bluuebunny/crossref_metadata_2025 huggingface dataset:
NRPreTo: A Machine Learning Based Nuclear Receptor and Subfamily Prediction Tool
Authors: Madugula Sita Sirisha , Pandey Suman , Amalapurapu Shreya , Bozdag Serdar
Published: November 2022

The Nuclear Receptor (NR) superfamily includes phylogenetically related ligand-activated proteins, which play a key role in various cellular activities. NR proteins are subdivided into seven subfamilies based on their function, mechanism, and nature of the interacting ligand. Developing robust tools to identify NR could give insights into their functional relationships and involvement in disease pathways. Existing NR prediction tools only use a few types of sequence-based features and are tested on relatively similar independent datasets; thus, they may suffer from overfitting when extended to new genera of sequences. To address this problem, we developed Nuclear Receptor Prediction Tool (NRPreTo); a two-level NR prediction tool with a unique training approach where in addition to the sequence-based features used by existing NR prediction tools, six additional feature groups depicting various physiochemical, structural and evolutionary features of proteins were utilized. The first level of NRPreTo allows for the successful prediction of a query protein as NR or non-NR, and further subclassifies the protein into one of the seven NR subfamilies in the second level. We developed Random Forest classifiers to test on benchmark datasets, as well as the entire human protein datasets from RefSeq and Human Protein Reference Database (HPRD). We observed that using additional feature groups improved performance. We also observed that NRPreTo achieved high performance on the external datasets and predicted 59 novel NRs in the human proteome. The source code of NRPreTo is publicly available athttps://github.com/bozdaglab/NRPreTo.
Colonisation debt: when invasion history impacts current range expansion
Authors: Morel-Journel Thibaut , Haond Marjorie , Dunan Lana , Mailleret Ludovic , Vercken Elodie
Published: November 2022

Demographic processes that occur at the local level, such as positive density dependence in growth or dispersal, are known to shape population range expansion, notably by linking carrying capacity to invasion speed. As a result of these processes, the advance of an invasion front depends both on populations in the core of the invaded area and on small populations at the edge. While the impact on velocity is easily tractable in homogeneous environment, information is lacking on how speed varies in heterogeneous environment due to density dependence. In this study, we tested the existence of a ‘colonisation debt’, which corresponds to the impact of conditions previously encountered by an invasion front on its future advances. Due to positive density dependence, invasions are expected to spread respectively slower and faster, along the gradients of increasing and decreasing carrying capacity, with stronger differences as the gradient slope increases. Using simulated invasions in a one-dimensional landscape with periodically varying carrying capacity, we confirmed the existence of the colonisation debt when density-dependent growth or dispersal was included. Additional experimental invasions using a biological model known to exhibit positive density-dependent dispersal confirmed the impact of the carrying capacity of the patch behind the invasion front on its progression, the mechanism behind the colonisation debt.
The insulating activity of theDrosophilaBX-C chromatin boundaryFub-1is parasegmentally regulated by lncRNA read-through
Authors: Ibragimov Airat , Bing Xin Yang , Shidlovskii Yulii , Levine Mike , Georgiev Pavel , Schedl Paul
Published: November 2022

Though long non-coding RNAs (lncRNAs) represent a substantial fraction of the Pol II transcripts in multicellular animals, only a few have known functions. Here we report that the blocking activity of the Bithorax complex (BX-C)Fub-1boundary is segmentally regulated by its own lncRNA. TheFub-1boundary is located between theUltrabithorax(Ubx) gene and thebxd/pbxregulatory domain, which is responsible for regulatingUbxexpression in parasegment PS6/segment A1.Fub-1consists of two hypersensitive sites,HS1andHS2. HS1is an insulator whileHS2functions primarily as a lncRNA promoter. To activateUbxexpression in PS6/A1 enhancers in thebxd/pbxdomain must be able to bypassFub-1blocking activity. We show that expression of theFub-1lncRNAs in PS6/A1 from theHS2promoter inactivatesFub-1insulating activity. Inactivation is due to readthrough as theHS2promoter must be directed towardsHS1to disrupt blocking.
Formation Of Small-World Network Containing Module Networks In Globally And Locally Coupled Map System With Changes In Global Connection With Time Delay Effects
Authors: Nakanishi Taito , Awazu Akinori
Published: November 2022

In this study, we performed comprehensive morphological investigations of spontaneously formed network structures among elements in coupled map systems involving global connections that change depending on the synchronicity of states of elements and spatially local connections. The model formed various hierarchical networks, some of which were classified as small-world networks containing multiple module networks, similar to the neural network of mammalian brains. Moreover, such complex networks were formed in wider parameter regions when the global connection to an element from the other element was strengthened by the synchronization between the present and past states of the former and latter elements, respectively. This study suggests that the time delay effects for connection changed among elements and local interactions promoted the self-organization of small-world networks containing module networks, such as neural networks; neural networks contain them as spike-timing-dependent plasticity and inter-neuron interaction through glial cells.
Long-term COVID-19 booster effectiveness by infection history and clinical vulnerability and immune imprinting
Authors: Chemaitelly Hiam , Ayoub Houssein H. , Tang Patrick , Coyle Peter , Yassine Hadi M. , Al Thani Asmaa A. , Al-Khatib Hebah A. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Faust Jeremy Samuel , Abu-Raddad Laith J.
Published: November 2022

Background

Long-term effectiveness of COVID-19 mRNA boosters in populations with different prior infection histories and clinical vulnerability profiles is inadequately understood.

Methods

A national, matched, retrospective, target trial cohort study was conducted in Qatar to investigate effectiveness of a third mRNA (booster) dose, relative to a primary series of two doses, against SARS-CoV-2 omicron infection and against severe COVID-19. Associations were estimated using Cox proportional-hazards regression models.

Results

Booster effectiveness relative to primary series was 41.1% (95% CI: 40.0-42.1%) against infection and 80.5% (95% CI: 55.7-91.4%) against severe, critical, or fatal COVID-19, over one-year follow-up after the booster. Among persons clinically vulnerable to severe COVID-19, effectiveness was 49.7% (95% CI: 47.8-51.6%) against infection and 84.2% (95% CI: 58.8-93.9%) against severe, critical, or fatal COVID-19. Effectiveness against infection was highest at 57.1% (95% CI: 55.9-58.3%) in the first month after the booster but waned thereafter and was modest at only 14.4% (95% CI: 7.3-20.9%) by the sixth month. In the seventh month and thereafter, coincident with BA.4/BA.5 and BA.2.75* subvariant incidence, effectiveness was progressively negative reaching -20.3% (95% CI: -55.0-29.0%) after one year of follow-up. Similar levels and patterns of protection were observed irrespective of prior infection status, clinical vulnerability, or type of vaccine (BNT162b2 versus mRNA-1273).

Conclusions

Boosters reduced infection and severe COVID-19, particularly among those clinically vulnerable to severe COVID-19. However, protection against infection waned after the booster, and eventually suggested an imprinting effect of compromised protection relative to the primary series. However, imprinting effects are unlikely to negate the overall public health value of booster vaccinations.
The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants
Authors: Pandit Jay A. , Radin Jennifer M. , Chiang Danielle , Spencer Emily , Pawelek Jeff , Diwan Mira , Roumani Leila , Mina Michael
Published: November 2022

Introduction

The uptake of Paxlovid in individuals infected with COVID-19 has been significantly limited by concerns around the Paxlovid rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of Paxlovid rebound in treated and untreated participants with acute COVID-19 infection

Methods

We designed a decentralized, digital, prospective observational study in which participants who tested positive for COVID-19 using eMed Test-to-Treat telehealth kits and were clinically eligible for Paxlovid were recruited to be evaluated for viral and symptom clearance, as well as rebound. Participants were assigned to a Paxlovid or control group based on their decision to take Paxlovid. Following initial diagnosis based on a telehealth proctored test both groups were provided 12 telehealth proctored rapid antigen home tests and asked to test on a regular frequent schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient reported symptoms were evaluated.

Results

Viral rebound incidence was 14.2% in the Paxlovid group (n=127) and 9.3% in the control group (n=43). COVID-19 symptom rebound incidence was higher in the Paxlovid group (18.9%) compared to the control group (7.0%). There were no notable differences in viral rebound by age, gender, pre-existing conditions, or major symptom groups during the acute phase or at the 1-month interval.

Conclusion

This preliminary report of our prospective study suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, we observed a similar rate of rebound in both in the Paxlovid and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.
Cerebellar-driven cortical dynamics enable task acquisition, switching and consolidation
Authors: Pemberton Joseph , Chadderton Paul , Costa Rui Ponte
Published: November 2022

To drive behavior, the cortex must bridge sensory cues with future outcomes. However, the principles by which cortical networks learn such sensory-behavioural transformations remain largely elusive. Here, we posit that the cerebellum assumes a crucial role in driving cortical dynamics, thereby enabling rapid and flexible task acquisition. We introduce a computational model of cerebellar networks which learn to drive cortical networks with task-outcome predictions. First, using sensorimotor tasks we show that cerebellar feedback in the presence of minimal cortical plasticity is suffcient for rapid task acquisition and multiple task switching. Next, we demonstrate that, when trained in working memory tasks, the cerebellum can also underlie the maintenance of cognitive-specific dynamics, explaining a range of optogenetic and behavioural observations. Finally, using our model we introduce a systems consolidation theory in which task information is gradually transferred from the cerebellum to the cortex. In summary, our findings suggest that cortico-cerebellar loops play a pivotal role in task acquisition, switching, and consolidation within the brain.
Targeting long non-coding RNANUDT6enhances smooth muscle cell survival and limits vascular disease progression
Authors: Winter Hanna , Winski Greg , Busch Albert , Chernogubova Ekaterina , Fasolo Francesca , Wu Zhiyuan , Bäcklund Alexandra , Khomtchouk Bohdan B. , Van Booven Derek J. , Sachs Nadja , Eckstein Hans-Henning , Wittig Ilka , Boon Reinier A. , Jin Hong , Maegdefessel Lars
Published: November 2022

Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6)and its antisense target Fibroblast Growth Factor 2 (FGF2)in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase ofNUDT6, whereasFGF2was downregulated. TargetingNudt6 in vivowith antisense oligonucleotides in three murine and one porcine animal models of carotid artery disease and AAA limited disease progression. Restoration of FGF2 uponNudt6knockdown improved vessel wall morphology and fibrous cap stability. Overexpression ofNUDT6 in vitroimpaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another directNUDT6interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifiesNUDT6as a well-conserved antisense transcript ofFGF2. NUDT6silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases.
The adenomatous polyposis coli protein 3o years on
Authors: Abbott James , Näthke Inke S.
Published: November 2022

Mutations in the gene encoding the Adenomatous polyposis coli protein (APC) were discovered as driver mutations in colorectal cancers almost 30 years ago. Since then, the importance of APC in normal tissue homeostasis has been confirmed in a plethora of other (model) organisms spanning a large evolutionary space. APC is a multifunctional protein, with roles as a key scaffold protein in complexes involved in diverse signalling pathways, most prominently the Wnt signalling pathway. APC is also a cytoskeletal regulator with direct and indirect links to and impacts on all three major cytoskeletal networks. Here, we interrogate the enormous depth of sequencing data now available to reveal the conservation of APC across taxonomy and relationships between different APC protein families.
The lncRNASweetheartregulates compensatory cardiac hypertrophy after myocardial injury
Authors: Rogala Sandra , Ali Tamer , Melissari Maria-Theodora , Währisch Sandra , Schuster Peggy , Sarre Alexandre , Boettger Thomas , Rogg Eva-Maria , Kaur Jaskiran , Krishnan Jaya , Dimmeler Stefanie , Ounzain Samir , Pedrazzini Thierry , Herrmann Bernhard G , Grote Phillip
Published: November 2022

After myocardial infarction in the adult heart the remaining, non-infarcted tissue adapts to compensate the loss of functional tissue. This adaptation requires changes in gene expression networks, which are mostly controlled by transcription regulating proteins. Long non-coding transcripts (lncRNAs) are now recognized for taking part in fine-tuning such gene programs. We identified and characterized the cardiomyocyte specific lncRNASweetheart RNA(Swhtr), an approximately 10 kb long transcript divergently expressed from the cardiac core transcription factor coding geneNkx2-5. We show thatSwhtris dispensable for normal heart development and function, but becomes essential for the tissue adaptation process after myocardial infarction. Re-expressingSwhtrfrom an exogenous locus rescues theSwhtr nullphenotype. Genes depending onSwhtrafter cardiac stress are significantly occupied, and therefore most likely regulated by NKX2-5. Our results indicate a synergistic role forSwhtrand the developmentally essential transcription factor NKX2-5 in tissue adaptation after myocardial injury.
An MR-based brain template and atlas for optical projection tomography and light sheet fluorescence microscopy
Authors: Willekens Stefanie M.A. , Morini Federico , Mediavilla Tomas , Nilsson Emma , Orädd Greger , Hahn Max , Chotiwan Nunya , Visa Montse , Berggren Per-Olof , Ilegemns Erwin , Överby Anna K. , Ahlgren Ulf , Marcellino Daniel
Published: November 2022

Optical projection tomography (OPT) and light sheet fluorescence microscopy (LSFM) are high-resolution optical imaging techniques operating in the mm-cm range, ideally suited forex vivo3D whole mouse brain imaging. Although these techniques exhibit high sensitivity and specificity for antibody-labeled targets, the provided anatomical information remains limited. To allow anatomical mapping of fluorescent signal in whole brain, we developed a novel magnetic resonance (MR) – based template with its associated tissue priors and atlas labels, specifically designed for brains subjected to tissue processing protocols required for 3D optical imaging. We investigated the effect of tissue pre-processing and clearing on brain size and morphology and developed optimized templates for BABB/Murrays clear (OCUM) and DBE/iDISCO (iOCUM) cleared brains. By creating optical-(i)OCUM fusion images using our mapping procedure, we localized dopamine transporter and translocator protein expression and tracer innervation from the eye to the lateral geniculate nucleus of thalamus and superior colliculus. These fusion images allowed for precise anatomical identification of fluorescent signal in discrete brain areas. As such, these templates enable applications in a broad range of research areas integrating optical 3D brain imaging by providing an MR template for cleared brains.
Concurrent remodelling of nucleolar 60S subunit precursors by the Rea1 ATPase and Spb4 RNA helicase
Authors: Mitterer Valentin , Thoms Matthias , Buschauer Robert , Berninghausen Otto , Hurt Ed , Beckmann Roland
Published: November 2022

Biogenesis intermediates of nucleolar ribosomal 60S precursor particles undergo a number of structural maturation steps before they transit to the nucleoplasm and are finally exported into the cytoplasm. The AAA+-ATPase Rea1 participates in the nucleolar exit by releasing the Ytm1–Erb1 heterodimer from the evolving pre-60S particle. Here, we show that the DEAD-box RNA helicase Spb4 with its interacting partner Rrp17 is further integrated into this maturation event. Spb4 binds to a specific class of late nucleolar pre-60S intermediates, whose cryo-EM structure revealed how its helicase activity facilitates melting and restructuring of 25S rRNA helices H62 and H63/H63a prior to Ytm1–Erb1 release.In vitromaturation of such Spb4-enriched pre-60S particles, incubated with purified Rea1 and its associated pentameric Rix1-complex in the presence of ATP, combined with cryo-EM analysis depicted the details of the Rea1-dependent large-scale pre-ribosomal remodelling. Our structural insights unveil how the Rea1 ATPase and Spb4 helicase remodel late nucleolar pre-60S particles by rRNA restructuring and dismantling of a network of several ribosomal assembly factors.
Structure of theSaccharolobus solfataricustype III-D CRISPR effector
Authors: Cannone Giuseppe , Kompaniiets Dmytro , Graham Shirley , White Malcolm F , Spagnolo Laura
Published: November 2022

CRISPR-Cas is a prokaryotic adaptive immune system, classified into six different types, each characterised by a signature protein. Type III systems, classified based on the presence of a Cas10 subunit, are rather diverse multi-subunit assemblies with a range of enzymatic activities and downstream ancillary effectors. The broad array of current biotechnological CRISPR applications is mainly based on proteins classified as Type II, however recent developments established the feasibility and efficacy of multi-protein Type III CRISPR-Cas effector complexes as RNA-targeting tools in eukaryotes. The crenarchaeonSaccharolobus solfataricushas two type III system subtypes (III-B and III-D). Here, we report the cryo-EM structure of the Csm Type III-D complex fromS. solfataricus(SsoCsm), which uses CRISPR RNA to bind target RNA molecules, activating the Cas10 subunit for antiviral defence. The structure reveals the complex organisation, subunit/subunit connectivity and protein/guide RNA interactions of the SsoCsm complex, one of the largest CRISPR effectors known.
Forgetting Dynamics For Items of Different Categories
Authors: Georgiou Antonios , Katkov Mikhail , Tsodyks Misha
Published: November 2022

Abstract

How the dynamic evolution of forgetting changes for different materials is unexplored. By using a common experimental paradigm with stimuli of different types, we were able to directly cross-examine the emerging dynamics and we found that even though the presentation sets differ minimally by design, the obtained curves appear to fall on a discrete spectrum. Furthermore, we have previously proposed a model of forgetting based on the notion of retrograde interference with a single integer parameter. All measured curves were compatible with the model with different values of the parameter, hinting to a potential common underlying mechanism of forgetting.
Epigenetic age acceleration predicts subject-specific white matter degeneration in the human brain
Authors: Newman Benjamin T. , Danoff Joshua S. , Lynch Morgan E. , Giamberardino Stephanie N. , Gregory Simon G. , Connelly Jessica J. , Druzgal T. Jason , Morris James P.
Published: November 2022

Epigenetic clocks provide powerful tools for estimating health and lifespan but their ability to predict brain degeneration and neuronal damage during the aging process is unknown. In this study, we use GrimAge, an epigenetic clock correlated to several blood plasma proteins, to longitudinally investigate brain cellular microstructure in axonal white matter from a cohort of healthy aging individuals. Given the blood plasma correlations used to develop GrimAge, a specific focus was made on white matter hyperintensities, a visible neurological manifestation of small vessel disease, and the axonal pathways throughout each individual’s brain affected by their unique white matter hyperintensity location and volume. 98 subjects over 55 years of age were scanned at baseline with 41 returning for a follow-up scan 2 years later. Using diffusion MRI lesionometry, we reconstructed subject-specific networks of affected axonal tracts and examined the diffusion cellular microstructure composition of these areas, both at baseline and longitudinally, for evidence of cellular degeneration. A chronological age-adjusted version of GrimAge was significantly correlated with baseline WMH volume and markers of neuronal decline, indicated by increased extracellular free water, increased intracellular signal, and decreased axonal signal within WMH. By isolating subject-specific axonal regions ‘lesioned’ by crossing through a WMH, age-adjusted GrimAge was also able to predict longitudinal development of similar patterns of neuronal decline throughout the brain. This study is the first to establish a relationship between accelerated epigenetic GrimAge and brain cellular microstructure in humans.
Circuit-specific selective vulnerability in the DMN persists in the face of widespread amyloid burden
Authors: Brunwasser Samuel J. , Farris Clayton , Elmore Halla , Dyer Eva L. , Nair Kiran Bhaskaran , Whitesell Jennifer D. , Harris Julie A. , Hengen Keith B.
Published: November 2022

The relationship between brainwide functional decline and accumulation of pathological protein aggregates in Alzheimer’s disease (AD) is complex and not well understood. A set of highly interconnected cortical regions known as the default mode network (DMN) exhibits selective vulnerability to both functional decline and amyloid beta (Aβ) plaques in early AD. One possibility is that early Aβ accumulation in the DMN drives vulnerability. However, it is unknown whether there is something intrinsic to neuronal projections within the DMN that biases these circuits towards dysfunction. Here we directly test this hypothesis using long-term recordings of the spiking activity of ensembles of single units in freely behaving mice characterized by global cortical and hippocampal Aβ burden (APP/PS1). Specifically, we track the interactions of a population of neurons within a DMN region and two additional populations that comprise monosynaptic targets, one within and the other outside the DMN. In addition, we record single neurons in hippocampus and examine interactions between in-DMN and out-DMN cortical circuits triggered on hippocampal sharp-wave ripples, stereotyped hippocampal events that contribute to memory consolidation in the cortex. We examine the statistics of local activity as well as inter-regional communication in a region, genotype, and brain-state dependent manner. Our data reveal dysfunction restricted to in-DMN projecting circuits. In contrast, communication along neuronal projections that originate in the DMN but target out-DMN populations are equivalent in APP/PS1 and WT mice. Circuit dysfunction is most evident throughout sleep as well as within sharp-wave ripples. Our results indicate that cells in the DMN exhibit differential intrinsic vulnerability to amyloid injury dependent on their projection targets.
Interpreting transient interactions of intrinsically disordered proteins
Authors: Wohl Samuel , Zheng Wenwei
Published: November 2022

The flexible nature of intrinsically disordered proteins (IDPs) gives rise to a conformational ensemble with a diverse set of conformations. The simplest way to describe this ensemble is through a homopolymer model without any specific interactions. However, there has been growing evidence that the conformational properties of IDPs and their relevant functions can be affected by transient interactions between specific and non-local pairs of amino acids. Interpreting these interactions from experimental methods, each of which is most sensitive to a different distance regime referred to as probing length, remains a challenging and unsolved problem. Here, we first show that transient interactions can be realized between short fragments of charged amino acids by generating conformational ensembles using model disordered peptides and coarse-grained simulations. Using these ensembles, we investigate how sensitive different types of experimental measurements are to the presence of transient interactions. We find methods with shorter probing lengths to be more appropriate to detect these transient interactions, but one experimental method is not sufficient due to the existence of other weak interactions typically seen in IDPs. Finally, we develop an adjusted polymer model with an additional short-distance peak which can robustly reproduce the distance distribution function from two experimental measurements with complementary short and long probing lengths. This new model can suggest whether a homopolymer model is insufficient for describing a specific IDP, and meet the challenge of quantitatively identifying specific transient interactions from a background of nonspecific weak interactions.
Promoter-adjacent DNA hypermethylation can downmodulate gene expression:TBX15in the muscle lineage
Authors: Ehrlich Kenneth C. , Lacey Michelle , Baribault Carl , Sen Sagnik , Esteve Pierre Olivier , Pradhan Sriharsa , Ehrlich Melanie
Published: November 2022

TBX15, which encodes a differentiation-related transcription factor, displays promoter-adjacent DNA hypermethylation in myoblasts and skeletal muscle (psoas) that is absent from non-expressing cells in other lineages. By whole-genome bisulfite sequencing (WGBS) and enzymatic methyl-seq (EM-seq), these hypermethylated regions were found to border both sides of a constitutively unmethylated promoter. To understand the functionality of this DNA hypermethylation, we cloned the differentially methylated sequences (DMRs) in CpG-free reporter vectors and tested them for promoter or enhancer activity upon transient transfection. These cloned regions exhibited strong promoter activity and, when placed upstream of a weak promoter, strong enhancer activity specifically in myoblast host cells.In vitroCpG methylation targeted to the DMR sequences in the plasmids resulted in 86 - 100% loss of promoter or enhancer activity, depending on the insert sequence. These results as well as chromatin epigenetic and transcription profiles for this gene in various cell types support the hypothesis that DNA hypermethylation immediately upstream and downstream of the unmethylated promoter region suppresses enhancer/extended promoter activity, thereby downmodulating, but not silencing, expression in myoblasts and certain kinds of skeletal muscle. This promoter-border hypermethylation is not found in cell types with a silentTBX15gene probably because they have no transcription to modulate.TBX18, TBX2, TBX3andTBX1displayTBX15-like hypermethylated DMRs at their promoter borders and preferential expression in myoblasts. Therefore, promoter-adjacent DNA hypermethylation for downmodulating transcription to prevent overexpression may be used more frequently for transcription regulation than currently appreciated.
Mutations inrpoBthat confer rifampicin resistance can alter levels of peptidoglycan precursors and affect β-lactam susceptibility
Authors: Patel Yesha , Soni Vijay , Rhee Kyu Y. , Helmann John D.
Published: November 2022

Bacteria can adapt to stressful conditions through mutations affecting the RNA polymerase core subunits that lead to beneficial changes in transcription. In response to selection with rifampicin (RIF), mutations arise in the RIF resistance determining region (RRDR) ofrpoBthat reduce antibiotic binding. These changes can also alter transcription and thereby have pleiotropic effects on bacterial fitness. Here, we studied the evolution of resistance inBacillus subtilisto the synergistic combination of RIF and the β-lactam cefuroxime (CEF). Two independent evolution experiments led to the recovery of a singlerpoBallele (S487L) that was able to confer resistance to RIF and CEF through a single mutation. Two other common RRDR mutations made the cells 32x more sensitive to CEF (H482Y) or led to only modest CEF resistance (Q469R). The diverse effects of these three mutations on CEF resistance are correlated with differences in the expression of peptidoglycan (PG) synthesis genes and in the levels of two metabolites crucial in regulating PG synthesis, glucosamine-6-phosphate (GlcN-6-P) and UDP-N-acetylglucosamine (UDP-GlcNAc). We conclude that RRDR mutations can have widely varying effects on pathways important for cell wall biosynthesis, and this may restrict the spectrum of mutations that arise during combination therapy.

Importance

Rifampicin (RIF) is one of the most valued drugs in the treatment of tuberculosis. TB treatment relies on a combination therapy, and for multidrug resistant strains may include β-lactams. Mutations inrpoBpresent a common route for emergence of resistance to RIF. In this study, usingB. subtilisas a model, we evaluate the emergence of resistance for the synergistic combination of RIF and the β-lactam cefuroxime (CEF). One clinically-relevantrpoBmutation conferred resistance to both RIF and CEF, whereas two others increased CEF sensitivity. We were able to link these phenotypes to accumulation of specific PG precursors. Mainly, UDP-GlcNAc through its GlmR mediated influence on GlmS activity has a strong impact on CEF resistance. Since these mutations are clinically relevant, these effects on CEF sensitivity may help refine the use of β-lactams in TB therapy.
Fast and accurate mapping of long reads to complete genome assemblies with VerityMap
Authors: Bzikadze Andrey V. , Mikheenko Alla , Pevzner Pavel A.
Published: November 2022

Recent advancements in long-read sequencing have enabled the telomere-to-telomere (complete) assembly of a human genome and are now contributing to the haplotype-resolved complete assemblies of multiple human genomes. Because the accuracy of read mapping tools deteriorates in highly repetitive regions, there is a need to develop accurate,error-exposing(detecting potential assembly errors), anddiploid-aware (distinguishing different haplotypes) tools for read mapping in complete assemblies. We describe the first accurate, error-exposing, and partially diploid-aware VerityMap tool for long-read mapping to complete assemblies.
Rapid genome sequencing identifies a novel de novoSNAP25variant for neonatal congenital myasthenic syndrome
Authors: Reynolds Hayley M. , Wen Ting , Farrell Andrew , Mao Rong , Moore Barry , Boyden Steven E. , Bayrak-Toydemir Pinar , Nicholas Thomas J. , Rynearson Shawn , Holt Carson , Miller Christine , Noble Katherine , Bentley Dawn , Palmquist Rachel , Ostrander Betsy , Manberg Stephanie , Bonkowsky Joshua L. , Shayota Brian J. , Jenkins Sabrina Malone
Published: November 2022

Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al.,Lancet Neurol14: 420 [2015]; Finsterer,Orphanet J Rare Dis14: 57 [2019]; Prior and Ghosh,J Child Neurol36: 610 [2021]). TheSNAP25-related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novoSNAP25c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reportedSNAP25variant phenotype, and paves a foundation for personalized management for CMS18.
Social visibility and substance in corporate social sustainability disclosures
Authors: Pollach Irene , Schaper Stefan
Published: November 2022

Purpose

Social and environmental reports have become an increasingly regulated area of corporate reporting and communication. Nevertheless, the substance and level of detail present in such disclosures is largely at the discretion of companies, which has implications for the value of such disclosures to stakeholders. The purpose of this study is to shed light on social visibility as a determinant of the variation in substance found in social disclosures in order to understand underlying reasons for why some firms offer more substance than others in their social disclosures.

Design/methodology/approach

Based on a number of hypotheses, which are combined into social visibility, the paper investigates whether a firm's social visibility is a determinant of substance in social disclosures. To this end, the case of modern slavery statements is used as a recently introduced and legally mandated form of social sustainability disclosures.

Findings

The findings suggest that social visibility can explain part of the variation in the substance of social disclosures. However, for the remaining part, it is argued that substance in social disclosures can also be driven by institutional logics, which shape organizational outcomes in specific contexts, but are largely unobservable.

Originality/value

This article contributes new insights to the literature on the relationship between corporate social visibility and the substance of social disclosures.
Health status and elderly care: theory and evidence from a randomized trial with COPD patients in China
Authors: ZONG Qingqing , ZHANG Yi , CHEN Yuyu
Published: November 2022

Purpose

This paper theoretically and empirically analyzes the effects of the elderly’s physical health status on their need for care and the choice of care models in China.

Design/methodology/approach

Empirically, the estimation results of a large-sample randomized intervention trial with chronic obstructive pulmonary disease (COPD) patients through the difference-in-difference method indicated the following: (1) After the COPD intervention trial, the physical health status of the elderly in the treatment group improved significantly, the need for care was substantially reduced and the health improvement led to a 35.5% reduction in the probability of using elderly care. (2) The reduction in the need for care regarding the treatment group occurred mainly in social care. The probability of using social care decreased by 67.8% due to the elderly’s health improvement, while that of home care remained unchanged generally. (3) Further heterogeneity tests suggested that families with fewer potential internal resources for caregiving had a more pronounced decline in the need for social care.

Findings

Theoretically, these empirical results support the existence of the “pecking order” theory in the family’s choice of elderly care model, that is, families tend to employ all internal resources for caregiving before resorting to social care, resulting in a higher sensitivity of social care to health.

Originality/value

The main policy implication of this paper is that ex ante preventive health intervention policies can significantly alleviate the burden of care, especially social care, on families. And preventive health intervention policies are particularly effective in reducing the burden of the families with relatively few resources for informal internal care.
Two dimensional MHD nanofluid flow analysis of fractional dual-phase-lag heat conduction between inclined cylinders with variable thickness
Authors: Jiang Jinxia , Zhao Haojie , Zhang Yan
Published: November 2022

Purpose

This study aims to investigate the two-dimensional magnetohydrodynamic flow and heat transfer of a fractional Maxwell nanofluid between inclined cylinders with variable thickness. Considering the cylindrical coordinate system, the constitutive relation of the fractional viscoelastic fluid and the fractional dual-phase-lag (DPL) heat conduction model, the boundary layer governing equations are first formulated and derived.

Design/methodology/approach

The newly developed finite difference scheme combined with the L1 algorithm is used to numerically solve nonlinear fractional differential equations. Furthermore, the effectiveness of the algorithm is verified by a numerical example.

Findings

Based on numerical analysis, the effects of parameters on velocity and temperature are revealed. Specifically, the velocity decreases with the increase of the fractional derivative parameter α owing to memory characteristics. The temperature increase with the increase of fractional derivative parameter ß due to a decrease in thermal resistance. From a physical perspective, the phase lag of the heat flux vector and temperature gradients τq and τT exhibit opposite trends to the temperature. The ratio τT/τq plays an important role in controlling different heat conduction behaviors. Increasing the inclination angle θ, the types and volume fractions of nanoparticles Φ can increase velocity and temperature, respectively.

Originality/value

Fractional Maxwell nanofluid flows from a fixed-thickness pipe to an inclined variable-thickness pipe, and the fractional DPL heat conduction model based on materials is considered, which provides a basis for the safe and efficient transportation of high-viscosity and condensable fluids in industrial production.
Examining prison entrepreneurship programs, self-efficacy and entrepreneurial resilience as drivers for prisoners' entrepreneurial intentions
Authors: Ciptono Wakhid Slamet , Anggadwita Grisna , Indarti Nurul
Published: November 2022

Purpose

Ex-prisoners often experience negative stigma from society, making it difficult to find employment upon release. Prison institutions play an active role in building character and improving prisoners' skills by providing various empowerment programs to increase opportunities for their economic potential. However, these programs are considered not optimal in increasing the entrepreneurial intentions of prisoners. This study aims to identify the effects of prison entrepreneurship programs, entrepreneurial resilience and self-efficacy as drivers in increasing prisoners' entrepreneurial intentions. This study also examines the effect of these variables focusing on prisoners with neither entrepreneurial experience nor entrepreneurial training.

Design/methodology/approach

This study deployed a quantitative method by distributing a questionnaire to prisoners involved in talent and skill development activities (called BIMKER, an abbreviation in Indonesian, which means Work Guidance), a compulsory program provided by prison institutions. A total of 204 prisoners, including 70 with no entrepreneurial experience, completed the research questionnaire in one of the prison institutions in Indonesia. Partial least sequential-structural equation modeling (PLS-SEM) was used as the analytical technique.

Findings

The study findings show that the prison entrepreneurship program has not been able to influence prisoners' entrepreneurial intentions directly. However, the prison entrepreneurship program has a positive and significant effect on increasing prisoners' self-efficacy and entrepreneurial resilience that ultimately encourages the emergence of entrepreneurial intentions. Entrepreneurial resilience was found not to affect entrepreneurial intentions for prisoners with no entrepreneurial experience and who have never attended entrepreneurship training.

Originality/value

This study identifies the drivers of prisoners' entrepreneurial intentions, including prison entrepreneurship programs, self-efficacy and entrepreneurial resilience. These can be used as references to build understanding at the theoretical level and can be adopted practically. This study expands the social cognitive theory (SCT) and entrepreneurial intention models (EIMs) by adding new insights into the context of prison entrepreneurship that underline the potential of prisoners engaging in entrepreneurship, once released, to expand opportunities, learning and employment. This study highlights the importance of implementing prison entrepreneurship programs to reduce crime, recidivism rates, poverty and inequality.
Post-COVID-19 poverty in France: magnitude, manifestations and actors from nine case studies
Authors: Bouchet Célia , Duvoux Nicolas
Published: November 2022

Purpose

Drawing on the French case, this article examines the size and scope of poverty resulting from the coronavirus disease 2019 (COVID-19) pandemic, the diversity of poverty's manifestations and the role of public action (among other actors) in addressing the poverty. This reflection unfolds at the confluence between the international literature on the economic effects of COVID-19 around the world and the methodological and conceptual issues on poverty.

Design/methodology/approach

Following a research report to the French Government in 2021, a new academic collaboration is initiated to assess the conceptual issues underlying the report's nine quantitative, qualitative and participatory studies. A thematic analysis is used to elaborate on an original framework.

Findings

COVID-19 not only had detrimental economic effects on specific groups, such as precarious workers and students, but also serious effects on social isolation, mental health, access to welfare and public services. Together with assessing the consequences of the COVID-19 pandemic on poverty in France, this paper highlights the lack of recognition of community support in the face of hard times.

Originality/value

The COVID-19 outbreak has not only deteriorated socioeconomic situations in France, but has also unmasked structural, long-term components of poverty. The paper discusses three policy implications of these revelations, concerning (1) the monitoring of non-monetary dimensions of poverty, (2) the needs of various groups under a welfare state with a dual structure and (3) the role of communities in public policy schemes.
A review of public policies on Covid-19: the New Zealand experience
Authors: Gauld Robin
Published: November 2022

Purpose

This article reviews New Zealand's journey through managing Covid-19. It provides a chronological overview of key developments. The article analyses the impacts of Covid-19 on business and society and offers lessons for others from the New Zealand case.

Design/methodology/approach

The article draws on various sources, primarily media pieces and government information. It also critically analyses and interprets the New Zealand response.

Findings

The initial onset and response from the New Zealand government, albeit with closed borders, was effective in terms of keeping the country relatively Covid free. The country was slow to introduce vaccinations, but the uptake was swift. A vaccine mandate to coincide with a Delta outbreak was controversial. Importantly, the New Zealand case is characterised by political leadership strongly and explicitly informed by public health expertise and advice which was routinely demonstrated throughout the period in discussion.

Originality/value

The article offers an important overview and analysis of New Zealand's experience with Covid-19 and its response, with particular focus on the way in which the government and public health specialist advisors interacted.
Inward foreign direct investment in emerging economies: a review and future research avenues
Authors: Chowdhury Sharmistha , Sharma Revti Raman , Yu Yang
Published: November 2022

Purpose

Given the surge in foreign direct investment (FDI) in emerging economies (EEs) during the past four decades, inward FDI (IFDI) has spawned a rich, scholarly conversation on the topic. This paper aims to review the literature regarding EE IFDI determinants and the impact of IFDI on those economies. It also aims to provide some future research directions.

Design/methodology/approach

A systematic review with thematic analysis of 372 articles on the topic, published between 1991 and 2021, is undertaken. In addition to using the relevant keywords, the snowballing approach was used to manually track the literature.

Findings

This review highlights EE IFDI determinants such as institutional quality, corruption and intellectual property rights, regional trade agreements and distances, formal and informal institutions and their interactions, national and subnational diversity and policy expectations. Further, IFDI impacts EEs both at macro- and micro-levels. This review also indicates a substantial increase in research during the period 2000 to 2010 and a decline thereafter; it also indicates Africa and Latin America being under-researched, with a focus on Africa recently increasing.

Research limitations/implications

Rich research opportunities exist in examining the mechanisms (mediators) and conditions (moderators) that influence relationships between the antecedents of IFDI and their outcomes. Further opportunities exist in examining the role of the context and in undertaking a multilevel analysis.

Originality/value

This review provides an understanding of what influences multinational enterprises’ FDI to EEs and how it impacts those economies. It also raises potential future research questions. It provides a holistic understanding of the chosen scope and domain.