bluuebunny/crossref_metadata_2025 huggingface dataset:
Current Challenges and Controversies in Colorectal Carcinoma Pathologic Staging—A Practical Guide
Authors: Clark Ian , Mehreen Ansa , Dickson Paxton V. , Shibata David , Glazer Evan S. , Choudhury Nabajit , Jain Richa
Published: December 2023

The pathologic assessment of colorectal carcinoma specimens plays a crucial role in the therapeutic management of patients and disease prognostication. The TNM staging system is used globally and is a critical component of colorectal carcinoma pathology reporting. However, our experience informs us that there are significant variations in the assignment of the TNM stage, both between pathologists and between hospital centers. We identify several potential reasons for this, among them suboptimal gross and microscopic assessment of colorectal resection specimens and, later, nonuniformity in applying criteria set forth in pathologic TNM staging guidelines. In addition, some defining characteristics of the staging system remain poorly defined. We aim to enlist those issues with potential remedies to improve reproducibility and, therefore, multidisciplinary discussion.
Population age and household structures shape transmission dynamics of emerging infectious diseases: a longitudinal microsimulation approach
Authors: Møgelmose Signe , Vijnck Laurens , Neven Frank , Neels Karel , Beutels Philippe , Hens Niel
Published: December 2023

Host population demographics and patterns of host-to-host interactions are important drivers of heterogeneity in infectious disease transmission. To improve our understanding of how population structures and changes therein influence disease transmission dynamics at the individual and population level, we model a dynamic age- and household-structured population using longitudinal microdata drawn from Belgian census and population registers. At different points in time, we simulate the spread of a close-contact infectious disease and vary the age profiles of infectiousness and susceptibility to reflect specific infections (e.g. influenza and SARS-CoV-2) using a two-level mixing model, which distinguishes between exposure to infection in the household and exposure in the community. We find that the strong relationship between age and household structures, in combination with social mixing patterns and epidemiological parameters, shape the spread of an emerging infection. Disease transmission in the adult population in particular is to a large degree explained by differential household compositions and not just household size. Moreover, we highlight how demographic processes alter population structures in an ageing population and how these in turn affect disease transmission dynamics across population groups.
Transcriptomic signatures associated with underlying rapid changes in the early phase brain of bi-directional sex change in
Trimma okinawae
Authors: Tamagawa Katsunori , Sunobe Tomoki , Makino Takashi , Kawata Masakado
Published: December 2023

Teleost fish exhibit remarkable sexual plasticity and divergent developmental systems, including sequential hermaphroditism. One of the more fascinating models of sexual plasticity is socially controlled sex change, which is often observed in coral reef fish. The Okinawa rubble goby,
Trimma okinawae,
is a bi-directional sex-changing fish. It can rapidly change sex in either direction based on social circumstances. Although behavioural and neuroendocrine sex change occurs immediately and is believed to trigger gonadal changes, the underlying mechanisms remain poorly understood. In this study, we conducted a
de novo
transcriptome analysis of the
T. okinawae
brain and identified genes that are differentially expressed between the sexes and genes that were immediately controlled by social stimulation implicating sex change. Several genes showed concordant expression shifts regardless of the sex change direction and were associated with histone modification in nerve cells. These genes are known to function in the neuroendocrine control of reproduction in nerve cells. Overall, we identified genes associated with the initiation of sex change, which provides insight into the regulation of sex change and sexual plasticity.
Prediction of general high-order lump solutions in the Davey–Stewartson II equation
Authors: Yan Xue-Wei , Long Haie , Chen Yong
Published: December 2023

Under investigation in this work is the Davey–Stewartson (DS) II equation. Based on the Kadomtsev–Petviashvili (KP) reduction method and Schur polynomial theory, we construct the general high-order lump solutions. The prediction solutions consisting of fundamental lumps and their positions are derived by extracting leading-order asymptotics of the Schur polynomials of true solutions. When indexes of the solutions are chosen as different positive integer combinations, the prediction solutions at large time reflect two classes of lump patterns of the true solutions. The first class of lump pattern with triangle shape is analytically described by root structure of the Yablonskii–Vorob’ev polynomial. When time

t

evolves from large negative to large positive, the triangle lump reverses itself along the

y

-direction. The second class of lump pattern consists of non-triangle in outer region, which is analytically described by non-zero root structure of the Wronskian–Hermit polynomial, together with possible triangle in the inner region, which is analytically described by root structure of the Yablonskii–Vorob’ev polynomial. In addition, the non-triangle lump pattern in outer regions rotates at an angle while the possible triangle lump pattern in the inner region reverses itself along the

y

-direction when time

t

evolves from large negative to large positive. The obtained results improve our understanding of time evolution mechanisms of high-order lumps.
DNA methylation extends lifespan in the bumblebee
Bombus terrestris
Authors: Renard Thibaut , Martinet Baptiste , De Souza Araujo Natalia , Aron Serge
Published: December 2023

Epigenetic alterations are a primary hallmark of ageing. In mammals, age-related epigenetic changes alter gene expression profiles, disrupt cellular homeostasis and physiological functions and, therefore, promote ageing. It remains unclear whether ageing is also driven by epigenetic mechanisms in invertebrates. Here, we used a pharmacological hypomethylating agent (RG108) to evaluate the effects of DNA methylation (DNAme) on lifespan in an insect—the bumblebee
Bombus terrestris
. RG108 extended mean lifespan by 43% and induced the differential methylation of genes involved in hallmarks of ageing, including DNA damage repair and chromatin organization. Furthermore, the longevity gene
sirt1
was overexpressed following the treatment. Functional experiments demonstrated that SIRT1 protein activity was positively associated with lifespan. Overall, our study indicates that epigenetic mechanisms are conserved regulators of lifespan in both vertebrates and invertebrates and provides new insights into how DNAme is involved in the ageing process in insects.
Insect exoskeletons react to hypergravity
Authors: Stamm Karen , Dirks Jan-Henning
Published: December 2023

A typical feature of biological materials is their ability to adapt to mechanical load. However, it is not known whether the cuticle exoskeleton, one of the most common biological structures, also shares this trait. Here, we show direct experimental evidence that prolonged exposure to hypergravity conditions affects the morphology and biomechanics of an insect exoskeleton. Locusts were raised for several weeks in a custom-designed centrifuge at various levels of hypergravity. Biomechanical measurements and X-ray microtomography show that up to 3 g load Young’s modulus of the tibiae increased by about 67%. Higher gravitational loads however decreased the survival rate, body mass and endocuticle thickness. These results directly show that cuticle exoskeletons can react to hypergravity. This ability has so far only been known for bone endoskeletons and plants. Our findings thus add important context to the discussion on general ultimate factors in the evolution of adaptive biological materials and skeletal systems.
Engineering of the LAMP-CRISPR/Cas12b platform for Chlamydia psittaci detection
Authors: Wang Rong , Mao Xujian , Xu Jian , Yao Ping , Jiang Jingyi , Li Qiong , Wang Fengming
Published: December 2023

Introduction.

Chlamydia psittaci

(

C. psittaci

) is a zoonotic infection, that causes psittacosis (parrot fever) in humans, leading to severe clinical manifestations, including severe pneumonia, adult respiratory distress syndrome, and, in rare cases, death.

Gap Statement. Rapid, sensitive and specific detection of

C. psittaci

facilitates timely diagnosis and treatment of patients.

Aim. This study aimed to engineer the LAMP-CRISPR/Cas12b platform for

C. psittaci

detection.

Methodology. The loop-mediated isothermal amplification (LAMP) technique and clustered regularly interspaced short palindromic repeats-CRISPR associated protein 12b (CRISPR-Cas12b) assay were combined to establish two-step and one-tube LAMP-CRISPR/Cas12b reaction systems, respectively, for rapidly detecting

C. psittaci

.

Results. The two-step and one-tube LAMP-CRISPR/Cas12b assay could complete detection within 1 h. No cross-reactivity was observed from non-

C. psittaci

templates with specific LAMP amplification primers and single-guide RNA (sgRNA) targeting the highly conserved short fragment CPSIT_0429 gene of

C. psittaci

. The detection limits of the two-step and one-tube LAMP-CRISPR/Cas12b reaction were 102 aM and 103 aM, respectively. The results were consistent with qPCR for nucleic acid detection in 160 clinical samples, including 80 suspected

C. psittaci

samples, kept in the laboratory.

Conclusions. The LAMP-CRISPR/Cas12b assay developed in this study provides a sensitive and specific method for rapidly detecting

C. psittaci

and offers technical support for its rapid diagnosis.
CC-Tempo: A cell-cell communication aware temporal model of cellular dynamics
Authors: Jony Sheikh Saifur Rahman , Rahman M. Sohel , Samee Md. Abul Hassan
Published: December 2023

Delineating the mechanisms underlying cell state changes is key to gaining insights into organismal development and disease prognosis. Various methods have been proposed to study cellular differentiation and cell fate specification. However, they either do not incorporate temporal information or do not consider the vital role of intercellular communication in cellular differentiation and cell fate determination. Furthermore, many of these methods lack interpretability, making it difficult to identify the critical genes and pathways that influence the differentiation process. Here we propose CC-Tempo, a cell-cell communication-aware model of cellular dynamics that leverages intercellular communication scores and can help identify important genes and pathways crucial for different stages of differentiation in various lineages. While previous studies have indicated that scRNA-seq data alone may not suffice for accurately predicting cell fates, CC-Tempo demonstrates that incorporating intercellular communication significantly enhances the performance of such models. CC-Tempo can predict the significance of genes and pathways at different stages of the differentiation process. By perturbing these genes in silico, CC-Tempo reveals their efficacy for manipulating cell fate, which can be crucial for defining efficient reprogramming factors.
Healthy microbiome - moving towards functional interpretation
Authors: Zielińska Kinga , Udekwu Klas I. , Rudnicki Witold , Frolova Alina , Łabaj Paweł P
Published: December 2023

Microbiome-based disease prediction has significant potential as an early, non-invasive marker of multiple health conditions linked to dysbiosis of the human gut microbiota, thanks in part to decreasing sequencing and analysis costs. Microbiome health indices and other computational tools currently proposed in the field often are based on a microbiome’s species richness and are completely reliant on taxonomic classification. A resurgent interest in a metabolism-centric, ecological approach has led to an increased understanding of microbiome metabolic and phenotypic complexity revealing substantial restrictions of taxonomy-reliant approaches. In this study, we introduce a new metagenomic health index developed as an answer to recent developments in microbiome definitions, in an effort to distinguish between healthy and unhealthy microbiomes, here in focus, inflammatory bowel disease (IBD). The novelty of our approach is a shift from a traditional Linnean phylogenetic classification towards a more holistic consideration of the metabolic functional potential underlining ecological interactions between species. Based on well-explored data cohorts, we compare our method and its performance with the most comprehensive indices to date, the taxonomy-based Gut Microbiome Health Index (GMHI), and the high dimensional principal component analysis (hiPCA)methods, as well as to the standard taxon-, and function-based Shannon entropy scoring. After demonstrating better performance on the initially targeted IBD cohorts, in comparison with other methods, we retrain our index on an additional 27 datasets obtained from different clinical conditions and validate our index’s ability to distinguish between healthy and disease states using a variety of complementary benchmarking approaches. Finally, we demonstrate its superiority over theGMHIand thehiPCAon a longitudinal COVID-19 cohort and highlight the distinct robustness of our method to sequencing depth. Overall, we emphasize the potential of this metagenomic approach and advocate a shift towards functional approaches in order to better understand and assess microbiome health as well as provide directions for future index enhancements. Our method,q2-predict-dysbiosis (Q2PD),is freely available (https://github.com/Kizielins/q2-predict-dysbiosis).
Integrated Molecular-Phenotypic Profiling Reveals Metabolic Control of Morphological Variation in Stembryos
Authors: Villaronga Luque Alba , Savill Ryan , López-Anguita Natalia , Bolondi Adriano , Garai Sumit , Gassaloglu Seher Ipek , Poddar Aayush , Bulut-Karslioglu Aydan , Veenvliet Jesse V
Published: December 2023

Mammalian stem-cell-based models of embryo development (stembryos) hold great promise in basic and applied research. However, considerable phenotypic variation despite identical culture conditions limits their potential. The biological processes underlying this seemingly stochastic variation are poorly understood. Here, we investigate the roots of this phenotypic variation by intersecting transcriptomic states and morphological history of individual stembryos across stages modeling post-implantation and early organogenesis. Through machine learning and integration of time-resolved single-cell RNA-sequencing with imaging-based quantitative phenotypic profiling, we identify early features predictive of the phenotypic end-state. Leveraging this predictive power revealed that early imbalance of oxidative phosphorylation and glycolysis results in aberrant morphology and a neural lineage bias that can be corrected by metabolic interventions. Collectively, our work establishes divergent metabolic states as drivers of phenotypic variation, and offers a broadly applicable framework to chart and predict phenotypic variation in organoid systems. The strategy can be leveraged to identify and control underlying biological processes, ultimately increasing the reproducibility of in vitro systems.

Highlights

Time-resolved single-cell RNA-sequencing and imaging-based quantitative charting of hundreds of individual stembryos generates molecular and phenotypic fingerprints

Machine learning and integration of molecular and phenotypic fingerprints identifies features and biological processes predictive of phenotypic end-state

Early imbalance of oxidative phosphorylation and glycolysis results in aberrant morphology and cellular composition

Metabolic interventions tune stembryo end-state and can correct derailment of differentiation outcomes
Four-Core Genotypes mice harbour a 3.2MB X-Y translocation that perturbs Tlr7 dosage
Authors: Panten Jasper , Prete Stefania Del , Cleland James P. , Saunders Lauren M. , van Riet Job , Schneider Anja , Ginno Paul , Schneider Nina , Koch Marie-Luise , Gerstung Moritz , Stegle Oliver , Turner James M. A. , Heard Edith , Odom Duncan T.
Published: December 2023

The Four Core Genotypes (FCG) is a mouse model system heavily used to disentangle the function of sex chromosomes and hormones. We report that a copy of a 3.2 MB region of the X chromosome has translocated to the YSry-chromosome and thus increased the expression of multiple genes including the auto-immune master regulatorTlr7. This previously-unreported X-Y translocation complicates the interpretation of studies reliant on FCG mice.
Functional displacement of cortical neuromagnetic somatosensory responses: enhancing embodiment in the rubber hand illusion
Authors: Isabella Silvia L. , D’Alonzo Marco , Mioli Alessandro , Arcara Giorgio , Pellegrino Giovanni , Pino Giovanni Di
Published: December 2023

The integration of an artificial limb as part of one’s body involves complex neuroplastic changes resulting from various sensory inputs to the brain. While sensory feedback is known to be crucial for embodiment, current evidence points merely to the attenuation of somatosensory processing, while the positive contributions of somatosensory areas to embodiment remain unknown. This study investigated the relationship between embodiment and adaptive neuroplasticity of early-latency somatosensory evoked fields (SEFs) in the primary somatosensory cortex (S1) following the Rubber Hand Illusion (RHI), known to induce short-term artificial limb embodiment. Nineteen healthy adults underwent neuromagnetic recordings during electrical stimulation of the little finger and thumb, before and after the RHI. We found a displacement of early SEF sources. In particular, we observed a correlation between the extent of rubber hand embodiment and specific changes to the m20 component (magnetic equivalent to the N20) in Brodmann Area 3b: a larger displacement and a greater reduction in m20 magnitude predicted the amount of embodiment, highlighting an important functional contribution of this first cortical input. Furthermore, we observed a posteriorly directed m35 displacement towards Area 1, known to be important for visual integration during touch perception (Rosenthal et al., 2023). Our finding that the larger displacement for the m35 did not correlate with the extent of embodiment implies a functional distinction between neuroplastic changes across these two components and areas in their contributions to successful artificial limb embodiment: (i) the earlier neuroplastic changes to m20 may shape the extent of artificial limb ownership, and (ii) the posteriorward shift of the m35 into Area 1 is suggestive of a mechanistic contribution to early visual-tactile integration that initially establishes the embodiment. Taken together, these findings suggest that multiple distinct changes occur during early-latency SEFs and their displacement in S1 last beyond the duration of the illusion and are important for the successful integration of an artificial limb within the body representation.
Spatial heterogeneity in myelin sheathing impacts signaling reliability and susceptibility to injury
Authors: Talidou Afroditi , Lefebvre Jérémie
Published: December 2023

Axons in the mammalian brain show significant diversity in myelination motifs, displaying spatial heterogeneity in sheathing along individual axons and across brain regions. However, its impact on neural signaling and susceptibility to injury remains poorly understood. To address this, we leveraged cable theory and developed model axons replicating the myelin sheath distributions observed experimentally in different regions of the mouse central nervous system. We examined how the spatial arrangement of myelin affects propagation and predisposition to conduction failure in axons with cortical versus callosal myelination motifs. Our results indicate that regional differences in myelination significantly influence conduction timing and signaling reliability. Sensitivity of action potential propagation to the specific positioning, lengths, and ordering of myelinated and exposed segments reveals non-linear and path-dependent conduction. Furthermore, myelination motifs impact signaling vulnerability to demyelination, with callosal motifs being particularly sensitive to myelin changes. These findings highlight the crucial role of myelinating glia in brain function and disease.
Genotype, antimicrobial resistance and virulence profiles of livestock-derived enterotoxigenicEscherichia coli(ETEC) in the United States, 1970-2023
Authors: Fu Yezhi , Nawrocki Erin M. , M’ikanatha Nkuchia M. , Dudley Edward G.
Published: December 2023

EnterotoxigenicEscherichia coli(ETEC) is a significant pathogen in both cattle and pigs, causing diarrhea in these animals and leading to economic losses in the livestock industry. Understanding the dissimilarity in genotype, antimicrobial resistance (AMR), and virulence between bovine and swine ETEC is crucial for development of targeted preventive and therapeutic approaches for livestock. However, a comprehensive study on this area remains lacking. Here, we performed whole-genome sequencing-based analyses of bovine (n= 554) and swine (n= 623) ETEC collected in the US over a 53-year period. We identified distinct ETEC genotypes (fimHtype, O antigen, H antigen, sequence type) in cattle and pigs. Further, specific AMR and virulence profiles were associated with bovine and swine ETEC. Compared to swine ETEC, bovine ETEC were less diverse in genotypes, had a significantly (p< 0.001) lower number of AMR genes per isolate but higher co-occurrence of Shiga toxin and enterotoxin genes. Our results provide an overview of the key genomic differences between bovine and swine ETEC in the US, which might be attributed to host adaptation and antibiotic usage practice. Ongoing surveillance and research are essential to monitor the genetic diversity and AMR patterns of ETEC in different host species.
Characterization of the mutational landscape of high-grade gliomas in a Latin American cohort
Authors: Fernández-Gajardo Rodrigo , Urra Hery , Saéz Mauricio , Pihán Philippe , Fonseca Beatriz , Sanchez-Doñas Carolina , Ali Maruf M. U. , Rouse Sarah L. , Cavada Gabriel , Tissera Claudia , Melo Rómulo , Rojas David , Matamala José M. , Hetz Claudio
Published: December 2023

Background

Glioblastoma, an aggressive form of high-grade glioma, exhibits variations in the incidence and mortality patterns between populations of different ancestry. However, Hispanic and Latino populations remain largely underrepresented in studies of molecular characterization. Here we characterized the mutagenic landscape of high-grade gliomas within a Chilean population focusing on well characterized genetic variants associated with glioblastoma classification, progression, and prognosis.

Methods

We conducted a targeted genomic analysis using next-generation sequencing techniques in 70 Chilean patients with high-grade gliomas from a national single-center referral institution. We focused on the most relevant molecular markers such as isocitrate dehydrogenase 1/2 (IDH) mutations, telomerase reverse transcriptase promoter (TERTp) mutations, histone 3 (H3) gene family mutations, TP53 and PTEN mutations, epidermal growth factor receptor (EGFR) gene amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) deletions. Survival analyses were performed to assess the clinical relevance of these markers and their impact on patient prognosis. Additionally, due to our interest in the role of proteostasis and glioblastoma, we investigated possible ERN1 variants in our Chilean cohort.

Results

Our findings mostly align with other international cohorts of non-Latin-American origin, confirming the importance of established molecular markers in glioblastoma. Notably, we identified novel TP53 and PTEN mutations with a predicted damaging effect, expanding the genetic spectrum of alterations in these brain tumors. Furthermore, a lower-than-expected mutation rate in the NF1 gene was observed, emphasizing a distinctive genetic profile of glioblastoma in this Latin American population. Prognostic assessments based on TERT promoter and IDH mutations mirrored previous studies on non-Latino American and European populations. Of note, we identified the germline ERN1 variant rs139229826 in 11% of our patient cohort, a variant previously unreported in glioblastoma patients.

Conclusion

This study underscores the importance of conducting glioblastoma research in underrepresented populations, providing insights into the molecular characteristics of high-grade gliomas within a Latin American context. Our findings contribute to the growing body of evidence suggesting molecular diversity across diverse glioblastoma populations, offering a foundation for future international comparative studies.
Intronic polyadenylation isoforms in the 5’ part of genes constitute a source of microproteins and are involved in cell response to cisplatin
Authors: Devaux Alexandre , Tanaka Iris , Cadix Mandy , Heneman-Masurel Amélie , Michallet Sophie , Fouilleul Quentin , Chakraborty Alina , Labbe Céline M. , Fontrodona Nicolas , Claude Jean-Baptiste , Deloger Marc , Gestraud Pierre , Tessier Ludovic , Mortada Hussein , Lameiras Sonia , Raynal Virginie , Baulande Sylvain , Servant Nicolas , Auboeuf Didier , Eymin Béatrice , Vagner Stéphan , Dutertre Martin
Published: December 2023

Transcript isoforms generated by intronic polyadenylation (IPA) are widely regulated in various biological processes and often encode protein isoforms. Microproteins are small proteins translated from small open reading frames (sORFs) in noncoding RNAs and mRNAs, but their production by IPA isoforms is unknown. Using 3’-seq and long-read RNA-seq analyses in lung cancer cells, we show that cisplatin, a DNA-crosslinking anticancer agent, upregulates IPA isoforms relative to full-length mRNAs in long genes. A subset of cisplatin-regulated IPA isoforms are poorly associated with heavy polysomes and terminate upstream of the annotated translation initiation codon of genes. Such IPA isoforms in thePHF20andPRKAR1Bgenes are associated with light polysomes, contain Ribo-Seq-supported sORFs in an alternative last exon within the annotated 5’UTR part of genes, and are translated into microproteins. ForPRKAR1B, the microprotein was detected by Western blot and immunofluorescence after transfection of a tagged isoform; and siRNA depletion of the endogenous IPA isoform, CRISPR deletion of the IPA site, or CRISPR mutation of the sORF initiation codon led to increased cell survival to cisplatin. Based on Ribo-Seq and mass-spectrometry data sets, we identified 156 genes producing both a canonical protein-coding mRNA and a microprotein-coding 5’UTR-located IPA isoform (coined miP-5’UTR-IPA isoform) regulated by cisplatin. Finally, the regulation of (miP-5’UTR-)IPAversusfull-length isoforms by cisplatin involved an inhibition of transcription processivity in a FANCD2 and senataxin-dependent manner. Altogether, these findings reveal the novel paradigm of miP-5’UTR-IPA genes and their role in cancer cell response to a genotoxic agent.

HIGHLIGHTS

- Cisplatin increases intronic-polyadenylationversusfull-length transcript isoforms in long genes through a FANCD2 and senataxin-dependent decrease of transcription processivity

- A subset of cisplatin-regulated intronic-polyadenylation isoforms terminate in the annotated 5’UTR part of genes and encode microproteins, thus we coined them miP-5’UTR-IPA isoforms

- The miP-5’UTR-IPA isoform ofPRKAR1Bimpacts cisplatin sensitivity and its effect is mediated by its small ORF

- We identify 156 genes producing both a canonical protein-coding mRNA and a microprotein-coding miP-5’UTR-IPA transcript
Bacteria-induced activation of a fungal silent gene cluster is controlled by histone deacetylase Sirtuin E
Authors: Jäger Nils , Rosin Maira , Stroe Maria C. , Brakhage Axel A. , Heinzel Thorsten
Published: December 2023

Filamentous fungi encode an untapped reservoir of natural products whose biosynthesis enzymes are often encoded by gene clusters. The majority of these gene clusters are only activated under distinct environmental conditions such as the presence of distinct neighbouring microorganisms but not under standard laboratory conditions. Previously, we provided evidence for such a scenario with the specific activation of the silentorsgene cluster in the filamentous fungusAspergillus nidulansby the bacteriumStreptomyces rapamycinicus. The bacterium triggered the activation of the GcnE histone acetyltransferase that acetylated histone 3 in nucleosomes of theorsgene cluster and thebasRtranscription factor, and thereby the gene cluster. The inducing compound was shown to be the bacterial arginoketide azalomycin F. Here, by inhibitor studies with the pan-sirtuin inhibitor nicotinamide (NAM) the involvement of a sirtuin HDAC was implied. Accordingly, deletion of all six putative sirtuin-encoding genes (sirA-EandhstA) revealed that only deletion ofsirEled to production of orsellinic acid byA. nidulanswithout the need of the bacterium. Also other effects on growth and colony morphology due to NAM were phenocopied by thesirEdeletion mutant. Addition of NAM did not compensate for the loss of the BasR transcription factor required for activation of theorsgene cluster. Collectively, SirE is the negative regulator of the bacteria-induced activation of theorsBGC. In line, addition of NAM to monocultures ofAspergillus mulundensisencoding a sirtuin E with highest similarity to theA. nidulansprotein also activated theorsBGC in this fungus.
Elevated mutation rates in the multi-azole resistantAspergillus fumigatusclade drives rapid evolution of antifungal resistance
Authors: Bottery Michael J. , van Rhijn Norman , Chown Harry , Rhodes Johanna L. , Celia-Sanchez Brandi N. , Brewer Marin T. , Momany Michelle , Fisher Matthew C. , Knight Christopher G. , Bromley Michael J.
Published: December 2023

The evolution of antifungal resistance is an emerging global threat. Particularly concerning is the widespread occurrence of azole resistance withinAspergillus fumigatus, a globally ubiquitous environmental mould that causes over 1 million life-threatening invasive infections in humans each year. It is increasingly evident that the environmental use of azoles has led to selective sweeps across multiple genomic loci resulting in the rapid expansion of a genetically distinct cluster of genotypes (clade A) that results in resistance to clinically deployed azoles. Isolates within this cluster are more likely to be cross resistant to agricultural antifungals with unrelated modes of action suggesting they may be adapting rapidly to antifungal challenge. Here we show that this cluster is not only multi-azole resistant but has increased propensity to develop resistance to new antifungals because of variants in the DNA mismatch repair system. A variant inmsh6is found almost exclusively within clade A, occurs in 88% of multi-azole resistant isolates harbouring the canonicalcyp51Aazole resistance allelic variant TR34/L98H, and is globally distributed. Naturally occurring isolates with thismsh6variant display a 4 to 9-times higher rate of mutation, leading to an increased propensity to evolve resistance to current and next generation antifungals. We argue that pervasive environmental use of fungicides creates selective arenas whereby genotypes ofA. fumigatuswith increased adaptive capability thrive in the face of strong directional selection, leading to the genesis and amplification of antifungal resistance. These results help explain the pronounced clustering of multiple independent resistance mechanisms within the mutable clade A. Our findings further suggest that resistance to next generation antifungals is more likely to emerge within organisms that are already multi-azole resistant, posing a major problem due to the prospect of dual use of novel antifungals in clinical and agricultural settings.
An improved chromosome-level genome assembly of perennial ryegrass (Lolium perenneL.)
Authors: Chen Yutang , Kölliker Roland , Mascher Martin , Copetti Dario , Himmelbach Axel , Stein Nils , Studer Bruno
Published: December 2023

This work is an update and extension of the previously published article “Ultralong Oxford Nanopore Reads Enable the Development of a Reference-Grade Perennial Ryegrass Genome Assembly”, by Frei et al.. The published genome assembly of the doubled haploid perennial ryegrass (Lolium perenneL.) genotype Kyuss marked a milestone for forage grass research and breeding. However, order and orientation errors may exist in the pseudo-chromosomes of Kyuss, since barley (Hordeum vulgareL.), which diverged 30 million years ago from perennial ryegrass, was used as the reference to scaffold Kyuss. To correct for structural errors possibly present in the published Kyuss assembly, wede novoassembled the genome again and generated 50-fold coverage high-throughput chromosome conformation capture (Hi-C) data to assist pseudo-chromosome construction. The resulting new chromosome-level assembly showed improved quality with high contiguity (contig N50 = 120 Mb), high completeness (total BUSCO score = 99%), high base-level accuracy (QV = 50) and correct pseudo-chromosome structure (validated by Hi-C contact map). This new assembly will serve as a better reference genome forLoliumspp. and greatly benefit the forage and turf grass research community.
Segregation-to-Integration Transformation Model of Memory Evolution
Authors: Bavassi Luz , Fuentemilla Lluís
Published: December 2023

Abstract

Memories are thought to use coding schemes that dynamically adjust their representational structure to maximize both persistence and utility. However, the nature of these coding scheme adjustments and their impact on the temporal evolution of memory after initial encoding is unclear. Here we introduce the Segregation-to-Integration Transformation (SIT) Model, a neural network formalization that offers a unified account of how the representational structure of a memory is transformed over time. SIT Model asserts that memories initially adopt a highly modular or segregated network structure, functioning as an optimal storage buffer by striking a balance between protection from disruptions and accommodating substantial information. Over time, a repeated combination of neural network reactivations, spreading, and synaptic plasticity transforms the initial modular memory structure into an integrated memory form, facilitating intercommunity spreading and fostering generalization. In addition, SIT Model reveals the existence of an optimal window during this transformation where memories are most susceptible to malleability, suggesting a non-linear or inverted U-shaped function in memory evolution. The results of our model integrate a wide range of experimental phenomena along with accounts of memory consolidation and reconsolidation, offering a unique perspective on memory evolution by leveraging simple architectural neural network property rules.
Discovery of high affinity and specificity stapled peptide Bcl-xL inhibitors using bacterial surface display
Authors: Case Marshall , Vinh Jordan , Kopp Anna , Smith Matthew , Thurber Greg
Published: December 2023

Intracellular protein-protein interactions are involved in many different diseases, making them prime targets for therapeutic intervention. Several diseases are characterized by their overexpression of Bcl-xL, an anti-apoptotic B cell lymphoma 2 (Bcl-2) protein expressed on mitochondrial membranes. Bcl-xLoverexpression inhibits apoptosis, and selective inhibition of Bcl-xLhas the potential to increase cancer cell death while leaving healthy cells comparatively less affected. However, high homology between Bcl-xLand other Bcl-2 proteins has made it difficult to selectively inhibit this interaction by small molecule drugs. We engineered stapled peptides, a chemical modification that can improve cell penetration, protease stability, and conformational stability, towards the selective inhibition of Bcl-xL. To accomplish this task, we built a focused combinatorial mutagenesis library of peptide variants on the bacterial cell surface, used copper catalyzed click chemistry to form stapled peptides, and sorted the library for high binding to Bcl-xLand minimal binding towards other Bcl-2 proteins. We characterized the sequence and staple placement trends that governed specificity and identified molecules with ∼10 nM affinity to Bcl-xLand greater than 100-fold selectivity versus other Bcl-2 family members on and off the cell surface. We confirmed the mechanism of action of these peptides is consistent with apoptosis biology through mitochondrial outer membrane depolarization assays (MOMP). Overall, high affinity (10 nM Kd) and high specificity (100-fold selectivity) peptides were developed to target the Bcl-xLprotein. These results demonstrate that stapled alpha helical peptides are promising candidates for the specific treatment of cancers driven by Bcl-2 dysregulation.
Noncoding function of super enhancer derived mRNA in modulating neighboring gene expression and TAD interaction
Authors: Xie Bingning , Dean Ann
Published: December 2023

Super enhancers are important regulators of gene expression that often overlap with protein-coding genes. However, it is unclear whether the overlapping protein-coding genes and the mRNA derived from them contribute to enhancer activity. Using an erythroid-specific super enhancer that overlaps theCpoxgene as a model, we found thatCpoxmRNA has a non-coding function in regulating neighboring protein-coding genes, eRNA expression and TAD interactions. Depletion ofCpoxmRNA leads to accumulation of H3K27me3 and release of p300 from theCpoxlocus, activating an intra-TAD enhancer and gene expression. Additionally, we identified a head-to-tail interaction between the TAD boundary genesCpoxandDcbld2that is facilitated by a novel type of repressive loop anchored by p300 and PRC2/H3K27me3. Our results uncover a regulatory role for mRNA transcribed within a super enhancer context and provide insight into head-to-tail inter-gene interaction in the regulation of gene expression and oncogene activation.
Ligand Response of Guanidine-IV riboswitch at Single-molecule Level
Authors: Gao Lingzhi , Chen Dian , Liu Yu
Published: December 2023

Riboswitches represent a class of non-coding RNA that possess the unique ability to specifically bind ligands and, in response, regulate gene expression. A recent report unveiled a type of riboswitch, known as the guanidine-IV riboswitch, which responds to guanidine levels to regulate downstream genetic transcription. However, the precise molecular mechanism through which the riboswitch senses its target ligand and undergoes conformational changes remain elusive. This gap in understanding has impeded the potential applications of this riboswitch. To bridge this knowledge gap, our study investigated the conformational dynamics of the guanidine-IV riboswitch RNA upon ligand binding. We employed single-molecule fluorescence resonance energy transfer (smFRET) to dissect the behaviors of the aptamer, terminator, and full-length riboswitch. Our findings indicated that the aptamer portion exhibited higher sensitivity to guanidine compared to the terminator and full-length constructs. Additionally, we utilized Position-specific Labelling of RNA (PLOR) combined with smFRET to observe, at the single-nucleotide and single-molecule level, the structural transitions experienced by the guanidine-IV riboswitch during transcription. Notably, we discovered that the influence of guanidine on the riboswitch RNA’s conformations was significantly reduced after the transcription of 88 nucleotides. Furthermore, we proposed a folding model for the guanidine-IV riboswitch in the absence and presence of guanidine, thereby providing insights into its ligand-response mechanism.

Impact statement

The aptamer domain of the guanidine-IV riboswitch exhibits a greater sensitivity to guanidine, surpassing that observed in both the terminator and full-length riboswitch. A finely-tuned transcriptional window of the guanidine-IV riboswitch was detected to be responsive to ligand binding. Furthermore, a folding-function model for the guanidine-IV riboswitch under both guanidine-free and guanidine-present conditions offers valuable insights into its regulatory mechanism.
A genome-wide survey of DNA methylation inPanax notoginsengreveals CHH hyper-methylation regulates the after-ripening and dormancy of recalcitrant seeds
Authors: Ge Na , Jia Jin-Shan , Wang Qing-Yan , Li Chao-Lin , Huang Min , Chen Jun-Wen
Published: December 2023

DNA methylation plays a crucial role in regulating fruit ripening and seed development. It remains unknown about the dynamic characteristics of DNA methylation and its regulation mechanisms in morpho-physiological dormancy (MPD)-typed seeds with recalcitrant characteristics. TheP. notoginsengseeds are defined by the MPD and are characterized by a strong sensitivity to dehydration during the after-ripening process. We performed DNA methylomes, siRNA profiles, and transcriptomes of embryo and endosperm inP. notoginsengseeds at different after-ripening stages. Herein, we find that the CHH hyper-methylation contributes to the global increase in DNA methylation during the after-ripening process ofP. notoginsengseeds. The endosperm genome is hyper-methylated compared to the embryo genome. The CHH hyper-methylation is caused by the high expression level of DNA methyltransferasePnCMT2in the embryo, andPnDRM2in the endosperm, respectively. The CHH hyper-methylation alters gene transcription levels to regulate the after-ripening and dormancy of recalcitrant seeds. For example, it inhibits the expression of genes in embryo development to make seeds maintain a dormant status, whereas it activates the expression of genes in the hormone-mediated signaling pathway, and energy metabolism to accomplish the MPD-typed seed after-ripening process. Together, our findings reveal a global increase in DNA methylation and its vital driver in gene expression, and thus elucidate how global CHH hyper-methylation regulates the after-ripening in recalcitrant MPD-typed seeds. This work establishes a key role for epigenetics in regulating the dormancy of MPD-typed seeds with recalcitrant characteristics.
Mr. Smith goes to flatland: institutions, public policy and the bossless company
Authors: McCaffrey Matthew
Published: December 2023

Purpose

This study aims to explore a range of institutional, environmental and policy conditions that influence the creation of “bossless” or “flat” companies, i.e. firms with little or no formal hierarchy.

Design/methodology/approach

The author builds on the theory and evidence presented by Foss and Klein (2022) in their study of the costs and benefits of organizing without hierarchy. The author also draws on a variety of related theoretical insights and empirical evidence. The paper is exploratory and anecdotal though and is intended to motivate further research rather than provide a definitive account of bossless organizing.

Findings

The paper develops nine propositions. It suggests that high levels of economic freedom create maximum scope for entrepreneurs to experiment with different organizational forms (1). Likewise, a lack of economic freedom increases the scope for the government to experiment (2). Markets characterized by technological innovation and uncertainty are likely to discourage bossless organizing (3 and 4), while stagnating industries with major capital requirements are likely to encourage it (5). Labor market interventions that increase the cost of employment contracts sometimes encourage firms to flatten (6), but more generally, these interventions encourage expanding management layers (7). In environments with strong intellectual property (IP) laws, companies with more modular and knowledge-based work are more likely to flatten (8). The creation of low-hierarchy firms such as cooperatives is encouraged by public subsidies, access to cheap credit and preferential tax treatment (9).

Originality/value

Studies of bossless or flat firms focus almost exclusively on describing their internal organization and evaluating their performance; little attention is paid to the conditions that encourage or discourage the emergence of these firms. This paper focuses on the latter, with a view to encouraging more scholarly interest in this field.
Effect of board structure on stakeholders’ centric perspective of sustainable corporate world
Authors: Bhat Basit Ali , Makkar Manpreet Kaur , Gupta Nitin
Published: December 2023

Purpose

Corporate leadership and environmental, social and governance (ESG) performance are closely intertwined, as effective corporate leadership can facilitate the achievement of strong ESG performance. Thus, the purpose of the study is to investigate the impact of corporate board leadership on the ESG performance of listed firms.

Design/methodology/approach

The sample has been taken from the listed firms of the Nifty 500 index spanning the period of 10 years from 2012 to 2022. Dynamic panel data estimations are applied through a fixed effect model.

Findings

The findings of this study revealed that board size, board independence and board qualification have a significant positive influence on ESG performance. It is evident that good corporate governance practices can positively influence ESG performance by fostering accountability, transparency and ethical behavior, as well as better integrating ESG considerations into their decision-making processes and ensuring that ESG issues are prioritized at the highest levels of management. Further findings also revealed that chief executive officer (CEO) duality has a significant negative relationship with ESG performance, which goes against the belief of stakeholder theory.

Social implications

It has practical implications for policymakers, as they can enact new regulations pertaining to the CEO’s position in the organizations to make corporate governance responsible for improved sustainability and ESG performance.

Originality/value

There are very few studies analyzing the impact of corporate board structure on ESG performance related to emerging markets. Thus, this study contributes to that literature by using the methodology GMM panel data for the first time as per our knowledge
Exploring the role of organizational developmental HR practices in enhancing employees' commitment to organizational career: a multilevel investigation
Authors: Deng Ting , Tang Chunyong , Lai Yanzhao
Published: December 2023

Purpose

Drawing upon the conservation of resources (COR) theory, this study examined the relationship between organizational developmental human resource (HR) practices and employees' commitment to the organizational career (COC), while considering the mediating role of psychological availability and the moderating effects of links and fit.

Design/methodology/approach

A hierarchical linear modeling analysis was conducted to analyze the data from a 3-wave time-lagged study with 394 employees and 65 supervisors in ten Chinese firms.

Findings

The study's findings suggest that organizational developmental HR practices have a positive and indirect impact on employees' COC, with psychological availability serving as a mediator. The indirect effects were stronger for employees with stronger links and better fit.

Practical implications

This study provides managers with guidelines to improve employees' COC. Managers should also focus on supporting employees' psychological resources. Furthermore, organizations should be aware that employees with varying levels of links and fit may respond differently to psychological availability.

Originality/value

The study offers a new understanding of how and under what conditions organizational developmental HR practices can increase employees' COC. It also highlights the role of psychological availability as the psychological mechanism mediating this relationship and adds to the limited literature on the potential positive impact of strong links and fit.