bluuebunny/crossref_metadata_2025 huggingface dataset:
The genetic and dietary landscape of the muscle insulin signalling network
Authors: van Gerwen Julian , Masson Stewart W. C. , Cutler Harry B. , Díaz-Vegas Alexis , Potter Meg , Stöckli Jacqueline , Madsen Søren , Nelson Marin E. , Humphrey Sean J. , James David E.
Published: June 2023

Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acutein vivoinsulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway’s organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasizing the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.
Re-investigating the correctness of decoy-based false discovery rate control in proteomics tandem mass spectrometry
Authors: Freestone Jack , Noble William Stafford , Keich Uri
Published: June 2023

Traditional database search methods for the analysis of bottom-up proteomics tandem mass spectrometry (MS/MS) data are limited in their ability to detect peptides with post-translational modifications (PTMs). Recently, “open modification” database search strategies, in which the requirement that the mass of the database peptide closely matches the observed precursor mass is relaxed, have become popular as a way to find a wider variety of types of PTMs. Indeed, in one study, Konget al. reported that the open modification search tool MSFragger can achieve higher statistical power to detect peptides than a traditional “narrow window” database search. At the same time, Konget al. reported that their empirical results suggest a problem with false discovery (FDR) control in the narrow window setting. We investigated these claims empirically and, in the process, uncovered a potential problem with FDR control in the machine learning post-processors Percolator and PeptideProphet. However, we also found that, after accounting for chimeric spectra as well as for the inherent difference in the number of candidates in open and narrow searches, the data does not provide sufficient evidence that FDR control in proteomics MS/MS database search is problematic.
Pathway Centric Analysis for single-cell RNA-seq and Spatial Transcriptomics Data with GSDensity
Authors: Liang Qingnan , Huang Yuefan , He Shan , Chen Ken
Published: June 2023

Advances in single-cell technology have enabled molecular cellular dissection of heterogeneous biospecimens at unprecedented scales and resolutions. Although cluster-centric approaches followed by gene-set analysis can reveal distinct cell types and states, they have limited power in dissecting and interpretating highly heterogenous, dynamically evolving data. Here, we present GSDensity, a graph-modeling approach that allows users to obtain pathway-centric interpretation and dissection of single-cell and spatial transcriptomics (ST) data without performing clustering. We show that GSDensity can not only accurately detect biologically distinct gene sets but also reveal novel cell-pathway associations that are ignored by existing methods. This is particularly evident in characterizing cancer cell states that are transcriptomically distinct but are driven by shared tumor-immune interaction mechanisms. Moreover, we show that GSDensity, combined with trajectory analysis can identify pathways that are active at various stages of mouse brain development. Finally, we show that GSDensity can identify spatially relevant pathways in mouse brains including those following a high-order organizational patterns in the ST data. We also created a pan-cancer pathway activity ST map, which revealed pathways spatially relevant and recurrently active across six different tumor types. GSDensity is available as an open-source R package and can be widely applied to single-cell and ST data generated by various technologies.
Nonequilibrium switching of segmental states can influence compaction of chromatin
Authors: Sahoo Soudamini , Kadam Sangram , Padinhateeri Ranjith , Kumar P. B. Sunil
Published: June 2023

Knowledge about the dynamic nature of chromatin organization is essential to understand the regulation of processes like DNA transcription and repair. While most models assume protein organization and chemical states along chromatin as static, experiments have shown that these are dynamic and lead to the switching of chromatin segments between different physical states. To understand the implications of this inherent nonequilibrium switching, we present a diblock copolymer model of chromatin, with switching of its segmental states between two states, mimicking active/repressed or protein unbound/bound states. We show that competition between switching timescaleTt, polymer relaxation timescaleτp, and segmental relaxation timescaleτscan lead to non-trivial changes in chromatin organization, leading to changes in local compaction and contact probabilities. As a function of the switching timescale, the radius of gyration of chromatin shows a non-monotonic behavior with a prominent minimum whenTt≈τpand a maximum whenTt≈τs. We find that polymers with a small segment length exhibit a more compact structure than those with larger segment lengths. We also find that the switching can lead to higher contact probability and better mixing of far-away segments. Our study also shows that the nature of the distribution of chromatin clusters varies widely as we change the switching rate.

Significance statement

Different cells in multicellular organisms have the same DNA but different functions. The function of any given cell type can be time-dependent. The current understanding is that differences in gene expression arising from local compaction and the probability for far-away regulatory segments to come in contact play an important role in establishing these differences. The necessary structural variations are achieved through a combination of changes in the chemical and physical states of chromatin regions. In this paper, we present a model for chromatin accounting for the dynamic switching of chromatin regions between different chemical and physical states. We demonstrate the implications of such switching in determining the local 3D structure of chromatin.
Stuck on a small tropical island: widein-situdiversification of an urban-dwelling bat
Authors: Aguillon Samantha , Castex Clara , Duchet Avril , Turpin Magali , Minter Gildas Le , Lebarbenchon Camille , Hoarau Axel O. G. , Toty Céline , Joffrin Léa , Tortosa Pablo , Mavingui Patrick , Goodman Steven M. , Dietrich Muriel
Published: June 2023

Bats are often the only mammals naturally colonizing isolated islands and are thus an excellent model to study evolutionary processes of insular ecosystems. Here, we studied the Reunion free-tailed bat (Mormopterus francoismoutoui), an endemic species to Reunion Island that has adapted to urban settings. At regional scale, we investigated the evolutionary history ofMormopterusspecies, as well as on Reunion Island sex-specific and seasonal patterns of genetic structure. We used an extensive spatio-temporal sampling including 1,136 individuals from 18 roosts and three biological seasons (non-reproductive/winter, pregnancy/summer, and mating), with additional samples fromMormopterusspecies from neighbouring islands (M. jugularisof Madagascar andM. acetabulosusof Mauritius). Complementary information gathered from both microsatellite and mitochondrial markers revealed a high genetic diversity but no signal of spatial genetic structure and weak evidence of female philopatry. Regional analysis suggests a single colonization event forM. francoismoutoui, dated around 175,000 years ago, and followed byin-situdiversification and the evolution of divergent ancestral lineages, which today form a large metapopulation. Population expansion was relatively ancient (55,000 years ago) and thus not linked to human colonization of the island and the availability of new anthropic day-roost sites. Discordant structure between mitochondrial and microsatellite markers suggests the presence of yet-unknown mating sites, or the recent evolution of putative ecological adaptations. Our study illustrates how understanding mechanisms involved in speciation can be challenging and the importance of both mitochondrial and nuclear DNA in resolving the widein-situdiversification of an urban-dwelling bat, endemic to a small island.
Genomic characterization of a nematode tolerance locus in sugar beet
Authors: Sielemann Katharina , Pucker Boas , Orsini Elena , Elashry Abdelnaser , Schulte Lukas , Viehöver Prisca , Müller Andreas E. , Schechert Axel , Weisshaar Bernd , Holtgräwe Daniela
Published: June 2023

Background

Infection by beet cyst nematodes (BCN,Heterodera schachtii) causes a serious disease of sugar beet, and climatic change is expected to improve the conditions for BCN infection. Yield and yield stability under adverse conditions are among the main breeding objectives. Breeding of BCN tolerant sugar beet cultivars offering high yield in the presence of the pathogen is therefore of high relevance.

Results

To identify causal genes providing tolerance against BCN infection, we combined several experimental and bioinformatic approaches. Relevant genomic regions were detected through mapping-by-sequencing using a segregating F2 population. DNA sequencing of contrasting F2 pools and analyses of allele frequencies for variant positions identified a single genomic region which confers nematode tolerance. The genomic interval was confirmed and narrowed down by genotyping with newly developed molecular markers. To pinpoint the causal genes within the potential nematode tolerance locus, we generated long read-based genome sequence assemblies of the tolerant parental breeding line Strube U2Bv and the susceptible reference line 2320Bv. We analyzed continuous sequences of the potential locus with regard to functional gene annotation and differential gene expression upon BCN infection. A cluster of genes with similarity to theArabidopsis thalianagene encoding nodule inception protein-like protein 7 (NLP7) was identified. Gene expression analyses confirmed transcriptional activity and revealed clear differences between susceptible and tolerant genotypes.

Conclusions

Our findings provide new insights into the genomic basis of plant-nematode interactions that can be used to design and accelerate novel management strategies against BCN.
In-situ spectroscopic detection of large-scale reorientations of transmembrane α-helices during viroporin channel opening
Authors: Paschke Ronja , Mohr Swantje , Lange Sascha , Lange Adam , Kozuch Jacek
Published: June 2023

Viroporins are small ion channels in membranes of enveloped viruses that play key roles during viral life cycles. To use viroporins as drug targets against viral infection requires in-depth mechanistic understanding and, with that, methods that enable investigations under in-situ conditions. Here, we apply surface-enhanced infrared absorption (SEIRA) spectroscopy to Influenza A M2 reconstituted within a solid-supported membrane, to shed light on the mechanics of its viroporin function. M2 is a paradigm of pH-activated proton channels and controls the proton flux into the viral interior during viral infection. We use SEIRA to track the large-scale reorientation of M2’s transmembrane α-helices in-situ during pH-activated channel opening. We quantify this event as a helical tilt from 26° to 40° by correlating the experimental results with solid-state NMR-informed computational spectroscopy. This mechanical motion is impeded upon addition of the inhibitor rimantadine, giving a direct spectroscopic marker to test antiviral activity. The presented approach provides a spectroscopic tool to quantify large-scale structural changes and to track the function and inhibition of the growing number of viroporins from pathogenic viruses in future studies.
Functional precision oncology for follicular lymphoma with patient-derived xenograft in avian embryos
Authors: Zala Manon , Lipinski Boris , Costechareyre Clélia , Jarrosson Loraine , Teinturier Romain , Julia Edith , Lacourrège Marjorie , Verney Aurélie , Guitton Jérôme , Traverse-Glehen Alexandra , Bachy Emmanuel , Salles Gilles , Huet Sarah , Genestier Laurent , Castellani Valérie , Delloye-Bourgeois Céline , Sujobert Pierre
Published: June 2023

Background

Follicular lymphoma (FL) is an incurable B-cell malignancy that constitutes a quarter of all lymphomas. Although RCHOP immuno-chemotherapy induces high rates of complete remission, almost all FL patients experience multiple relapses post-treatment. The limited understanding of treatment response heterogeneity is due to the absence ofin vitroorin vivoexperimental models, primarily because tumor cells heavily rely on their microenvironment to survive. In this study, we present an innovative xenograft model of primary FL cells in avian embryos, circumventing these limitations.

Methods

We developed the FL-AVI-PDX model by transplanting 20 biopsy FL samples, including good (n=11) and poor clinical responders (POD24, n=9), into chicken embryos. Each set of embryos was treated with RCHOP or vehicle intravenously. We evaluated the effect of immuno-chemotherapy on tumor volume by light sheet microscopy and on tumor biology by transcriptomic analysis at the single-cell level.

Results

We successfully engrafted all samples in avian embryos. We found that RCHOP treatmentin ovoled to tumor volume reduction, which predicted progression-free survival in multivariate analysis, demonstrating the model’s capacity to capture clinical heterogeneity at the patient level. The FL-AVI-PDX model also provided a unique opportunity to analyze the transcriptomic impact of RCHOP on FL cells using single-cell RNA sequencing. We identified a signature of 21 genes upregulated after RCHOP exposure, displaying significant intra-tumoral heterogeneity. As a proof of concept, we validated the functional involvement ofBAX, a gene from the RCHOP-induced signature, as a critical effector of immuno- chemotherapyin vitroand in avian embryos.

Conclusions

The FL-AVI-PDX model is a platform for functional precision oncology in primary FL cells that captures both inter- and intra-patient heterogeneity of clinical response to a complex therapeutic regimen. It offers a unique opportunity to better understand FL biology, opening perspectives for the development of new drugs.
The molecular basis of parental conflict driven regulation of endosperm cellularization
Authors: Butel N. , Qiu Y. , Xu W. , Santos-González J. , Köhler C.
Published: June 2023

The endosperm is a seed tissue supporting embryo growth, similar to the placenta in mammals. It originates after fertilization of the maternal central cell by one of the paternal sperm cells. In the early stages ofArabidopsis thalianaseed development, nuclei divisions in the endosperm are not followed by cellularization. After a defined number of mitotic cycles, the endosperm cellularizes and stops dividing. The timing of endosperm cellularization impacts on final seed size and is differentially controlled by maternal and paternal genome contributions. While increased maternal genome dosage causes early endosperm cellularization and the formation of small seeds, the opposite is caused by increased paternal genome dosage. The parental factors controlling the differential timing of endosperm cellularization remain largely unexplored. Here, we show that a family of maternally expressed auxin response factors (ARFs) promotes endosperm cellularization and regulates final seed size.

One-Sentence Summary

Endosperm cellularization is under antagonistic parental control that converges on Auxin Response Factors.
Modeling the motion of disease-associated KIF1A heterodimers
Authors: Kita Tomoki , Sasaki Kazuo , Niwa Shinsuke
Published: June 2023

KIF1A is a member of the kinesin-3 family motor protein that transports synaptic vesicle precursors in axons. Mutations in theKif1agene cause neuronal diseases. Most patients are heterozygous and have both mutated and intact KIF1A alleles, suggesting that heterodimers composed of wild-type KIF1A and mutant KIF1A are likely involved in pathogenesis. In this study, we propose mathematical models to describe the motility of KIF1A heterodimers composed of wild-type KIF1A and mutant KIF1A. Our models precisely describe run length, run time, and velocity of KIF1A heterodimers using a few parameters obtained from two homodimers. The independent head model is a simple hand-over-hand model in which stepping and detachment rates from a microtubule of each head are identical to those in the respective homodimers. Although the velocities of heterodimers expected from the independent head model were in good agreement with the experimental results, this model underestimated the run lengths and run times of some heterodimeric motors. To address this discrepancy, we propose the coordinated head model, in which we hypothesize a tethered head, in addition to a microtubule-binding head, contributes to microtubule binding in a vulnerable one-head-bound state. The run lengths and run times of the KIF1A heterodimers predicted by the coordinated head model matched well with experimental results, suggesting a possibility that the tethered head affects the microtubule binding of KIF1A. Our models provide insights into how each head contributes to the processive movement of KIF1A and can be used to estimate motile parameters of KIF1A heterodimers.

SIGNIFICANCE

KIF1A is responsible for transporting synaptic vesicle precursors in axons. KIF1A mutations are associated with neurodegener-ative diseases. Most of these mutations are de novo and autosomal dominant, suggesting that half of the motors in patients are heterodimers composed of wild-type and mutant KIF1A. However, reliable theoretical models to explain the behavior of heterodimeric motors are lacking. In this study, we obtained exact analytical solutions to describe run length, run time, and velocity of heterodimeric motors which move in a hand-over-hand fashion. Our models provide valuable tools for quantitatively understanding the impact of heterodimerization with mutant KIF1A and the cooperative behavior of KIF1A dimers.
C9orf72 polyPR directly binds to various nuclear transport components
Authors: Jafarinia Hamidreza , Van der Giessen Erik , Onck Patrick R.
Published: June 2023

The disruption of nucleocytoplasmic transport (NCT) is an important mechanism in neurodegenerative diseases. In the case of C9orf72-ALS, trafficking of macromolecules through the nuclear pore complex (NPC) might get frustrated by the binding of C9orf72-translated arginine-containing dipeptide repeat proteins (R-DPRs) to the Kapβ family of nuclear transport receptors. Beside Kapβs, several other types of transport components have been linked to NCT impairments in R-DPRs expressed cells, but the molecular origin of these observations has not been clarified. Here, we adopt a coarse-grained molecular dynamics model at amino-acid resolution to study the direct interaction between polyPR, the most toxic DPR, and various nuclear transport components to elucidate the binding mechanisms and provide a complete picture of potential polyPR-mediated NCT defects. We found polyPR to directly bind to several isoforms of the Impα family, CAS (the specific exporter of Impα) and RanGAP. We observe no binding between polyPR and Ran. Longer polyPRs at lower salt concentrations also make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on the transport components reveals that polyPR potentially interferes with RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing cargoes (cargo-NLS) binding to Impα, with cargo-NLS release from Impα, and with Impα export from the nucleus. The abundance of polyPR binding sites on multiple transport components combined with the inherent polyPR length dependence makes direct polyPR interference of NCT a potential mechanistic pathway of C9orf72 toxicity.
Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction
Authors: Latini Sara , Venafra Veronica , Massacci Giorgia , Bica Valeria , Graziosi Simone , Pugliese Giusj Monia , Iannuccelli Marta , Frioni Filippo , Minnella Gessica , Marra John Donald , Chiusolo Patrizia , Pepe Gerardo , Helmer-Citterich Manuela , Mougiakakos Dimitrios , Boettcher Martin , Fischer Thomas , Perfetto Livia , Sacco Francesca
Published: June 2023

Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, patient-specific genomic and transcriptomic data with a prior-knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.
Reorganization of the Flagellum Scaffolding Induces a Sperm Standstill During Fertilization
Authors: Jabloñski Martina , Luque Guillermina M. , Gómez-Elías Matías D. , Sanchez-Cardenas Claudia , Xu Xinran , de la Vega-Beltran Jose Luis , Corkidi Gabriel , Linares Alejandro , Abonza Amaro Victor X. , Arenas-Hernandez Aquetzalli , Del Pilar Ramos-Godinez María , López-Saavedra Alejandro , Krapf Dario , Krapf Diego , Darszon Alberto , Guerrero Adan , Buffone Mariano G.
Published: June 2023

Mammalian sperm delve into the female reproductive tract to fertilize the female gamete. The available information about how sperm regulate their motility during the final journey to the fertilization site is extremely limited. In this work, we investigated the structural and functional changes in the sperm flagellum after AE and during the interaction with the eggs. The evidence demonstrates that the double helix actin network surrounding the mitochondrial sheath of the midpiece undergoes structural changes prior to the motility cessation. This structural modification is accompanied by a decrease in diameter of the midpiece and is driven by intracellular calcium changes that occur concomitant with a reorganization of the actin helicoidal cortex. Midpiece contraction occurs in a subset of cells that undergo AE, live-cell imaging during in vitro fertilization showed that the midpiece contraction is required for motility cessation after fusion is initiated. These findings provide the first evidence of the F-actin network’s role in regulating sperm motility, adapting its function to meet specific cellular requirements during fertilization, and highlighting the broader significance of understanding sperm motility.

Significant statement

In this work, we demonstrate that the helical structure of polymerized actin in the flagellum undergoes a rearrangement at the time of sperm-egg fusion. This process is driven by intracellular calcium and promotes a decrease in the sperm midpiece diameter as well as the arrest in motility, which is observed after the fusion process is initiated.
The impact of non-lineage defining mutations in the structural stability for variants of concern of SARS-CoV-2
Authors: Martins Yasmmin , da Silva Ronaldo Francisco
Published: June 2023

Motivation

The identification of the most important mutations, that lead to a structural and functional change in a highly transmissible virus variants, is essential to understand the impacts and the possible chances of vaccine and antibody escape. Strategies to rapidly associate mutations to functional and conformational properties are needed to rapidly analyze mutations in proteins and their impacts in antibodies and human binding proteins.

Results

Comparative analysis showed the main structural characteristics of the essential mutations found for each variant of concern in relation to the reference proteins. The paper presented a series of methodologies to track and associate conformational changes and the impacts promoted by the mutations.

Contact

yasmmin.c.martins@gmail.com.br

Supplementary information

Supplementary data are available atBioinformaticsonline.
Unraveling the mechanisms of PAMless DNA interrogation by SpRY Cas9
Authors: Hibshman Grace N. , Bravo Jack P. K. , Zhang Hongshan , Dangerfield Tyler L. , Finkelstein Ilya J. , Johnson Kenneth A. , Taylor David W.
Published: June 2023

CRISPR-Cas9 is a powerful tool for genome editing, but the strict requirement for an “NGG” protospacer-adjacent motif (PAM) sequence immediately adjacent to the DNA target limits the number of editable genes. To overcome the PAM requirement, a recently developed Cas9 variant, called SpRY-Cas9 was engineered to be “PAMless” (1, 2). However, the molecular mechanisms of how SpRY can recognize all potential PAM sequences and still accurately identify DNA targets have not been investigated. Here, we combined enzyme kinetics, cryo-EM, and single-molecule imaging to determine how SpRY interrogates DNA and recognizes target sites for cleavage. Divergent PAM sequences can be accommodated through conformational flexibility within the PAM-interacting region of SpRY, which facilitates tight binding to off-target DNA sequences. Once SpRY correctly identifies a target site, nuclease activation occurs ∼1,000-fold slower than forStreptococcus pyogenesCas9, enabling us to directly visualize multiple on-pathway intermediate states. Insights gained from our intermediate structures prompted rationally designed mutants with improved DNA cleavage efficiency. Our findings shed light on the molecular mechanisms of PAMless genome editing with SpRY and provide a framework for the design of future genome editing tools with improved versatility, precision, and efficiency.
Mitochondrial genome fragmentation is correlated with increased rates of molecular evolution
Authors: Najer Tomáš , Doña Jorge , Buček Aleš , Sweet Andrew D. , Sychra Oldřich , Johnson Kevin P.
Published: June 2023

Animal mitochondrial genomes (mitogenomes) typically exhibit a highly conserved gene content and organisation, with genes encoded on a single circular chromosome. However, many species of parasitic lice (Insecta: Phthiraptera) are notable exceptions, having mitogenomes fragmented into multiple circular chromosomes. To understand the process of mitogenome fragmentation, we conducted a large-scale genomic study of a major group of lice, Amblycera, with extensive taxon sampling. Analyses of the evolution of mitogenome structure across a phylogenomic tree of 90 samples from 53 genera, revealed evidence for multiple independent origins of mitogenome fragmentation, some inferred to have occurred less than five million years ago. We leveraged these many independent origins of fragmentation to compare the rates of DNA substitution and gene rearrangement, specifically contrasting branches with fragmented and non-fragmented mitogenomes. We found that lineages with fragmented mitochondrial genomes had significantly higher rates of mitochondrial sequence evolution. In addition, lineages with fragmented mitochondrial genomes were more likely to have mitogenome gene rearrangements than those with single-chromosome mitochondrial genomes. By combining phylogenomics and mitochondrial genomics we provide a detailed portrait of mitogenome evolution across this group of insects with a remarkably unstable mitogenome structure, identifying processes of molecular evolution that are correlated with mitogenome fragmentation.

Author Summary

Mitochondria are organelles that play a key role in providing energy to cells essential for life. The structure of the mitochondrial genome is conserved across most animal groups, being a single circular chromosome containing 37 genes. Deviations from this structure are typically detrimental and associated with some human diseases. However, in very few animal groups, the mitochondrial genome is fragmented into multiple circular chromsomes. In one group of insects, parasitic lice, fragmentation varies among species, with some having a complete circular genome and others having their mitochondrial genome fragmented in two or more smaller chromosomes. Here, we use whole genome sequencing reads to analyze an unprecedented number of species from a diverse group of lice (Amblycera) that exhibits both single-chromosome and fragmented mitochondrial genomes to understand how this fragmentation evolved. We found that fragmentation evolved many times independently in this group and this fragmentation is correlated faster rates mitochondrial molecular evolution and with an increased frequency of gene rearrangement. We also provide evidence that the rate of mitochondrial genome fragmentation changes over time. Altogether, our combination of broad sampling and phylogenomic and comparative analyses provide new insights into the mechanisms and dynamics of mitochondrial genome fragmentation.
Longitudinal associations between language network characteristics in the infant brain and school-age reading abilities are mediated by early-developing phonological skills
Authors: Tang Xinyi , Turesky Ted K. , Escalante Elizabeth S. , Loh Megan Yf , Xia Mingrui , Yu Xi , Gaab Nadine
Published: June 2023

Reading acquisition is a prolonged learning process relying on language development starting in utero. Behavioral longitudinal studies reveal prospective associations between infant language abilities and preschool/kindergarten phonological development that relates to subsequent reading performance. While recent pediatric neuroimaging work has begun to characterize the neural network underlying language development in infants, how this neural network scaffolds long-term language and reading acquisition remains unknown. We addressed this question in a 7-year longitudinal study from infancy to school-age. Seventy-six infants completed resting-state fMRI scanning, and underwent standardized language assessments in kindergarten. Of this larger cohort, forty-one were further assessed on their emergent word reading abilities after receiving formal reading instructions. Hierarchical clustering analyses identified a modular infant language network in which functional connectivity (FC) of the inferior frontal module prospectively correlated with kindergarten-age phonological skills and emergent word reading abilities. These correlations were obtained when controlling for infant age at scan, nonverbal IQ and parental education. Furthermore, kindergarten-age phonological skills mediated the relationship between infant FC and school-age reading abilities, implying a critical mid-way milestone for long-term reading development from infancy. Overall, our findings illuminate the neurobiological mechanisms by which infant language capacities could scaffold long-term reading acquisition.

Highlights

Clustering analyses revealed a modular language network in the infant brain

Infant language network characteristics associate with school-age reading outcomes

These longitudinal associations are mediated by kindergarten-age phonological skills
Evasion of APOBEC1-mediated Intrinsic Immunity by a Herpesvirus Uracil DNA Glycosylase Is a Determinant of Viral Encephalitis
Authors: Kato Akihisa , Harima Hayato , Tsunekawa Yuji , Igarashi Manabu , Kitamura Kouichi , Wakae Kousho , Kozuka-Hata Hiroko , Oyama Masaaki , Watanabe Mizuki , Takeshima Kousuke , Maruzuru Yuhei , Koyanagi Naoto , Okada Takashi , Muramatsu Masamichi , Kawaguchi Yasushi
Published: June 2023

Herpes simplex virus 1 (HSV-1) is the most common cause of viral encephalitis, which can be lethal or result in severe neurological defects, even when treated with antiviral therapy. We demonstrated that activation of HSV-1 uracil-DNA glycosylase (vUNG) by phosphorylation, essential for its enzymatic activity, counteracted APOBEC1 to promote viral replication and encephalitis in the central nervous system (CNS) of mice. The activation of vUNG protected HSV-1 genomes from APOBEC1-mediated DNA editing, allowing efficient viral replication to occur. The presence of APOBEC1 markedly improved lethal encephalitis in mice infected with an HSV-1 mutant carrying a mutation in the phosphorylation site and an UNG inhibitor protected wild-type HSV-1-infected mice from lethal encephalitis. These findings re-define vUNG as an important factor that allows evasion from intrinsic anti-viral immunity mediated by APOBEC1 in the CNS, and suggest a new therapeutic approach for the treatment of fetal and critical HSV-1 encephalitis.
Response of soil microbiome composition to selection on methane oxidation rate
Authors: Morris Andrew H. , Bohannan Brendan J. M.
Published: June 2023

Microbiomes mediate important ecosystem functions, yet it has proven difficult to determine the relationship between microbiome composition and the rate of ecosystem functions. This challenge remains because it is difficult to manipulate microbiome composition directly, we often cannot knowa prioriwhich microbiome members influence the rate of an ecosystem function, and microbiomes can covary strongly with other drivers of ecosystem function, such as the environment. To address these challenges, we imposed artificial selection on whole soil ecosystems over multiple generations to select for microbial communities with a high rate of CH4oxidation. This approach is potentially powerful because it is biologically “agnostic” in that it makes few assumptions about which taxa are important to function, and repeated passaging with fresh substrate weakens the covariance between microbes and the environment. As a response to selection, we observed a 50.7% increase in CH4oxidation rate per passage relative to a control that experienced random selection. We estimated that 31.5% of the variation in CH4oxidation rate in these soils can be attributed to microbiome variation (though this was not significant). We also found that selection did not enrich for known CH4oxidizers; instead, 12 families not known to oxidize CH4, includingFimbriimonadaceae,Cytophagaceae, andDiplorickettsiaceae, were enriched by selection. This result is in contrast to the typical assumption that the rate of an ecosystem function is limited by the final step in the associated microbial pathway. Our study demonstrates that variation in microbiome composition can contribute to variation in the rate of ecosystem function independent of the environment and that this may not always be limited by the final step in a pathway. This suggests that manipulating microbiome composition directly without altering the environment could be a viable strategy for managing ecosystem functions.
Loss of endothelial cell heterogeneity in arteries after obesogenic diet
Authors: Dunaway Luke S. , Luse Melissa A. , Nyshadham Shruthi , Bulut Gamze , Alencar Gabriel F. , Chavkin Nicholas W. , Cortese-Krott Miriam , Hirschi Karen K. , Isakson Brant E.
Published: June 2023

Background

It is well recognized that obesity leads to arterial endothelial dysfunction and cardiovascular disease. However, the progression to endothelial dysfunction is not clear. Endothelial cells (ECs) adapt to the unique needs of their resident tissue and respond to systemic metabolic perturbations. We sought to better understand how obesity affects EC phenotypes in different tissues specifically focusing on mitochondrial gene expression.

Methods

We performed bulk RNA sequencing (RNA-seq) and single cell RNA-seq (scRNA-seq) on mesenteric and adipose ECs isolated from normal chow (NC) and high fat diet (HFD) fed mice. Differential gene expression, gene ontology pathway, and transcription factor analyses were performed. We further investigated our hypothesis in humans using published human adipose single nuclei RNA-seq (snRNA-seq) data.

Results

Bulk RNA-seq revealed higher mitochondrial gene expression in adipose ECs compared to mesenteric ECs in both NC and HFD mice. We then performed scRNA-seq and categorized EC clusters as arterial, capillary, venous, or lymphatic. HFD decreased the number of differentially expressed genes between mesenteric and adipose ECs in all subtypes, but the largest effect was seen in arterial ECs. Further analysis of arterial ECs revealed genes coding for mitochondrial oxidative phosphorylation proteins were enriched in adipose compared to mesentery under NC conditions. In HFD mice, these genes were decreased in adipose ECs becoming similar to mesenteric ECs. Transcription factor analysis revealed C/EBPα and PPARγ, both known to regulate lipid handling and metabolism, had high specificity scores in the NC adipose artery ECs. These findings were recapitulated in snRNA-seq data from human adipose.

Conclusions

These data suggest mesenteric and adipose arterial ECs metabolize lipids differently and the transcriptional phenotype of these two vascular beds converge in obesity, in part, due to downregulation of PPARγ and C/EBPα in adipose artery ECs. This work lays the foundation for investigating vascular bed specific adaptations to obesity.
Structure evolution of Bi4O7 under high pressure
Authors: Wang Jianzong , Wang Luhong , Liu Fuyang , Yuan Shuhua , Zhang Dongzhou , Prakapenka Vitali B. , Klein Wilhelm , Liu Haozhe
Published: June 2023

X-ray diffraction and Raman spectroscopy measurements were used to study the structure evolution of Bi4O7 during compression. Two isostructural phase transitions were observed under high pressure, with the first transition to phase II occurring at approximately 3.0 (2) GPa and the second to phase III occurring at approximately 13.0 (5) GPa. The pressure–volume (P–V) curve was found to be discontinuous at those two pressure transition boundaries. By fitting the P–V curves in three different stages, the bulk moduli were estimated to be approximately 101 (2), 68 (2) and 172 (3) GPa. Such large differences in the bulk moduli confirm two isostructural phase changes in the three stages. An irreversible amorphization process was found to start at approximately 20 (1) GPa, and the sample gradually becomes fully amorphous during compression at 30 (1) GPa.
Synthesis, structure, ADME and biological activity of three 2,6-disubstituted thiosemicarbazone derivatives
Authors: Ziembicka Dagmara , Olczak Andrzej , Gobis Katarzyna , Korona-Głowniak Izabela , Pietrzak Anna , Augustynowicz-Kopeć Ewa , Głogowska Agnieszka , Zaborowski Marcin , Szczesio Małgorzata
Published: June 2023

Three new 2,6-disubstituted thiosemicarbazone derivatives of pyridine, namely, 2-{amino[6-(pyrrolidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C13H20N6S, 2-{amino[6-(piperidin-1-yl)pyridin-2-yl]methylidene}-N,N-dimethylhydrazine-1-carbothioamide, C14H22N6S, and 2-[amino(6-phenoxypyridin-2-yl)methylidene]-N,N-dimethylhydrazine-1-carbothioamide monohydrate, C15H17N5OS·H2O, have been synthesized and characterized by NMR spectroscopy and low-temperature single-crystal X-ray diffraction. In addition, their antibacterial and anti-yeast activities have been determined. The ability of the tested compounds to inhibit bacterial growth was comparable to vancomycin as a reference drug. Compared to isoniazid (MIC 0.125 and 8 µg ml−1), the compounds showed the ability to inhibit the growth of Mycobacterium tuberculosis to a moderate degree for the standard strain and at the same level or higher (MIC 4–8 µg ml−1) for the resistant strain. All three compounds adopt the zwitterionic form in the crystal structure regardless of the presence or absence of solvent molecules.
Exploring success factors in food waste prevention initiatives of retailers: the critical role of digital technologies
Authors: Corsini Filippo , Annesi Nora , Annunziata Eleonora , Frey Marco
Published: June 2023

Purpose

Food waste is a severe problem affecting the supply chain due to its significant adverse social and environmental effects. Even if the topic is hotly debated in the literature, there is a lack of research about the success factors influencing food waste prevention initiatives retailers undertake.

Design/methodology/approach

The research analyzes how several variables (i.e. product-related variables and technology-enabling variables) might impact the success of the sales of products close to the expiration date that is sold at a discounted price. Data from 390.000 products sold at a discounted price in 2020 and 2021 by a large Italian food retailer were examined with a regression analysis.

Findings

The results highlight that both product-related and technology-enabling variables influence the success of food prevention initiatives aimed at selling products close to the expiration date at a discounted price. In particular, the authors stress the importance of digital technologies in supporting food waste prevention initiatives.

Practical implications

The study offers several practical implications for managers in structuring a waste prevention initiative. The introduction of digital technologies, the monitoring of specific variables or the ability to find synergies with other food waste prevention initiatives are discussed to support retailers in reducing food losses.

Originality/value

The paper is focused on the retailer perspective, which is barely investigated due to the difficulty in finding data.
Integrated customer lifetime value models to support marketing decisions in the complementary and alternative medicine industry
Authors: Kanchanapoom Kessara , Chongwatpol Jongsawas
Published: June 2023

Purpose

Customer lifetime value (CLV) is one of the key indicators to measure the success or health of an organization. How can an organization assess the organization's customers' lifetime value (LTV) and offer relevant strategies to retain prospective and profitable customers? This study offers an integrated view of different methods for calculating CLVs for both loyalty members and non-membership customers.

Design/methodology/approach

This study outlines eleven methods for calculating CLV considering (1) the deterministic aspect of NPV (Net present value) models in both finite and infinite timespans, (2) the geometric pattern and (3) the probabilistic aspect of parameter estimates through simulation modeling along with (4) the migration models for including “the probability that customers will return in the future” as a key input for CLV calculation.

Findings

The CLV models are validated in the context of complementary and alternative medicine (CAM)in the healthcare industry. The results show that understanding CLV can help the organization develop strategies to retain valuable customers while maintaining profit margins.

Originality/value

The integrated CLV models provide an overview of the mathematical estimation of LTVs depending on the nature of the customers and the business circumstances and can be applied to other business settings.
Risk spillovers connectedness between the US Fintech industry VaR, behavioral biases and macroeconomic instability factors: COVID-19 implications
Authors: Gharbi Oumayma , Trichilli Yousra , Boujelbéne Mouna
Published: June 2023

Purpose

The main objective of this paper is to analyze the dynamic volatility spillovers between the investor's behavioral biases, the macroeconomic instability factors and the value at risk of the US Fintech stock market before and during the COVID-19 pandemic.

Design/methodology/approach

The authors used the methodologies proposed by Diebold and Yilmaz (2012) and the wavelet approach.

Findings

The wavelet coherence results show that during the COVID-19 period, there was a strong co-movement among value at risk and each selected variables in the medium-run and the long-run scales. Diebold and Yilmaz's (2012) method proved that the total connectedness index raised significantly during the COVID-19 period. Moreover, the overconfidence bias and the financial stress index are the net transmitters, while the value at risk and herding behavior variables are the net receivers.

Research limitations/implications

This study offers some important implications for investors and policymakers to explain the impact of the COVID-19 pandemic on the risk of Fintech industry.

Practical implications

The study findings might be useful for investors to better understand the time–frequency connectedness and the volatility spillover effects in the context of COVID-19 pandemic. Future research may deal with investors' ability of constructing portfolios with another alternative index like cryptocurrencies which seems to be a safer investment.

Originality/value

To the best of the authors' knowledge, this is the first study that relies on the continuous wavelet decomposition technique and spillover volatility to examine the connectedness between investor behavioral biases, uncertainty factors, and Value at Risk of US Fintech stock markets, while taking into account the recent COVID-19 pandemic.
Ajay Foods: the sweet spot within service design and menu expansion
Authors: Dikkatwar Ramkrishna , De Tanmoy , Laeequddin Mohammed
Published: June 2023

Learning outcomes

To understand a firm’s service concept and process; to explain the service design that differentiates itself by making trade-offs in operations and service offering; to identify the importance of deliberately designed interrelated systems and resources to achieve growth in services and to evaluate the fit of new design elements in the service offering.

Case overview/synopsis

Ajay Takeaway Foods LLP (Ajay Foods) is a food venture founded by Mr Jaideep Solanki and Mr Ajay Solanki and operates as a chain of quick service restaurants with a simple mission to sell food that is good, affordable and accessible to all. Ajay Foods serves only pure vegetarian and limited variants of burger, pizza and cold coffee. Ajay Foods rolled out 75 stores in just 18 months during the COVID 19 pandemic. Ajay Foods’ founders were contemplating on expanding menu. There was growing demand for food items such as samosa, wraps, sandwiches and French fries. One of the founders got into dilemma: How many items? and Which item(s) to add to the menu?

Complexity academic level

This case can be used at post-graduate level to teach basic frameworks of service concept and design. The case covers a range of topics such as service processes, service elements and product offerings in a service setting. It can be used effectively with MBAs and Hospitality Management program in courses that focus on Service Management, Service Operations or Service Marketing Strategy.

Supplementary materials

Teaching notes are available for educators only.

Subject code

CSS 9: Operations and Logistics.