bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated transcriptome and lineage analyses reveal novel catecholaminergic cardiomyocytes contributing to the cardiac conduction system in murine heart
Authors: Sun Tianyi , Grassam-Rowe Alexander , Pu Zhaoli , Ren Huiying , An Yanru , Guo Xinyu , Hu Wei , Liu Ying , Li Yangpeng , Liu Zhu , Kou Kun , Ou Xianhong , Chen Tangting , Fan Xuehui , Liu Yangyang , Shu Tu , He Yu , Ren Yue , Chen Ao , Shang Zhouchun , Xia Zhidao , Miquerol Lucile , Smart Nicola , Zhang Henggui , Tan Xiaoqiu , Shou Weinian , Lei Ming
Published: November 2022

Cardiac conduction system (CCS) morphogenesis is essential for correct heart function yet is incompletely understood. Here we established the transcriptional landscape of cell types populating the developing heart by integrating single-cell RNA sequencing and spatial enhanced resolution omics-sequencing (Stereo-seq). Stereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS. This led to the identification of a previously unrecognized cardiomyocyte population expressing dopamine beta-hydroxylase (Dbh+-CMs), which is closely associated with the CCS in transcriptomic analyses. To confirm this finding, genetic fate mapping by usingDbhCre/Rosa26-tdTomato reporter mouse line was performed with Stereo-seq, RNAscope, and immunohistology. We revealed thatDbh+-derived CMs first emerged in the sinus venosus at E12.5, then populated the atrial and ventricular CCS components at E14.5, with increasing abundance towards perinatal stages. Further tracing by usingDbhCFPreporter andDbhCreERT/Rosa26-tdTomato inducible reporter, we confirmed thatDbh+-CMs are mostly abundant in the AVN and ventricular CCS and this persists in the adult heart. By usingDbhCre/Rosa26-tdTomato/Cx40-eGFP compound reporter line, we validated a clear co-localization of tdTomato and eGFP signals in both left and right ventricular Purkinje fibre networks. Finally, electrophysiological optogenetic study using cell-type specific Channelrhodopsin2 (ChR2) expression further elucidated thatDbh+-derived CMs form a functional part of the ventricular CCS and display similar photostimulation-induced electrophysiological characteristics to Cx40CreERT/ChR2-tdTomato CCS components. Thus, by utilizing advanced transcriptomic, mouse genetic, and optogenetic functional analyses, our study provides new insights into mammalian CCS development and heterogeneity by revealing novelDbh+-CMs.

Highlights

Stereo-seq provided a spatiotemporal transcriptomic cell fate map of the murine heart with a panoramic field of view and in situ cellular resolution of the CCS.

Established the transcriptional landscape of cell types populating the developing murine heart.

Revealed previously unreported catecholaminergic cardiomyocyte populations contributing to the developing and mature murine cardiac conduction system.
pHAPE: a plasmid for production of DNA size marker ladders for gel electrophoresis
Authors: Allen Angel G , Barthelson Karissa , Lardelli Michael
Published: November 2022

DNA size markers (also known as “molecular weight markers” or “DNA ladders”) are an essential tool when using gel electrophoresis to identify and purify nucleic acids. However, the cost of these DNA ladders is not insignificant and, over time, impinges on the funds available for research and training in molecular biology. Here, we describe a method for the generation of “pHAPE”, a plasmid from which a variety of DNA ladders can be generated via simple restriction enzyme digestions. The pHAPE plasmid can be generated by mutagenesis of the commonly used pBluescript II SK+ phagemid followed by insertion of a custom 7,141 bp sequence (made up of three smaller fragments). Our use of pHAPE allows us some small relief from the ever-rising costs of performing molecular biology experiments (“Don’t worry, pHAPE”).
Rapid assessment of susceptibility of bacteria and erythrocytes to antimicrobial peptides by single-cell impedance cytometry
Authors: Troiano Cassandra , De Ninno Adele , Casciaro Bruno , Riccitelli Francesco , Park Yoonkyung , Massoud Renato , Mangoni Maria Luisa , Bisegna Paolo , Stella Lorenzo , Caselli Federica
Published: November 2022

Antimicrobial peptides (AMPs) represent a promising class of compounds to fight antibiotic-resistant infections. In most cases, they kill bacteria by making their membrane permeable and therefore exhibit low propensity to induce bacterial resistance. In addition, they are often selective, killing bacteria at concentrations lower than those at which they are toxic to the host. However, clinical applications of AMPs are hindered by a limited understanding of their interactions with bacteria and human cells. Standard susceptibility testing methods are based on the analysis of the growth of a bacterial population and therefore require several hours. Moreover, different assays are required to assess the toxicity to host cells. In this work, we propose the use of microfluidic impedance cytometry to explore the action of AMPs on both bacteria and host cells, in a rapid manner and with single-cell resolution. We show that the electrical signatures ofBacillus megaterium (B. megaterium)cells and human red blood cells (RBCs) reflect the action of a representative antimicrobial peptide, DNS-PMAP23. In particular, the impedance phase at high frequency (e.g., 11 or 20 MHz) is a reliable label-free metric for monitoring DNS-PMAP23 bactericidal activity and toxicity to RBCs. The impedance-based characterization is validated by comparison with standard antibacterial activity assays and absorbance-based hemolytic activity assays. Furthermore, we demonstrate the applicability of the technique to a mixed sample ofB. megateriumcells and RBCs, which paves the way to study AMP selectivity for bacterial versus eukaryotic cells in presence of both cell types.
Energetic costs of bill heat exchange demonstrate contributions to thermoregulation at high temperatures in toco toucans (Ramphastos toco)
Authors: Chaves Jussara N. , Tattersall Glenn J. , Andrade Denis V.
Published: November 2022

Body temperature regulation in the face of changes in ambient temperature and/or in metabolic heat production involves adjustments in heat exchange rates between the animal and the environment. One of those mechanisms include the modulation of the surface temperature of specific areas of the body through vasomotor adjustment and blood flow control, to change the thermal conductance of this region, thereby promoting dissipation or conservation of body heat. In homeotherms, this thermoregulatory adjustment is essential for the maintenance of body temperature over a moderate temperature range, known as the thermal neutral zone (TNZ), without increasing metabolic rate (MR). Thermal windows are poorly insulated body regions and highly vascularized that are particularly efficient for heat dissipation through that mechanism. The bill of the toco toucan (Ramphastos toco) has been described as a highly efficient thermal window and hypothesized to assist in the thermal homeostasis of this bird. Herein, we directly evaluated the contribution of heat exchange through the bill of the toco toucan and role of the bill in the delimitation of the TNZ. To do this, we measured metabolic rate, via oxygen consumption, over a range of ambient temperature from 0 to 35°C (every 5°C). MR measurements were made in birds with the bill intact (control group) and with the bill artificially insulated (experimental group). The limits of the TNZ, 10.9-25.0°C for the control group and 10.8-24.1°C for the experimental group, did not differ between the treatments. MR differed among treatments only at elevated temperatures (30 and 35°C), reaching values of 0.97 ml O2·g-1·h-1·°C-1(± 0.06) for the control group and 1.20 ml O2·g-1·h-1·°C-1(± 0.07) for the experimental group at 35°C. These results indicate that while heat dissipation through the bill does not contribute significantly to widening of the TNZ, it may well be critically important in assisting body temperature regulation at higher temperatures extending above the upper limit of the TNZ. We estimate that the contribution of the bill to total heat exchange approaches 31% of basal metabolic heat production, providing evidence of the substantial role of peripheral heat exchange and linking the role of appendage size as a key factor in the evolution of thermoregulatory responses in endotherms.
Lipidomic alterations in the cerebral cortex and white matter in sporadic Alzheimer’s disease
Authors: Obis Elia , Sol Joaquim , Andres-Benito Pol , Martín-Gari Meritxell , Mota-Martorell Natàlia , Galo-Licona José Daniel , Piñol-Ripoll Gerard , Portero-Otin Manuel , Ferrer Isidro , Jové Mariona , Pamplona Reinald
Published: November 2022

Aims

Non-targeted lipidomics analysis was conducted in post-mortem human frontal cortex area 8 (GM) and white matter of the frontal lobecentrum semi-ovale(WM) to identify lipidomes in middle-aged individuals with no neurofibrillary tangles and senile plaques, and cases at progressive stages of sporadic Alzheimer’s disease (sAD).

Methods

Lipidomic analysis using an LC-MS/MS platform was carried out in selected cases with suitable post-mortem lacking co-morbidities and concomitant brain pathologies. Complementary data were obtained using RT-qPCR and immunohistochemistry.

Results

The WM shows an adaptive lipid phenotype resistant to lipid peroxidation, characterized by a lower fatty acid unsaturation, peroxidizability index, and higher ether lipid content than the GM. Changes in the lipidomic profile more marked in the WM than in GM occur in AD with disease progression. WM alterations are characterized by a decline in the content of branched fatty acid esters of hydroxy fatty acids (FAHFA), diacylglycerols (DG), triacylglycerols (TG), glycerophospholipids (GP) (especially ether lipids), and sphingolipids (especially sulfatides, ceramides, and glycosphingolipids). The GM acquires a fatty acid profile prone to peroxidation in sAD, while WM reinforces its peroxidation-resistant trait. Transcriptomic data point to additional defects of peroxisomal function.

Conclusions

Four functional categories are associated with the different lipid classes affected in sAD: membrane structural composition, bioenergetics, antioxidant protection, and bioactive lipids, with deleterious consequences affecting both neurons and glial cells favoring disease progression.
Musculotendon Parameters in Lower Limb Models: Simplifications, Uncertainties, and Muscle Force Estimation Sensitivity
Authors: Chen Ziyu , Franklin David W.
Published: November 2022

Objective

Musculotendon parameters are key factors in the Hill-type muscle contraction dynamics, determining the muscle force estimation accuracy of a musculoskeletal model. Their values are mostly derived from muscle architecture datasets, whose emergence has been a major impetus for model development. However, it is often not clear if such parameter update indeed improves simulation accuracy. Our goal is to explain to model users in which way and how accurate these parameters are derived, and to what extent errors in parameter values might influence force estimation.

Methods

We examine in detail the derivation of musculotendon parameters in six muscle architecture datasets and four prominent OpenSim models of the lower limb, and then identify simplifications which could add uncertainties to the derived parameter values. Finally, we analyze the sensitivity of muscle force estimation to these parameters both numerically and analytically.

Results

Nine typical simplifications in parameter derivation are identified. Partial derivatives of the Hill-type contraction dynamics are derived. Tendon slack length is determined as the musculotendon parameter that muscle force estimation is most sensitive to, whereas pennation angle is the least impactful.

Conclusion

Anatomical measurements alone are not enough to calibrate musculotendon parameters, and the improvement on muscle force estimation accuracy will be limited if the source muscle architecture datasets are the only main update.

Significance

Model users may check if a dataset or model is free of concerning factors for their research or application requirements. The derived partial derivatives may be used as gradients for musculotendon parameter calibration. For model development, we demonstrate that it is more promising to focus on other model parameters or components and seek alternative strategies to further increase simulation accuracy.
Identification of key residues of the DNA glycosylase OGG1 controlling efficient DNA scanning and recruitment to oxidized bases in living cells
Authors: D’Augustin Ostiane , Gaudon Virginie , Siberchicot Capucine , Smith Rebecca , Chapuis Catherine , Depagne Jordane , Veaute Xavier , Busso Didier , Di Guilmi Anne-Marie , Castaing Bertrand , Radicella J. Pablo , Campalans Anna , Huet Sébastien
Published: November 2022

The DNA-glycosylase OGG1 oversees the detection and clearance of the 7,8-dihydro-8-oxoguanine (8-oxoG), which is the most frequent form of oxidized base in the genome. This lesion is deeply buried within the double-helix and its detection requires careful inspection of the bases by OGG1 via a mechanism that remains only partially understood. By analyzing OGG1 dynamics in the nucleus of living human cells, we demonstrate that the glycosylase constantly scans the DNA by rapidly alternating between diffusion within the nucleoplasm and short transits on the DNA. This scanning process, that we find to be tightly regulated by the conserved residue G245, is crucial for the rapid recruitment of OGG1 at oxidative lesions induced by laser micro-irradiation. Furthermore, we show that residues Y203, N149 and N150, while being all involved in early stages of 8-oxoG probing by OGG1 based on previous structural data, differentially regulate the scanning of the DNA and recruitment to oxidative lesions.
Molecular Machines Stimulate Intercellular Calcium Waves and Cause Muscle Contraction
Authors: Beckham Jacob L. , van Venrooy Alexis R. , Kim Soonyoung , Li Gang , Li Bowen , Duret Guillaume , Arnold Dallin , Zhao Xuan , Santos Ana L. , Chaudhry Gautam , Robinson Jacob T. , Tour James M.
Published: November 2022

Intercellular calcium waves (ICW) are complex signaling phenomena that control many essential biological activities, including smooth muscle contraction, vesicle secretion, gene expression, and changes in neuronal excitability. Accordingly, the remote stimulation of ICW may result in versatile new biomodulation and therapeutic strategies. Here, we demonstrate that light-activated molecular machines (MM), molecules that rotate and perform mechanical work on the molecular scale, can remotely stimulate ICW. Live-cell calcium tracking and pharmacological experiments reveal that MM-induced ICW are driven by the activation of inositol triphosphate (IP3) mediated signaling pathways by unidirectional, fast-rotating MM. We then demonstrated that MM-induced ICW can be used to control muscle contractionin vitroin cardiomyocytes and animal behaviorin vivoinHydra vulgaris. Consequentially, this work demonstrates a new strategy for the direct control of cell signaling and downstream biological function using molecular-scale devices.
SYRINGAE: A web-based application forPseudomonas syringaeisolate characterization
Authors: Fautt Chad , Couradeau Estelle , Hockett Kevin L.
Published: November 2022

ThePseudomonas syringaespecies complex (PSSC) is a diverse group of plant pathogens with a collective host range encompassing almost every food crop grown throughout the world. As a threat to global food security, rapid detection and characterization of epidemic and emerging pathogenic lineages is essential. However, phylogenetic identification and prediction of virulence is often complicated by an unclarified taxonomy and the diversity of virulence factor repertoires carried by PSSC isolates. To address these issues, we have built SYRINGAE (www.syringae.org), a web-based phylogenetic placement and functional inference pipeline for PSSC. SYRINGAE contains a comprehensive phylogeny of 2,161 quality-checked genome assemblies annotated with 120 virulence genes. From this dataset, naïve Baye classification models trained from life identification numbers (LINs) and common marker gene sequences can be used for accurate identification of isolates. SYRINGAE efficiently articulates taxonomical and functional data generated over the last several decades on PSSC and constitutes a unique tool tailored towards the rapid characterization of PSSC emerging strains of concern.
A peptide-centric quantitative proteomics dataset for the phenotypic assessment of Alzheimer’s disease
Authors: Merrihew Gennifer E. , Park Jea , Plubell Deanna , Searle Brian C. , Keene C. Dirk , Larson Eric B. , Bateman Randall , Perrin Richard J. , Chhatwal Jasmeer P. , Farlow Martin R. , McLean Catriona A. , Ghetti Bernardino , Newell Kathy L. , Frosch Matthew P. , Montine Thomas J. , MacCoss Michael J.
Published: November 2022

Alzheimer’s disease (AD) is a looming public health disaster with limited interventions. Alzheimer’s is a complex disease that can present with or without causative mutations and can be accompanied by a range of age-related comorbidities. This diverse presentation makes it difficult to study molecular changes specific to AD. To better understand the molecular signatures of disease we constructed a unique human brain sample cohort inclusive of autosomal dominant AD dementia (ADD), sporadic ADD, and those without dementia but with high AD histopathologic burden, and cognitively normal individuals with no/minimal AD histopathologic burden. All samples are clinically well characterized, and brain tissue was preserved postmortem by rapid autopsy. Samples from four brain regions were processed and analyzed by data-independent acquisition LC-MS/MS. Here we present a high-quality quantitative dataset at the peptide and protein level for each brain region. Multiple internal and external control strategies were included in this experiment to ensure data quality. All data are deposited in the ProteomeXchange repositories and available from each step of our processing.
How bumblebees coordinate path integration and body orientation at the start of their first learning flight
Authors: Collett TS , Robert T , Frasnelli E , Philippides A. , de Ibarra N Hempel
Published: November 2022

The start of a bumblebee’s first learning flight from its nest provides an opportunity to examine the bee’s learning behaviour on its initial view of the nest’s unfamiliar surroundings. Bumblebees like many other ants, bees and wasps learn views of their nest surroundings while facing their nest. A bumblebee’s first fixation of the nest is a coordinated manoeuvre in which the insect faces the nest with its body oriented towards a particular visual feature within its surroundings. The manoeuvre’s utility is that during return flights after foraging bees, when close to the nest, adopt the same preferred body-orientation (Hempel de Ibarra et al., 2009; Robert et al., 2018). A translational scan oriented orthogonally to the bee’s body-orientation helps the bee reach the preferred conjunction of nest-fixation and body-orientation.

How does a bee, unacquainted with its surroundings, know when it is facing its nest? The details of nest-fixation argue that, like desert ants (Fleischmann et al., 2018), the bee relies on path integration. Path integration gives bees continuously updated information about the current direction of their nest and enables them to fixate the nest when the body points in the appropriate direction. We relate the three components of the coordinated manoeuvre to events in the central complex, noting that nest fixation is in egocentric coordinates, whereas body orientation and flight direction within the visual surroundings of the nest are in geocentric coordinates.
Subcytoplasmic location of translation controls protein output
Authors: Horste Ellen L. , Fansler Mervin M. , Cai Ting , Chen Xiuzhen , Mitschka Sibylle , Zhen Gang , Lee Flora C. Y. , Ule Jernej , Mayr Christine
Published: November 2022

The cytoplasm is highly compartmentalized, but the extent and consequences of subcytopIasmic mRNA localization in non-polarized cells are largely unknown. We determined mRNA enrichment in TIS granules (TGs) and the rough endopIasmic reticuIum (ER) through particle sorting and isolated cytosolic mRNAs by digitonin extraction. When focusing on non-membrane protein-encoding mRNAs, we observed that 52% have a biased transcript distribution across these compartments. Compartment enrichment is determined by a combinatorial code based on mRNA length, exon length, and 3′UTR-bound RNA-binding proteins. Compartment-biased mRNAs differ in the functional classes of their encoded proteins: TG-enriched mRNAs encode low-abundance proteins with strong enrichment of transcription factors, whereas ER-enriched mRNAs encode large and highly expressed proteins. Compartment localization is an important determinant of mRNA and protein abundance, which is supported by reporter experiments showing that redirecting cytosolic mRNAs to the ER increases their protein expression. In summary, the cytoplasm is functionally compartmentaIized by local translation environments.
Regulatory fine-tuning and horizontal gene transfer stabilize mobile colistin resistance
Authors: Ogunlana Lois , Shaw Liam , Kaur Divjot , Jangir Pramod , Walsh Timothy , Uphoff Stephan , MacLean R.C.
Published: November 2022

Antibiotic resistance tends to carry fitness costs, making it difficult to understand how resistance can be stably maintained in pathogen populations over the long-term. Here, we investigate this problem in the context ofmcr-1, a fitness-costly gene that confers resistance to the ‘last-resort’ antibiotic, colistin. Here we show that regulatory evolution has fine-tuned the expression ofmcr-1, allowingE. colito reduce the cost ofmcr-1while simultaneously increasing colistin resistance. Conjugative plasmids have transferred low cost/high resistancemcr-1alleles across an incredible diversity ofE. colistrains, further stabilizingmcr-1at the species level. Crucially, regulatory mutations were associated with increasedmcr-1stability in pig farms following a ban on the use of colistin as a growth promoter that decreased colistin consumption by 90%. Our study shows how the rapid evolution and horizontal transmission of resistance genes can combine to stabilize resistance and reduce the efficiency of interventions aimed at reducing AMR by limiting antibiotic consumption.
Accurate Mutation Effect Prediction using RoseTTAFold
Authors: Mansoor Sanaa , Baek Minkyung , Juergens David , Watson Joseph L. , Baker David
Published: November 2022

Predicting the effects of mutations on protein function is an outstanding challenge. Here we assess the performance of the deep learning based RoseTTAFold structure prediction and design method for unsupervised mutation effect prediction. Using RoseTTAFold in inference mode, without any additional training, we obtain state of the art accuracy on predicting mutation effects for a set of diverse protein families. Thus, although the architecture of RoseTTAFold was developed to address the protein structure prediction problem, during model training RoseTTAFold acquired an understanding of the mutational landscapes of proteins comparable to that of large recently developed language models. The ability to reason over structure as well as sequence could enable even more precise mutation effect predictions following supervised training.
Autophagy is required to prevent early pro-inflammatory responses and neutrophil recruitment duringMycobacterium tuberculosisinfection without affecting pathogen replication in macrophages
Authors: Kinsella Rachel L. , Kimmey Jacqueline M. , Smirnov Asya , Woodson Reilly , Gaggioli Margaret R. , Chavez Sthefany M. , Kreamalmeyer Darren , Stallings Christina L.
Published: November 2022

The immune response toMycobacterium tuberculosisinfection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models duringM. tuberculosisinfection and, therefore, must be tightly regulated. ATG5 is an essential autophagy protein that is required in innate immune cells to control neutrophil-dominated inflammation and promote survival duringM. tuberculosisinfection, however, the mechanistic basis for how ATG5 regulates neutrophil recruitment is unknown. To interrogate what innate immune cells require ATG5 to control neutrophil recruitment duringM. tuberculosisinfection, we used different mouse strains that conditionally deleteAtg5in specific cell types. We found that ATG5 is required in CD11c+cells (lung macrophages and dendritic cells) to control the production of proinflammatory cytokines and chemokines duringM. tuberculosisinfection, which would otherwise promote neutrophil recruitment. This role for ATG5 is autophagy-dependent, but independent of mitophagy, LC3-associated phagocytosis, and inflammasome activation, which are the most well-characterized ways that autophagy proteins regulate inflammation. In addition to the increase in proinflammatory cytokine production duringM. tuberculosisinfection, loss of ATG5 in innate immune cells also results in an early induction of TH17 responses. Despite prior publishedin vitrocell culture experiments supporting a role for autophagy in controllingM. tuberculosisreplication in macrophages, loss of autophagy does not affectM. tuberculosisburden in macrophagesin vivoand, therefore, the effects of autophagy on inflammatory responses occur without changes in pathogen numbers. These findings reveal new roles for autophagy proteins in lung resident macrophages and dendritic cells that are required to suppress inflammatory responses that are associated with poor control ofM. tuberculosisinfection.
Consistent individual positions within roosts in Spix’s disc-winged bats
Authors: Giacomini Giada , Chaves-Ramírez Silvia , Hernández-Pinsón H. Andrés , Barrantes José Pablo , Chaverri Gloriana
Published: November 2022

Individuals within both moving and stationary groups arrange themselves in a predictable manner; for example, some individuals are consistently found at the front of the group or in the periphery and others in the center. Each position may be associated with various costs, such as greater exposure to predators, and benefits, such as preferential access to food. In social bats, we would expect a similar consistent arrangement for groups at roost-sites, which is where these mammals spend the largest portion of their lives. Here we study the relative position of individuals within a roost-site and establish if sex, age, and vocal behavior are associated with a given position. We focus on the highly cohesive and mobile social groups found in Spix’s disc-winged bats (Thyroptera tricolor) given this species’ use of a tubular roosting structure that forces individuals to be arranged linearly within its internal space. We obtained high scores for linearity measures, particularly for the top and bottom positions, indicating that bats position themselves in a predictable way despite constant roost-switching. We also found that sex and age were associated with the use of certain positions within the roost; for example, males and subadults tend to occupy the top part (near the roost’s entrance) more often than expected by chance. Our results demonstrate, for the first time, that bats are capable of maintaining a consistent and predictable position within their roosts despite having to relocate daily, and that there is a link between individual traits and position preferences.
Higher-order epistasis shapes natural variation in germ stem cell niche activity
Authors: Fausett Sarah R , Sandjak Asma , Billard Bénédicte , Braendle Christian
Published: November 2022

Natural quantitative variation in developmental processes must be driven by allelic variation. Yet, the genotype-phenotype relationships underlying developmental system variation are understudied due to their inherent complexity. Taking advantage of the simpleCaenorhabditis elegansgermline stem cell system, we characterized natural differences in the germ stem cell niche activity of two distinct wild isolates—measured as differences in germline progenitor zone (PZ) size. Through quantitative trait locus (QTL) analysis, we detected multiple candidate causal loci, including two large-effect QTL on chromosomes II and V. Resolving the chromosome V QTL, we show that the isolate with a smaller PZ exhibits a unique 148 bp deletion in the promoter region of the Notch ligand,lag-2, a central signal promoting germ stem cell fate and proliferation. As predicted, introducing this deletion into the isolate with a large PZ resulted in a smaller PZ. Unexpectedly, re-introducing the deleted ancestral sequence in the isolate with a smaller PZ further reduced PZ size. Using allelic replacement lines, we show that these contradictory phenotypic effects are due to epistatic interactions among thelag-2promoter, the chromosome II QTL, and additional loci in the genome. Although thelag-2deletion appeared to explain natural variation in germ stem cell niche activity, its effects across multiple genetic backgrounds were unpredictable due to higher-order epistasis. Studying the genetic architecture of quantitative developmental systems without taking into account its natural variation may be misleading, emphasizing the need for a better integration of developmental and quantitative genetics.
Low input capture Hi-C (liCHi-C) identifies promoter-enhancer interactions at high-resolution
Authors: Tomás-Daza Laureano , Rovirosa Llorenç , López-Martí Paula , Nieto-Aliseda Andrea , Serra François , Planas-Riverola Ainoa , Molina Oscar , McDonald Rebecca , Ghevaert Cedric , Cuatrecasas Esther , Costa Dolors , Camós Mireia , Bueno Clara , Menéndez Pablo , Valencia Alfonso , Javierre Biola M.
Published: November 2022

Long-range interactions between regulatory elements and promoters are key in gene transcriptional control; however, their study requires large amounts of starting material, which is not compatible with clinical scenarios nor the study of rare cell populations. Here we introduce low input capture Hi-C (liCHi-C) as a cost-effective, flexible method to map and robustly compare promoter interactomes at high resolution. As proof of its broad applicability, we implement liCHi-C to study normal and malignant human hematopoietic hierarchy in clinical samples. We demonstrate that the dynamic promoter architecture identifies developmental trajectories and orchestrates transcriptional transitions during cell-state commitment. Moreover, liCHi-C enables the identification of new disease-relevant cell types, genes and pathways potentially deregulated by non-coding alterations at distal regulatory elements. Finally, we show that liCHi-C can be harnessed to uncover genome-wide structural variants, resolve their breakpoints and infer their pathogenic effects. Collectively, our optimized liCHi-C method expands the study of 3D chromatin organization to unique, low-abundance cell populations, and offers an opportunity to uncover novel factors and regulatory networks involved in disease pathogenesis.
Oral Feeding of Nanoplastics reduces Brain function of Mice by Inducing Intestinal IL-1β-producing Macrophages
Authors: Yang Qianyu , Dai Huaxing , Cheng Ying , Wang Beilei , Xu Jialu , Zhang Yue , Chen Yitong , Xu Fang , Ma Qingle , Fei Ziying , Lin Fang , Wang Chao
Published: November 2022

Background and Aims

Nanoplastics (NPs) as contaminants in food and water have drawn an increasing public attention. However, little is known about how NPs shape the gut immune landscape after entering the body. The objective of the study was to explore indirect effects caused by the interaction of NPs with the mammalian gut and whole immune system after entering the body.

Methods

In this study, we fabricated NPs (∼500 nm) and microplastics (MPs) (∼2 μm) and aimed to evaluate their in vivo effects by feeding them in mice. The mechanism was then investigated by various technology including single-cell RNA sequencing of gut and brain tissue.

Results

The results suggested that NPs showed a better ability to induce gut macrophage activation than did MPs. In addition, NPs triggered gut interleukin 1 beta (IL-1β)-producing macrophage reprogramming via inducing lysosomal damage after phagocytosis. More importantly, IL-1β released from the intestine could affect brain immunity, leading to microglial activation and Th17 differentiation, all of which correlated with a decline in cognitive and short-term memory in NPs-fed mice

Conclusions

Thus, this study provides new insight into the mechanism of action of the gut-brain axis and delineates the way NPs reduce brain function, highlights the importance to fix the plastic pollution problem worldwide.
Defects in lipid homeostasis reflect the function of TANGO2 in Acyl-CoA metabolism
Authors: Lujan Agustin , Foresti Ombretta , Brouwers Nathalie , Farre Alex Mateo , Vignoli Alessio , Wojnacki Jose , Malhotra Vivek
Published: November 2022

We show that TANGO2, which lacks a transmembrane domain localizes predominantly to mitochondria and transiently to endoplasmic reticulum (ER) and lipid droplets (LDs). Evaluation of lipids in HepG2 cells lacking TANGO2 revealed an increase in the size of lipid droplets and reactive oxygen species production. There is also a marked increase lysophosphatidic acid (LPA) and a concomitant decrease in its biosynthetic precursor phosphatidic acid (PA). These changes are exacerbated in nutrient starved cells. Based on our data, we suggest that the principle function of TANGO2 is in acyl-CoA metabolism, which is necessary for the acylation of LPA to generate PA. This defect subsequently affects metabolism of many other fatty acids. These data help explain the physiological consequence of TANGO2 that induce acute metabolic crisis including rhabdomyolysis, cardiomyopathy and cardiac arrhythmias often leading to fatality upon starvation and stress.
Key supply chain strategies for post-COVID-19 recovery: evidence from an Indian smart furniture industry
Authors: Sachan Sandeep , Kumar Vimal , Vardhan Sachit , Mittal Ankesh , Verma Pratima , Bag Surajit
Published: November 2022

Purpose

Smart furniture is an essential part of research that has been designed to best complement easy and safe human interaction. The purpose of smart furniture is to save the space of the house and make the products unique, awesome and safe, functional, strong and also make it works better so the people can live better with it. This research aims to explore the key supply chain strategies implemented by the Indian smart furniture industry to reduce the impact of a post-COVID-19 pandemic.

Design/methodology/approach

This work utilized a case study and conducted semi-structured interviews with the top leadership of the smart furniture manufacturing industry to explore key supply chain strategies to reduce the influence of the post-COVID-19 pandemic. Additionally, key supply chain strategies have been analyzed using a multi-criteria decision-making technique known as grey relational analysis (GRA) to determine their ranking significance in the smart furniture industry.

Findings

The results of this study discovered that “Inventory-Categorization” is essential in ensuring business continuity during the COVID-19 pandemic and helps reduce the amount of stock they have on hand. It enhanced the opportunity for employees to properly focus on their work and an opportunity for better work-life balance. The results of the study can also help supply chain stakeholders in their establishment of critical strategies.

Research limitations/implications

The implications of this research work help the Indian furniture industry to make supply chain investment decisions that benefit the organization to sustain itself.

Originality/value

This is the first study to explore key supply chain strategies for the post-COVID-19 era. This work will assist managers and practitioners in helping the organization decide which supply chain strategies are more critical to the betterment of the organization.
Exploring the contributions of concepts of time to pension studies in Hong Kong and the United Kingdom
Authors: Foster Liam , Yu Sam Wai Kam , Chau Ruby Chui Man
Published: November 2022

Purpose

This article aims to link discussions of the role of earnings-related pension measures with time in Hong Kong (HK) and the United Kingdom (UK). It presents a new conceptual “time-based framework” to explore two related types of government response to the way people accumulate pension incomes through participation in paid work. The first is to consider governments' perceptions of appropriate time in work and retirement. The second is to consider how governments use pension measures to influence the connection between the amount of time people spend in paid work and retirement.

Design/methodology/approach

This is a conceptual paper. The time-based framework is developed using literature concerning discretionary time and the social construction of time. To explore the empirical significance of this framework, the authors discuss how it can be applied to the analysis of earnings-related pension measures in HK and the UK.

Findings

The evidence generated from the discussion of the earnings-related pension measures in HK and the UK shows that pension policies can serve both as a financial and time instrument. At the same time as influencing the connection between the amount of time people spend in paid work and the pensions they can accumulate, pension policies can be used to convey the government's views on important time issues, namely the appropriate length of time in work and retirement, and the relative value of the time spent in paid work and providing informal care.

Originality/value

A new framework is developed to explore the connection between the studies of earnings-related pension measures and time, which is an understudied area.
Defining CSR disclosure quality: a review and synthesis of the accounting literature
Authors: Stuart Andrew C. , Fuller Stephen H. , Heron Nicole M. , Riley Tracey J.
Published: November 2022

Purpose

This paper aims to review and synthesize the corporate social responsibility (CSR) disclosure literature in order to (1) develop a comprehensive definition of disclosure quality; (2) review the evolution of disclosure quality proxies used by accounting researchers; (3) describe the antecedents to disclosure quality; (4) describe the outcomes of disclosure quality; and (5) identify gaps in the current literature and offer suggestions for future research.

Design/methodology/approach

This study conducted a systematic review capturing articles examining CSR disclosure quality. The researchers first searched EBSCO, identifying all relevant articles by searching for “corporate social responsibility,” “CSR,” “ESG” and “sustainability reporting” anywhere in the article. Then, the results were filtered to focus on 23 of the most prominent accounting journals. The search resulted in 592 articles which were individually reviewed for relevance to the authors’ review. This study includes all articles that examine disclosure and provide insight into elements that influence disclosure quality or provide evidence of the effects of disclosure quality on user decision-making.

Findings

It is found that a comprehensive definition of CSR disclosure quality has yet to be developed and that proxies for CSR disclosure quality have evolved over time. This study synthesizes the literature on the antecedents of CSR disclosure quality, and how CSR disclosure quality affects users' decision-making and related outcomes. Overall, the review of this study suggests that assurance and a number of corporate features have important effects on disclosure quality. Also, high-quality disclosures are positively associated with many benefits to market participants.

Originality/value

This study complements Huang and Watson's (2015) CSR literature review by comprehensively reviewing and synthesizing the CSR disclosure quality literature that was only emerging when their review was published. Importantly, this study contributes to the CSR disclosure literature by developing a comprehensive definition of CSR disclosure quality that is grounded in the accounting literature and aligned with current frameworks.
Remanufacturing mode selection considering uncertain EOL products’ quality and differential consumers’ WTP
Authors: Li Bangyi , Tang Juan , Liu Zhi , Gong Bengang
Published: November 2022

Purpose

The purpose of this paper is to investigate remanufacturing operational strategies considering uncertain quality of end-of-life (EOL) products and differential consumers’ willingness-to-pay (WTP) for new products and provide suggestions on the remanufacturing mode selection for the original equipment manufacturer (OEM).

Design/methodology/approach

This study considers three remanufacturing modes, i.e. in-house, outsourcing and authorization modes. By establishing and comparing decision models of three modes from the perspectives of profit, consumer surplus and environment, the optimal remanufacturing mode is discussed.

Findings

The results suggest that if the OEM’s remanufacturing capability is high, the in-house mode brings to the highest environmental performance, OEM’s profit and consumer surplus. Otherwise, the outsourcing mode (authorization) is the best benefit to environment (consumers if the unit production cost of new products is not too high). As for the preference of two decision-makers to outsourcing and authorization modes, if the difference of consumers’ WTP for new products is low, the OEM prefers the outsourcing mode; otherwise, the OEM prefers the authorization mode. The preference of the third-party remanufacturer (TPR) to remanufacturing mode is affected by consumers’ WTP for remanufactured products, WTP difference for new products and remanufacturing quality level standard.

Practical implications

These results can provide operational insights into how to select remanufacturing mode when the quality of EOL products is uncertain and consumers’ WTP for new products is different under three remanufacturing modes.

Originality/value

This paper is among the first to investigate the joint effects of EOL products’ uncertain quality and differential consumers’ WTP for new products on the operational strategies and performance under different remanufacturing modes.
Deciphering interactions between the marine dinoflagellate Prorocentrum lima and the fungus Aspergillus pseudoglaucus
Authors: Berry Olivier , Briand Enora , Bagot Alizé , Chaigné Maud , Meslet‐Cladière Laurence , Wang Julien , Grovel Olivier , Jansen Jeroen J. , Ruiz Nicolas , du Pont Thibaut Robiou , Pouchus Yves François , Hess Philipp , Bertrand Samuel
Published: November 2022

The comprehension of microbial interactions is one of the key challenges in marine microbial ecology. This study focused on exploring chemical interactions between the toxic dinoflagellate Prorocentrum lima and a filamentous fungal species, Aspergillus pseudoglaucus, which has been isolated from the microalgal culture. Such interspecies interactions are expected to occur even though they were rarely studied. Here, a co‐culture system was designed in a dedicated microscale marine‐like condition. This system allowed to explore microalgal–fungal physical and metabolic interactions in presence and absence of the bacterial consortium. Microscopic observation showed an unusual physical contact between the fungal mycelium and dinoflagellate cells. To delineate specialized metabolome alterations during microalgal–fungal co‐culture metabolomes were monitored by high‐performance liquid chromatography coupled to high‐resolution mass spectrometry. In‐depth multivariate statistical analysis using dedicated approaches highlighted (1) the metabolic alterations associated with microalgal–fungal co‐culture, and (2) the impact of associated bacteria in microalgal metabolome response to fungal interaction. Unfortunately, only a very low number of highlighted features were fully characterized. However, an up‐regulation of the dinoflagellate toxins okadaic acid and dinophysistoxin 1 was observed during co‐culture in supernatants. Such results highlight the importance to consider microalgal–fungal interactions in the study of parameters regulating toxin production.
When does ideology matter? Party lists, personal attributes and the effect of ideology on intra‐party success
Authors: ISOTALO VEIKKO , HELIMÄKI THEODORA , MATTILA MIKKO , SCHOULTZ ÅSA VON
Published: November 2022

Choosing a candidate can be difficult in open‐list proportional representation systems, with many candidates on display. Under such circumstances, candidates' personal vote‐earning attributes (PVEAs) become useful for voters since PVEAs function as information shortcuts (heuristics) that reduce the cognitive costs of casting a ballot. However, recent research has demonstrated that more cognitively demanding information, namely candidates' ideological positions, also matters for candidates' electoral success. Yet, much is unknown about the circumstances under which ideology comes into play. In this study, we demonstrate that the availability of easily applied heuristics (operationalized via the level of recognizable candidates on party lists) conditions the effect of candidates' ideological positioning on intra‐party success. Our analyses show that ideology matters most when the share of recognizable candidates with typical PVEAs on the list is limited. The effect of ideological distance from the party gradually disappears as the share of recognizable candidates on the list increases. The results suggest that when the supply of candidates with PVEAs is limited, voters use ideological cues as the base for their voting decisions.
Prognostic factors for survival in extensive‐stage small cell lung cancer: An Italian real‐world retrospective analysis of 244 patients treated over the last decade
Authors: Longo Vito , Pizzutilo Pamela , Catino Annamaria , Montrone Michele , Pesola Francesco , Marerch Ilaria , Galetta Domenico
Published: November 2022

Background

Potential relationships with the prognosis of patients with extensive‐stage non‐small cell lung cancer (ES‐SCLC) have been investigated without valid results.

Methods

A retrospective analysis of real‐world data of consecutive patients with ES‐SCLC admitted to our Medical Thoracic Oncology Unit was carried out from 2010 to 2020, focusing on identification of prognostic factors. Kaplan–Meier analysis was used to represent progression‐free survival (PFS) and overall survival (OS). Univariable and multivariable Cox models were used to investigate prognostic factors.

Results

The analysis included 244 patients. The median OS was 8 months (95% confidence interval [CI]: 8–10) and the median PFS was 5 months (95% CI: 5–6). The univariable analysis showed that factors associated with shorter OS were older age (p = 0.047), TNM stage 4 versus 3 (p < 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 and 2 versus 0 (p < 0.001), and >2 metastatic sites (p = 0.004). Mediastinal radiotherapy (RT) (p < 0.001), >1 irradiated site (p = 0.026), 3 and 4 chemotherapy (CT) lines versus 1 (p = 0.044 and 0.001, respectively), prophylactic cranial irradiation (PCI) (p < 0.001), and surgery (p = 0.001) correlated with longer OS. The multivariable analysis revealed statistically significant associations for TNM, ECOG PS 2 versus 0, number of CT lines, PCI, and surgery. A total of 23 patients (9.4%) survived ≥24 months, 39% of whom had received four CT lines and 48% had mediastinal RT.

Conclusions

Our data suggest that tumor burden, PS, and mediastinal RT strongly correlate with outcome. With the addition of immunotherapy to CT, the identification of new biomarkers as predictive factors is urgently required.