, which have a main role in the regulation of the timing of vegetative change, and also in the response to environmental stresses in plants. Our results outlined that ssG-WAS was more powerful in detecting regions that affect resistance than conventional GWAS approaches. Additionally, suggest a polygenic genetic architecture for the heteroblastic transition inE. globulusand identified useful SNP markers for the development of marker-assisted selection strategies for resistance.
Co-occurring mutations in the POLE exonuclease and non-exonuclease domains define a unique subset of highly mutagenic tumors
Authors: Shah Shreya M. , Demidova Elena V. , Ringenbach Salena , Faezov Bulat , Andrake Mark , Mur Pilar , Viana-Errasti Julen , Xiu Joanne , Swensen Jeffrey , Valle Laura , Dunbrack Roland L. , Hall Michael J. , Arora Sanjeevani
Published: December 2022

SomaticPOLEmutations in the exonuclease domain (ExoD) are prevalent in colorectal cancer (CRC), endometrial cancer (EC), and others and typically lead to dramatically increased tumor mutation burden (TMB). To understand whether non-ExoD mutations also play a role in mutagenesis, we assessed TMB in 447/14541POLE-mutated CRCs, ECs, and ovarian cancers (OC) based on classification TMB-High (TMB-H) or TMB-Low (TMB-L). TMB-H tumors were segregated as ‘POLEExoD driver’, ‘POLEExoD driver plusPOLEVariant’, and ‘POLEVariant TMB-H’. Intriguingly, TMB was highest in tumors bearing ‘POLEExoD driver plusPOLEVariant’ (p<0.001 in CRC and EC, p<0.05 in OC). Integrated analysis of AlphaFold2-modeled POLE models and quantitative estimate of stability indicated that multiple variants had significant impact on functionality. These data indicate that co-occurringPOLEvariants categorize a unique subset ofPOLE-driven tumors defined by ultra-high TMB, which has implications for abundance of tumor neoantigens, therapeutic response, and patient outcomes.

Significance

SomaticPOLEExoD driver mutations cause proofreading deficiency that induces high tumor mutation burden (TMB). This study defines a novel modifier role for non-ExoD mutations inPOLEExoD-driven tumors, associated with ultra-high TMB. These data may inform acquisition of tumor neoantigens, tumor classification, therapeutic response, and patient outcomes.
Cell non-autonomous control of autophagy and metabolism by glial cells
Authors: Metcalf Melissa G. , Monshietehadi Samira , Sahay Arushi , Frakes Ashley E. , Durieux Jenni , Velichkovska Martina , Mena Cesar , Farinas Amelia , Sanchez Melissa , Dillin Andrew
Published: December 2022

Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity inC. elegans. Expression of the UPRERtranscription factor, XBP-1s, in these glia increases stress resistance, longevity, and activates the UPRERin intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.
Functional dissociations between prefrontal and parietal cortex during task switching: A combined fMRI and TMS study
Authors: Periáñez José A. , Viejo-Sobera Raquel , Lubrini Genny , Álvarez-Linera Juan , Rodríguez Toscano Elisa , Moreno María Dolores , Arango Celso , Redolar-Ripoll Diego , Muñoz Marrón Elena , Ríos-Lago Marcos
Published: December 2022

Preparatory control in task-switching has been suggested to rely upon a set of distributed regions within a frontoparietal network, with frontal and parietal cortical areas cooperating to implement switch-specific preparation processes. Although recent causal evidences using transcranial magnetic stimulation (TMS) have generally supported this model, alternative evidences from both functional neuroimaging and neurophysiological studies have questioned the switch-specific role of both frontal and parietal cortices. The aim of the present study was to clarify the role of prefrontal and parietal areas supporting preparatory cognitive control in task-switching. Within this purpose, an fMRI study during task-switching performance was conducted to identify the specific brain areas involved in preparatory control during performance of a task-switching paradigm. Then, TMS was applied over the specific coordinates previously identified through fMRI, that is, the anterior portion of the inferior frontal junction (aIFJ) and the intraparietal sulcus (IPS). Results revealed that TMS over the aIFJ disrupted performance in both switch and repeat trails in terms of delayed responses as compared to Sham condition. In contrast, TMS over the IPS selectively interfered performance in switch trials. These findings support a multicomponent model of executive control with the aIFJ being involved in more general switch-unspecific process such as the episodic retrieval of goals, and the IPS being related to the implementation of switch-specific preparation mechanisms for activating stimulus-response mappings. The results help conciliating preceding evidences about the role of a frontoparietal network during task-switching, and support current models about a hierarchical organization within prefrontal cortex.

Significance Statement

A combined fMRI and TMS study was conducted to clarify the brain areas involved in the executive control of attention during a cueing task-switching paradigm.

Functional dissociations were observed during TMS stimulation, with prefrontal and parietal areas playing different roles during task-switching preparation. While the anterior portion of the inferior prefrontal junction seemed to be involved in a general mechanism of memory retrieval for goal identification, the intraparietal sulcus seemed to be engaged in a switch-specific mechanism for the translation of abstract task goals into action rules.

The results help conciliating preceding evidences about the role of a frontoparietal network during task-switching, and support current models about a hierarchical organization within prefrontal cortex.
Effectiveness of community non-pharmacological interventions for mild cognitive impairment and dementia: a systematic review of economic evaluations and a review of reviews
Authors: Eaglestone Gillian , Gkaintatzi Evdoxia , Stoner Charlotte , Pacella Rosana , McCrone Paul
Published: December 2022

Background

Dementia prevalence is increasing with no cure at present. Drug therapies have limited efficacy and potential side effects. People with dementia are often offered non-pharmacological interventions to improve quality of life and relieve symptoms. Identifying which interventions are cost-effective is important due to finite resources in healthcare services.

Aims

To review published economic evaluations of community non-pharmacological interventions for people with mild cognitive impairment or dementia and assess usefulness for decision making in health services.

Methods

Systematic review (PROSPERO CRD42021252999) included economic evaluations of non-pharmacological interventions for dementia or mild cognitive impairment with a narrative approach to data synthesis. Exclusions: interventions for dementia prevention/early detection or end of life care. Databases searched: Academic search premier, MEDLINE, Web of Science, EMBASE, Google Scholar, CINAHL, PsycInfo, Psychology and behavioural sciences collection, PsycArticles, Cochrane Database of Systematic Reviews, Business Source Premier and Regional Business News; timeframe 01 January 2011 to 30 June 2021 (13 September 2021 for Embase). Study quality assessed using CHEERS.

Results

Included thirty-two studies and five reviews, evaluating community dementia interventions worldwide across several distinct forms of care: physical activity, cognition, training, multi-disciplinary interventions and other (telecare/assistive technology, specialist dementia care, group living, home care versus care home). No single intervention was shown to be cost-effective across all economic evaluations.

Conclusion

More economic evidence on the cost-effectiveness of specific dementia care interventions is needed, with consistency around measurement of costs and outcomes data. Better information and higher-quality studies could improve decision makers’ confidence to promote future cost-effective dementia interventions.
Prevalence of Olfactory Dysfunction with the Omicron Variant of SARS-CoV-2: A Systematic Review and Meta-analysis
Authors: von Bartheld Christopher S. , Wang Lingchen
Published: December 2022

The omicron variant is thought to cause less olfactory dysfunction than previous variants of SARS-CoV-2, but the reported prevalence differs greatly between populations and studies. Our systematic review and meta-analysis provide information about regional differences in prevalence as well as an estimate of the global prevalence of olfactory dysfunction based on 62 studies reporting on 626,035 patients infected with the omicron variant. Our estimate of the omicron-induced prevalence of olfactory dysfunction in populations of European ancestry is 11.7%, while it is significantly lower in all other populations, ranging between 1.9% and 4.9%. When ethnic differences and population sizes are taken into account, the global prevalence of omicron-induced olfactory dysfunction in adults is estimated at 3.7%. Omicron’s effect on olfaction is twofold to tenfold lower than that of the alpha or delta variant, according to previous meta-analyses and our analysis of studies that directly compared prevalence of olfactory dysfunction between omicron and previous variants. The profile of prevalence differences between ethnicities mirrors the results of a recent genome-wide association study that implicated a gene locus encoding an odorant-metabolizing enzyme, UDP glycosyltransferase, to be linked to the extent of COVID-related loss of smell. Our analysis is consistent with the hypothesis that this enzyme contributes to the observed population differences.
Extracellular vesicle cargo metabolome changes in response to the mesenchymal stromal cell microenvironment and influences cell quiescence and activation in a human breast cancer cell model
Authors: Bartlome Sara , Xiao Yinbo , Ross Ewan , Dalby Matthew John , Berry Catherine Cecilia
Published: December 2022

Breast cancer is the leading cause of cancer mortality in women worldwide and commonly metastasizes to the bone marrow, drastically reducing patient prognosis and survival. In the bone marrow niche, metastatic cells can enter into a dormant state, thereby evading immune surveillance and treatment, and can be reactivated to enter a proliferative state due to poorly understood cues. Mesenchymal stromal cells (MSCs) maintain cells in this niche partly by secreting extracellular matrix and paracrine factors and by responding to regenerative cues. MSCs also produce extracellular vesicles (EVs) that carry a range of cargoes, some of which are implicated in cell signalling. Here, we investigate if the changing metabolic state of MSCs alters the cargoes they package into EVs, and how these changing cargoes act on dormant breast cancer cells (BCCs) using an in vitro BCC spheroid model and a scratch assay to create a regenerative demand on MSCs. Our findings show that EVs produced by standard MSCs contain glycolytic metabolites that maintain BCC dormancy. When MSCs are placed under a regenerative demand and increase their respiration to fuel differentiation, these metabolites disappear from the EV cargo and their absence encourages rapid growth in the BCC spheroids. This work implicates EVs in cancer cell dormancy in the bone marrow niche and indicates that pressures on the niche, such as regeneration, can be a driver of BCC activation.
Study of emerging avenues in supply chain resilience; the case of integration of additive manufacturing with spare parts procurement
Authors: Bhattacharyya Som Sekhar , Kulkarni Onkar , Mishra Ashutosh
Published: December 2022

Purpose

The purpose of this research was to study the impacts of adoption of additive manufacturing (AM) for spare parts procurement, specifically in the context of supply chain resilience (SCR) especially regarding efficient spare parts inventory management. Furthermore, key narratives in the adoption of AM toward better SCR are explored.

Design/methodology/approach

In-depth interviews with semi-structured open-ended questionnaire were conducted to collect primary qualitative data from 24 supply chain management (SCM) experts. Respondents consisted of experts across various industries. The data were analyzed by thematic content analysis method.

Findings

The results indicated that AM could be a suitable tool to reduce dependence on original equipment manufacturers (OEMs) for spare parts procurement. Data analysis also revealed that AM adoption might lead to significant cost and lead time reduction. Designs protected as intellectual properties (IP), substantive post-processing requirements and material compatibility were revealed to be barriers in adoption.

Research limitations/implications

The impacts of utilizing AM for procurement of spare parts on the overall resilience of the supply chain were highlighted. Theoretical analysis of the findings was based on theoretical aspects of SCR. This was especially regarding efficient spare parts inventory management. The study results revealed the factors responsible adoption of the AM technology. A novel approach was undertaken to study the effect of AM adoption on “time-to-market” of newly launched products.

Practical implications

The research provided insights regarding practical applications of AM adoption in spare parts procurement. The study could be beneficial to the early adopters of AM across industries for making managerial decisions. Unfamiliarity of supply chain managers with the AM technology was believed to be a major reason to adopt the technology. The study provided essential inputs regarding challenges and alternate adoption strategies of AM. Thus, the research was believed to be of potential value for creating awareness among supply chain managers regarding AM technology.

Originality/value

The research provided new insights on the impact of AM adoption in the context of SCR toward efficient spare parts inventory management. Various limiting and facilitating factors specific to Indian context were also explored.
The limited role of African strategic communication practitioners in ethical communication practices
Authors: Nhedzi Abyshey , Azionya Caroline Muyaluka
Published: December 2022

Purpose

This study answers the call for research and theorising exploring ethical communication and brand risk from the African continent. The study's purpose was to identify the challenges that strategic communication practitioners face in enacting ethical crisis communication in South Africa.

Design/methodology/approach

The researchers conducted ten in-depth interviews with South African strategic communication professionals.

Findings

The dominant theme emerging from the study is the marginalisation and exclusion of the communication function in decision-making during crisis situations. Communicators were viewed as implementers, technicians and not strategic counsel. The protection of organisational reputation was done at the expense of the ethics and moral conscience of practitioners. Practitioners were viewed and deployed as spin doctors and tools to face unwanted media interactions.

Originality/value

The article sheds light on the concepts of ethical communication and decision-making in a multicultural African context using the moral theory of Ubuntu and strategic communication. It demonstrates the tension professionals experience as they toggle between unethical capitalist approaches and African values. The practitioner's role as organisational moral conscience is hindered, suppressed and undermined by organisational leadership's directives to use opaque, complex communication, selective transparency and misrepresentation of facts.
Essential? COVID-19 and highly educated Africans in Finland’s segmented labour market
Authors: Ndomo Quivine , Bontenbal Ilona , Lillie Nathan A.
Published: December 2022

Purpose

The purpose of this paper is to characterise the position of highly educated African migrants in the Finnish labour market and to examine the impact of the COVID-19 pandemic on that position.

Design/methodology/approach

The paper is based on the biographical work stories of 17 highly educated African migrant workers in four occupation areas in Finland: healthcare, cleaning, restaurant and transport. The sample was partly purposively and partly theoretically determined. The authors used content driven thematic analysis technique, combined with by the biographical narrative concept of turning points.

Findings

Using the case of highly educated African migrants in the Finnish labour market, the authors show how student migration policies reinforce a pattern of division of labour and occupations that allocate migrant workers to typical low skilled low status occupations in the secondary sector regardless of level of education, qualification and work experience. They also show how the unique labour and skill demands of the COVID-19 pandemic incidentally made these typical migrant occupations essential, resulting in increased employment and work security for this group of migrant workers.

Research limitations/implications

This research and the authors’ findings are limited in scope owing to sample size and methodology. To improve applicability of findings, future studies could expand the scope of enquiry using e.g. quantitative surveys and include other stakeholders in the study group.

Originality/value

The paper adds to the knowledge on how migration policies contribute to labour market dualisation and occupational segmentation in Finland, illustrated by the case of highly educated African migrant workers.
Institutional structures and strength of auditing and financial reporting standards in Africa
Authors: Adela Vincent , Abeka Mac Junior , Tackie George , Anipa Comfort Ama Akorfa , Mbir Deborah Esi Gyanba , Adorm-Takyi Cornelius
Published: December 2022

Purpose

The purpose of this paper is to investigate the effect of institutional structures on the strength of auditing and financial reporting standards.

Design/methodology/approach

This paper employs a panel data of 36 African countries over the period 2000–2018. System generalised method of moments (SGMM) was employed to estimate the relationship between institutional structures and the strength of auditing and financial reporting standards in Africa.

Findings

The findings of this paper indicate a positive and statistically significant relationship between institutional structures and the strength of auditing and financial reporting standards. As a further analysis, the study finds that the relationship between institutional structures and the strength of auditing and financial reporting standards is stronger for economies with common-law accounting traditions than those with civil-law origin.

Practical implications

The paper has important implications for countries striving to adopt and implement auditing and financial reporting standards fully. Such efforts must begin with establishing strong institutional structures in those countries.

Originality/value

This study presents the first empirical panel data evidence on the effect of institutional structures on the strength of auditing and financial reporting standards in Africa. Further, the methodology employed in this study can be regarded as effective in testing the phenomenon in other regions, or it can be employed as a guiding model for future research in the area.
Women's access and perception of decent work: a case study on Egypt
Authors: Khairy Yasmine Hossam , Ghoneim Hebatallah
Published: December 2022

Purpose

The purpose of this study is to assess the gender disparities in the workers' perception of whether “decent work” standards exist in their current job and workplace in the Egyptian context.

Design/methodology/approach

This study uses quantitative data. A survey was utilised to assess workers' perceptions of decent work. The sample was selected based on age as the study aims to measure gender disparities in the perception among Generation Y and Z. Frequency table for each question and independent sample T-test were utilised in order to compare the variable means between females and males and whether any of those means are significantly different from each other.

Findings

The key findings of this research show that women in Egypt believe they have fewer opportunity to progress professionally and raise their salaries than males, particularly in male-dominated fields like engineering, construction and information technology. Furthermore, the women surveyed, particularly working mothers, emphasised that they struggle with their workload and working time more than men, affecting their work–life balance. However, there was no significant disparity between men and women in the other aspects of decent work examined in this article, which included social protection, health and safety, and meaningful compensation.

Originality/value

To the best of authors’ knowledge, this study is among the first group of studies assessing the gender disparities in the workers' perception of whether “decent work” standards exist in the Egyptian workplace.