bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletion of a conserved genomic region associated with adolescent idiopathic scoliosis leads to vertebral rotation in mice
Authors: McCallum-Loudeac Jeremy , Moody Edward , Johnstone Georgia , Sircombe Kathy , Clarkson Andrew N. , Wilson Megan J.
Published: June 2023

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis, in which spinal curvature develops in adolescence, and 90% of patients are female. Scoliosis is a debilitating disease that often requires bracing or surgery in severe cases. AIS affects 2-5.2 percent of the population; however, the biological origin of the disease remains poorly understood. In this study, we aimed to determine the function of a highly conserved genomic region previously linked to AIS using a mouse model generated by CRISPR-CAS9 gene editing to knockout this area of the genome to better understand the biological cause of AIS, which we named AIS_CRMΛ.We also investigated the upstream factors that regulate the activity of this enhancerin vivo, whether the spatial expression of the LBX1 protein would change with the loss of AIS-CRM function, and whether any phenotype would arise after deletion of this region. We found a significant increase in mRNA expression in the developing neural tube at E10.5, and E12.5, for not onlyLbx1but also other neighboring genes. Adult knockout mice showed vertebral rotation and proprioceptive deficits, also observed in human AIS patients. In conclusion, our study sheds light on the elusive biological origins of AIS, by targeting and investigating a highly conserved genomic region linked to AIS in humans. These findings provide valuable insights into the function of the investigated region and contribute to our understanding of the underlying causes of this debilitating disease.
Human colorectal cancer: upregulation of the adaptor protein Rai in TILs leads to cell dysfunction by sustaining GSK-3 activation and PD-1 expression
Authors: Montecchi Tommaso , Nannini Giulia , Domiziana De Tommaso , Cassioli Chiara , Coppola Federica , Ringressi Maria Novella , Carraro Fabio , Naldini Antonella , Taddei Antonio , Marotta Giuseppe , Amedei Amedeo , Baldari Cosima , Ulivieri Cristina
Published: June 2023

Background

The immunosuppressive tumor microenvironment (TME) of colorectal cancer (CRC) is a major hurdle for immune checkpoint inhibitor-based therapies. Hence characterization of the signaling pathways driving T cell exhaustion within TME is a critical need for the discovery of novel therapeutic targets and the development of effective therapies. We previously showed that i) the adaptor protein Rai is a negative regulator of T cell receptor signaling and T helper 1 (Th1)/Th17 cell differentiation; and ii) Rai deficiency is implicated in the hyperactive phenotype of T cells in autoimmune diseases.

Methods

The expression level of Rai was measured by qRT-PCR in paired peripheral blood T cells and T cells infiltrating tumor tissue and the normal adjacent tissue in CRC patients. The impact of HIF-1α on Rai expression was evaluated in T cells exposed to hypoxia and by performing chromatin immunoprecipitation assays and RNA interference assays. The mechanism by which upregulation of Rai in T cells promotes T cell exhaustion were evaluated by flow cytometric, qRT-PCR and western blot analyses.

Results

We show that Rai is a novel HIF-1α-responsive gene that is upregulated in tumor infiltrating lymphocytes of CRC patients compared to patient-matched circulating T cells. Rai upregulation in T cells promoted PD-1 expression and impaired antigen-dependent degranulation of CD8+T cells by inhibiting phospho-inactivation of glycogen synthase kinase (GSK)-3, a central regulator of PD- 1 expression and T cell-mediated anti-tumor immunity.

Conclusions

Our data identify Rai as a hitherto unknown regulator of the TME-induced exhausted phenotype of human T cells.

What is already known on this topic

Tumor hypoxia contributes to establish an immunosuppressive microenvironment that unleashes T cell function and limits the efficacy of immunotherapy in CRC.

The molecular mechanisms underlying the impact of hypoxia on the signaling pathways controlling PD-1 expression are unknown.

What this study adds

A Rai/Akt/GSK-3 axis regulates PD-1 expression following TCR/CD28 co-stimulation

This study uncovers the signaling pathway controlling hypoxia-dependent T cell exhaustion.

How this study might affect research, practice or policy

Rai expression levels in TILs of CRC patients might be explored as a potential new biomarker of T cell exhaustion and a predictive biomarker for anti-PD-1 response.
Divergent iron-regulatory states contribute to heterogeneity in breast cancer aggressiveness
Authors: Leineweber William D. , Rowell Maya Z. , Ranamukhaarachchi Sural , Walker Alyssa , Li Yajuan , Villazon Jorge , Farrera Aida Mestre , Hu Zhimin , Yang Jing , Shi Lingyan , Fraley Stephanie I.
Published: June 2023

Primary tumors with similar mutational profiles can progress to vastly different outcomes where transcriptional state, rather than mutational profile, predicts prognosis. A key challenge is to understand how distinct tumor cell states are induced and maintained. In triple negative breast cancer cells, invasive behaviors and aggressive transcriptional signatures linked to poor patient prognosis can emerge in response to contact with collagen type I. Herein, collagen-induced migration heterogeneity within a TNBC cell line was leveraged to identify transcriptional programs associated with invasive versus non-invasive phenotypes and implicate molecular switches. Phenotype-guided sequencing revealed that invasive cells upregulate iron uptake and utilization machinery, anapleurotic TCA cycle genes, actin polymerization promoters, and a distinct signature of Rho GTPase activity and contractility regulating genes. The non-invasive cell state is characterized by actin and iron sequestration modules along with glycolysis gene expression. These unique tumor cell states are evident in patient tumors and predict divergent outcomes for TNBC patients. Glucose tracing confirmed that non-invasive cells are more glycolytic than invasive cells, and functional studies in cell lines and PDO models demonstrated a causal relationship between phenotype and metabolic state. Mechanistically, the OXPHOS dependent invasive state resulted from transient HO-1 upregulation triggered by contact with dense collagen that reduced heme levels and mitochondrial chelatable iron levels. This induced expression of low cytoplasmic iron response genes regulated by ACO1/IRP1. Knockdown or inhibition of HO-1, ACO1/IRP1, MRCK, or OXPHOS abrogated invasion. These findings support an emerging theory that heme and iron flux serve as important regulators of TNBC aggressiveness.
Hippocampal sharp-wave ripples correlate with naturally occurring self-generated thoughts in humans
Authors: Iwata Takamitsu , Yanagisawa Takufumi , Ikegaya Yuji , Smallwood Jonathan , Fukuma Ryohei , Oshino Satoru , Tani Naoki , Khoo Hui Ming , Kishima Haruhiko
Published: June 2023

Core features of human cognition, for example, the experience of mind wandering, highlight the importance of the capacity to focus on information separate from the here and now. However, the brain mechanisms that underpin these self-generated states remain unclear. An emerging hypothesis is that self-generated states depend on the process of memory replay, which, in animals, is linked to sharp-wave ripples (SWRs) originating in the hippocampus. SWRs are transient high-frequency oscillations that exhibit circadian fluctuations and, in the laboratory, are important for memory and planning. Local field potentials were recorded from the hippocampus of 11 patients with epilepsy for up to 15 days, and experience sampling was used to describe their association with ongoing thought patterns. SWRs were correlated with patterns of vivid, intrusive ongoing thoughts unrelated to the task being performed, establishing their contribution to the ongoing thoughts that humans experience in daily life.
Cognitive Model Discovery via Disentangled RNNs
Authors: Miller Kevin J. , Eckstein Maria , Botvinick Matthew M. , Kurth-Nelson Zeb
Published: June 2023

Computational cognitive models are a fundamental tool in behavioral neuroscience. They instantiate in software precise hypotheses about the cognitive mechanisms underlying a particular behavior. Constructing these models is typically a difficult iterative process that requires both inspiration from the literature and the creativity of an individual researcher. Here, we adopt an alternative approach to learn parsimonious cognitive models directly from data. We fit behavior data using a recurrent neural network that is penalized for carrying information forward in time, leading to sparse, interpretable representations and dynamics. When fitting synthetic behavioral data from known cognitive models, our method recovers the underlying form of those models. When fit to laboratory data from rats performing a reward learning task, our method recovers simple and interpretable models that make testable predictions about neural mechanisms.
Targeting the Microbiome to Improve Gut Health and Breathing Function After Spinal Cord Injury
Authors: Wilson Jessica N. , Kigerl Kristina A. , Sunshine Michael D. , Taylor Chase E. , Speed Sydney L. , Rose Breanna C. , Calulot Chris M. , Dong Brittany E. , Hawkinson Tara R. , Clarke Harrison A. , Bachstetter Adam D. , Waters Christopher M. , Sun Ramon C. , Popovich Phillip G. , Alilain Warren J.
Published: June 2023

Spinal cord injury (SCI) is a devastating condition characterized by impaired motor and sensory function, as well as internal organ pathology and dysfunction. This internal organ dysfunction, particularly gastrointestinal (GI) complications, and neurogenic bowel, can reduce the quality of life of individuals with an SCI and potentially hinder their recovery. The gut microbiome impacts various central nervous system functions and has been linked to a number of health and disease states. An imbalance of the gut microbiome, i.e., gut dysbiosis, contributes to neurological disease and may influence recovery and repair processes after SCI. Here we examine the impact of high cervical SCI on the gut microbiome and find that transient gut dysbiosis with persistent gut pathology develops after SCI. Importantly, probiotic treatment improves gut health and respiratory motor function measured through whole-body plethysmography. Concurrent with these improvements was a systemic decrease in the cytokine tumor necrosis factor-alpha and an increase in neurite sprouting and regenerative potential of neurons. Collectively, these data reveal the gut microbiome as an important therapeutic target to improve visceral organ health and respiratory motor recovery after SCI.

Research Highlights

Cervical spinal cord injury (SCI) causes transient gut dysbiosis and persistent gastrointestinal (GI) pathology.

Treatment with probiotics after SCI leads to a healthier GI tract and improved respiratory motor recovery.

Probiotic treatment decreases systemic tumor necrosis factor-alpha and increases the potential for sprouting and regeneration of neurons after SCI.

The gut microbiome is a valid target to improve motor function and secondary visceral health after SCI.
Liquid-like condensates mediate competition between actin branching and bundling
Authors: Graham Kristin , Chandrasekaran Aravind , Wang Liping , Yang Noel , Lafer Eileen M. , Rangamani Padmini , Stachowiak Jeanne C.
Published: June 2023

Cellular remodeling of actin networks underlies cell motility during key morphological events, from embryogenesis to metastasis. In these transformations there is an inherent competition between actin branching and bundling, because steric clashes among branches create a mechanical barrier to bundling. Recently, liquid-like condensates consisting purely of proteins involved in either branching or bundling of the cytoskeleton have been found to catalyze their respective functions. Yet in the cell, proteins that drive branching and bundling are present simultaneously. In this complex environment, which factors determine whether a condensate drives filaments to branch versus becoming bundled? To answer this question, we added the branched actin nucleator, Arp2/3, to condensates composed of VASP, an actin bundling protein. At low actin to VASP ratios, branching activity, mediated by Arp2/3, robustly inhibited VASP-mediated bundling of filaments, in agreement with agent-based simulations. In contrast, as the actin to VASP ratio increased, addition of Arp2/3 led to formation of aster-shaped structures, in which bundled filaments emerged from a branched actin core, analogous to filopodia emerging from a branched lamellipodial network. These results demonstrate that multi-component, liquid-like condensates can modulate the inherent competition between bundled and branched actin morphologies, leading to organized, higher-order structures, similar to those found in motile cells.

SIGNIFICANCE STATEMENT

Reorganization of actin filaments allows cells to migrate, which is required for embryonic development, wound healing, and cancer metastasis. During migration, the leading-edge of the cell consists of needle-like protrusions of bundled actin, which emanate from a sheet of branched actin. Given that the proteins responsible for both architectures are present simultaneously, what determines whether actin filaments will be branched or bundled? Here we show that liquid-like condensates, composed of both branching and bundling proteins, can mediate the inherent competition between these fundamentally different ways of organizing actin networks. This work demonstrates that by tuning the composition of condensates, we can recapitulate the transition from branched to bundled networks, a key step in cell migration.
The presence of a G-quadruplex prone sequence upstream of a minimal promoter increases transcriptional activity in the yeastS. cerevisiae
Authors: Kratochvilová Libuše , Vojsovič Matúš , Valková Natália , Šislerová Lucie , El Rashed Zeinab , Inga Alberto , Monti Paola , Brázda Václav
Published: June 2023

Non-canonical secondary structures in DNA are increasingly being revealed as critical players in DNA metabolism, including modulating the accessibility and activity of promoters. These structures comprise the so-called G-quadruplexes (G4s) that are formed from sequences rich in guanine bases. Using a well-defined transcriptional reporter system, we sought to systematically investigate the impact of the presence of G4 structures on transcription in yeastS. cerevisiae. To this aim, different G4 prone sequences were modeled to vary the chance of intramolecular G4 formation, analyzedin vitroby Thioflavin T binding test and circular dichroism and then placed at the yeastADE2locus on chromosome XV, downstream and adjacent to a P53 response element (RE) and upstream from a minimalCYC1promoter and Luciferase 1 (LUC1) reporter gene in isogenic strains. While the minimalCYC1promoter provides for basal reporter activity, the P53 RE enablesLUC1transactivation under the control of the human P53 family proteins expressed under the inducibleGAL1promoter. Thus, the impact of the different G4 prone sequences on both basal and P53 family proteins dependent expression was measured after shifting the yeast cells onto galactose containing medium. The results showed that the presence of G4 prone sequences upstream of a yeast minimal promoter can increase its basal activity proportionally to their potential to form intramolecular G4 structures; consequently, this improved accessibility, when present near the target binding site of P53 family transcription factors can be exploited in order to regulate the transcriptional activity of P53, P63 and P73 proteins.
Connexin 43 and Cell Culture Substrate Differentially Regulate OCY454 Osteocytic Differentiation and Signaling to Primary Bone Cells
Authors: Hoppock Gabriel A. , Buettmann Evan G. , Denisco Joseph A. , Goldscheitter Galen M , Condyles Sebastian N. , Juhl Otto J. , Friedman Michael A. , Zhang Yue , Donahue Henry J.
Published: June 2023

Connexin 43 (Cx43), the predominate gap junction protein in bone, is essential for intercellular communication and skeletal homeostasis. Previous work suggests osteocyte-specific deletion of Cx43 leads to increased bone formation and resorption, however the cell-autonomous role of osteocytic Cx43 in promoting increased bone remodeling is unknown. Recent studies using 3D culture substrates in OCY454 cells suggest 3D cultures may offer increased bone remodeling factor expression and secretion, such as sclerostin and RANKL. In this study, we compared culturing OCY454 osteocytes on 3D Alvetex scaffolds to traditional 2D tissue culture, both with (WT) and without Cx43 (Cx43 KO). Conditioned media from OCY454 cell cultures was used to determine soluble signaling to differentiate primary bone marrow stromal cells into osteoblasts and osteoclasts. OCY454 cells cultured on 3D portrayed a mature osteocytic phenotype, relative to cells on 2D, shown by increased osteocytic gene expression and reduced cell proliferation. In contrast, OCY454 differentiation based on these same markers was not affected by Cx43 deficiency in 3D. Interestingly, increased sclerostin secretion was found in 3D cultured WT cells compared to Cx43 KO cells. Conditioned media from Cx43 KO cells promoted increased osteoblastogenesis and increased osteoclastogenesis, with maximal effects from 3D cultured Cx43 KO cells. These results suggest Cx43 deficiency promotes increased bone remodeling in a cell autonomous manner with minimal changes in osteocyte differentiation. Finally, 3D cultures appear better suited to study mechanisms from Cx43-deficient OCY454 osteocytesin vitrodue to their ability to promote osteocyte differentiation, limit proliferation, and increase bone remodeling factor secretion.

New and Noteworthy

3D cell culture of OCY454 cells promoted increased differentiation compared to traditional 2D culture. While Cx43 deficiency did not affect OCY454 differentiation, it resulted in increased signaling, promoting osteoblastogenesis and osteoclastogenesis. Our results suggest Cx43 deficiency promotes increased bone remodeling in a cell autonomous manner with minimal changes in osteocyte differentiation. Also, 3D cultures appear better suited to study mechanisms in Cx43-deficient OCY454 osteocytes.
Specific prostaglandins are produced in the migratory cells and the surrounding substrate to promoteDrosophilaborder cell migration
Authors: Mellentine Samuel Q. , Ramsey Anna S. , Li Jie , Brown Hunter N. , Tootle Tina L.
Published: June 2023

A key regulator of collective cell migration is prostaglandin (PG) signaling. However, it remains largely unclear whether PGs act within the migratory cells or their microenvironment to promote migration. Here we useDrosophilaborder cell migration as a model to uncover the cell-specific roles of two PGs in collective migration. Prior work shows PG signaling is required for on-time migration and cluster cohesion. We find that the PGE2synthase cPGES is required in the substrate, while the PGF2αsynthase Akr1B is required in the border cells for on-time migration. Akr1B acts in both the border cells and their substrate to regulate cluster cohesion. One means by which Akr1B regulates border cell migration is by promoting integrin-based adhesions. Additionally, Akr1B limits myosin activity, and thereby cellular stiffness, in the border cells, whereas cPGES limits myosin activity in both the border cells and their substrate. Together these data reveal that two PGs, PGE2and PGF2α, produced in different locations, play key roles in promoting border cell migration. These PGs likely have similar migratory versus microenvironment roles in other collective cell migrations.
The haplolethal genewupAof Drosophila exhibits potential as a target for an X-poisoning gene drive
Authors: Lawler Clancy D. , Parra Nuñez Ana Karla , Hernandes Natalia , Bhide Soumitra , Lohrey Isabelle , Baxter Simon , Robin Charles
Published: June 2023

A synthetic gene drive that targets haplolethal genes on the X-chromosome can skew the sex ratio towards males. Like an ‘X-shredder’ it does not involve ‘homing’ and that has advantages including the reduction of gene drive resistance allele formation. We examine this ‘X-poisoning’ strategy by targeting four of the 11 known X-linked haplolethal/haplosterile genes ofDrosophila melanogasterwith CRISPR/Cas9. We find that targeting thewupAgene during spermatogenesis skews the sex ratio so fewer than 14% of progeny are daughters. That is unless we cross the mutagenic males to X^XY female flies that bear attached-X chromosomes, which reverses the inheritance of the poisoned X chromosome so that sons inherit it from their father; in which case only 2% of the progeny are sons. These sex ratio biases suggests that most of the CRISPR/Cas9 mutants we induced in thewupAgene are haplolethal but some are recessive lethal. The males generatingwupAmutants do not suffer from reduced fertility rather the haplolethal mutants arrest development in the late stages of embryogenesis well after fertilized eggs have been laid. This provides a distinct advantage over genetic manipulation strategies involving sterility which can be countered by the remating of females. We also find thatwupAmutants that destroy the nuclear localization signal of shorter isoforms are not haplolethal as long as the open reading frame remains intact. LikeD. melanogaster wupAorthologs ofD. suzukiiandAnophelesmosquitos are found on X chromosomes makingwupAa viable X-poisoning target in multiple species.
Converging on consistent functional connectomics
Authors: Luppi Andrea I. , Gellersen Helena M. , Liu Zhen-Qi , Peattie Alexander R. D. , Manktelow Anne E. , Adapa Ram , Owen Adrian M. , Naci Lorina , Menon David K. , Dimitriadis Stavros I. , Stamatakis Emmanuel A.
Published: June 2023

Functional interactions between brain regions can be viewed as a network, empowering neuroscientists to leverage network science to investigate distributed brain function. However, obtaining a brain network from functional neuroimaging data involves multiple steps of data manipulation, which can drastically affect the organisation and validity of the estimated brain network and its properties. Here, we provide a systematic evaluation of 576 unique data-processing pipelines for functional connectomics from resting-state functional MRI, obtained from all possible recombinations of popular choices for brain atlas type and size, connectivity definition and selection, and global signal regression. We use the portrait divergence, an information-theoretic measure of differences in network topology across scales, to quantify the influence of analytic choices on the overall organisation of the derived functional connectome. We evaluate each pipeline across an entire battery of criteria, seeking pipelines that (i) minimise spurious test-retest discrepancies of network topology, while simultaneously (ii) mitigating motion confounds, and being sensitive to both (iii) inter-subject differences and (iv) experimental effects of interest, as demonstrated by propofol-induced general anaesthesia. Our findings reveal vast and systematic variability across pipelines’ suitability for functional connectomics. Choice of the wrong data-processing pipeline can lead to results that are not only misleading, but systematically so, distorting the functional connectome more drastically than the passage of several months. We also found that the majority of pipelines failed to meet at least one of our criteria. However, we identified 8 candidates satisfying all criteria across each of four independent datasets spanning minutes, weeks, and months, ensuring the generalisability of our recommendations. Our results also generalise to alternative acquisition parameters and preprocessing and denoising choices. By providing the community with a full breakdown of each pipeline’s performance across this multi-dataset, multi-criteria, multi-scale and multi-step approach, we establish a comprehensive set of benchmarks to inform future best practices in functional connectomics.
New genetic tools for mushroom body output neurons in Drosophila
Authors: Rubin Gerald M. , Aso Yoshinori
Published: June 2023

How memories of past events influence behavior is a key question in neuroscience. The major associative learning center in Drosophila, the Mushroom Body (MB), communicates to the rest of the brain through Mushroom Body Output Neurons (MBONs). While 21 MBON cell types have their dendrites confined to small compartments of the MB lobes, analysis of EM connectomes revealed the presence of an additional 14 MBON cell types that are atypical in having dendritic input both within the MB lobes and in adjacent brain regions. Genetic reagents for manipulating atypical MBONs and experimental data on their functions has been lacking. In this report we describe new cell-type-specific GAL4 drivers for many MBONs, including the majority of atypical MBONs. Using these genetic reagents, we conducted optogenetic activation screening to examine their ability to drive behaviors and learning. These reagents provide important new tools for the study of complex behaviors in Drosophila.
Fusion Neural Network (FusNet) for predicting protein-mediated loops
Authors: Tang Li , Huang Wenjie , Hill Matthew C. , Ellinor Patrick T. , Li Min
Published: June 2023

The organization of the three-dimensional (3D) genome is a complex, and requires a plethora of proteins to ensure the proper formation and regulation of chromatin loops as well as higher order structures. Studying protein-mediated loop regulation can help unravel the intricate interplay between these loops and their crucial roles in modulating gene expression across different cellular contexts. However, current targeted chromatin conformation capture experiments face limitations in capturing protein-mediated loops across various cell types, and existing computational methods fail to predict diverse protein-mediated loops. To address these issues, we propose a fusion neural network (FusNet) designed for predicting protein-mediated loops. FusNet leverages genome sequence information, open chromatin, and ChIP-seq data to efficiently represent and analyze the positions of loop anchors. To extract informative features and reduce the complexity of FusNet, we constructed a convolutional neural network, which compresses the dimensionality of the features while also preserving the most significant ones. To enhance the accuracy and generalization capacity of FusNet, we built a fusion layer by stacking the prediction of fundamental models with a meta-model. FusNet demonstrated its effectiveness in predicting protein-mediated loops, exhibiting high consistency with Hi-C data. Moreover, we find that the loops output from FusNet are highly associated with regulatory functions. Through association analysis with genetic risk variants, FusNet further revealed its potential for unraveling disease-related mechanisms. In conclusion, our study offers a novel computational approach for predicting various protein-mediated chromatin loops, which could substantially enhance research on the functional significance of protein-mediated loop structures in diverse cellular contexts.

Significance Statement

The intricate spatial organization of the three-dimensional (3D) genome involves functional proteins critically contributing to chromatin loop formation and regulation. Understanding these protein-mediated loops is vital for elucidating their influence on 3D genome architecture and gene regulation across different cellular types and disease-related contexts. In this study, we propose a Fusion Neural Network (FusNet) for predicting protein-mediated loops. FusNet can concurrently capture and analyze multiple protein-mediated loops in various cell types to advance our understanding of the multitude of protein-mediated loop structures and their functional significance. Importantly, through association analysis with risk variants, FusNet manifests potential in revealing disease-related mechanisms.
The rules of sex and strain: deciphering the chemical language of inbred and wild mouse conspecific scents
Authors: Nagel Maximilian , Niestroj Marco , Bansal Rohini , Fleck David , Lampert Angelika , Stopkova Romana , Stopka Pavel , Ben-Shaul Yoram , Spehr Marc
Published: June 2023

In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex- / strain-selective “raw” chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animal’s sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary ‘secretome’, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.
Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence
Authors: Dasgupta Nirmalya , Lei Xue , Shi Christina Huan , Arnold Rouven , Teneche Marcos G. , Miller Karl N. , Rajesh Adarsh , Davis Andrew , Anschau Valesca , Campos Alexandre R. , Gilson Rebecca , Havas Aaron , Yin Shanshan , Chua Zong Ming , Liu Tianhui , Proulx Jessica , Alcaraz Michael , Rather Mohammed Iqbal , Baeza Josue , Schultz David C. , Yip Kevin Y. , Berger Shelley L. , Adams Peter D.
Published: June 2023

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory Senescence-Associated Secretory Phenotype (SASP), is a cause of aging. In senescent cells, Cytoplasmic Chromatin Fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. PML protein organizes PML nuclear bodies (NBs), also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRA’s localization to PML NBs. Inactivation of HIRA does not directly block expression of NF-κB target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-κB pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in regulation of SASP.
Comparative analysis of N-terminal cysteine dioxygenation and prolyl-hydroxylation as oxygen sensing pathways in mammalian cells
Authors: Tian Ya-Min , Holdship Philip , To Trang Quynh , Ratcliffe Peter J , Keeley Thomas P
Published: June 2023

In animals, adaptation to changes in cellular oxygen levels is coordinated largely by the 2-oxoglutarate dependent prolyl-hydroxylase domain (PHD) dioxygenase family, which regulate the stability of their hypoxia-inducible factor (HIF) substrates to promote expression of genes that adapt cells to hypoxia. Recently, 2-aminoethanethiol dioxygenase (ADO) was identified as a novel O2-sensing enzyme in animals. Through N-terminal cysteine dioxygenation and the N-degron pathway, ADO regulates the stability of a set of non-transcription factor substrates; the regulators of G-protein signalling 4, 5 and 16, and interleukin-32. Here, we set out to compare and contrast thein cellulocharacteristics of ADO and PHD enzymes in an attempt to better understand their co-evolution in animals. We find that ADO operates to regulate the stability of its substrates rapidly and with similar O2-sensitivity to the PHD/HIF pathway. ADO appeared less sensitive to iron chelating agents or transition metal exposure than the PHD enzymes, possibly due to tighter catalytic-site Fe2+coordination. Unlike the PHD/HIF pathway, the ADO/N-degron pathway was not subject to feedback by hypoxic induction of ADO and induction of ADO substrates was well sustained in response to prolonged hypoxia. The data also reveal strong interactions between proteolytic regulation of targets by ADO and transcriptional induction of those targets, that shape integrated cellular responses to hypoxia.
How does China economic policy uncertainty (EPU) impact copper-firms stock returns and copper prices returns?
Authors: Maquieira Carlos , Gahona-Flores Orlando , Espinosa-Méndez Christian
Published: June 2023

Purpose

This study focuses on how China EPU may impact copper-firms stock returns and also how China EPU mediates between stock returns and copper prices returns.

Design/methodology/approach

The sample consists of 44 copper firms from January 2011 to March 2022. The study also considers a subsample of 29 net-exporters countries. Panel data methodology is used, allowing to control for unobservable heterogeneity and endogeneity problems. The equations are estimated through a dynamic panel using the generalized methods of moments (GMM).

Findings

China EPU has a negative and statistically significant relationship with stock returns. Copper price returns are positively associated with stock returns. This research also considers two scenarios: high and low levels of China EPU. For high levels of China EPU states it is reported a negative relationship between stock returns and China EPU and copper price returns show a positive relationship with stock returns.

Research limitations/implications

There is need to explore other metals for what China exhibits a high demand and observe if China EPU and Global EPU have similar impacts on stock returns. It will be useful to identify main firm's consumers of copper and these other metals to explore the relationship between EPU and stock returns.

Originality/value

To the best of the authors’ knowledge, this is the first paper that analyzes China EPU index and its impact on both copper-firms stocks returns and on changes in copper prices. This is done using all public copper firms worldwide.
Fractal model of thermal contact conductance of micro-segment gear considering friction coefficient
Authors: Sun Xianguang , Xin Xicheng
Published: June 2023

Purpose

The purpose of this study is to establish a fractal model of thermal contact conductance (TCC) of micro-segment gear considering friction coefficient.

Design/methodology/approach

The influences of friction coefficient, fractal dimension, fractal roughness and contact type on the TCC of the rough surface were studied by using numerical simulation.

Findings

The results show that with the increase of the friction coefficient, the TCC of the rough surface will decrease. As the fractal dimension increases or the fractal roughness decreases, the rough surface becomes smoother and the TCC becomes larger. Under the same load conditions, the TCC of the internal contact type is greater than that of the external contact type. In engineering practice, the desired TCC can be achieved by changing the contact type.

Originality/value

A fractal model of TCC of micro-segment gear considering friction coefficient was established in this study. The achievements of this study provide some theoretical basis for the investigation of the TCC of the gear.
Worker cooperatives in Italy: legislation, prevalence and recent trends
Authors: Lomuscio Marco , Tortia Ermanno Celeste , Cori Andrea
Published: June 2023

Purpose

In Italy, worker cooperatives (WCs), whose workers hold major control rights over collectively-owned assets, are the leading vehicle for the promotion and development of employee ownership. Worker cooperatives are present in all regions and in most economic sectors, employing about 506,000 workers and generating a turnover of about €22 bn. Despite their history and diffusion, the high prevalence of WCs in Italy is under-researched and -thematised and requires new research.

Design/methodology/approach

The paper leverages unpublished primary and secondary data from Centro Studi Legacoop databank, the Aida-Bureau Van Dijk databank and the Cooperative Registry of the Ministry of Economic Development (CRMED) to explain the spread of WCs in Italy.

Findings

This paper reveals descriptive statistics of WCs and investigates their distribution across economic sectors and regions, their economic and financial performance and gives an overview of the relevant legislation. The paper indicates that older small- and medium-sized cooperatives located in central and north-eastern Italy perform best economically. However, in recent years, an increasing number of young cooperatives has emerged in South Italy thanks to favourable legislation, cooperative finance and the diffusion of cooperative know-how. Limitations to such results are reported in the conclusions.

Originality/value

The paper sheds light on past and recent development trends of WCs in Italy, highlights their growth in South Italy and revitalises the debate on the drivers, structures and rationales of employee-owned enterprises in Italy. Findings generate implications for research and practice. Given the tendency of WCs to better protect jobs than investor-owned enterprises, the spread of these enterprises may help workers find better and more stable jobs, counter-cyclically mitigating the dangerous effects of macro- and meso-economic fluctuations and instability.
Improving the performance of a conveyor belt through lean philosophy and Industry 4.0
Authors: Mendes David S.F.T. , Navas Helena V.G. , Charrua-Santos Fernando M.B.
Published: June 2023

Purpose

The purpose of this study was to develop and implement a new model to improve maintenance management and the production system through the concepts: maintenance, lean philosophy and Industry 4.0.

Design/methodology/approach

The methodology employed in this study includes conducting a bibliographic survey of existing models exploring the joint application of the concepts under study, critically analyzing these models, developing a model proposal and subsequently analyzing the results obtained. The model is implemented on a belt conveyor of a feed mill to improve its performance.

Findings

The proposed model contributes to improve maintenance and production system management, proving to be a useful tool to improve real-time decision-making. After its application, it was possible to verify that it increased the performance of the conveyor belt, as well as improved the skills of the operators who operate on it.

Research limitations/implications

Limitation about the distance between the devices that make up the model. The implementation of autonomous maintenance can highlight some challenges within the company. The implementation was only in the belt conveyor, being useful to introduce this in the remaining areas of the factory.

Originality/value

The study presents an innovative, versatile, low-cost and easy-to-apply model to improve maintenance management by combining the three concepts. The model can be easily adapted to monitor condition parameters such as temperature, noise, among others, through the correct choice of devices and proper programming. This work also contributed to help in real-time decision-making for both the maintenance and production departments.
Distribution of N and recently fixed C among a common mycorrhizal network linking an invasive plant, Solidago canadensis, and a native plant, Kummerowia striata
Authors: Awaydul Awagul , Xiao Jing , Chen Xin , Koide Roger , Yuan Yongge , Cheng Lei
Published: June 2023

The invasive plant species, Solidago canadensis, often shares a common mycorrhizal network (CMN) with native plant species in southeast China. We ask whether the transfer of carbon (C) and nitrogen (N) among the invasive S. canadensis, the native Kummerowia striata and their CMN could contribute to the invasiveness of S. canadensis.

We conducted a microcosm experiment in which a CMN was established on S. canadensis and K. striata. We used 13CO2 pulse‐labelling to quantify the relative contribution of recently fixed C from the two host species to the CMN. We also calculated the relative N distribution to each host species from the CMN.

We found that 89% of the recently fixed C in the CMN originated from S. canadensis, while 11% originated from K. striata. We also found that the CMN distributed 77% of the N it absorbed to S. canadensis and 23% to K. striata.

Our results suggest that the unequal distribution of N from a CMN to the invasive and native plant species is related to the unequal contribution of C from the plant species. This mechanism could contribute to invasion of native communities by alien species when there is a stoichiometric exchange of limiting nutrients for C, and when alien species contribute more C to the CMN than natives.

Read the free Plain Language Summary for this article on the Journal blog.
Climate resilience, yield and geographical suitability of sweet potato under the changing climate: A review
Authors: Pushpalatha Raji , Gangadharan Byju
Published: June 2023

Sweet potato is one of the important tropical tuber crops across the world. This review analyzes the studies on the climate resilience of sweet potato to various environmental parameters, the impact of climate change on its yield, and geographical suitability to exploit more about this crop and find out the knowledge gap in its existing research. Drought tolerance studies indicate the suitability of sweet potato in drought‐prone areas in terms of their survival rate, and their leaves can tolerate up to a wilting point of −1.3 MPa. The optimum night and daytime temperatures for sweet potato are 18°C and 28°C. There are 82 crop varieties available globally with heat‐stress tolerance without compromising the yield. The elevated atmospheric CO2 enhanced the growth and yield of sweet potato and increased the water use efficiency. The salinity tolerance of sweet potato is observed as 11 dS m−1, and it is superior to other major food crops. Sweet potato's ozone tolerance is higher than other crops (59 ppb). The impact studies on crop yield and geographical suitability also recommend its superiority to other major food crops with similar crop duration. As an outcome of this study, further research is needed to explore this crop as sweet potato can substitute for major food grain crops in developing countries regarding food, feed, medicine, and fuel. Research on value‐added products and their marketing is another area that needs immediate attention. Studies must exploit sweet potato leaves to ensure nutritional security in developing countries. The researchers also need to focus on developing climate‐resilient varieties to ensure a continuous supply of planting materials to needy people to ensure food security. This review also demands more studies on the modeling of sweet potato worldwide to issue crop yield forecasts and monitor the spatial distribution of its major pests worldwide.
Odorant‐binding protein 19 in Monochamus alternatus involved in the recognition of a volatile strongly emitted from ovipositing host pines
Authors: Yang Ruinan , Li Dongzhen , Yi Shancheng , Wei Yi , Wang Manqun
Published: June 2023

Monochamus alternatus is the primary carrier of pine wood nematodes, which pose a serious threat to Pinus spp. in many countries. Newly emerging M. alternatus adults feed on heathy host pines, while matured adults transfer to stressed host pines for mating and oviposition. Several odorant‐binding proteins (OBPs) of M. alternatus have been proved to aid in the complex process of host location. To clarify the corresponding relations between OBPs and pine volatiles, more OBPs need to be studied. In this research, MaltOBP19 showed a specific expression in the antennae and mouthparts of M. alternatus, and it was marked in 4 types of antenna sensilla by immunolocalization. Fluorescence binding assays demonstrated the high binding affinity of MaltOBP19 with camphene and myrcene in vitro. In Y‐tube olfactory experiments, M. alternatus adults were attracted by camphene and RNAi of OBP19 via microinjection significantly decreased their attraction index. Myrcene induced phobotaxis, but RNAi had no significant effect on this behavior. Further, we found that ingesting dsOBP19 produced by a bacteria‐expressed system with a newly constructed vector could lead to the knockdown of MaltOBP19. These results suggest that MaltOBP19 may play a role in the process of host conversion via the recognition of camphene, which has been identified to be strongly released in stressed host pines. In addition, it is proved that knockdown of OBP can be achieved by oral administration of bacteria‐expressed double‐stranded RNA in M. alternatus adults, providing a new perspective in the control of M. alternatus.
Deficiency for scavenger receptors Stabilin‐1 and Stabilin‐2 leads to age‐dependent renal and hepatic depositions of fasciclin domain proteins TGFBI and Periostin in mice
Authors: Leibing Thomas , Riedel Anna , Xi Yannick , Adrian Monica , Krzistetzko Jessica , Kirkamm Christof , Dormann Christof , Schledzewski Kai , Goerdt Sergij , Géraud Cyrill
Published: June 2023

Stabilin‐1 (Stab1) and Stabilin‐2 (Stab2) are two major scavenger receptors of liver sinusoidal endothelial cells that mediate removal of diverse molecules from the plasma. Double‐knockout mice (Stab‐DKO) develop impaired kidney function and a decreased lifespan, while single Stabilin deficiency or therapeutic inhibition ameliorates atherosclerosis and Stab1‐inhibition is subject of clinical trials in immuno‐oncology. Although POSTN and TFGBI have recently been described as novel Stabilin ligands, the dynamics and functional implications of these ligands have not been comprehensively studied. Immunofluorescence, Western Blotting and Simple Western™ as well as in situ hybridization (RNAScope™) and qRT‐PCR were used to analyze transcription levels and tissue distribution of POSTN and TGFBI in Stab‐KO mice. Stab‐POSTN‐Triple deficient mice were generated to assess kidney and liver fibrosis and function in young and aged mice. TGFBI and POSTN protein accumulated in liver tissue in Stab‐DKO mice and age‐dependent in glomeruli of Stabilin‐deficient mice despite unchanged transcriptional levels. Stab‐POSTN‐Triple KO mice showed glomerulofibrosis and a reduced lifespan comparable to Stab‐DKO mice. However, alterations of the glomerular diameter and vascular density were partially normalized in Stab‐POSTN‐Triple KO. TGFBI and POSTN are Stabilin‐ligands that are deposited in an age‐dependent manner in the kidneys and liver due to insufficient scavenging in the liver. Functionally, POSTN might partially contribute to the observed renal phenotype in Stab‐DKO mice. This study provides details on downstream effects how Stabilin dysfunction affects organ function on a molecular and functional level.