bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolving the haplotypes of arbuscular mycorrhizal fungi highlights the role of two nuclear populations in host interactions
Authors: Sperschneider Jana , Yildirir Gokalp , Rizzi Yanina , Malar C Mathu , Sorwar Essam , Chen Eric CH , Iwasaki Wataru , Brauer Elizabeth K. , Bosnich Whynn , Gutjahr Caroline , Corradi Nicolas
Published: January 2023

Arbuscular mycorrhizal fungi (AMF) are prominent root symbionts with a multinucleate cytoplasm that can carry thousands of nuclei deriving from two parental strains and varying in relative abundance in a large syncytium. Here, we set out to improve our understanding of such remarkable genetics by resolving the nuclear genomes of all publicly available AMF heterokaryons using PacBio HiFi and Hi-C sequencing. We find that all AMF heterokaryons carry two sets of homologous chromosomes, where genes associated with plant colonization reside in gene-sparse, repeat-rich compartments. The co-existing nuclear genomes are phylogenetically related but differ significantly in content and epigenetics, resulting in nucleus-specific regulatory programs during mycorrhizal interactions. AMF heterokaryons carry signatures of past genetic exchange indicative of sexual reproduction, followed by clonal haplotype evolution. This work uncovers the contribution and origin of nuclear genomes present in AMF heterokaryons and opens avenues for improvement and environmental application of these strains.
Circuit and cell-specific contributions to decision making involving risk of explicit punishment in male and female rats
Authors: Truckenbrod Leah M. , Betzhold Sara M. , Wheeler Alexa-Rae , Shallcross John , Singhal Sarthak , Harden Scott , Schwendt Marek , Frazier Charles J. , Bizon Jennifer L. , Setlow Barry , Orsini Caitlin A.
Published: January 2023

Decision making is a complex cognitive process that recruits a distributed network of brain regions, including the basolateral amygdala (BLA) and nucleus accumbens shell (NAcSh). Recent work suggests that communication between these structures, as well as activity of cells expressing dopamine D2 receptors (D2R) in the NAcSh, are necessary for some forms of decision making; however, the contributions of this circuit and cell population during decision making under risk of punishment are unknown. The current experiments addressed this question using circuit- and cell type-specific optogenetic approaches in rats during a decision-making task involving risk of punishment. In Experiment 1, Long-Evans rats received intra-BLA injections of halorhodopsin or mCherry (control) and in Experiment 2, D2-Cre transgenic rats received intra-NAcSh injections of Cre-dependent halorhodopsin or mCherry. Optic fibers were implanted in the NAcSh in both experiments. Following training in the decision-making task, BLA→NAcSh or D2R-expressing neurons were optogenetically inhibited during different phases of the decision process. Inhibition of the BLA→NAcSh during deliberation (the time between trial initiation and choice) increased choice of the large, risky reward (increased risk taking). Similarly, inhibition during delivery of the large, punished reward increased risk taking, but only in males. Inhibition of D2R-expressing neurons in the NAcSh during deliberation increased risk taking. In contrast, inhibition of these neurons during delivery of the small, safe reward decreased risk taking. These findings extend our knowledge of the neural dynamics of risk taking, revealing sex-dependent circuit recruitment and dissociable activity of selective cell populations during decision making.
AliSim-HPC: parallel sequence simulator for phylogenetics
Authors: Ly-Trong Nhan , Barca Giuseppe M.J. , Minh Bui Quang
Published: January 2023

Motivation

Sequence simulation plays a vital role in phylogenetics with many applications, such as evaluating phylogenetic methods, testing hypotheses, and generating training data for machine-learning applications. We recently introduced a new simulator for multiple sequence alignments called AliSim, which outperformed existing tools. However, with the increasing demands of simulating large data sets, AliSim is still slow due to its sequential implementation; for example, to simulate millions of sequence alignments, AliSim took several days or weeks. Parallelization has been used for many phylogenetic inference methods but not yet for sequence simulation.

Results

This paper introduces AliSim-HPC, which, for the first time, employs high-performance computing for phylogenetic simulations. AliSim-HPC parallelizes the simulation process at both multi-core and multi-CPU levels using the OpenMP and MPI libraries, respectively. AliSim-HPC is highly efficient and scalable, which reduces the runtime to simulate 100 large alignments from one day to 9 minutes using 256 CPU cores from a cluster with 6 computing nodes, a 162-fold speedup.

Availability and implementation

AliSim-HPC is open source and available as part of the new IQ-TREE version v2.2.2.2 athttps://github.com/iqtree/iqtree2/releaseswith a user manual athttp://www.iqtree.org/doc/AliSim.

Contact

m.bui@anu.edu.au
Using a self-attention architecture to automate valence categorization of French teenagers’ free descriptions of their family relationships. A proof of concept
Authors: Sedki Mohammed , Vidal Nathan , Roux Paul , Barry Caroline , Speranza Mario , Falissard Bruno , Brunet-Gouet Eric
Published: January 2023

This paper proposes a proof of concept of using natural language processing techniques to categorize valence of family relationships described in free texts written by french teenagers. The proposed study traces the evolution of techniques for word embedding. After decomposing the different texts in our possession into short texts composed of sentences and manual labeling, we tested different word embedding scenarios to train a multi-label classification model where a text can take several labels : labels describing the family link between the teenager and the person mentioned in the text and labels describing the teenager’s relationship with them positive/negative/neutral valence). The natural baseline for word vector representation of our texts is to build a TF-IDF and train classical classifiers (Elasticnet logistic regression, gradient boosting, random forest, support vector classifier) after selecting a model by cross validation in each class of machine learning models. We then studied the strengths of word-vectors embeddings by an advanced language representation technique via the CamemBERT transformer model, and, again, used them with classical classifiers to compare their respective performances. The last scenario consisted in augmenting the CamemBERT with output dense layers (perceptron) representing a classifier adapted to the multi-label classification and fine-tuning the CamemBERT original layers. The optimal fine-tuning depth that achieves a bias-variance trade-off was obtained by a cross-validation procedure. The results of the comparison of the three scenarios on a test dataset show a clear improvement of the classification performances of the scenario with fine-tuning beyond the baseline and of a simple vectorization using CamemBERT without fine-tuning. Despite the moderate size of the dataset and the input texts, fine-tuning to an optimal depth remains the best solution to build a classifier.
Differences Between Reported COVID-19 Deaths and Estimated Excess Deaths in Counties Across the United States, March 2020 to February 2022
Authors: Paglino Eugenio , Lundberg Dielle J. , Zhou Zhenwei , Wasserman Joe A. , Raquib Rafeya , Hempstead Katherine , Preston Samuel H. , Elo Irma T. , Stokes Andrew C.
Published: January 2023

Accurate and timely tracking of COVID-19 deaths is essential to a well-functioning public health surveillance system. The extent to which official COVID-19 death tallies have captured the true toll of the pandemic in the United States is unknown. In the current study, we develop a Bayesian hierarchical model to estimate monthly excess mortality in each county over the first two years of the pandemic and compare these estimates to the number of deaths officially attributed to Covid-19 on death certificates. Overall, we estimated that 268,176 excess deaths were not reported as Covid-19 deaths during the first two years of the Covid-19 pandemic, which represented 23.7% of all excess deaths that occurred. Differences between excess deaths and reported COVID-19 deaths were substantial in both the first and second year of the pandemic. Excess deaths were less likely to be reported as COVID-19 deaths in the Mountain division, in the South, and in nonmetro counties. The number of excess deaths exceeded COVID-19 deaths in all Census divisions except for the New England and Middle Atlantic divisions where there were more COVID-19 deaths than excess deaths in large metro areas and medium or small metro areas. Increases in excess deaths not assigned to COVID-19 followed similar patterns over time to increases in reported COVID-19 deaths and typically preceded or occurred concurrently with increases in reported COVID-19 deaths. Estimates from this study can be used to inform targeting of resources to areas in which the true toll of the COVID-19 pandemic has been underestimated.
Cutaneous immune-related adverse events are associated with longer overall survival in advanced cancer patients on immune checkpoint inhibitors: a multi-institutional cohort study
Authors: Zhang Shijia , Tang Kimberly , Wan Guihong , Nguyen Nga , Lu Chenyue , Ugwu-Dike Pearl , Raval Neel , Seo Jayhyun , Alexander Nora A. , Jairath Ruple , Phillipps Jordan , Leung Bonnie W. , Roster Kathleen , Chen Wenxin , Zubiri Leyre , Boland Genevieve , Chen Steven T. , Tsao Hensin , Demehri Shadmehr , LeBoeuf Nicole R. , Reynolds Kerry L. , Yu Kun-Hsing , Gusev Alexander , Kwatra Shawn G. , Semenov Yevgeniy R.
Published: January 2023

Background

Cutaneous immune-related adverse events (cirAEs) occur in up to 40% of immune checkpoint inhibitor (ICI) recipients. However, the association of cirAEs with survival remains unclear.

Objective

To investigate the association of cirAEs with survival among ICI recipients.

Methods

ICI recipients were identified from the Mass General Brigham healthcare system (MGB) and Dana-Farber Cancer Institute (DFCI). Patient charts were reviewed for cirAE development within 2 years after ICI initiation. Multivariate time-varying Cox proportional hazards models, adjusted for age, sex, race/ethnicity, Charlson Comorbidity Index, ICI type, cancer type, and year of ICI initiation were utilized to investigate the impact of cirAE development on overall survival.

Results

Of the 3,731 ICI recipients, 18.1% developed a cirAE. 6-month landmark analysis and time-varying Cox proportional hazards models demonstrated that patients who developed cirAEs were associated with decreased mortality (HR=0.87,p=0.027), particularly in melanoma patients (HR=0.67,p=0.003). Among individual morphologies, lichenoid eruption (HR=0.51,p<0.001), psoriasiform eruption (HR=0.52,p=0.005), vitiligo (HR=0.29,p=0.007), isolated pruritus without visible manifestation of rash (HR=0.71,p=0.007), acneiform eruption (HR =0.34,p=0.025), and non-specific rash (HR=0.68, p<0.001) were significantly associated with better survival after multiple comparisons adjustment.

Limitations

Retrospective design; single geography.

Conclusion

CirAE development is associated with improved survival among ICI recipients, especially melanoma patients.

Capsule Summary

Patients on immune checkpoint inhibitors (ICIs) who developed cutaneous immune-related adverse events (cirAEs) had favorable outcomes. This was especially notable for melanoma patients who had cirAEs, both those with vitiligo and other morphologies.

Development of cirAEs in ICI-treated patients can be used to prognosticate survival and guide treatment decisions.
Patulin contamination of hard apple cider by Paecilomyces niveus and other postharvest apple pathogens: assessing risk factors
Authors: Wang Tristan W. , Wilson Amanda G. , Peck Gregory M. , Gibney Patrick A. , Hodge Kathie T.
Published: January 2023

Hard apple cider is considered to be a low-risk product for food spoilage and mycotoxin contamination due to its alcoholic nature and associated food sanitation measures. However, the thermotolerant mycotoxin-producing fungusPaecilomyces niveusmay pose a significant threat to hard cider producers.Pa. niveusis known to infect apples (Malusxdomestica), and previous research indicates that it can survive thermal processing and contaminate finished apple juice with the mycotoxin patulin. To determine if hard apple cider is susceptible to a similar spoilage phenomenon, cider apples were infected withPa. niveusor one of three patulin-producingPenicilliumspecies and the infected fruits underwent benchtop fermentation. Cider was made with lab inoculated Dabinett and Medaille d’Or apple cultivars, and patulin was quantified before and after fermentation. Results show that all four fungi can infect cider apples and produce patulin, some of which is lost during fermentation. OnlyPa. niveuswas able to actively grow throughout the fermentation process. To determine if apple cider can be treated to hinderPa. niveusgrowth, selected industry-grade sanitation measures were tested, including chemical preservatives and pasteurization. High concentrations of preservatives inhibitedPa. niveusgrowth, but apple cider flash pasteurization was not found to significantly impact spore germination. This study confirms that hard apple cider is susceptible to fungal-mediated spoilage and patulin contamination.Pa. niveusshould be of great concern to hard apple cider producers due to its demonstrated thermotolerance, survival in fermentative environments, and resistance to sanitation measures.

Highlights

Apple fruits of traditional cider cultivars Dabinett and Medaille d’Or were found to be susceptible to infection by three patulin-producingPenicilliumspp. andPaecilomyces niveus

Pa. niveuscan grow in finished fermented hard cider at 5.22% ethanol

Patulin levels in cider were reduced by fermentation but still exceeded 50 µg/kg, a maximum limit set by various regulatory agencies

Pa. niveuswas observed to be able to grow in low concentrations of three preservatives: potassium sorbate, sulfur dioxide, and sodium benzoate
Antibody-drug conjugates to treat bacterial biofilms
Authors: Tvilum Anne , Johansen Mikkel I. , Glud Lærke N. , Ivarsen Diana M. , Khamas Amanda B. , Carmali Sheiliza , Mhatre Snehit Satish , Søgaard Ane B. , Faddy Emma , de Vor Lisanne , Rooijakkers Suzan H.M. , Østergaard Lars , Jørgensen Nis P. , Meyer Rikke L. , Zelikin Alexander N.
Published: January 2023

Implant-associated infections remain a grand unmet medical need because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells. There is an urgent need for new biofilm-targeting therapies with antimicrobials, to treat these infections via a non-surgical way. In this work, we address this urgent medical need and engineer antibody-drug conjugates (ADC) that kill bacteria in suspension and in biofilms,in vitroandin vivo. The ADC contains an anti-neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. While most ADCs are clinically validated as anti-cancer therapeutics where the drug is released after internalisation of the ADC in the target cell, the ADCs designed herein release the conjugated drug without cell entry. This is achieved with a novel mechanism of drug, which likely involves an interaction of ADC with thiols on the bacterial cell surface. ADC targeted towards bacteria were superior by the afforded antimicrobial effects compared to the non-specific counterpart, in suspension and within biofilms,in vitroandin vivo. An implant-associated murine osteomyelitis model was then used to demonstrate the ability of the antibody to reach the infection, and the superior antimicrobial efficacy compared to standard antibiotic treatmentin vivo. Our results illustrate the development of ADCs into a new area of application with a significant translational potential.
Cluster size determines morphology of transcription factories in human cells
Authors: Semeraro Massimiliano , Negro Giuseppe , Forte Giada , Suma Antonio , Gonnella Giuseppe , Cook Peter R. , Marenduzzo Davide
Published: January 2023

Transcription is a fundamental cellular process, and the first step of gene expression. In human cells, it depends on the binding to chromatin of various proteins, including RNA polymerases and numerous transcription factors (TFs). Observations indicate that these proteins tend to form macromolecular clusters, known astranscription factories, whose morphology and composition is still debated. While some microscopy experiments have revealed the presence ofspecialised factories, composed of similar TFs transcribing families of related genes, sequencing experiments suggest instead that mixed clusters may be prevalent, as a panoply of different TFs binds promiscuously the same chromatin region. The mechanisms underlying the formation of specialised or mixed factories remain elusive. With the aim of finding such mechanisms, here we develop a chromatin polymer model mimicking the chromatin binding-unbinding dynamics of different types of complexes of TFs. Surprisingly, both specialised (i.e., demixed) and mixed clusters spontaneously emerge, and which of the two types forms depends mainly on cluster size. The mechanism promoting mixing is the presence of non-specific interactions between chromatin and proteins, which become increasingly important as clusters become larger. This result, that we observe both in simple polymer models and more realistic ones for human chromosomes, reconciles the apparently contrasting experimental results obtained. Additionally, we show how the introduction of different types of TFs strongly affects the emergence of transcriptional networks, providing a pathway to investigate transcriptional changes following gene editing or naturally occurring mutations.
Divergent Proteome Reactivity Influences Arm-Selective Activation of Pharmacological Endoplasmic Reticulum Proteostasis Regulators
Authors: Kline Gabriel M. , Paxman Ryan J , Lin Chung-Yon , Madrazo Nicole , Grandjean Julia M. , Lee Kyunga , Nugroho Karina , Powers Evan T. , Wiseman R. Luke , Kelly Jeffery W.
Published: January 2023

Pharmacological activation of the activating transcription factor 6 (ATF6) arm of the Unfolded Protein Response (UPR) has proven useful for ameliorating proteostasis deficiencies in a variety of etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino-p-cresol substructure affording a quinone methide, which then covalently modifies a subset of ER protein disulfide isomerases (PDIs). Intriguingly, another compound identified in this screen, AA132, also contains a 2-amino-p-cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent PDI modification. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. Paradoxically, activated AA132 reacts slower with PDIs, indicating it is less reactive than activated AA147. This suggests that the higher labeling of PDIs observed with activated AA132 can be attributed to its lower reactivity, which allows this activated compound to persist longer in the cellular environment prior to quenching by endogenous nucleophiles. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and allows for selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.
Isoginkgetin and Madrasin are poor splicing inhibitors
Authors: Tellier Michael , Ansa Gilbert , Murphy Shona
Published: January 2023

The production of eukaryotic mRNAs requires transcription by RNA polymerase (pol) II and co-transcriptional processing, including capping, splicing, and cleavage and polyadenylation. Pol II can positively affect co-transcriptional processing through interaction of factors with its carboxyl terminal domain (CTD), comprising 52 repeats of the heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7, and pol II elongation rate can regulate splicing. Splicing, in turn, can also affect transcriptional activity and transcription elongation defects are caused by some splicing inhibitors. Multiple small molecule inhibitors of splicing are now available, some of which specifically target SF3B1, a U2 snRNP component. SF3B1 inhibition results in a general downregulation of transcription elongation, including premature termination of transcription caused by increased use of intronic poly(A) sites. Here, we have investigated the effect of Madrasin and Isoginkgetin, two non-SF3B1 splicing inhibitors, on splicing and transcription. Surprisingly, we found that both Madrasin and Isoginkgetin affect transcription before any effect on splicing, indicating that their effect on pre-mRNA splicing is likely to be indirect. Both small molecules promote a general downregulation of transcription. Based on these and other published results, we conclude that these two small molecules should not be considered as primarily pre-mRNA splicing inhibitors.
Anti-CRISPR AcrIIC5 is a dsDNA mimic that inhibits type II-C Cas9 effectors by blocking PAM recognition
Authors: Sun Wei , Zhao Xiaolong , Wang Jinlong , Yang Xiaoqi , Cheng Zhi , Liu Shuo , Wang Jiuyu , Sheng Gang , Wang Yanli
Published: January 2023

Anti-CRISPR proteins are encoded by phages to inhibit the CRISPR-Cas systems of the hosts. AcrIIC5 inhibits several naturally high-fidelity type II-C Cas9 enzymes, including orthologs fromNeisseria meningitidis(Nme1Cas9) andSimonsiella muelleri(SmuCas9). Here, we solve the structure of AcrIIC5 in complex with Nme1Cas9 and sgRNA. We show that AcrIIC5 adopts a novel fold to mimic the size and charge distribution of double-stranded DNA, and uses its negatively charged grooves to bind and occlude the protospacer adjacent motif (PAM) binding site in the target DNA cleft of Cas9. AcrIIC5 is positioned into the crevice between the WED and PI domains of Cas9, and one end of the anti-CRISPR interacts with the phosphate lock loop and a linker between the RuvC and BH structural domains. We employ biochemical and mutational analyses to build a model for AcrIIC5’s mechanism of action, and identify residues on both the anti-CRISPR and Cas9 that are important for their interaction and inhibition. Together, the structure and mechanism of AcrIIC5 reveal convergent evolution among disparate anti-CRISPR proteins that use a DNA-mimic strategy to inhibit diverse CRISPR-Cas surveillance complexes, and provide new insights into a tool for potent inhibition of type II-C Cas9 orthologs.
An insular cortex to lateral amygdala pathway in fear learning
Authors: Palchaudhuri Shriya , Osypenko Denys , Kochubey Olexiy , Schneggenburger Ralf
Published: January 2023

During fear learning, associations between an aversive stimulus (the US), and a sensory cue (CS) are formed at specific brain synapses. Nevertheless, how US information is transmitted to brain areas involved in value processing, like the amygdala, is still elusive. Using optogenetics,in-vivoCa2+imaging, and circuit tracing, we investigate the role of the posterior insular cortex (pInsCx) and relevant output pathways of this cortical area in fear learning. Optogenetic suppression of US-signaling in pInsCx principal neurons compromises auditory-cued fear learning. The pInsCx makes a robust glutamatergic synapse in the lateral amygdala (LA), which undergoes long-term potentiation after fear learning, and transmits US-information to a sub-population of LA neurons. Suppressing US-signaling in LA-projectors recapitulates the fear learning deficits observed after silencing pInsCx principal neurons. Thus, the pInsCx, via a plastic output synapse, transmits US-information to the LA and critically contributes to the formation of auditory-cued fear memories.
p53 controls choice between apoptotic and non-apoptotic death following DNA damage
Authors: Honeywell Megan E. , Isidor Marie S. , Harper Nicholas W. , Fontana Rachel E. , Gordillo Peter Cruz- , Porto Sydney A. , Fraser Cameron S. , Sarosiek Kristopher A. , Guertin David A. , Spinelli Jessica B. , Lee Michael J.
Published: January 2023

DNA damage can activate apoptotic and non-apoptotic forms of cell death; however, it remains unclear what features dictate which type of cell death is activated. We report that p53 controls the choice between apoptotic and non-apoptotic death following exposure to DNA damage. In contrast to the conventional model, which suggests that p53-deficient cells should be resistant to DNA damage-induced cell death, we find that p53-deficient cells die at high rates following DNA damage, but exclusively using non-apoptotic mechanisms. Our experimental data and computational modeling reveal that non-apoptotic death in p53-deficient cells has not been observed due to use of assays that are either insensitive to cell death, or that specifically score apoptotic cells. Using functional genetic screening – with an analysis that enables computational inference of the drug-induced death rate – we find in p53-deficient cells that DNA damage activates a mitochondrial respiration-dependent form of cell death, called MPT-driven necrosis. Cells deficient for p53 have high basal respiration, which primes MPT-driven necrosis. Finally, using metabolite profiling, we identified mitochondrial activity-dependent metabolic vulnerabilities that can be targeted to potentiate the lethality of DNA damage specifically in p53-deficient cells. Our findings reveal how the dual functions of p53 in regulating mitochondrial activity and the DNA damage response combine to facilitate the choice between apoptotic and non-apoptotic death.
Migrating neurons adapt motility modes to brain microenvironments via a mechanosensor, PIEZO1
Authors: Nakazawa Naotaka , Grenci Gianluca , Kameo Yoshitaka , Takeda Noriko , Sawada Tsuyoshi , Kurisu Junko , Zhang Zhejing , Adachi Taiji , Nonomura Keiko , Kengaku Mineko
Published: January 2023

Migration of newborn neurons is essential for brain morphogenesis and circuit formation, yet controversy exists regarding how neurons generate the driving force against strong mechanical stresses in crowded neural tissues. We found that cerebellar granule neurons adopt differential motility modes in distinct extracellular environments. In 3-dimensional (3D) confinement, actomyosin produces contractile forces at the posterior cell membrane, in addition to the traction force in the leading process that is exclusively observed in 2D cultures. The 3D migration is initiated by activation of a mechanosensitive channel PIEZO1. PIEZO1-induced calcium influx in the soma triggers the PKC-ezrin cascade, which recruits actomyosin to the posterior plasma membrane. Thus, migrating neurons use a mechano-sensing mechanism to activate multiple driving forces to maneuver in irregular brain tissue.

One-Sentence Summary

Cerebellar granule neurons use a mechanosensor PIEZO1 to switch migratory modes in confined spaces.
A deep generative model of the SARS-CoV-2 spike protein predicts future variants
Authors: Dhodapkar Rahul M.
Published: January 2023

Abstract

SARS-CoV-2 has demonstrated a robust ability to adapt in response to environmental pressures—increasing viral transmission and evading immune surveillance by mutating its molecular machinery. While viral sequencing has allowed for the early detection of emerging variants, methods to predict mutations before they occur remain limited. This work presents SpikeGPT2, a deep generative model based on ProtGPT2 and fine-tuned on SARS-CoV-2 spike (S) protein sequences deposited in the NIH Data Hub before May 2021. SpikeGPT2 achieved 88.8% next-residue prediction accuracy and successfully predicted amino acid substitutions found only in a held-out set of spike sequences deposited on or after May 2021, to which SpikeGPT2 was never exposed. When compared to several other methods, SpikeGPT2 achieved the best performance in predicting such future mutations. SpikeGPT2 also predicted several novel variants not present in the NIH SARS-CoV-2 Data Hub. A binding affinity analysis of all 54 generated substitutions identified 5 (N439A, N440G, K458T, L492I, and N501Y) as predicted to simultaneously increase S/ACE2 affinity, and decrease S/tixagevimab+cilgavimab affinity. Of these, N501Y has already been well-described to increase transmissibility of SARS-CoV-2. These findings indicate that SpikeGPT2 and other similar models may be employed to identify high-risk future variants before viral spread has occurred.
Matching queried single-cell open-chromatin profiles to large pools of single-cell transcriptomes and epigenomes for reference supported analysis
Authors: Mishra Shreya , Pandey Neetesh , Chawla Smriti , Sharma Madhu , Chandra Omkar , Jha Indra Prakash , SenGupta Debarka , Natarajan Kedar Nath , Kumar Vibhor
Published: January 2023

The true benefits of large single-cell transcriptome and epigenome data sets can be realized only with the development of new approaches and search tools for annotating individual cells. Matching a single-cell epigenome profile to a large pool of reference cells remains a major challenge. Here, we present scEpiSearch, which enables searching, comparison, and independent classification of single-cell open-chromatin profiles against a large reference of single-cell expression and open-chromatin data sets. Across performance benchmarks, scEpiSearch outperformed multiple methods in accuracy of search and low-dimensional coembedding of single-cell profiles, irrespective of platforms and species. Here we also demonstrate the unconventional utilities of scEpiSearch by applying it on single-cell epigenome profiles of K562 cells and samples from patients with acute leukaemia to reveal different aspects of their heterogeneity, multipotent behavior, and dedifferentiated states. Applying scEpiSearch on our single-cell open-chromatin profiles from embryonic stem cells (ESCs), we identified ESC subpopulations with more activity and poising for endoplasmic reticulum stress and unfolded protein response. Thus, scEpiSearch solves the nontrivial problem of amalgamating information from a large pool of single cells to identify and study the regulatory states of cells using their single-cell epigenomes.
A temporal in vivo catalog of chromatin accessibility and expression profiles in pineoblastoma reveals a prevalent role for repressor elements
Authors: Idriss Salam , Hallal Mohammad , El-Kurdi Abdullah , Zalzali Hasan , El-Rassi Inaam , Ehli Erik A. , Davis Christel M. , Chung Philip E.D. , Gendoo Deena M.A. , Zacksenhaus Eldad , Saab Raya , Khoueiry Pierre
Published: January 2023

Pediatric pineoblastomas (PBs) are rare and aggressive tumors of grade IV histology. Although some oncogenic drivers are characterized, including germline mutations in RB1 and DICER1, the role of epigenetic deregulation andcis-regulatory regions in PB pathogenesis and progression is largely unknown. Here, we generated genome-wide gene expression, chromatin accessibility, and H3K27ac profiles covering key time points of PB initiation and progression from pineal tissues of a mouse model ofCCND1-driven PB. We identified PB-specific enhancers and super-enhancers, and found that in some cases, the accessible genome dynamics precede transcriptomic changes, a characteristic that is underexplored in tumor progression. During progression of PB, newly acquired open chromatin regions lacking H3K27ac signal become enriched for repressive state elements and harbor motifs of repressor transcription factors like HINFP, GLI2, and YY1. Copy number variant analysis identified deletion events specific to the tumorigenic stage, affecting, among others, the histone gene cluster andGas1, the growth arrest specific gene. Gene set enrichment analysis and gene expression signatures positioned the model used here close to human PB samples, showing the potential of our findings for exploring new avenues in PB management and therapy. Overall, this study reports the first temporal and in vivocis-regulatory, expression, and accessibility maps in PB.
Caregivers experiences of caring for people with intellectual disability and dementia: a qualitative evidence synthesis
Authors: Acton Daniel James , Jaydeokar Sujeet , Jones Steven
Published: January 2023

Purpose

A systematic review of the literature was completed to examine the needs of those who provide care to people with intellectual disability and dementia. The purpose of this paper was to develop an understanding of the complexities, challenges and support available to meet the needs of an ageing population.

Design/methodology/approach

A qualitative evidence synthesis was used to appraise 12 studies. An evidence synthesis approach was used to better understand the challenges caregivers experience in caring for a person with intellectual disability and dementia. Aggregating and integrating findings from multiple studies allowed to identify inconsistencies, quality, relationships and trends to enhance the awareness of gaps in care provision.

Findings

There were six main domains identified from the available literature which included: gaps in knowledge and skills, early identification of dementia and associated difficulties, managing behaviour, coping, burden of care and Impact on confidence.

Originality/value

To the best of the authors’ knowledge, this is the first paper to use qualitative evidence synthesis to understand the challenges of caring for a person with intellectual disability and dementia.
As easy as OEE: enabling productivity improvement in schools by using overall equipment effectiveness as framework for classroom data analysis
Authors: Doyer Ilse , Bean Wilna L.
Published: January 2023

Purpose

The purpose of this paper was to develop a quantitative classroom observation method that is able to analyse the school day to identify Time-on-Task losses comprehensively and systematically, at a level of detail that can be used by teachers and principals to stimulate and focus practical improvement efforts.

Design/methodology/approach

The novel Time-on-Task Analysis (TOTA) model was developed by triangulating the conceptual framework of the Overall Equipment Effectiveness metric with the semantics and structure of the target domain. Once developed, the model was tested structurally against a time-series classroom observation data set, after which the resulting TOTA was presented to a sample of 52 education stakeholders, who then gave their perspectives of the analysis in a structured survey.

Findings

The ontological model was found to be accurate, complete and without conceptual incongruencies, and its output novel and useful by the sample of education stakeholders. Of the participants, 90.3% found the analysis to provide a new perspective, 94.2% reported that the analysis triggered improvement ideas and 80.8% thought that their school(s) could benefit from a TOTA study.

Originality/value

The TOTA model introduces a time-loss-focused perspective to the field of quantitative classroom observation studies, which is dominated by more sociologic- and pedagogic-focused topics. Its grounding in Overall Equipment Effectiveness also gives it a more detailed and systematic approach than the few Time-on-Task studies done to date, resulting in a model made for the “Gemba”: the school classroom.
Women entrepreneurs in the craft industry: a case study of the batik industry during the COVID-19 pandemic
Authors: Anggadwita Grisna , Indarti Nurul , Ratten Vanessa
Published: January 2023

Purpose

Batik is a craft in the creative industry, which is the identity of the Indonesian nation. One of the main batik tourism areas in Indonesia is Trusmi, and women entrepreneurs have a strategic role in developing the batik craft industry in the region. The batik industry faced various challenges during coronavirus disease 2019 (COVID-19). Therefore, this study aims to explore the impact and identify strategic options during the COVID-19 period on batik businesses owned by women entrepreneurs in the Trusmi area.

Design/methodology/approach

This study uses a qualitative case study method by interviewing ten batik women entrepreneurs in the Trusmi area.

Findings

This study elaborates findings about the impact of COVID-19, the technology role, collaboration, the government role and strategic options.

Originality/value

This study provides academic and practical implications, which are discussed further about the role of the craft industry in dealing with economic and social turmoil.
The impact of remote working on employee productivity during COVID-19 in the UAE: the moderating role of job level
Authors: Kurdy Dania M. , Al-Malkawi Husam-Aldin Nizar , Rizwan Shahid
Published: January 2023

Purpose

The purpose of this study is to examine the various factors that influence the productivity (PR) of employees who worked remotely in the United Arab Emirates (UAE) during the COVID-19 pandemic.

Design/methodology/approach

This study adopts a quantitative approach to analyze data collected online from 110 respondents using the snowball sampling technique during the pandemic. The analysis of the data is conducted using the structural equation modeling (SEM) technique of Smart PLS (Partial least squares) to evaluate the direct and moderating variables.

Findings

The results indicate that direct variables such as workload, job satisfaction, work–life balance and social support have a significant positive impact on employee PR in the UAE. However, the analysis of the moderating variable indicates that job level is not a significant moderator of the above relationships. The findings, generally, provide support for social exchange theory.

Practical implications

The findings of this study will help businesses of various domains in a variety of industries in understanding the core factors that should be considered to enhance the overall PR of their employees while working from home. Businesses can achieve their organizational goals by ensuring steady growth even during uncertain times.

Originality/value

This paper answers the question of whether remote working affects employee PR during the pandemic in an emerging market, namely the UAE. The current study contributes to the existing literature by combining the variables investigated in previous studies into a single study and by considering job level as a moderator variable.
Ghana’s green building assessment journey: an appraisal of the thermal performance of an office building in Accra
Authors: Koranteng Christian , Simons Barbara , Abrokwa Gyimah Kwabena , Nkrumah Jimmy
Published: January 2023

Purpose

Accra, the capital city of Ghana, is seeing high-rise buildings springing up with extensive glazing. Given the challenges of the country concerning energy provision, guaranteeing comfort in buildings and sustainability aspects, this trend is questionable and worrying in this pandemic era. Therefore, the purpose of this paper is to evaluate how glazing types and their properties could reduce cooling loads and provide comfort by following the recommendations set by the Ghana Green Building Council (GHGBC) after the Green Star of South Africa, as well as other references found in literature.

Design/methodology/approach

Indoor thermal conditions were monitored to evaluate prevailing indoor conditions. Using a simulation application, various options were probed based on the Green recommendations and others found in literature to improve thermal comfort within the structure. Moreover, a questionnaire survey with observation was undertaken with 250 architects to understand the basis of decisions taken when specifying glazing for buildings.

Findings

The results indicate that cooling loads increased by 2% when the GHGBC after the Green Star of South Africa recommendations were applied. However, the use of the recommendations of previous research conducted in Ghana could reduce cooling loads by 38% to save energy. Suggested strategies of air velocity up to 1.0 m/s as well as thermal mass, comfort ventilation, conventional dehumidification and air-conditioning were found to be means to improve indoor comfort. Furthermore, the architects revealed that around 40% of multi-storey buildings are 70%–100% glazed. Of all the buildings, 62.4% was found to be glazed with single pane windows, making them use so much energy in cooling. Additionally, the survey underlined the client’s preference, cost and functionality as the three main bases for the choice of glazing in multi-storey office buildings.

Originality/value

A significant contribution of this study to the body of knowledge is the provision of empirical evidence to support the fact that due to climate difference, each country needs to undertake more experimental research works to be able to come out with standards that work. Thus, the GHGBC after the Green Star of South Africa does not necessarily work within the climatic context of Ghana.
Determinants of sustainability of participatory budgeting: Slovak perspective
Authors: Murray Svidroňová Mária , Benzoni Baláž Martina , Klimovský Daniel , Kaščáková Alena
Published: January 2023

Purpose

The purpose of this research is to identify and test selected economic and organisational factors influencing the sustainability of participatory budgeting (PB) in Slovakia.

Design/methodology/approach

The data were collected from websites and publicly available documents from all local governments with urban municipality status in Slovakia, for a total of 155 municipalities, 59 of which have established a participatory budget. The main method applied was correlation analysis.

Findings

The findings indicate: (1) a weak inverse correlation between debt level and the continuous existence of PB in municipalities; (2) a moderate direct correlation between the duration of PB in a municipality and integration of PB in its programme budgeting; (3) a moderate direct correlation between the duration of PB in a municipality and the political experience of the mayor.

Research limitations/implications

The findings are derived from a quantitative analysis of cases localised in a single country, and therefore interpretation requires an awareness of the context of local democracy in Slovakia. In this regard, any generalisation beyond the context under study needs to be considered with caution.

Originality/value

This research fills a gap in the role of PB in the context of sustainability, especially in the context of a post-communist country like Slovakia. It applies a quantitative approach to the analysis of PB, which is relatively rare in this field of study (qualitative case studies are predominant in PB research).
Which brands do consumers become attached to? The roles of brand concepts and brand positioning in the context of COVID-19
Authors: Cai Yuanyuan , Wang Mengmeng , Huang Haiyang , Jiang Quanyu
Published: January 2023

Purpose

The COVID-19 pandemic has dramatically disrupted everyday life, leading to a cascade of negative emotional responses such as death anxiety. Against this backdrop, the purpose of this paper is to focus on the buffering effect of brand attachment on death anxiety by exploring the roles of brand concepts and brand positioning on psychological compensation for security.

Design/methodology/approach

This multi-method paper features four studies and shows how brands can offer emotional support under high-risk circumstances.

Findings

Study 1 includes two surveys which offer preliminary evidence that death anxiety can enhance consumers’ brand attachment. Study 2 reveals a causal effect wherein consumers experiencing death anxiety are more likely to attach to brands with a self-transcendence (vs self-enhancement) concept. Study 3 examines the mediating role of need for security in the relationship between death anxiety and attachment to brands with a self-transcendence concept. Further, Study 4 indicates the moderating role of brand positioning: self-transcendence brands adopting local (vs global) positioning strategies are more likely to satisfy consumers’ need for security, thereby leading to strong brand attachment.

Originality/value

The findings of this paper contribute to the brand attachment literature and to the global branding literature regarding consumers’ emotional responses in the context of COVID-19. This paper innovatively frames brand concepts and brand positioning and provides actionable guidelines to help brands satisfy consumers’ needs amid a worldwide crisis.
The career of a suicidologist
Authors: Lester David
Published: January 2023

Purpose

This essay aims to describe how the author began his career as a suicidologist and his style that made him so productive.

Design/methodology/approach

The author used autobiographical details to illustrate the elements of his career.

Findings

Childhood experiences include sleeping in air raid shelter from 1942 to 1945 in London (UK), while his style includes obsessiveness in reading everything on suicide, applying ideas from other fields (such as economics) to the study of suicide and obtaining academic freedom early in his career.

Originality/value

The essay offers guidelines for others who are in the early stages of a career as a researcher.
Synergistic effect of TQM-SCM initiatives in organizational performance: evidence from the service (logistics) sector
Authors: Shaikh Shazia Shaheen , Huaming Song , Ameer Muhammad Saad
Published: January 2023

Purpose

This study aims to explore the synergetic effects of total quality management and supply chain management (TQM–SCM) initiatives and their effects on organizational performance (OP). This research has been conducted in Pakistan’s logistics sector. The research reveals the synergistic effect of TQM and SCM initiatives and their effects on OP.

Design/methodology/approach

The constructs of the TQM and SCM were chosen after reviewing the literature that was critical for the logistics sector. The synergetic effect of TQM–SCM on OP has been evaluated. The mediating, direct and indirect effects were also evaluated in different models independently. Structural equation modelling was applied to drive the results via using AMOS.

Findings

It was observed during the analysis that both the TQM and SCM have a significant effect on OP. Both TQM initiatives have directly correlated to the improvement in SCM, and both have a positive effect on an organization. This research study has aided logistics firms that are focusing on TQM and SCM planning and implementation. The results can give management a better and more in-depth knowledge of the TQM initiatives and OP.

Research limitations/implications

The data was collected through email and personal visits from different organizations. The data was collected through an adopted questionnaire. It is found in the study that many people at the managerial level have limited knowledge regarding SCM and TQM. The results may vary if the knowledge of the employees is improved.

Practical implications

The current study presents an upscale addition by examining the function of SCM and TQM linkage in OP as well as their relationship. The evaluated model serves as a guideline for firms looking to expand and achieve maximal OP.

Social implications

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Originality/value

The evaluated model is developed in this study that serves as a guideline for firms looking to expand a new method to reach maximum OP.