bluuebunny/crossref_metadata_2025 huggingface dataset:
A signature of pre-operative biomarkers of cellular senescence to predict risk of cardiac and kidney adverse events after cardiac surgery
Authors: Entwistle Amy , Walker Susan , Knecht Anne , Strum Susan L. , Shah Asad , Podgoreanu Mihai V. , Pustavoitau Aliaksei , Mitin Natalia , Williams Judson B.
Published: April 2023

Objective

Understand the potential for pre-operative biomarkers of cellular senescence, a primary aging mechanism, to predict risk of cardiac surgery-associated adverse events.

Methods

Biomarkers of senescence were assessed in blood samples collected prior to surgery in 331 patients undergoing CABG +/-valve repair or replacement. Patients were followed throughout the hospital stay and at a 30-day follow-up visit. Logistic regression models for pre-operative risk prediction were built for age-related clinical outcomes with high incidence including KDIGO-defined acute kidney injury (AKI), decline in eGFR ≥25% between pre-op and 30 days, and MACKE30, a composite endpoint of major adverse cardiac and kidney events at 30d.

Results

AKI occurred in 19.9% of patients, persistent decline in kidney function at 30d occurred in 11.0%, and MACKE30 occurred in 13.4%. A network of six biomarkers of senescence (p16, p14, LAG3, CD244, CD28 and suPAR) were able to identify patients at risk for AKI (AUC 0.76), kidney decline at 30d (AUC 0.73), and MACKE30 (AUC 0.71). Comparing the top and bottom tertiles of senescence-based risk models, patients in the top tertile had 7.8 (3.3-8.4) higher odds of developing AKI, 4.5 (1.6-12.6) higher odds of developing renal decline at 30d, and 5.7 (2.1-15.6) higher odds of developing MACKE30. All models remained significant when adjusted for clinical variables. Patients with kidney function decline at 30d were largely non-overlapping and clinically distinct from those who experienced AKI, suggesting a different etiology. Typical clinical factors that predispose to AKI (e.g., age, CKD, surgery type) associated with AKI but not the 30d decline endpoint which was instead associated with new-onset atrial fibrillation.

Conclusions

A six-member network of biomarkers of senescence, a fundamental mechanism of aging, can identify patients for risk of adverse kidney and cardiac events when measured pre-operatively.
Sensitive quantification of cerebellar speech abnormalities using deep learning models
Authors: Vattis Kyriakos , Luddy Anna C. , Ouillon Jessey S. , Eklund Nicole M. , Stephen Christopher D. , Schmahmann Jeremy D. , Nunes Adonay S. , Gupta Anoopum S.
Published: April 2023

Objective

Objective, sensitive, and meaningful disease assessments are critical to support clinical trials and clinical care. Speech changes are one of the earliest and most evident manifestations of cerebellar ataxias. The purpose of this work is to develop models that can accurately identify and quantify these abnormalities.

Methods

We use deep learning models such asResNet 18, that take the time and frequency partial derivatives of the log-mel spectrogram representations of speech as input, to learn representations that capture the motor speech phenotype of cerebellar ataxia. We train classification models to separate patients with ataxia from healthy controls as well as regression models to estimate disease severity.

Results

Our model was able to accurately distinguish healthy controls from individuals with ataxia, including ataxia participants with no detectable clinical deficits in speech. Furthermore the regression models produced accurate estimates of disease severity, were able to measure subclinical signs of ataxia, and captured disease progression over time in individuals with ataxia.

Conclusion

Deep learning models, trained on time and frequency partial derivatives of the speech signal, can detect sub-clinical speech changes in ataxias and sensitively measure disease change over time.

Significance

Such models have the potential to assist with early detection of ataxia and to provide sensitive and low-burden assessment tools in support of clinical trials and neurological care.
The epidemiological characteristics of stroke phenotypes defined with ICD-10 and free-text: a cohort study linked to electronic health records
Authors: Davidson Emma M , Casey Arlene , Grover Claire , Alex Beatrice , Wu Honghan , Campbell Archie , Chalmers Fionna , Adams Mark , Iveson Matthew , McIntosh Andrew M , Ball Emily , Rannikmae Kristiina , Whalley Heather , Whiteley William N
Published: April 2023

Background

Coded healthcare data may not capture all stroke cases and has limited accuracy for stroke subtypes. We sought to determine the incremental value of adding natural language processing (NLP) of free-text radiology reports to international classification of disease (ICD-10) codes to phenotype stroke, and stroke subtypes, in routinely collected healthcare datasets.

Methods

We linked participants in a community-based prospective cohort study, Generation Scotland, to clinical brain imaging reports (2008-2020) from five Scottish health boards. We used five combinations of NLP outputs and ICD-10 codes to define stroke phenotypes. With these phenotype models we measured the: stroke incidence standardised to a European Standardised Population; adjusted hazard ratio (aHR) of baseline hypertension for later stroke; and proportion of participants allocated stroke subtypes.

Results

Of 19,026 participants, over a mean follow-up of 10.2 years, 1938 had 3493 brain scans. Any stroke was identified in 534 participants: 319 with NLP alone, 59 with ICD-10 codes alone and 156 with both ICD-10 codes and an NLP report consistent with stroke. The stroke aHR for baseline hypertension was 1.47 (95%CI: 1.12-1.92) for NLP-defined stroke only; 1.57 (95%CI: 1.18-2.10) for ICD-10 defined stroke only; and 1.81 (95%CI: 1.20-2.72) for cases with ICD 10 stroke codes and NLP stroke phenotypes. The age-standardised incidence of stroke for these phenotype models was 1.35, 1.34, and 0.65 per 1000 person years, respectively. The proportion of strokes not subtyped was 26% (57/215) using only ICD-10, 9% (42/467) using only NLP, and 12% (65/534) using both NLP and ICD-10.

Conclusions

Addition of NLP derived phenotypes to ICD-10 stroke codes identified approximately 2.5 times more stroke cases and greatly increased the proportion with subtyping. The phenotype model using ICD 10 stroke codes and NLP stroke phenotypes had the strongest association with baseline hypertension. This information is relevant to large cohort studies and clinical trials that use routine electronic health records for outcome ascertainment.
The characterisation of antimicrobial resistantEscherichia colifrom dairy calves
Authors: Mwenifumbo Merning , Cookson Adrian L , Zhao Shengguo , Fayaz Ahmed , Benschop Jackie , Burgess Sara A
Published: April 2023

Dairy calves, particularly pre-weaned calves have been identified as a common source of multidrug (MDR) resistantE. coli. However, the strains and whether their resistance genes are plasmid or chromosomally located have not been well characterised. Our study examined the phenotype and genotype of antimicrobial resistantE. coliisolated from young calves (≤ 14 days old). Recto-anal swab enrichments from 40 dairy calves located on four dairy farms were examined for tetracycline, streptomycin, ciprofloxacin, and third-generation cephalosporin resistantE. coli. Fifty-eight percent (23/40) of calves harboured antimicrobial resistantE. coli: 18/40 (45%) harboured tetracycline resistant and 25% (10/40) harboured chromosomal mediated AmpC producingE. coli. Whole genome sequencing of 27 isolates revealed five sequence types, with ST88 being the dominant ST (17/27, 63% of the sequenced isolates) followed by ST1308 (3/27, 11%), along with the extraintestinal pathogenicE. colilineages ST69 (3/27), ST10 (2/27, 7%), and ST58 (1/27, 4%). Additionally, 16 isolates were MDR, harbouring additional resistance genes that were not tested phenotypically. Oxford Nanopore long-read sequencing technologies enabled the location of multiple resistant gene cassettes in IncF plasmids to be determined. A phylogenetic comparison of the ST10 and ST69 isolates demonstrated that the calf derived isolates were distinct from other New Zealand animal, human, and environmental isolates. and highlights the importance of understanding the sources of antimicrobial resistance.
Identifying determinants of synaptic specificity by integrating connectomes and transcriptomes
Authors: Yoo Juyoun , Dombrovski Mark , Mirshahidi Parmis , Nern Aljoscha , LoCascio Samuel A. , Zipursky S. Lawrence , Kurmangaliyev Yerbol Z.
Published: April 2023

How do developing neurons select their synaptic partners? To identify molecules matching synaptic partners, we integrated the synapse-level connectome of neural circuits with the developmental expression patterns and binding specificities of cell adhesion molecules (CAMs) on pre- and postsynaptic neurons. We focused on parallel synaptic pathways in the Drosophila visual system, in which closely related neurons form synapses onto closely related target neurons. We show that the choice of synaptic partners correlates with the matching expression of receptor-ligand pairs of Beat and Side proteins of the immunoglobulin superfamily (IgSF) CAMs. Genetic analysis demonstrates that these proteins determine the choice between alternative synaptic targets. Combining transcriptomes, connectomes, and protein interactome maps provides a framework to uncover the molecular logic of synaptic connectivity.
The genomic architecture of a continuous color polymorphism in the European barn owl (Tyto alba)
Authors: Cumer Tristan , Machado Ana Paula , San-Jose Luis M. , Ducrest Anne-Lyse , Simon Céline , Roulin Alexandre , Goudet Jérôme
Published: April 2023

The maintenance of color polymorphism in populations has fascinated evolutionary biologists for decades. Studies of color variation in wild populations often focus on discrete color traits exhibiting simple inheritance patterns, while studies on continuously varying traits remain rare. Here, we studied the continuous white to rufous color polymorphism in the European barn owl (Tyto alba). Using a Genome Wide Association approach on whole-genome data of 75 barn owls sampled across Europe, we identified, in addition to a previously knownMC1Rmutation, two regions involved in this color polymorphism. We show that the combination of the three explains 80.37% (95% credible interval 58.45 to 100%) of the color variation. Among the two newly identified regions, the one on the sexual chromosome (Z) shows a large signal of differentiation in the Swiss population when contrasting individuals with different morph but the sameMC1Rgenotype. We suggest it may play a role in the sexual dimorphism observed locally in the species. These results, uncovering two new genomic regions, provide keys to better understand the molecular bases of the color polymorphism as well as the mechanisms responsible for its maintenance in the European barn owl at both continental and local scales.
High-throughput colocalization pipeline quantifies efficacy of mitochondrial targeting signals across different protein types
Authors: Lear Sierra K. , Nunez Jose A. , Shipman Seth L.
Published: April 2023

Efficient metabolic engineering and the development of mitochondrial therapeutics often rely upon the specific and strong import of foreign proteins into mitochondria. Fusing a protein to a mitochondria-bound signal peptide is a common method to localize proteins to mitochondria, but this strategy is not universally effective with particular proteins empirically failing to localize. To help overcome this barrier, this work develops a generalizable and open-source framework to design proteins for mitochondrial import and quantify their specific localization. By using a Python-based pipeline to quantitatively assess the colocalization of different proteins previously used for precise genome editing in a high-throughput manner, we reveal signal peptide-protein combinations that localize well in mitochondria and, more broadly, general trends about the overall reliability of commonly used mitochondrial targeting signals.
Gut bacteria translocation to the brain after ischaemic stroke occurs via the sympathetic nervous system
Authors: Peh Alex , Dinakis Evany , Nakai Michael , Muralitharan Rikeish R. , Rupasinghe Samoda , Wilson Jenny L. , Wong Connie H.Y. , Jama Hamdi , Barker Charlotte M.O. , Modarresi Mahnaz , Kemp-Harper Barbara K. , Zheng Tenghao , Marques Francine Z. , Broughton Brad R.S.
Published: April 2023

We provide evidence that stroke-induced gut breakdown results in bacteria translocation to the ischaemic mouse brain. Inhibition of sympathetic tone reduced bacterial load in the post-stroke brain and reduced functional deficits without altering cerebral apoptosis, neuroinflammation or infarct volume. These findings indicate that the activation of the sympathetic nervous system after stroke promotes gut-derived bacteria to enter to the brain, and this process worsens motor function in mice.

Abstract Figure
Analytical solutions for the short-term plasticity
Authors: Protachevicz Paulo R. , Batista Antonio M. , Caldas Iberê L. , Baptista Murilo S.
Published: April 2023

Synaptic dynamics plays a key role in neuronal communication. Due to its high-dimensionality, the main fundamental mechanisms triggering different synaptic dynamics and its relation with the neurotransmitters release regimes (facilitation, biphasic, and depression) are still elusive. For a general set of parameters, and by means of an approximated solution for a set of differential equations associated with a synaptic model, we obtain a discrete map that provides analytical solutions that shed light into the dynamics of synapses. Assuming that the presynaptic neuron perturbing the neuron whose synapse is being modelled is spiking periodically, we derive the stable equilibria and the maximal values for the release regimes as a function of the percentage of neurotransmitter released and the mean frequency of the presynaptic spiking neuron. Assuming that the presynaptic neuron is spiking stochastically following a Poisson distribution, we demonstrate that the equations for the time average of the trajectory are the same as the map under the periodic presynaptic stimulus, admitting the same equilibrium points. Thus, the synapses under stochastic presynaptic spikes, emulating the spiking behaviour produced by a complex neural network, wander around the equilibrium points of the synapses under periodic stimulus, which can be fully analytically calculated.

Author summary

Based on the model proposed by Tsodyks et al., we obtained a map approximation to study analytically the dynamics of short-term synaptic plasticity. We identified the synaptic regimes named facilitation, depression, and biphasic in the parameters space, and determined the maximal and equilibrium points of active neurotransmitters for presynaptic neurons spiking periodically and stochastically following a Poisson process. Besides that, we verify that the time average of the variables for the synaptic dynamics driven by presynaptic neurons spiking following a Poisson distribution presents the equilibrium points obtained for the synaptic driven by periodic presynaptic neurons, spiking with a frequency that is the mean frequency of the Poisson distribution. These results shed analytical light into the understanding of synaptic dynamics.
Ribosomal protein RPL39L is an efficiency factor in the cotranslational folding of proteins with alpha helical domains
Authors: Banerjee Arka , Ataman Meric , Smialek Maciej Jerzy , Mookherjee Debdatto , Rabl Julius , Mironov Aleksei , Mues Lea , Enkler Ludovic , Coto-Llerena Mairene , Schmidt Alexander , Boehringer Daniel , Piscuoglio Salvatore , Spang Anne , Mittal Nitish , Zavolan Mihaela
Published: April 2023

Increasingly many studies reveal how ribosome composition can be tuned to optimally translate the transcriptome of individual cell types. In this study, we investigated the expression pattern, structure within the ribosome and effect on protein synthesis of the ribosomal protein paralog 39L (RPL39L). With a novel mass spectrometric approach we have quantified the expression of RPL39L in human pluripotent cells, cancer cell lines and tissue samples, and in mouse germ cells. We generatedRPL39Lknock-out mouse embryonic stem cell (mESC) lines and demonstrated that RPL39L impacts the dynamics of translation, to support the pluripotency and differentiation, spontaneous and along the germ cell lineage. Most differences in protein abundance between WT and RPL39L KO lines were explained by widespread proteasomal activity. By CryoEM analysis of purified RPL39 and RPL39L-containing ribosomes we found that, unlike RPL39, RPL39L has two distinct conformations in the exposed segment of the nascent peptide exit tunnel, creating a distinct hydrophobic patch that has been predicted to support the efficient co-translational folding of alpha helices. Our study shows that ribosomal protein paralogs provide switchable modular components that can tune translation to the protein production needs of individual cell types.
Modification of amyloplast size in wheat endosperm through mutation of PARC6 affects starch granule morphology
Authors: Esch Lara , Ngai Qi Yang , Barclay J. Elaine , McNelly Rose , Hayta Sadiye , Smedley Mark A. , Smith Alison M. , Seung David
Published: April 2023

Starch granule morphology is a major factor determining the functional and nutritional properties of starch. Here, we reveal amyloplast structure plays an important role in starch granule morphogenesis in wheat endosperm. Wheat amyloplasts contain large discoid A-type granules and small spherical B-type granules. We isolated a mutant in durum wheat defective in the plastid division protein PARC6, which had increased plastid size in both leaves and endosperm. Endosperm amyloplasts of the mutant contained more A- and B-type granules than those of the wild type. In mature grains, the mutant had larger A- and B-type granules than the wild type, and its A-type granules had a highly aberrant, lobed surface. This defect in granule morphology was already evident at early stages of grain development, when granule size was identical between the mutant and the wild type, and occurred without obvious alterations in starch polymer structure and composition. Plant growth and photosynthetic efficiency, as well as the size, number and starch content of grains, were not affected in theTtparc6mutants despite the large changes in plastid size. Interestingly, mutation of the PARC6 paralog, ARC6, in durum wheat did not increase plastid or starch granule size. We suggest this is becauseTtPARC6 can complement disruptedTtARC6 function by interacting with PDV2, the outer plastid envelope protein that typically interacts with ARC6 to promote plastid division. We propose that amyloplast compartment size and available stromal volume play important roles in determining starch granule size, shape and number per amyloplast.
Comparative analysis of the effects of retinoic acid versus paclitaxel and everolimus on HL60 cells proliferation and viability
Authors: Zampouka Athanasia , Papadimitropoulou Triantafyllia , Salagianni Maria , Vaiou Maria , Moula Amalia I , Giannoukas Athanasios , Moulas Anargyros N
Published: April 2023

Purpose

All trans-retinoic acid (atRA) has been proposed as a novel drug for drug eluting stents (DES). Currently complications of DES have been at least partially attributed to the drugs that are used: paclitaxel and sirolimus and its derivatives like everolimus. We compared the effects of atRA, paclitaxel and everolimus on the proliferation and viability of human leukemia cells (HL60).

Methods

Cells were cultured with 0.1μM and 10μM of atRA, paclitaxel or everolimus. Cell proliferation and viability was evaluated with trypan blue at 24, 48 and 72 hours.

Results

All drugs caused a statistically significant, dose-dependent reduction of cell proliferation rate from the first 24 hours. atRA and everolimus did not affect cell viability as the treated cells showed high viability (95-98%), while paclitaxel decreased significantly the viability to below 16% at 72 hours. Unlike the cytotoxic effect of paclitaxel on HL60, atRA demonstrated a cytostatic effect comparable to everolimus.

Conclusion

The ability of atRA to limit cell proliferation without affecting cell viability in a manner similar to everolimus, highlights its potential to be used on DES as a novel drug for treatment of restenosis with potentially minimal side-effects. Further research with different cell types, is needed in order to elucidate the possible usefulness of RA on DES.
The DEAD-box helicase RCF1 plays roles in miRNA biogenesis and RNA splicing inArabidopsis
Authors: Xu Chi , Zhang Zhanhui , He Juan , Bai Yongsheng , Liu Lin , Tang Jihua , Tang Guiliang , Chen Xuemei , Mo Beixin
Published: April 2023

RCF1 is a highly conserved DEAD-box helicase found in yeast, plants and mammals. Studies about the functions of RCF1 in plants are limited. Here we uncovered the functions of RCF1 inArabidopsis thalianaas a player in pri-miRNA processing and splicing, as well as in pre-mRNA splicing. A mutant with miRNA biogenesis defects was isolated and the defect was traced to a recessive point mutation inRCF1(rcf1-4). We show that RCF1 promotes D-body formation and facilitates the interaction between pri-miRNAs and HYL1. Finally, we show that intron-containing pri-miRNAs and pre-mRNAs exhibit a global splicing defect inrcf1-4. Together, this work uncovers roles for RCF1 in miRNA biogenesis and RNA splicing inArabidopsis.

One-sentence summary

RCF1 promotes not only the processing of pri-miRNAs, but also the splicing of intron-containing pri-miRNAs, therefore promotes miRNA biogenesis.
Transsynaptic labeling and transcriptional control of zebrafish neural circuits
Authors: Coomer Cagney , Naumova Daria , Talay Mustafa , Zolyomi Bence , Snell Nathaniel J. , Sorkaç Altar , Chanchu Jean-Michale , Cheng Ji , Roman Ivana , Li Jennifer , Robson Drew , Barnea Gilad , Halpern Marnie E.
Published: April 2023

Deciphering the connectome, the ensemble of synaptic connections that underlie brain function, is a central goal of neuroscience research. Here, we report mapping of connections between presynaptic and postsynaptic partners in a living vertebrate nervous system, that of the zebrafish, through the successful adaptation of thetrans-Tango genetic approach, first developed for anterograde transsynaptic tracing inDrosophila. Neural connections were visualized between synaptic partners in the larval retina and brain and followed over development. Results were corroborated by functional experiments in which optogenetic activation of retinal ganglion cells elicited responses in neurons of the optic tectum, as measured bytrans-Tango-dependent expression of a genetically encoded calcium indicator.

Transsynaptic signaling throughtrans-Tango reveals predicted as well as previously undescribed synaptic connections in the zebrafish brain, providing a valuablein vivotool to monitor and interrogate neural circuits over time.
Alphafold-multimer predicts cross-kingdom interactions at the plant-pathogen interface
Authors: Homma Felix , Huang Jie , van der Hoorn Renier A. L.
Published: April 2023

Adapted plant pathogens from various microbial kingdoms produce hundreds of unrelated small secreted proteins (SSPs) with elusive roles. Some of these SSPs might be inhibitors targeting the most harmful hydrolases secreted by the host. Here, we used Alphafold-Multimer (AFM) to screen 1,879 SSPs of seven tomato pathogens for interacting with six defence-related hydrolases of tomato that accumulate to high levels in the apoplast during infection. This screen of 11,274 protein pairs identified 15 SSPs that are predicted to obstruct the active site of chitinases and proteases with an intrinsic fold. Four SSPs were experimentally verified to be inhibitors of pathogenesis-related subtilase P69B, including extracellular protein-36 (Ecp36) and secreted-into-xylem-15 (Six15) of the fungal tomato pathogensCladosporium fulvumandFusarium oxysporum, respectively. Together with a novel P69B inhibitor from the bacterial pathogenXanthomonas perforansand the previously reported Kazal-like inhibitors of the oomycete pathogenPhytophthora infestans, P69B emerges as an important effector hub targeted by different microbial kingdoms, consistent with the presence of a hyper-variant residue in P69B orthologs and gene duplication and diversification of P69B paralogs that could avoid inhibitor binding. This study demonstrates the power of artificial intelligence to accurately predict novel cross-kingdom interactions at the plant-pathogen interface.
Human gut bacteria tailor extracellular vesicle cargo for the breakdown of diet- and host-derived glycans
Authors: Sartorio Mariana G. , Pardue Evan J. , Scott Nichollas E. , Feldman Mario F.
Published: April 2023

Extracellular vesicles (EV) are produced in all three domains of life, and their biogenesis have common ancient origins in eukaryotes and archaea. Although bacterial vesicles were discovered several decades ago and multiple roles have been attributed to them, no mechanism has been established for vesicles biogenesis in bacteria. For this reason, there is a significant level of skepticism about the biological relevance of bacterial vesicles. InBacteroides thetaiotaomicron(Bt), a prominent member of the human intestinal microbiota, outer membrane vesicles (OMVs) have been proposed to play key physiological roles. By employing outer membrane- and OMV-specific markers fused to fluorescent proteins we visualized OMV biogenesis in live-cells. We performed comparative proteomic analyses to demonstrate thatBtactively tailors its vesicle cargo to optimize the breakdown of diet- and host-derived complex glycans. Surprisingly, our data suggests that OMV are not employed for mucin degradation. We also show that, inBt, a negatively-charged N-terminal motif acts as a signal for protein sorting into OMVs irrespective of the nutrient availability. We conclude that OMVs are the result of an exquisitely orchestrated mechanism. This work lays the foundation for further investigations into the physiological relevance of OMVs and their roles in gut homeostasis. Furthermore, our work constitutes a roadmap to guide EV biogenesis research in other bacteria.
An efficient hairy root system for genome editing of a β-ODAP pathway gene inLathyrus sativus
Authors: Verma Anjali , Kaur Lovenpreet , Kaur Navpreet , Bhardwaj Akanksha , Pandey Ajay K , Kandoth Pramod Kaitheri
Published: April 2023

Grass pea (Lathyrus sativus) is an ideal legume crop for resource-poor farmers, having resistance to various biotic and abiotic stresses. The seeds of this plant are rich in protein and are the only known dietary source of L-homoarginine. Moreover, it thrives with minimal inputs making it a promising crop in grain legume breeding programs with immense potential for food security. Despite these advantages, the global area under its cultivation has decreased because of the presence of an antinutrient compound, β-N-oxalyl-L-α,β-diamino propionic acid (β-ODAP), which results in neurolathyrism both in humans and animals. Multiple efforts in the past have resulted in the development of improved varieties with low ODAP. Still, due to variations in response to the environment, stable low-ODAP lines have not been developed for large-scale cultivation. In this paper, we report in planta characterization of Oxalyl-CoA Synthetase (OCS) involved in the oxalylating step leading to β-ODAP production. We established a hairy root transformation system forLathyrusand demonstrated the genome editing ofLsOCS. Further, we show that oxalate accumulates in these hairy roots due to loss-of-function of theOCSgene. This is the first report of functional analysis of aLathyrusgene inLathyrus. The hairy root genome editing system we developed can be used as a quick system for functional studies ofLathyrusgenes.
Rapid Quantification of First and Second Phase Insulin Secretion Dynamics using In vitro Platform for Improving Insulin Therapy
Authors: Thoduvayil Sikha , Weerakkody Jonathan S. , Topper Mackenzie , Bera Manindra , Coleman Jeff , Li Xia , Mariappan Malayalam , Ramakrishnan Sathish
Published: April 2023

High-throughput quantification of the first- and second-phase insulin secretion dynamics is intractable with current methods. The fact that independent secretion phases play distinct roles in metabolism necessitates partitioning them separately and performing high-throughput compound screening to target them individually. We developed an insulin-nanoluc luciferase reporter system to dissect the molecular and cellular pathways involved in the separate phases of insulin secretion. We validated this method through genetic studies, including knockdown and overexpression, as well as small-molecule screening and their effects on insulin secretion. Furthermore, we demonstrated that the results of this method are well correlated with those of single-vesicle exocytosis experiments conducted on live cells. Thus, we can quantitatively determine the number of vesicles that fuse when a stimulus is applied. We have developed a robust methodology for screening small molecules and cellular pathways that target specific phases of insulin secretion, resulting in a better understanding of insulin secretion, which in turn will result in a more effective insulin therapy through the stimulation of endogenous glucose-stimulated insulin secretion.
Spatial variation in excess mortality across Europe: a cross-sectional study of 561 regions in 21 countries
Authors: Bonnet Florian , Grigoriev Pavel , Sauerberg Markus , Alliger Ina , Mühlichen Michael , Camarda Carlo-Giovanni
Published: April 2023

Objective

To measure the burden of the COVID-19 pandemic in 2020 at the subnational level by estimating excess mortality, defined as the increase in all-cause mortality relative to an expected baseline mortality level.

Design

Statistical and demographic analyses of regional all-cause mortality data.

Setting

The vital statistics systems of 21 European countries.

Participants

The entire population of 561 spatial units in 21 European countries.

Main Outcome Measures

Losses of life expectancy at ages 0 and 60 for males and females.

Results

We found evidence of a loss in life expectancy in 391 regions, while only three regions exhibit notable gains in life expectancy in 2020. For 12 regions, losses of life expectancy amounted to more than 2 years, and three regions showed losses greater than 3 years. We highlight geographic clusters of high mortality in Northern Italy, Spain and Poland, while clusters of low mortality were found in Western France, Germany/Denmark and Norway/Sweden.

Conclusions

Regional differences of loss of life expectancy are impressive, ranging from a loss of more than 4 years to a gain of 8 months. These findings provide a strong rationale for regional analysis, as national estimates hide significant regional disparities.

‘What is already known’

Reported numbers of covid-19 deaths are subject to changes within and across countries due to inaccuracy, and incompleteness.

Excess mortality measured by loss in life expectancy is widely considered a relevant indicator for assessing the total mortality impact of the COVID-19 pandemic.

Whereas national estimates has been largely provided, few scattered regional studies for specific countries have been conducted.

‘What this study adds’

This study provides the first coherent analysis of excess mortality at regional level covering a large number of European countries.

It allows to properly map COVID-19 pandemic using official mortality data routinely collected by vital registration systems, which are less sensitive to misclassification.

How this study might affect research, practice or policy’

This study provides a strong rationale for regional analysis, as national estimates hide significant regional disparities
The gender differences in the association between fear of pain and dental anxiety using the Japanese version of the Fear of Pain questionnaire-III: a cross-sectional study
Authors: Ogawa Mika , Sago Teppei , Furukawa Hirokazu , Saito Akihiro
Published: April 2023

Background

The fear of pain is closely linked with chronic pain and the resultant impairment of daily life. It has been reported to have a correlation with dental anxiety, making its assessment crucial in dental practice. The present study aimed to develop a Japanese version of the Fear of Pain Questionnaire-III (FPQ-III), an international rating scale, to evaluate psychological characteristics and investigate its association with dental anxiety and gender differences.

Methods

After forward and backward translation and review, the Japanese version of the FPQ-III was administered to 400 internet monitors, and 100 of them were re-evaluated after a month. Convergent validity was assessed in relation to catastrophic thoughts of dental anxiety and pain, while discriminant validity was evaluated concerning the correlations between anxiety and depression. Confirmatory factor analysis was used to examine the factorial validity of the FPQ-III and a shortened version of the FPQ-9. Item response theory was applied to estimate the discriminative power of each item and draw a test information curve. Structural equation modeling was used to investigate the relationship between pain anxiety and dental anxiety and the gender differences in the model.

Results

Data from 400 participants (200 women [50.0%, mean 44.9 ± 14.5 years]) were analyzed. Total scores on the FPQ-III showed good internal validity, intra-examiner reliability, and discriminant validity, indicating convergent validity. Confirmatory factor analysis results supported a three-factor structure, and the FPQ-9 showed a good fit.

Discrimination was high, except for two items related to severe pain. Test information curves demonstrated that the FPQ-III and FPQ-9 were more accurate for latent characteristic values between -2 SD and +2 SD. Anxiety about medical pain fully mediated the relationship between fears of minor pain and dental anxiety. No gender differences were observed in this construct, and the factor means for anxiety about severe pain were significantly higher for women than for men.

Conclusion

The Japanese versions of the FPQ-III and FPQ-9 demonstrated high reliability and validity for measuring the Fear of Pain in this target population, with high accuracy for a wide range of latent characteristics. The fear of pain was deemed an endogenous factor that was linked to dental anxiety and common to both men and women.
A mechanosensory feedback that uncouples external and self-generated sensory responses in the olfactory cortex
Authors: Dehaqani Alireza A. , Michelon Filippo , Patella Paola , Petrucco Luigi , Piasini Eugenio , Iurilli Giuliano
Published: April 2023

Sampling behaviors have sensory consequences that can hinder perceptual stability. In olfaction, sniffing affects early odor encoding, mimicking a sudden change in odor concentration. Here, we examined how the inhalation speed impacts the representation of odor concentration in the main olfactory cortex. Neurons combine the odor input with a global top-down signal preceding the sniff and a mechanosensory feedback generated by the air passage through the nose during an inhalation. Still, the population representation of concentration is remarkably sniff-invariant. This is because the mechanosensory and olfactory responses are uncorrelated within and across neurons. Thus, a faster odor inhalation and a concentration increase change the cortical activity pattern in distinct ways. This encoding strategy affords tolerance to potential concentration fluctuations caused by varying inhalation speeds. Since mechanosensory reafferences are widespread across sensory systems, the coding scheme described here may be a canonical strategy to mitigate the sensory ambiguities caused by movements.
Competitive plasticity to reduce the energetic costs of learning
Authors: van Rossum Mark C.W.
Published: April 2023

The brain is not only constrained by energy needed to fuel computation, but it is also constrained by energy needed to form memories. Experiments have shown that learning simple conditioning tasks already carries a significant metabolic cost. Yet, learning a task like MNIST to 95% accuracy appears to require at least 108synaptic updates. Therefore the brain has likely evolved to be able to learn using as little energy as possible. We explored the energy required for learning in feedforward neural networks. Based on a parsimonious energy model, we propose two plasticity restricting algorithms that save energy: 1) only modify synapses with large updates, and 2) restrict plasticity to subsets of synapses that form a path through the network. Combining these two methods leads to substantial energy savings while only incurring a small increase in learning time. In biology networks are often much larger than the task requires. In particular in that case, large savings can be achieved. Thus competitively restricting plasticity helps to save metabolic energy associated to synaptic plasticity. The results might lead to a better understanding of biological plasticity and a better match between artificial and biological learning. Moreover, the algorithms might also benefit hardware because in electronics memory storage is energetically costly as well.
Fourier-synthesis approach for static charge-density reconstruction from theoretical structure factors of CaB6
Authors: Bergner Carina , Grin Yuri , Wagner Frank Richard
Published: April 2023

In a pilot study, electron-density (ED) and ED Laplacian distributions were reconstructed for the challenging case of CaB6 (Pearson symbol cP7) with conceptually fractional B—B bonds from quantum-chemically calculated structure-factor sets with resolutions 0.5 Å–1 ≤ [sin(θ)/λ]max ≤ 5.0 Å–1 by means of Fourier-synthesis techniques. Convergence of norm deviations of the distributions obtained with respect to the reference ones was obtained in the valence region of the unit cell. The QTAIM (quantum theory of atoms in molecules) atomic charges, and the ED and ED Laplacian values at the characteristic critical points of the Fourier-synthesized distributions have been analysed for each resolution and found to display a convergent behaviour with increasing resolution. The presented method(exponent) (ME) type of Fourier-synthesis approach can qualitatively reconstruct all characteristic chemical bonding features of the ED from valence-electron structure-factor sets with resolutions of about 1.2 Å–1 and beyond, and from all-electron structure-factor sets with resolutions of about 2.0 Å–1 and beyond. Application of the ME type of Fourier-synthesis approach for reconstruction of ED and ED Laplacian distributions at experimental resolution is proposed to complement the usual extrapolation to infinite resolution in Hansen–Coppens multipole model derived static ED distributions.
GEMMI and Servalcat restrain REFMAC5
Authors: Yamashita Keitaro , Wojdyr Marcin , Long Fei , Nicholls Robert A. , Murshudov Garib N.
Published: April 2023

Macromolecular refinement uses experimental data together with prior chemical knowledge (usually digested into geometrical restraints) to optimally fit an atomic structural model into experimental data, while ensuring that the model is chemically plausible. In the CCP4 suite this chemical knowledge is stored in a Monomer Library, which comprises a set of restraint dictionaries. To use restraints in refinement, the model is analysed and template restraints from the dictionary are used to infer (i) restraints between concrete atoms and (ii) the positions of riding hydrogen atoms. Recently, this mundane process has been overhauled. This was also an opportunity to enhance the Monomer Library with new features, resulting in a small improvement in REFMAC5 refinement. Importantly, the overhaul of this part of CCP4 has increased flexibility and eased experimentation, opening up new possibilities.
N-(4-Methoxy-3-nitrophenyl)acetamide
Authors: Hines III James E. , Agu Ogad A. , Deere Curtistine J. , Fronczek Frank R. , Uppu Rao M.
Published: April 2023

The title compound, C9H10N2O4, crystallizes with a disordered nitro group in twinned crystals. Both the methoxy group and the acetamide groups are nearly coplanar with the phenyl ring, and the C—N—C—O torsion angle [0.2 (4)°] is also insignificantly different from zero. Overall, the 12-atom methoxyphenylacetamide group is nearly planar, with an r.m.s. deviation of 0.042 Å. The nitro group is twisted out of this plane by about 30°, disordered into two orientations with opposite senses of twist. In the crystal, the N—H group donates a hydrogen bond to a nitro oxygen atom, generating chains propagating in the [101] direction. The amide carbonyl oxygen atom is not involved in the hydrogen bonding.
Psychiatry clerk reflections on the disruption of their clinical training during COVID-19 pandemic
Authors: Algahtani Haifa Mohammad , Jahrami Haitham , Husni Mariwan
Published: April 2023

Purpose

The COVID-19 pandemic has had a significant impact on medical education and training, with many medical schools and training programs having to adapt to remote or online learning, social distancing measures and other challenges. This paper aimed to examine the disruption for clinical training, as it has reduced the opportunities for students and trainees to gain hands-on experience and interact with patients in person.

Design/methodology/approach

The ethnographic qualitative research design was chosen as the research methodology. Using Gibbs' reflective cycle, the researcher explored the psychiatry clerks' (final-year medical students) reflections on the disruption of their clinical training during the COVID-19 pandemic.

Findings

The findings demonstrated that the students had a significant psychological impact on their coping capacities as the crisis progressed from shock and depression to resilience. The students being the key stakeholders provided a concrete foundation for the development of a framework for improving practices during uncertain times.

Originality/value

Students' reflections provided valuable insight into the pandemic’s impact on their psychosocial lives with uncertainty and incapacity to cope up with changing stressful dynamics. The results will assist in planning how to best support medical students' well-being during interruptions of their educational process brought about by similar future crises.
Does environmental, social and governance (ESG) affect market performance? The moderating role of competitive advantage
Authors: Dkhili Hichem
Published: April 2023

Purpose

This research aims to determine the influence of environmental, social and governance (ESG) factors on market performance. The study shows the perspective of ESG on market performance. The study attempted to test the relationship between ESG and Tobin’s Q and the effect of control variables.

Design/methodology/approach

The study used panel data from a sample covering 720 firms and ran a fixed-effects model regression during the 2007–2019 period for eight European countries’ listed companies.

Findings

The findings reveal that ESG positively impacts Tobin’s Q. According to the findings, high company ESG performance boosts market performance via the moderator effect of competitive advantage. The results indicate that all control variables are significant. The firm’s leverage has a negative relationship with ESG. The size of the firm impacts ESG positively. Also, the results prove that the firm’s size and industry positively affect Tobin’s Q.

Research limitations/implications

The findings of this study suggest that managers, practitioners and authorities interested in learning about ESG scores (ESGSs), market performance and competitive advantage might draw intriguing conclusions from the data. Managers can identify the appropriate levels of competitive advantage that improve market performance. Practitioners must determine whether fit, size, growth, leverage and industry could enhance market performance. The findings also give authorities and the board of directors information on future growth opportunities for the company and the country.

Originality/value

The research presents a vision of how ESG factors affect market performance. This study aims to identify the positive link between ESGSs and European market performance.
Earth observations into action: the systemic integration of earth observation applications into national risk reduction decision structures
Authors: Borges David Eley , Ramage Steven , Green David , Justice Christina , Nakalembe Catherine , Whitcraft Alyssa , Barker Brian , Becker-Reshef Inbal , Balagizi Charles , Salvi Stefano , Ambrosia Vincent , San-Miguel-Ayanz Jesus , Boschetti Luigi , Field Robert , Giglio Louis , Kuhle Laila , Low Fabian , Kettner Albert , Schumann Guy , Brakenridge G. Robert , Adler Robert , Kontoes Haris , De Boissezon Helene , Eddy Andrew , Kirschbaum Dalia , Emberson Robert , Cooley Savannah , Lloyd Simone , Blake Cecille , Reichenbach Kelsey
Published: April 2023

Purpose

As stated in the United Nations Global Assessment Report 2022 Concept Note, decision-makers everywhere need data and statistics that are accurate, timely, sufficiently disaggregated, relevant, accessible and easy to use. The purpose of this paper is to demonstrate scalable and replicable methods to advance and integrate the use of earth observation (EO), specifically ongoing efforts within the Group on Earth Observations (GEO) Work Programme and the Committee on Earth Observation Satellites (CEOS) Work Plan, to support risk-informed decision-making, based on documented national and subnational needs and requirements.

Design/methodology/approach

Promotion of open data sharing and geospatial technology solutions at national and subnational scales encourages the accelerated implementation of successful EO applications. These solutions may also be linked to specific Sendai Framework for Disaster Risk Reduction (DRR) 2015–2030 Global Targets that provide trusted answers to risk-oriented decision frameworks, as well as critical synergies between the Sendai Framework and the 2030 Agenda for Sustainable Development. This paper provides examples of these efforts in the form of platforms and knowledge hubs that leverage latest developments in analysis ready data and support evidence-based DRR measures.

Findings

The climate crisis is forcing countries to face unprecedented frequency and severity of disasters. At the same time, there are growing demands to respond to policy at the national and international level. EOs offer insights and intelligence for evidence-based policy development and decision-making to support key aspects of the Sendai Framework. The GEO DRR Working Group and CEOS Working Group Disasters are ideally placed to help national government agencies, particularly national Sendai focal points to learn more about EOs and understand their role in supporting DRR.

Originality/value

The unique perspective of EOs provide unrealized value to decision-makers addressing DRR. This paper highlights tangible methods and practices that leverage free and open source EO insights that can benefit all DRR practitioners.