bluuebunny/crossref_metadata_2025 huggingface dataset:
Isogenic hiPSC models of Turner syndrome development reveal shared roles of inactive X and Y in the human cranial neural crest network
Authors: Ahern Darcy T. , Bansal Prakhar , Faustino Isaac V. , Glatt-Deeley Heather R. , Massey Rachael , Kondaveeti Yuvabharath , Banda Erin C. , Pinter Stefan F.
Published: March 2023

Modeling the developmental etiology of viable human aneuploidy can be challenging in rodents due to syntenic boundaries, or primate-specific biology. In humans, monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which in contrast remain unaffected in 39,X-mice. To learn how human monosomy-X may impact early embryonic development, we turned to human 45,X and isogenic euploid induced pluripotent stem cells (hiPSCs) from male and female mosaic donors. Because neural crest (NC) derived cell types are hypothesized to underpin craniofacial and cardiovascular changes in TS, we performed a highly-powered differential expression study on hiPSC-derived anterior neural crest cells (NCCs). Across three independent isogenic panels, 45,X NCCs show impaired acquisition of PAX7+SOX10+markers, and disrupted expression of other NCC-specific genes, relative to their isogenic euploid controls. In particular, 45,X NCCs increase cholesterol biosynthesis genes while reducing transcripts that feature 5’ terminal oligopyrimidine (TOP) motifs, including those of ribosomal protein and nuclear-encoded mitochondrial genes. Such metabolic pathways are also over-represented in weighted co-expression gene modules that are preserved in monogenic neurocristopathy. Importantly, these gene modules are also significantly enriched in 28% of all TS-associated terms of the human phenotype ontology. Our analysis identifies specific sex-linked genes that are expressed from two copies in euploid males and females alike and qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. This study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as a powerful model of early NC development in TS and inform new hypotheses towards its etiology.
Early alterations of thalamo- and hippocampo-cortical functional connectivity are biomarkers of epileptogenesis after traumatic brain injury
Authors: Weiler Marina , Lutkenhoff Evan S. , de Campos Brunno M. , Casseb Raphael F. , Vespa Paul M. , Monti Martin M. ,   the EpiBioS4Rx Study Group
Published: March 2023

The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) study is a prospective multicenter clinical observational study to identify early biomarkers of epileptogenesis after moderate-to-severe traumatic brain injury (TBI). In this preliminary analysis of 37 patients, using a seed-based approach applied to acute (i.e., ≤ 14 days) functional magnetic resonance (MRI) imaging data, we directly test the hypothesis that the epileptogenic process following brain trauma is associated with functional changes within hippocampal and thalamo-cortical networks. Additionally, we hypothesize that the network connectivity involving thalamic and hippocampal circuits underlying early and late-onset epileptogenesis would differ. The three groups did not differ by sex distribution (χ2(2)= 1.8,p= .407), age (H(2)= 4.227,p= .121), admission Glasgow Coma Scale (H(2)= 3.850,p= .146) or postinjury day of the MRI session (H(2)= .695,p= .706). The primary finding is that patients with early seizures, a sign of early epileptogenesis, exhibited pattern 1, namely, an increased positive connectivity in thalamic and hippocampal networks, as compared to patients who had no epileptogenesis, or late epileptogenesis (p< .05, FWE-corrected at the cluster level). In contrast, this finding was absent in those patients who exhibited late seizures, with the latter group displayed pattern 2, namely, a lower positive and higher negative connectivity in the hippocampal network, as compared to patients who had no signs of epileptogenesis (p< .05, FWE-corrected at the cluster level). Patients with either pattern 1 or pattern 2 connectivity profiles in thalamic and hippocampal networks were significantly predictive of late (i.e., between 7 days and 2 years) epileptogenesis following brain trauma. A Receiver Operating Characteristic (ROC) Curve analysis model that included thalamic and hippocampal functional connectivity values presented an Area Under the Curve (AUC) 87.7, specificity 86.7, and sensitivity 84.6. Our results indicate that dysfunction in hippocampal and thalamo-cortical networks are potential biomarkers for early and late epileptogenesis following a TBI.
Genetic and neural bases of the neuroticism general factor
Authors: Kim Yuri , Saunders Gretchen R. B. , Giannelis Alexandros , Willoughby Emily A. , DeYoung Colin G. , Lee James J.
Published: March 2023

We applied structural equation modeling to conduct a genome-wide association study (GWAS) of the general factor measured by a neuroticism questionnaire administered to∼380,000 participants in the UK Biobank. We categorized significant genetic variants as acting either through the neuroticism general factor, through other factors measured by the questionnaire, or through paths independent of any factor. Regardless of this categorization, however, significant variants tended to show concordant associations with all items. Bioinformatic analysis showed that the variants associated with the neuroticism general factor disproportionately lie near or within genes expressed in the brain. Enriched gene sets pointed to an underlying biological basis associated with brain development, synaptic function, and behaviors in mice indicative of fear and anxiety. Psychologists have long asked whether psychometric common factors are merely a convenient summary of correlated variables or reflect coherent causal entities with a partial biological basis, and our results provide some support for the latter interpretation. Further research is needed to determine the extent to which causes resembling common factors operate alongside other mechanisms to generate the correlational structure of personality.
Cyclone: an accessible pipeline to analyze, evaluate and optimize multiparametric cytometry data
Authors: Patel Ravi K. , Jaszczak Rebecca G. , Kwok Im , Carey Nicholas D. , Courau Tristan , Bunis Daniel , Samad Bushra , Avanesyan Lia , Chew Nayvin W. , Stenske Sarah , Jespersen Jillian M. , Publicover Jean , Edwards Austin , Naser Mohammad , Rao Arjun A. , Lupin-Jimenez Leonard , Krummel Matthew F. , Cooper Stewart , Baron Jody , Combes Alexis J. , Fragiadakis Gabriela K.
Published: March 2023

In the past decade, high-dimensional single cell technologies have revolutionized basic and translational immunology research and are now a key element of the toolbox used by scientists to study the immune system. However, analysis of the data generated by these approaches often requires clustering algorithms and dimensionality reduction representation which are computationally intense and difficult to evaluate and optimize. Here we present Cyclone, an analysis pipeline integrating dimensionality reduction, clustering, evaluation and optimization of clustering resolution, and downstream visualization tools facilitating the analysis of a wide range of cytometry data. We benchmarked and validated Cyclone on mass cytometry (CyTOF), full spectrum fluorescence-based cytometry, and multiplexed immunofluorescence (IF) in a variety of biological contexts, including infectious diseases and cancer. In each instance, Cyclone not only recapitulates gold standard immune cell identification, but also enables the unsupervised identification of lymphocytes and mononuclear phagocytes subsets that are associated with distinct biological features. Altogether, the Cyclone pipeline is a versatile and accessible pipeline for performing, optimizing, and evaluating clustering on variety of cytometry datasets which will further power immunology research and provide a scaffold for biological discovery.
Memory systems integration in sleep complements rapid systems consolidation in wakefulness
Authors: Brodt Svenja , Schönauer Monika , Seewald Anna , Beck Jonas , Erb Michael , Scheffler Klaus , Gais Steffen
Published: March 2023

Sleep benefits memory performance by fostering systems consolidation, a process that embeds memories into neocortical networks and renders them independent of the hippocampus. Recent evidence shows that memory rehearsal during wakefulness likewise initiates systems consolidation and rapidly engenders neocortical engrams. Here, we investigate the effect of sleep-dependent consolidation for memories that have undergone rapid systems consolidation during wakefulness. After sleep compared to wakefulness, we find better memory retention and higher functional brain activity during memory retrieval in the medial parietal cortex, which hosts memory representations after rehearsal, and in the striatum and thalamus. Increased striatal and thalamic contributions were correlated with higher retrieval performance. Furthermore, all three regions decreased their functional connectivity to the hippocampus specifically after sleep. These findings show that besides continuing of systems consolidation initiated during wakefulness, sleep also acts to integrate different memory systems. Thus, rehearsal-induced and sleep-dependent consolidation seem to be complementary in nature.
TMS disruption of the lateral prefrontal cortex increases neural activity in the default mode network when naming facial expressions
Authors: Pitcher David , Sliwinska Magdalena W. , Kaiser Daniel
Published: March 2023

Recognizing facial expressions is dependent on multiple brain networks specialized for different cognitive functions. In the current study participants (N=20) were scanned using functional magnetic resonance imaging (fMRI) while they performed a covert facial expression naming task. Immediately prior to scanning thetaburst transcranial magnetic stimulation (TMS) was delivered over the right lateral prefrontal cortex (PFC), or the vertex control site. A group whole-brain analysis revealed that TMS induced opposite effects in the neural responses across different brain networks. Stimulation of the right PFC (compared to stimulation of the vertex) decreased neural activity in the left lateral PFC but increased neural activity in three nodes of the default mode network (DMN): the right superior frontal gyrus (SFG), right angular gyrus and the bilateral middle cingulate gyrus. A region of interest (ROI) analysis showed that TMS delivered over the right PFC reduced neural activity across all functionally localised face areas (including in the PFC) compared to TMS delivered over the vertex. These results causally demonstrate that visually recognizing facial expressions is dependent on the dynamic interaction of the face processing network and the DMN. Our study also demonstrates the utility of combined TMS / fMRI studies for revealing the dynamic interactions between different functional brain networks.
Water Hyacinth microbiome: metagenomic cues from environment and functionality in urban aquatic bodies
Authors: Yadav Rakeshkumar , Rajput Vinay , Dharne Mahesh
Published: March 2023

Water hyacinth (WH) is a widespread floating invasive aquatic plant having a prolific reproductive and dispersion rate. With the aid of its root-associated microbes, WH significantly modulates the ecosystem’s functioning. Despite their irrevocable importance, the WH microbiome remains unexplored in detail. Here, we present a shotgun analysis of WH rhizobiome (from urban rivers and a lake) and their surrounding water to unveil the diversity drivers and functional relationship. PCoA analysis revealed that microbial diversity of the WH is significantly shaped by the type of the aquatic bodies (River Vs Lake) (ANOSIM-R of 0.94 to 0.98 and R2of 0.36 to 0.54). Temporal variations (River WH_2020 vs WH_2022) (R of 0.8 to 1 and R2of 0.17 to 0.41) were observed in river WH, which could be mainly attributed to the transient taxa as there was higher sharing of core bacteria (48%). Also, the WH microbiome significantly differed (R= 0.46 to 1.0 and R2of 0.18 to 0.52) from its surrounding water. WH inhabited more unique core members (42 to 45%), suggesting vertical transfer and selectivity in the microbiome. Functional metagenomics depicted the WH microbiome to harbour 140 pollutant-degrading enzymes involved in the degradation of various xenobiotic pollutants such as hydrocarbons, plastics, and dye. Moreover, an observed higher prevalence of metal and biocide resistance genes highlighted the persistence of resistant microbes assisting WH in environmental remediation application.

Highlights

Water hyacinth (WH) from urban water bodies inhabited by diverse microbial population

First study to report variability in WH microbiome amid aquatic bodies and their environment

Lake WH showed more unique core (43%), and River WH shared core bacteria (48%) across time

140 Pollutant degrading enzymes and 341 metal resistance genes indicates remediation potential
Requirement of GrgA forChlamydiainfectious progeny production
Authors: Lu Bin , Wang Yuxuan , Wurihan Wurihan , Yeung Sydney , Fondell Joseph D. , Wu Xiang , Fan Huizhou
Published: March 2023

Hallmarks of the developmental cycle of the obligate intracellular pathogenic bacteriumChlamydiaare the primary differentiation of the infectious elementary body (EB) cell type into the proliferative reticulate body (RB) and the secondary differentiation of RBs back into EBs. The detailed mechanisms regulating these transitions are unclear. In this study, we developed a novel strategy termed DOPE (dependence on plasmid-mediated expression) that allows for the knockdown of essential genes inChlamydia. Importantly, we demonstrate that GrgA, aChlamydia-specific transcription factor, is essential for the secondary differentiation of RBs into EBs. Our development of a conditional GrgA-deficient chlamydiae should prove valuable for future studies examining chlamydial growth, development, and pathogenicity. Furthermore, because EB formation is absolutely required for chlamydial dissemination within infected individuals, and for chlamydial transmission to new hosts, our maturation-defective chlamydiae system may serve as an attractive attenuated vaccine methodology for the prevention of chlamydial diseases.
Ensemble-based genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer
Authors: Gelbach Patrick E. , Finley Stacey D.
Published: March 2023

1

Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment, which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the tumor microenvironment. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages.
Cryo-EM structures of human arachidonate 12S-Lipoxygenase (12-LOX) bound to endogenous and exogenous inhibitors
Authors: Mobbs Jesse I. , Black Katrina A. , Tran Michelle , Venugopal Hariprasad , Holman Theodore R. , Holinstat Michael , Thal David M. , Glukhova Alisa
Published: March 2023

Human 12-lipoxygenase (12-LOX) is an enzyme involved in platelet activation and is a promising target for antiplatelet therapies. Despite the clinical importance of 12-LOX, the exact mechanisms of how it affects platelet activation are unclear, and the lack of structural information has limited drug discovery efforts. In this study, we used single-particle cryoelectron microscopy to determine the high-resolution structures (1.7 Å - 2.8 Å) of human 12-LOX for the first time. Our results showed that 12-LOX can exist in multiple oligomeric states, from monomer to hexamer, which may impact its catalytic activity and membrane association. We also identified different conformations within a 12-LOX dimer, likely representing different time points in its catalytic cycle. Furthermore, we were able to identify small molecules bound to the 12-LOX structures. The active site of the 12-LOX tetramer is occupied by an endogenous 12-LOX inhibitor, a long-chain acyl-Coenzyme A. Additionally, we found that the 12-LOX hexamer can simultaneously bind to arachidonic acid and ML355, a selective 12-LOX inhibitor that has passed a phase I clinical trial for treating heparin-induced thrombocytopenia and has received fast-track designation by the FDA. Overall, our findings provide novel insights into the assembly of 12-LOX oligomers, its catalytic mechanism, and small molecule binding, paving the way for further drug development targeting the 12-LOX enzyme.

Key Points

The first full-length structures of human arachidonate 12S-Lipoxygenase (12-LOX)

Reveals mechanisms of oligomeric and conformational states

Uncovers natural inhibitor of 12S-Lipoxygenase (12-lox)

Reveals a binding site of inhibitor ML355
Mechanisms of low susceptibility to the disinfectant benzalkonium chloride in a multidrug-resistant environmental isolate ofAeromonas hydrophila
Authors: Chacón Luz , Kuropka Benno , González-Tortuero Enrique , Schreiber Frank , Rojas-Jiménez Keilor , Rodríguez-Rojas Alexandro
Published: March 2023

Excessive discharge of quaternary ammonium disinfectants such as benzalkonium chloride (BAC) into aquatic systems can trigger several physiological responses in environmental microorganisms. In this study, we isolated a low susceptible strain ofAeromonas hydrophila, namely INISA09, to from a wastewater treatment plant in Costa Rica. We characterized its phenotypic response upon exposure to three different concentrations of BAC and determined the primary mechanisms related to its resistance using genomic and proteomic tools. The genome of the strain is 4.6-Mb with 4,273 genes, and we found a propound genome rearrangement and thousands of missense mutations when compared to the reference strainA. hydrophilaATCC 7966. We identified 15,762 missense mutations mainly associated with transport, antimicrobial resistance, and outer membrane proteins. In addition, quantitative proteomic analysis revealed the significant upregulation of several efflux pumps and the downregulation of porins when the strain was exposed to three BAC concentrations. Other genes related to membrane fatty acid metabolism and redox metabolic reactions also showed an altered expression. Our findings suggest that the response ofA. hydrophilaINISA09 to BAC primarily occurs at the membrane level, which is BAC’s primary target. This study sheds light on the mechanisms of antimicrobial susceptibility in tropical aquatic environments against a widely-used disinfectant, using an environmental strain that could serve as a new study model.
Potentiation of host defense through sRNA packaged in OMVs ofXanthomonas oryzaepv.oryzicola
Authors: Wu Yan , Wang Sai , Wang Peihong , Nie Wenhan , Ahmad Iftikhar , Chen Gongyou , Zhu Bo
Published: March 2023

Bacterial outer membrane vesicles (OMVs)-packaged delivery of noncoding small RNAs (sRNAs) can function as novel mediators of interspecies communication. However, the role of which in the interaction between phytopathogenic bacteria and their host plants is unclear. In this study, we characterized differentially packaged sRNAs inXanthomonas oryzaepv.oryzicola(Xoc) BLS256 OMVs using RNA-Seq, and we selected the most abundant sRNA Xosr001 for further study based on its essential role in the induction of stomatal immunity in rice.Xocloads Xosr001 into OMVs, which are transferred specifically into the mechanical tissues of rice leaves. We uncovered that OMVs-mediated Xosr001 inhibitors attenuatedOsJMT1transcripts in vivo and reduced the endogenous MeJA contents in rice leaves. Stomatal conductance was measured to show that ΔXosr001 mutant weakened the ability of stomatal re-opening on rice leaves after spray inoculation. Most notably, the transgenic rice lines OsJMT1-HA-OE exhibited attenuated stomatal immunity and disease susceptibility after ΔXosr001 infection compared withXocinfection. These results define that Xosr001 packaged inXocOMVs highlights a smart molecular mechanism to activate stomatal immunity in rice.
Extraocular muscle stem cells exhibit distinct cellular properties associated with non-muscle molecular signatures
Authors: Di Girolamo Daniela , Benavente-Diaz Maria , Grimaldi Alexandre , Lopes Priscilla Thomas , Murolo Melania , Evano Brendan , Gioftsidi Stamatia , Laville Vincent , Mella Sebastian , Tajbakhsh Shahragim , Comai Glenda
Published: March 2023

The muscle stem cell (MuSC) population is recognized as functionally heterogeneous. Cranial muscle stem cells, which originate from head mesoderm, can have greater proliferative capacity in culture and higher regenerative potential in transplantation assays when compared to those in the limb. The existence of such functional differences in phenotypic outputs remain unresolved as a comprehensive understanding of the underlying mechanisms is lacking. We addressed this issue using a combination of clonal analysis, live imaging, and scRNA-seq, identifying critical biological features that distinguish extraocular (EOM) and limb (Tibialis anterior, TA) MuSC populations. Time-lapse studies using aMyogenintdTomatoreporter showed that the increased proliferation capacity of EOM MuSCs is accompanied by a differentiation delayin vitro. Unexpectedly, in vitro activated EOM MuSCs expressed a large array of distinct extracellular matrix (ECM) components, growth factors, and signaling molecules that are typically associated with mesenchymal non-muscle cells. These unique features are regulated by a specific set of transcription factors that constitute a coregulating module. This transcription factor network, which includes Foxc1 as one of the major players, appears to be hardwired to EOM identity as it is present in quiescent adult MuSCs, in the activated counterparts during growth and retained upon passages in vitro. These findings provide insights into how high-performing MuSCs regulate myogenic commitment by active remodeling of their local environment.
2’-Fucosyllactose helps butyrate producers outgrow competitors in infant gut microbiota simulations
Authors: Versluis David M. , Schoemaker Ruud , Looijesteijn Ellen , Geurts Jan M. W. , H. Merks Roeland M.
Published: March 2023

A reduced capacity for butyrate production by the early infant gut microbiota is associated with negative health effects, such as inflammation and the development of allergies. Here we develop new hypotheses on the effect of the prebiotic galacto-oligosaccharides (GOS) or 2’-fucosyllactose (2’-FL) on butyrate production by the infant gut microbiota using a multiscale, spatiotemporal mathematical model of the infant gut. The model simulates a community of cross-feeding gut bacteria at metabolic detail. It represents the gut microbiome as a grid of bacterial populations that exchange intermediary metabolites, using 20 different subspecies-specific metabolic networks taken from the AGORA database. The simulations predict that both GOS and 2’-FL promote the growth ofBifidobacterium, whereas butyrate producing bacteria are only consistently abundant in the presence of propane-1,2-diol, a product of 2’-FL metabolism. The results suggest that in absence of prebiotics or in presence of only GOS, bacterial species, includingCutibacterium acnesandBacteroides vulgatus, outcompete butyrate producers by feeding on intermediary metabolites. In presence of 2’-FL, however, production of propane-1,2-diol specifically supports butyrate producers.
Human immunodeficiency virus (HIV) dynamics in secondary lymphoid tissues and the evolution of cytotoxic T lymphocyte (CTL) escape mutants
Authors: Chung Wen-Jian , Connick Elizabeth , Wodarz Dominik
Published: March 2023

In the secondary lymphoid tissues, human immunodeficiency virus (HIV) can replicate both in the follicular and the extrafollicular compartments. Yet, virus is concentrated in the follicular compartment in the absence of antiretroviral therapy, in part due to the lack of cytotoxic T lymphocyte (CTL)-mediated activity there. CTL home to the extrafollicular compartment, where they can suppress virus load to relatively low levels. We use mathematical models to show that this compartmentalization can explain seemingly counterintuitive observations. First, it can explain the observed constancy of the viral decline slope during antiviral therapy irrespective of the presence of CTL in SIV-infected macaques, under the assumption that CTL-mediated lysis significantly contributes to virus suppression. Second, it can account for the relatively long times it takes for CTL escape mutants to emerge during chronic infection even if CTL-mediated lysis is responsible for virus suppression. The reason is the heterogeneity in CTL activity, and the consequent heterogeneity in selection pressure between the follicular and extrafollicular compartments. Hence, to understand HIV dynamics more thoroughly, this analysis highlights the importance of measuring virus populations separately in the extrafollicular and follicular compartments rather than using virus load in peripheral blood as an observable; this hides the heterogeneity between compartments that might be responsible for the particular patters seen in the dynamics and evolution of the HIVin vivo.
The Evolution of Centriole Degradation in Mouse Sperm
Authors: Khanal Sushil , Jaiswal Ankit , Chowdanayaka Rajanikanth , Puente Nahshon , Turner Katerina , Assefa Kebron Yeshitela , Nawras Mohamad , Back Ezekiel David , Royfman Abigail , Burkett James P. , Cheong Soon Hon , Fisher Heidi S. , Sindhwani Puneet , Gray John , Basappa Ramachandra Nallur , Avidor-Reiss Tomer
Published: March 2023

Centrioles are subcellular organelles found at the cilia base with an evolutionarily conserved structure and a shock absorber-like function. In sperm, centrioles are found at the flagellum base and are essential for embryo development in basal animals. Yet, sperm centrioles have evolved diverse forms, sometimes acting like a transmission system, as in cattle, and sometimes becoming dispensable, as in house mice. How the essential sperm centriole evolved to become dispensable in some organisms is unclear. Here, we test the hypothesis that this transition occurred through a cascade of evolutionary changes to the proteins, structure, and function of sperm centrioles and was possibly driven by sperm competition. We found that the final steps in this cascade are associated with a change in the primary structure of the centriolar luminal protein FAM161A in rodents. This information provides the first insight into the molecular mechanisms and adaptive evolution underlying a major evolutionary transition within the internal structure of the mammalian sperm neck.

Graphical abstract

Highlights

– Barrel-shaped centrioles are present in all rodents except members of the Muridae taxonomical family.

– The FAM161A sequence evolved selectively in rodents and specifically in a murid subgroup.

– The evolution of centriole degradation is correlated with the expression of a novel FAM161A isoform.

– The ancestral centriole remodeling program involves elongation followed by redistribution.

– The mouse centriole degradation program involves elongation followed by elimination.
A Living Organoid Biobank of Crohn’s Disease Patients Reveals Molecular Subtypes for Personalized Therapeutics
Authors: Tindle Courtney , Katkar Gajanan D. , Fonseca Ayden G. , Taheri Sahar , Lee Jasper , Maity Priti , Sayed Ibrahim M. , Ibeawuchi Stella-Rita , Vidales Eleadah , Pranadinata Rama F. , Fuller Mackenzie , Stec Dominik L. , Anandachar Mahitha Shree , Perry Kevin , Le Helen N. , Ear Jason , Boland Brigid S. , Sandborn William J. , Sahoo Debashis , Das Soumita , Ghosh Pradipta
Published: March 2023

ABSTRACT (Structured)

Crohn’s disease (CD) is a complex, clinically heterogeneous disease of multifactorial origin; there is no perfect pre-clinical model, little insight into the basis for such heterogeneity, and still no cure. To address these unmet needs, we sought to explore the translational potential of adult stem cell-derived organoids that not only retain their tissue identity, but also their genetic and epigenetic disease-driving traits. We prospectively created a biobank of CD patient-derived organoid cultures (PDOs) using biopsied tissues from colons of 34 consecutive subjects representing all clinical subtypes (Montreal Classification B1-B3 and perianal disease). PDOs were generated also from healthy subjects. Comparative gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and revealed that despite the clinical heterogeneity there are two major molecular subtypes: immune-deficient infectious-CD [IDICD] and stress and senescence-induced fibrostenotic-CD [S2FCD]. The transcriptome, genome and phenome show a surprising degree of internal consistency within each molecular subtype. The spectrum of morphometric, phenotypic, and functional changes within the “living biobank” reveals distinct differences between the molecular subtypes. These insights enabled drug screens that reversed subtype-specific phenotypes, e.g., impaired microbial clearance in IDICD was reversed using agonists for nuclear receptors, and senescence in S2FCD was rectified using senotherapeutics, but notvice versa. Phenotyped-genotyped CD-PDOs may fill the gap between basic biology and patient trials by enabling pre-clinical Phase ‘0’ human trials for personalized therapeutics.

GRAPHIC ABSTRACT

In Brief

This work creates a prospectively biobanked phenotyped-genotyped Crohn’s disease patient-derived organoids (CD-PDOs) as platforms for molecular subtyping of disease and for ushering personalized therapeutics.

HIGHLIGHTS

Prospectively biobanked CD-organoids recapitulate the disease epithelium in patients

The phenome-transcriptome-genome of CD-organoids converge on two molecular subtypes

One subtype shows impaired microbial clearance, another increased cellular senescence

Phenotyped-genotyped PDOs are then used for integrative and personalized therapeutics
Age-related brain mechanisms underlying short-term recognition of musical sequences: An EEG study
Authors: Costa M. , Vuust P. , Kringelbach M.L. , Bonetti L.
Published: March 2023

Recognition is the ability to correctly identify previously learned information. It is an important part of declarative episodic memory and a vital cognitive function, which declines with ageing. Several studies investigated recognition of visual elements, complex images, spatial patterns, and musical melodies, focusing especially on automatic and long-term recognition. Here, we studied the impact of ageing on the event-related potentials using electroencephalography (EEG) associated with short-term recognition of auditory sequences. To this end, we recruited 54 participants, which were divided into two groups: (i) 29 young adults (20-30 years old), (ii) 25 older adults (60-80 years old). We presented two sequences with an interval of a few seconds. Participants were asked to state how similar the second sequence was with regards to the first one. The neural results indicated a stronger negative, widespread activity associated with the recognition of the same sequence compared to the sequences that were transposed or completely different. This difference was widely distributed across the EEG sensors and involved especially temporo-parietal areas of the scalp. Notably, we reported largely reduced neural responses for the older versus young adults, even when no behavioral differences were observed. In conclusion, our study suggests that the combination of auditory sequences, music, and fast-scale neurophysiology may represent a privileged solution to better understand short-term memory and the cognitive decline associated with ageing.
Spectral detection of condition-specific biological pathways in single-cell gene expression data
Authors: Chin Wee Loong , dos Santos Leonardo Portes , Small Michael , Lesterhuis W. Joost , Lassmann Timo
Published: March 2023

Single cell RNA sequencing is an ubiquitous method for studying changes in cellular states within and across conditions. Differential expression (DE) analysis may miss subtle differences, especially where transcriptional variability is not unique to a specific condition, but shared across multiple conditions or phenotypes. Here, we present CDR-g (Concatenate-Decompose-Rotate genomics), a fast and scalable strategy based on spectral factorisation of gene coexpression matrices. CDR-g detects subtle changes in gene coexpression across a continuum of biological states in multi-condition single cell data. CDR-g collates these changes and builds a detailed profile of differential cell states. Applying CDR-g, we show that it identifies biological pathways not detected using conventional DE analysis and delineates novel, condition-specific subpopulations in single-cell datasets.
Multi-plateau force-extension curves of long double-stranded DNA
Authors: Afanasyev Alexander Y. , Onufriev Alexey V.
Published: March 2023

When highly stretched, double-stranded DNA exhibits a plateau region in its force-extension curve. Using a bead-spring coarse-grained dynamic model based on a non-convex potential, we predict that a long double-stranded DNA fragment made of several consecutive segments with substantially different plateau force values for each segment will exhibit multiple distinct plateau regions in the force-extension curve under physiologically relevant solvent conditions. For example, a long composite double-stranded (ds) DNA fragment consisting of two equal length segments characterized by two different plateau force values, such as the poly(dA-dT)-poly(dG-dC) fragment, is predicted to exhibit two distinct plateau regions in its force-extension curve; a long composite dsDNA fragment consisting of three segments having three different plateau force values is predicted to have three distinct plateau regions. The formation of mixed states of slightly and highly stretched DNA, co-existing with macroscopically distinct phases of uniformly stretched DNA is also predicted. When one of the segments overstretches, the extensions of the segments can differ drastically. For example, for the poly(dA-dT)-poly(dG-dC) composite fragment, in the middle of the first plateau, 96.7 % of the total extension of the fragment (relative to Lx/L0 ≈ 1.0) comes from the poly(dA-dT) segment, while only 3.3 % of it comes from the poly(dG-dC) segment. The order of the segments has little effect on the force-extension curve or the distribution of conformational states. We speculate that the distinct structural states of stretched double-stranded DNA may have functional importance. For example, these states may modulate, in a sequence-dependent manner, the rate of double-stranded DNA processing by key cellular machines.
Assessing the strategic levers in the discourse of best-performing CEOs: a three-dimensional model
Authors: Galan-Cubillo Javier , Garcia-Ortega Beatriz , de-Miguel-Molina Blanca
Published: March 2023

Purpose

The main purpose of this paper is to assess the patterns in the public discourse of successful chief executive officers (CEOs) in terms of performance, with the CEO's strengths and aspects to improve.

Design/methodology/approach

This paper aligns with the literature that appraises CEO public discourse and relevance. From the literature review, the strategic levers in CEO discourse toward high performance are identified. The CEO letters in the period 2017–2019 of the top 25 best performing CEOs (BPCs) according to Harvard Business Review ranking 2019 are qualitatively examined through a multiple close reading analytical technique and multiple correspondence analysis (MCA) is applied to assess the patterns.

Findings

The paper delivers a three-dimensional model representing how the identified strategic levers are articulated by BPCs in the BPC's discourse following diverse patterns. This paper points out BPC's strengths, among them a high level of moral reasoning compared to previous studies and improvable areas such as the extended absence of autocritique at the firm and personal level or the lack of leverage on the need for agility and proactive adaption.

Practical implications

This paper contributes further CEO awareness of the strategic role of the discourse and offers clues to enhance CEO awareness, as well as criteria for boards of directors to appraise CEO discourse.

Originality/value

Adopting a novel approach, this paper addresses the strategic levers triggered by CEOs in their letters from a managerial implication perspective, providing relevant theoretical insight on how they are articulated.
A study on mediation effect of relationship quality outcome between customer relationship management and mutual fund decision
Authors: Deb Suman Kumar , Jain Ruchi , Manohar Sridhar , Marwah Sanjiv
Published: March 2023

Purpose

Usage of updated technology is continuously empowering customer relationship management (CRM) to be convenient and user friendly, where customers are kept engaged with knowledge and information. This enables them on decision-making and managing their portfolio, especially in mutual fund investments. To improve toward a positive decision, certain quality related variables needed to be considered. Thus, this study aims to estimate the mediation effect of relationship quality and outcome (RQO) between CRM and investment decision-making in mutual funds (MFD).

Design/methodology/approach

The descriptive study adopted the constructs from existing empirical literatures to conceptualize the model with three higher order constructs with 12 dimensions. Survey method is used, and with a structured questionnaire, a total of 323 mutual fund investors were approached using nonprobability criterion sampling technique, of which 262 relevant responses were considered for estimating the structural model. Smart PLS was used to establish the relationship of the constructs.

Findings

The result emphasizes a significant direct and indirect relationship indicating that investors are more inclined to MFD through technology-enabled CRM and RQO plays a vital role in explaining the direct relationship between CRM and MFD. The results of the study are in-line with the existing literature.

Practical implications

The study highlights that financial institutions must focus not only on technological diffusion but also needs to ensure quality service by providing knowledge and information during every access of transactions by customers, making them independent and confident during investments.

Originality/value

This study indicates how capacity efficiency, which is a part of service productivity, can be managed without affecting the outcome efficiency by incorporating technology in the place of human interaction during relationship acquiring and retaining process.
Effects of reputation on guest satisfaction: from the perspective of two-sided reviews on Airbnb
Authors: Ye Qiang , Liang Sai , Wei Zaiyan , Law Rob
Published: March 2023

Purpose

From the perspective of two-sided review systems, this study aims to investigate how guests’ prior reputation influences their subsequent satisfaction on Airbnb.

Design/methodology/approach

This study applied a conceptual framework based on social capital theory to explain the effect of guests’ reputation decided by hosts’ prior evaluations on their subsequent satisfaction. The authors collected 96,204 guest reviews posted for 17,325 properties on Airbnb and used the review polarity to measure guest satisfaction. All historical evaluations generated by hosts for each guest were collected and treated as a proxy of guest reputation. Ordinary least squares regressions were conducted to estimate the effect of guests’ reputation on their subsequent satisfaction.

Findings

Results show that guests whose historical evaluations have higher valences or larger variations tend to be more satisfied in their subsequent bookings. However, the number of reviews that guests received from hosts in the past does not influence their subsequent satisfaction.

Research limitations/implications

This study provides new insights into the hospitality literature by identifying the influencing factors of guest satisfaction on peer-to-peer rental platforms from the perspective of two-sided review systems. Results also present practical implications to property owners and website designers to gain a deeper understanding of the determinants of guest satisfaction and the consequences of social interactions between hosts and guests.

Originality/value

This study is a novel attempt that analyzes the effect of guests’ reputation on their satisfaction with subsequent bookings based on two-sided review systems on peer-to-peer rental platforms. Thus, this study provides a starting point for investigating how two-sided review systems affect use behavior on peer-to-peer rental platforms.
The impact of transformational leadership on challenging influence strategies: an approach using structural equation models
Authors: López-Lemus Jorge Armando , De la Garza Carranza María Teresa
Published: March 2023

Purpose

The purpose of this study is to identify the impact that transformational leadership has on challenging influence strategies in business leaders of the micro, small and medium-sized enterprises (MSMEs) of the state of Guanajuato, Mexico.

Design/methodology/approach

The methodological design was quantitative, explanatory, observational and cross-sectional, where a sample of 343 leaders from the business sector of the MSMEs of the state of Guanajuato, Mexico was obtained. To check the hypotheses, a structural equation model (SEM) was developed using the AMOS v.21 statistical software. For the analysis of the data, SPSS v.21 was used. Regarding the goodness and fit indexes of the SEM (χ2 = 595,133 df = 244; CFI = 0.914 and TLI = 0.903; RMSEA = 0.06), which were acceptable (Jöreskog and Sörbom, 1981; López-Lemus and Zavala, 2019; Rigdon, 1996; Tucker and Lewis, 1973).

Findings

The results obtained through the present study, it is shown that leadership and transformational influences positively and significantly on challenging influence strategies: rational (β1 = 0.53, p < 0.01), inspiring (β2 = 0.65, p < 0.01) as well as the strategy of participatory influence (β3 = 0.62, p < 0.01) of the business leaders of the MSMEs of the state of Guanajuato, Mexico.

Originality/value

The findings are relevant and of great value because there is currently not enough research that focuses on the variables analysed on the leadership and influence strategies of business leaders of the MSMEs in the context of the state of Guanajuato, Mexico.
Perceived organizational politics, organizational disidentification and counterproductive work behaviour: moderating role of external crisis threats to work
Authors: De Clercq Dirk , Pereira Renato
Published: March 2023

Purpose

The purpose of this study is to unpack the relationship between employees’ perceptions of organizational politics and their counterproductive work behaviour, by postulating a mediating role of organizational disidentification and a moderating role of perceived external crisis threats to work.

Design/methodology/approach

The empirical assessment of the hypotheses relies on survey data collected among employees who work in a large banking organization.

Findings

Perceptions that organizational decision-making is marked by self-serving behaviour increase the probability that employees seek to cause harm to their employer, because they feel embarrassed by their organizational membership. This mediating role of organizational disidentification is especially prominent when they ruminate about the negative impact of external crises on their work.

Practical implications

This study details an important danger for employees who feel upset with dysfunctional politics: They psychologically distance themselves from their employer, which then prompts them to formulate counterproductive responses that likely make it more difficult to take on the problem in a credible manner. This detrimental dynamic is particularly risky if an external crisis negatively interferes with their work functioning.

Originality/value

This study adds to prior research by detailing an unexplored but relevant mechanism (organizational disidentification) and moderator (external crisis threats) by which perceived organizational politics translates into enhanced counterproductive work behaviour.
The impacts of capital inflows on bank lending in the ASEAN-6 countries
Authors: Le Trung H. , Nguyen Nhung , Pham Minh
Published: March 2023

Purpose

The authors investigate the impacts of international capital inflows on bank lending in the Association of Southeast Asian Nations-6 (ASEAN-6) countries on the dynamics of both bank loan volumes and credit risk-taking. The authors further explore the heterogenous impacts of different components of the foreign capital. As a robustness check, the authors also examine the role of crisis periods and agency problem on the relationship between international capital inflows and bank lending.

Design/methodology/approach

The authors explore the impacts of international capital inflows on bank lending in the ASEAN-6 countries, including Malaysia, Indonesia, Thailand, Philippines, Singapore and Vietnam. The authors employ quarterly data from 2005Q1 to 2021Q2 from 45 commercial banks in the ASEAN-6 countries. The article uses bank-fixed and time-fixed effects in the panel dataset to account for any unobserved heterogeneity.

Findings

The authors find that capital inflows to the ASEAN-6 countries are associated with higher bank loan growth and lower loan loss provisions to net interest income ratios. Moreover, the positive relationships between capital inflows to the bank loan growth and credit risk-taking are mainly driven by the dynamics in foreign direct investments (FDIs) and other inflow (OI) components. Contrary to the global financial crisis (GFC), the authors note that the mediating role of capital inflows on bank lending is of particular importance in the COVID-19 pandemic.

Research limitations/implications

This study has some limitations that provide vendors for future research. First, while the authors focus on the impact of capital inflows on bank-level lending activities, future research can also explore the role of foreign capital on bank efficiency and financial stability. Second, although foreign capital fluctuates the most during crisis periods, the movement of capital inflows is also sensitive to other periods of heightened global uncertainty. Thus, rather than focus on the behavior of foreign capital during crisis periods, future research can examine and explore the impacts of capital inflows in different periods of “stop” and “surge” for sudden contraction and boom in capital inflows to the ASEAN-6 countries.

Originality/value

First, the authors provide a comprehensive analysis of international capital inflows' impact on bank lending in the ASEAN region on both bank loan volumes and credit risk-taking. Second, the authors provide evidence of the impact of different forms of foreign capital on the bank lending. Third, the authors investigate the heterogeneous impact of foreign capital on crisis periods and bank sizes, which the authors emphasize the unusual characteristics of the COVID-19 crisis compared with the GFC.