bluuebunny/crossref_metadata_2025 huggingface dataset:
Mycorrhizal fungi modulate tree diversity effects on nutrient dynamics
Authors: Bönisch Elisabeth , Blagodatskaya Evgenia , Dirzo Rodolfo , Ferlian Olga , Fichtner Andreas , Huang Yuanyuan , Leonard Samuel J. , Maestre Fernando T. , von Oheimb Goddert , Ray Tama , Eisenhauer Nico
Published: December 2023

Species-specific differences in nutrient acquisition strategies allow for complementary use of resources among plants in mixtures, which may be further shaped by mycorrhizal associations. However, empirical evidence of these relationships is scarce, particularly for tree communities.

We investigated the impact of tree species richness and mycorrhizal types, arbuscular mycorrhizal fungi (AM) and ectomycorrhizal fungi (EM), on the above- and belowground carbon (C), nitrogen (N), and phosphorus (P) dynamics.

Soil and microbial biomass elemental pools did not strongly respond to tree species richness or mycorrhizal type. Tree species richness increased foliage C and P pools depending on mycorrhizal type. Additive partitioning analyses showed that net biodiversity effects for C, N, P pools in EM tree communities, and N pools in AM tree communities, were driven by selection effects, while mixtures of both mycorrhizal types were influenced by complementarity effects. Furthermore, tree species richness enhanced soil nitrate uptake over two years but had no impact on ammonium and phosphate levels.

Our results indicate that positive effects of tree diversity on aboveground nutrient storage are mediated by complementary mycorrhizal strategies. Given the prevalence of anthropogenic impacts on tree species richness globally, these results may have important implications for reforestation of multifunctional forests.
Unravelling neuronal and glial differences in ceramide composition, synthesis, and sensitivity to toxicity
Authors: McInnis John J. , Sood Disha , Guo Lilu , Dufault Michael R. , Garcia Mariana , Passaro Rachel , Gao Grace , Zhang Bailin , Dodge James C.
Published: December 2023

Ceramides are lipids that play vital roles in complex lipid synthesis, membrane function, and cell signaling. Disrupted ceramide homeostasis is implicated in cell-death and several neurologic diseases. Ceramides are often analyzed in tissue, but this approach fails to resolve cell-type differences in ceramide homeostasis that are likely essential to understanding cell and non-cell autonomous contributions to neurodegeneration. We show that human iPSC-derived neurons and glia differ in their rate of ceramide synthesis, ceramide isoform composition, and responses to altered ceramide levels. RNA-sequencing of cells treated to increase or decrease ceramides revealed connections to inflammation, ER stress, and apoptosis. Moreover, introducing labeled sphinganine showed that glia readily synthesize ceramide de novo and that neurons are relatively more sensitive to ceramide toxicity. Our findings provide a framework for understanding neurologic diseases with sphingolipid alternations and insights in to designing therapeutics that target ceramide for treating them.
A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma
Authors: Weiner Amber K. , Radaoui Alexander B. , Tsang Matthew , Martinez Daniel , Sidoli Simone , Conkrite Karina L. , Delaidelli Alberto , Modi Apexa , Rokita Jo Lynne , Patel Khushbu , Lane Maria V. , Zhang Bo , Zhong Chuwei , Ennis Brian , Miller Daniel P. , Brown Miguel A. , Rathi Komal S. , Raman Pichai , Pogoriler Jennifer , Bhatti Tricia , Pawel Bruce , Glisovic-Aplenc Tina , Teicher Beverly , Erickson Stephen W. , Earley Eric J. , Bosse Kristopher R. , Sorensen Poul H. , Krytska Kateryna , Mosse Yael P. , Havenith Karin E. , Zammarchi Francesca , van Berkel Patrick H. , Smith Malcolm A. , Garcia Benjamin A. , Maris John M. , Diskin Sharon J.
Published: December 2023

Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 60 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Moreover, DLK1 is highly expressed in several adult cancer types, including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG), hepatoblastoma, and small cell lung cancer (SCLC), suggesting potential clinical benefit beyond neuroblastoma. Taken together, our study demonstrates the utility of comprehensive cancer surfaceome characterization and credentials DLK1 as an immunotherapeutic target.

Highlights

Plasma membrane enriched proteomics defines surfaceome of neuroblastoma

Multi-omic data integration prioritizes DLK1 as a candidate immunotherapeutic target in neuroblastoma and other cancers

DLK1 expression is driven by a super-enhancer

DLK1silencing in neuroblastoma cells results in cellular differentiation

ADCT-701, a DLK1-targeting antibody-drug conjugate, shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma preclinical models
Comparative phosphoproteome analysis of primary and metastatic uveal melanoma cell lines
Authors: Glinkina K. , Prieto R. Gonzalez , Teunisse A.F.A.S. , Gelmi M.C. , Jager M.J. , Vertegaal A.C.O. , Jochemsen A.G.
Published: December 2023

Uveal melanoma (UM) is an ocular tumor that often develops asymptomatically. Statistically, every second patient eventually develops metastases that drastically worsen the prognosis by several months of overall survival. While isolated liver perfusion with melphalan and more recently immunotherapy (Tebentafusp) are the few treatment options available for metastatic UM patients, their application is complex or expensive. There is an urgent need to understand drug response and identify potential avenues for therapy. Hence, we focused on uncovering altered phosphorylation signaling events in metastatic UM using proteomics as an approach to identify potential drug targets.

We analyzed the phosphoproteomes of the primary UM cell line Mel270 and two cell lines OMM2.3 and OMM2.5, derived from metastatic lesions of the same patient. We found 177 phosphosites to be altered significantly between primary and metastatic cell lines. Pathway analysis of up-regulated phosphosites in metastatic lines suggests that Rho signaling and mitotic cell cycle to be significantly altered uncovering potential routes of signaling for metastasis. Clinical data from LUMC and TCGA datasets uncoveredMARK3expression (which links to Rho signaling) correlation with chromosome 3 status, a prognostic marker in UM, suggesting that MARK3 kinase might be involved in metastatic UM signaling.
NRPS genes provide antifungal activity to newBacillusandPaenibacillusstrains and change their expression in the presence of phytopathogens in a strain-specific manner
Authors: Vasilchenko N.G. , Kulikov M.P. , Prazdnova E.V. , Gorovtsov A.V. , Usatov A.V. , Chistyakov V.A.
Published: December 2023

Fusarium diseases pose a significant threat to agricultural crops. In agricultural practice, various chemical fungicides, typically triazole-based, are often used to control fusariosis. However, this practice contributes to the development of resistant strains among the pathogenic fungi. A potential alternative to chemical fungicide treatments involves utilizing biopreparations derived from natural antagonists ofFusarium.BacillusandPaenibacillusbacteria, isolated from farmland soils have shown notable antagonistic activity against phytopathogenicFusariumfungi. Genetic analysis via PCR has indicated the presence of nonribosomal peptide synthase genes in the isolated bacterial strains, with the absence of chitinase activity suggesting that the antifungal effect primarily stems from nonribosomal synthesized peptides. Furthermore, the expression of these genes is heightened in the presence of fungi during co-culturing, although the magnitude of this effect appears to be specific to each strain and dependent on the pathogen in question. Field trials have demonstrated the efficacy of a biocontrol preparation made from studiedBacillusandPaenibacillusstrains. These results suggest promising prospects for the development of pathogen-targeted treatments.
Democratizing biomedical simulation through automated model discovery and a universal material subroutine
Authors: Peirlinck Mathias , Linka Kevin , Hurtado Juan A. , Holzapfel Gerhard A. , Kuhl Ellen
Published: December 2023

Personalized computational simulations have emerged as a vital tool to understand the biomechanical factors of a disease, predict disease progression, and design personalized intervention. Material modeling is critical for realistic biomedical simulations, and poor model selection can have life-threatening consequences for the patient. However, selecting the best model requires a profound domain knowledge and is limited to a few highly specialized experts in the field. Here we explore the feasibility of eliminating user involvement and automate the process of material modeling in finite element analyses. We leverage recent developments in constitutive neural networks, machine learning, and artificial intelligence to discover the best constitutive model from thousands of possible combinations of a few functional building blocks. We integrate all discoverable models into the finite element workflow by creating a universal material subroutine that contains more than 60,000 models, made up of 16 individual terms. We prototype this workflow using biaxial extension tests from healthy human arteries as input and stress and stretch profiles across the human aortic arch as output. Our results suggest that constitutive neural networks can robustly discover various flavors of arterial models from data, feed these models directly into a finite element simulation, and predict stress and strain profiles that compare favorably to the classical Holzapfel model. Replacing dozens of individual material subroutines by a single universal material subroutine–populated directly via automated model discovery–will make finite element simulations more user-friendly, more robust, and less vulnerable to human error. Democratizing finite element simulation by automating model selection could induce a paradigm shift in physics-based modeling, broaden access to simulation technologies, and empower individuals with varying levels of expertise and diverse backgrounds to actively participate in scientific discovery and push the boundaries of biomedical simulation.
Method for Identifying Proteomic Biomarkers of Health
Authors: Zlobina Ksenia , Gopinath Ashwin , Thubagere Anu
Published: December 2023

Classification of proteomic samples from sick and non-sick individuals is important for developing high-quality diagnostics of diseases. Creating a shortlist of proteins useful for diagnostics is challenging. In this manuscript a simple algorithm of creating a multidimensional biomarker of health based on scanning proteomics data is provided. The algorithm is applied to several existing publicly available datasets and demonstrates a 9-protein indicator of atopic dermatitis, and 6-protein indicator of heart failure.
Knockdown ofNeuroD2leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in aXenopus laevistadpole model of DEE75
Authors: Banerjee S. , Szyszka P. , Beck C.W.
Published: December 2023

Developmental and Epileptic Encephalopathies (DEE) are a genetically diverse group of severe, early onset seizure disorders. DEE are normally identified clinically in the first six months of life by the presence of frequent, difficult to control seizures and accompanying stalling or regression of development. DEE75 results fromde novomutations of theNEUROD2gene that result in loss of activity of the encoded transcription factor, and the seizure phenotype was shown to be recapitulated inXenopus tropicalistadpoles. We used CRISPR/Cas9 to make a DEE75 model inXenopus laevis, to further investigate the developmental aetiology.NeuroD2.SCRISPR/Cas9 edited tadpoles were more active, swam faster on average, and had more unprovoked escape responses (C-starts) than their sibling controls. Live imaging of Ca2+signalling revealed prolongued, strong signals sweeping through the brain, indicative of neuronal hyperactivity. While the resulting tadpole brain appeared grossly normal, the blood-brain barrier was found to be leakier than that of controls. Additionally, the TGFβ antagonist Losartan was shown to have a short-term protective effect, reducing neuronal hyperactivity and reducing permeability of the blood- brain barrier. Severity of the behavioral phenotype correlated with increased with editing efficiency. Our results support a haploinsufficiency model of DEE75 resulting from reduced NeuroD2 activity during vertebrate brain development, and indicate that a leaky blood- brain barrier contributes to epileptogenesis.
Multi-omics analyses reveal novel effects of PLCγ2 deficiency in the mouse brain
Authors: Hopp Sarah C. , Rogers Juliet Garcia , Smith Sabrina , Campos Gabriela , Miller Henry , Barannikov Savannah , Kuri Eduardo Gutierrez , Wang Hu , Han Xianlin , Bieniek Kevin F. , Weintraub Susan T. , Palavicini Juan Pablo
Published: December 2023

Phospholipase C gamma-2 (PLCγ2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), which subsequently feed into numerous downstream signaling pathways. PLCG2 polymorphisms are associated with both reduced and increased risk of Alzheimer’s disease (AD) and with longevity. In the brain, PLCG2 is highly expressed in microglia, where it is proposed to regulate phagocytosis, secretion of cytokines/chemokines, cell survival and proliferation. We analyzed the brains of three-month-old PLCγ2 knockout (KO), heterozygous (HET), and wild-type (WT) mice using multiomics approaches, including shotgun lipidomics, proteomics, and gene expression profiling, and immunofluorescence. Lipidomic analyses revealed sex-specific losses of total cerebrum PIP2and decreasing trends of DAG content in KOs. In addition, PLCγ2 depletion led to significant losses of myelin-specific lipids and decreasing trends of myelin-enriched lipids. Consistent with our lipidomics results, RNA profiling revealed sex-specific changes in the expression levels of several myelin-related genes. Further, consistent with the available literature, gene expression profiling revealed subtle changes on microglia phenotype in mature adult KOs under baseline conditions, suggestive of reduced microglia reactivity. Immunohistochemistry confirmed subtle differences in density of microglia and oligodendrocytes in KOs. Exploratory proteomic pathway analyses revealed changes in KO and HET females compared to WTs, with over-abundant proteins pointing to mTOR signaling, and under-abundant proteins to oligodendrocytes. Overall, our data indicate that loss of PLCγ2 has subtle effects on brain homeostasis that may underlie enhanced vulnerability to AD pathology and aging via novel mechanisms in addition to regulation of microglia function.

Significance Statement

ThePLCG2gene contains a number of rare variants linked with increased and decreased risk for Alzheimer’s disease and longevity, but little is known about the role of PLCγ2 in normal brain function. The results described herein are significant because they describe the effects of knockout of PLCγ2 on brain cell types, thus mimicking the loss of function Alzheimer’s disease risk mutation. Our data describe novel effects of PLCγ2 deficiency on myelin homeostasis and mTOR signaling that have not been previously described that may underlie its association with Alzheimer’s disease pathogenesis and longevity.
Fungal pleural infection due toMicroascus graciliswith pulmonary aspergillosis after COVID-19 pneumonia
Authors: Hu Zhi-Min , Mao Li-Na , Deng Ti-Ying , Su Bin-Tao , Yang Yi , Dong Bi-Lin , Xu Qing , Yang Shuo
Published: December 2023

Abstract

Background

Scopulariopsis/Microascusis a rare but devastating pathogen due to its intrinsic resistance to nearly all available antifungal agents.Microascus gracilis, an ascomycetous mould in the orderMicroascales, familyMicroascaceae, has recently emerged as a significant invasive pathogen causing opportunistic infections.

Objectives and Methods

We present a case of pleural infection caused byM. graciliswith pulmonary aspergillosis in an immunocompromised man after COVID-19 pneumonia. To further understand the characteristics of the pathogen isolated from the patient, we identified the strain through mycological characteristics, matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS)-based sequencing, and performedin vitrodrug susceptibility testing against common antifungal agents. Moreover, we assessed lymphocyte subsets and programmed cell death protein 1 (PD-1) expression in peripheral blood and pleural effusion to monitor the efficacy of therapy with thymosin-α-1 and intravenous immunoglobulin.

Results

Filamentous fungi isolated from pleural fluid were identified asM. gracilisbased on classical morphology, mass spectrometry and molecular biology methods. The susceptibility resultsin vitrorevealed that multiple antifungal agents were inactive against the strain. Adjuvant immunomodulatory treatment successfully increased the levels of CD3+ T and CD4+ T cells while decreasing the levels of CD3+PD-1+ and CD4+PD-1+ T cells in both peripheral blood and pleural effusion.

Conclusions

The immunocompromised host with opportunisticM. gracilisinfection, rapid and accurate recognition through direct microscopic testing with calcofluor white and MOLDI-TOF MS, is the key to achieving a definite diagnosis, and a combination of antifungal therapy with immunomodulatory therapy is vital for improving survival.
Epidermal turnover in the planarianSchmidtea mediterraneainvolves basal cell extrusion and intestinal digestion
Authors: Lee Jun-Ru , Boothe Tobias , Mauksch Clemens , Rink Jochen C.
Published: December 2023

Planarian flatworms undergo continuous internal turnover, wherein old cells are replaced by the division progeny of adult pluripotent stem cells known as neoblasts. How dynamic cell turnover is executed at the organismal scale remains an intriguing question in planarians and biological systems in general. While previous studies have predominantly focused on neoblast proliferation, little is known about the processes that mediate cell loss during tissue homeostasis. Here, we use the planarian epidermis as a model to study the mechanisms of cell removal inSchmidtea mediterranea. We established a covalent dye-labeling assay and image analysis pipeline to quantify the cell turnover rate in the planarian epidermis. Our findings indicate that the ventral epidermis is highly dynamic, with a half-life of the constituent cells of approximately 4.5 days. Using live-imaging and pulse-chase assays, we find that epidermal cells undergo internalization via basal extrusion, followed by a migration towards the intestine and ultimately digestion by intestinal phagocytes. Overall, our studies reveal an intricate homeostatic cell clearance process that may reduce the metabolic costs of high turnover tissues in planarians.
Female-biased population sex ratios caused by genetic rather than ecological mechanisms
Authors: Mao Xiaomeng , Cortés Andres J. , Rixen Christian , Karrenberg Sophie
Published: December 2023

1. Biased sex ratios among reproductive individuals are common in plants, but the underlying mechanisms, as well as the evolutionary consequences, are not well understood. The classical theory of Düsing and Fisher predicts an equal primary sex ratio at seed production, based on the selective advantage of the rare sex. Biased sex ratios among reproductive plants can arise from sexual dimorphism in survival and flowering. Sex ratio biases can also be present from seed; in these cases, assumptions of Düsing’s and Fisher’s theory, for example, random mating or demographic equilibrium, were not met.

2. We investigated mechanisms leading to female-biased sex ratios in the arctic-alpine dwarf willowSalix herbaceaL. We studied sex ratios in three natural populations over three years as well as in 29 crosses (full-sib families) under controlled conditions over four growth periods. We tested whether sex ratio was associated with germination, survival or flowering, and whether females and males differed in habitat, size or flowering.

3. We detected a strong and consistent female bias, both in natural populations (sex ratio [proportion of females]: 0.71-0.82) and in our controlled experiment (overall sex ratio: 0.70-0-72). Our data did not support habitat segregation of the sexes or sexual dimorphism in size or flowering. Family sex ratios varied largely (from 0.25 to 1), including many female-biased families, but also unbiased families and two male-biased families. Families with lower germination, seedling establishment, survival or flowering did not have stronger female bias, indicating that intrinsically higher survival or flowering in females does not explain overall female bias.

4. Synthesis. Our results suggest that sex ratio bias inS. herbaceais already present in seeds and does not arise through intrinsic differences between sexes. Candidate mechanisms that can lead to both overall female bias and variation in sex ratio among families are meiotic drive or cyto-nuclear interactions. The pioneer habit ofSalixmay lead to non-equilibrium population dynamics that allow for the long-term persistence of variable genetic sex ratio distortion systems that arise from genetic conflict.
Functional genetic characterization of stress tolerance and biofilm formation inNakaseomyces glabratavia a novel CRISPR activation system
Authors: Maroc Laetitia , Shaker Hajer , Shapiro Rebecca S.
Published: December 2023

The overexpression of genes frequently arises inNakaseomyces(formerlyCandida)glabratavia gain-of-function mutations, gene duplication or aneuploidies, with important consequences on pathogenesis traits and antifungal drug resistance. This highlights the need to develop specific genetic tools to mimic and study genetic amplification in this important fungal pathogen. Here, we report the development, validation, and applications of the first CRISPR activation (CRISPRa) system inN. glabratafor targeted genetic overexpression. Using this system, we demonstrate the ability of CRISPRa to drive high levels of gene expression inN. glabrata, and further assess optimal guide RNA targeting for robust overexpression. We demonstrate the applications of CRISPRa to overexpress genes involved in fungal pathogenesis and drug resistance, and detect corresponding phenotypic alterations in these key traits, including the characterization of novel phenotypes. Finally, we capture strain variation using our CRISPRa system in two commonly usedN. glabratagenetic backgrounds. Together, this tool will expand our capacity for functional genetic overexpression in this pathogen, with numerous possibilities for future applications.
Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice
Authors: Nakai Ayaka , Lee Deokho , Zhang Yan , Shoda Chiho , Imanishi Tetsu , Jeong Heonuk , Ikeda Shin-ichi , Negishi Kazuno , Nakashizuka Hiroyuki , Yamagami Satoru , Kubo Akiharu , Kurihara Toshihide
Published: December 2023

The early and intermediate age-related macular degeneration (AMD) is characterized by the presence of drusen and pigmentary abnormalities in the retinal pigment epithelial (RPE) cells which form the outer blood retinal barrier (oBRB). Fluid leakage through the disrupted oBRB from the choroid to the neural retina has been implicated in the pathogenesis of AMD, however; the molecular mechanisms still remain unclear. The family of four transmembrane proteins, claudins are known to form tight junctions (TJs) in the oBRB. Nonetheless, there are few reports showing how they function in the oBRBin vivo. We found that claudin-1 is dominantly expressed in TJs of the mouse RPE. To investigate the role of claudin-1 in the RPE, we generated RPE-specificCldn1conditional knockout mice (Best1-Cre+/-Cldn1flox/floxmice:Cldn1cKO mice). Deficiency ofCldn1led to age-related lipid deposits such as subretinal drusenoid deposits (SDD), increased lipid droplets in the RPE, basal lamellar deposits (BlamD) and membranous debris in the Bruch’s membrane. In addition, pigmentary abnormalities such as RPE hypertrophy, multilayered-RPE cells, and ectopic pigment granules outside the RPE were observed inCldn1cKO mice. Our study provides new insights into the possible association of the TJ protein claudin-1 with lipid metabolism and cellular ageing in the RPE contributing to the early onset of AMD.
DisDock: A Deep Learning Method for Metal Ion-Protein Redocking
Authors: Lin Menghan , Li Keqiao , Zhang Yuan , Pan Feng , Wu Wei , Zhang Jinfeng
Published: December 2023

The structures of metalloproteins are essential for comprehending their functions and interactions. The breakthrough of AlphaFold has made it possible to predict protein structures with experimental accuracy. However, the type of metal ion that a metalloprotein binds and the binding structure are still not readily available, even with the predicted protein structure. In this study, we present DisDock, a physics-driven deep learning method for predicting protein-metal docking. DisDock takes distogram of randomly initialized protein-ligand configuration as input and outputs the distogram of the predicted binding complex. It combines the U-net architecture with self-attention modules to enhance model performance. Taking inspiration from the physical principle that atoms in closer proximity display a stronger mutual attraction, this predictor capitalizes on geometric information to uncover latent characteristics indicative of atom interactions. To train our model, we employ a high-quality metalloprotein dataset sourced from the Mother of All Databases (MOAD). Experimental results demonstrate that our approach outperforms other existing methods in prediction accuracy for various types of metal ions.
Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson’s disease and Dementia with Lewy bodies
Authors: Frigerio Irene , Bouwman Maud MA , Noordermeer Ruby TGMM , Podobnik Ema , Popovic Marko , Timmermans Evelien , Rozemuller Annemieke JM , van de Berg Wilma DJ , Jonkman Laura E
Published: December 2023

Regional differences in synaptic degeneration may underlie differences in clinical presentation and neuropathological disease progression in Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Here, we mapped and quantified synaptic degeneration in cortical brain regions in PD, PD with dementia (PDD) and DLB, and assessed whether regional differences in synaptic loss are linked to axonal degeneration and neuropathological burden. We included a total of 47 brain donors, 9 PD, 12 PDD, 6 DLB and 20 non-neurological controls. Synaptophysin+and SV2A+puncta were quantified in eight cortical regions using a high throughput microscopy approach. Neurofilament light chain (NfL) immunoreactivity, Lewy body (LB) density, phosphorylated-tau and amyloid-β load were also quantified. Group differences in synaptic density, and associations with neuropathological markers and Clinical Dementia Rating (CDR) scores, were investigated using linear mixed models. We found significantly decreased synaptophysin and SV2A densities in the cortex of PD, PDD and DLB cases compared to controls. Specifically, synaptic density was decreased in cortical regions affected at Braak α-synuclein stage 5 in PD (middle temporal gyrus, anterior cingulate and insula), and was additionally decreased in cortical regions affected at Braak α-synuclein stage 4 in PDD and DLB compared to controls (entorhinal cortex, parahippocampal gyrus and fusiform gyrus). Synaptic loss associated with higher NfL immunoreactivity and LB density. Global synaptophysin loss associated with longer disease duration and higher CDR scores. Synaptic neurodegeneration occurred in temporal, cingulate and insular cortices in PD, as well as in parahippocampal regions in PDD and DLB. In addition, synaptic loss was linked to axonal damage and severe α-synuclein burden. These results, together with the association between synaptic loss and disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical differences between PD and PDD/DLB. Our results might provide useful information for the interpretation of synaptic biomarkersin vivo.
Endoplasmic reticulum exit sites are segregated for secretion based on cargo size
Authors: Saxena Sonashree , Foresti Ombretta , Liu Aofei , Androulaki Stefania , Rodriguez Maria Pena , Raote Ishier , Cui Bianxiao , Aridor Meir , Malhotra Vivek
Published: December 2023

TANGO1-family proteins (TANGO1, TANGO1S and cTAGE5) form stable complexes at the Endoplasmic Reticulum Exit Sites (ERES) and mediate export of bulky cargoes. The C-terminal proline rich domain (PRD) of these proteins binds Sec23A and affects COPII assembly at ERES. These PRD interactions were replaced with light-responsive domains to control the binding between TANGO1S-DPRD and Sec23A. TANGO1SΔPRD was dispersed in the ER membrane but relocated rapidly, yet reversibly, to pre-exiting ERES by binding to Sec23A upon light-activation. Prolonged binding of these two proteins concentrated ERES in the juxtanuclear region by a microtubule dependent process, blocked secretory cargo export and relocated ERGIC53 into the ER, but had limited impact on Golgi complex organization. Under these conditions, bulky collagen VII, and endogenous collagen I were collected at less than 47% of the stalled ERES, whereas small cargo molecules were halted uniformly across the ER, indicating that ERES differentially adapt to cargo size. We suggest these differences in cargo-accumulation at ERES permit cells to balance trafficking of cargoes of different sizes and optimize secretion.
A Fluorescence-Based Sensor for Calibrated Measurement of Protein Kinase Stability in Live Cells
Authors: Paul Joseph W. , Muratcioğlu Serena , Kuriyan John
Published: December 2023

Oncogenic mutations can destabilize signaling proteins, resulting in increased or unregulated activity. Thus, there is considerable interest in mapping the relationship between mutations and the stability of proteins, to better understand the consequences of oncogenic mutations and potentially inform the development of new therapeutics. Here, we develop a tool to study protein-kinase stability in live mammalian cells and the effects of the HSP90 chaperone system on the stability of these kinases. We monitor the fluorescence of kinases fused to a fluorescent protein relative to that of a co-expressed reference fluorescent protein. We used this tool to study the dependence of Src- and Raf-family kinases on the HSP90 system. We demonstrate that this sensor reports on destabilization induced by oncogenic mutations in these kinases. We also show that Src-homology 2 (SH2) and Src-homology 3 (SH3) domains, which are required for autoinhibition of Src-family kinases, stabilize these kinase domains in the cell. Our expression-calibrated sensor enables the facile characterization of the effects of mutations and small-molecule drugs on protein-kinase stability.
The role of Miocene-Pleistocene environmental change in diversification of the genusHypoclinemusChabanaud, 1928
Authors: Rodrigues Alan Erik S. , Ready Jonathan Stuart , Pereira da Silva Lucas Gabriel , Silva Kamila de Fátima , Ferreira Silva Derlan José , Sabaj Mark H. , Andrade Marcelo C. , Vasconcelos Santelmo , Sales João Bráullio L.
Published: December 2023

The Neotropical region stands out as one of the most taxonomically diverse areas on the planet, garnering significant attention in the context of marine incursions and their role in shaping this diversity. Among marine-derived taxa, pleuronectiform fishes exhibit distinctive morphological characteristics that have attracted significant scientific interest. However, the biogeography ofHypoclinemus mentalis, initially described asSolea mentalisand subsequently assigned to the genusAchirus, was eventually reclassified into its current monotypic genus due to its limited distribution in freshwater environments, in contrast to the species ofAchirus. The broad distribution of a single species across multiple South American river basins positionsH. mentalisas an ideal candidate for biogeographic studies within South America, with an emphasis on the detection of cryptic lineages associated with major drainage basins. In our study, we employed mitochondrial and nuclear markers to investigate the potential existence of such lineages within the broader context of a molecular phylogeny that encompasses all valid genera in the flatfish family Achiridae. Our findings reveal thatHypoclinemuscomprises seven operational taxonomic units (OTUs), as deduced from specimens collected across the majority of its documented range. Furthermore, our phylogeographic analyses support the hypothesis that colonization of freshwater habitats occurred through connections between the Caribbean Sea and Lake Pebas approximately 21.28 million years ago. Moreover, we observed that differentiation of lineages within theHypoclinemusgenus was significantly influenced by pronounced sea level fluctuations during the Plio-Pleistocene epoch, underscoring the impact of glaciations and interglacial periods on the biogeographic patterns.
Detecting Rhythmic Gene Expression in Single Cell Transcriptomics
Authors: Xu Bingxian , Ma Dingbang , Abruzzi Katharine , Braun Rosemary
Published: December 2023

An autonomous, environmentally-synchronizable circadian rhythm is a ubiquitous feature of life on Earth. In multicellular organisms, this rhythm is generated by a transcription--translation feedback loop present in nearly every cell that drives daily expression of thousands of genes in a tissue--dependent manner. Identifying the genes that are under circadian control can elucidate the mechanisms by which physiological processes are coordinated in multicellular organisms. Today, transcriptomic profiling at the single-cell level provides an unprecedented opportunity to understand the function of cell-level clocks. However, while many cycling detection algorithms have been developed to identify genes under circadian control in bulk transcriptomic data, it is not known how best to adapt these algorithms to single-cell RNAseq data. Here, we benchmark commonly used circadian detection methods on their reliability and efficiency when applied to single cell RNAseq data. Our results provide guidance on adapting existing cycling detection methods to the single-cell domain, and elucidate opportunities for more robust and efficient rhythm detection in single-cell data. We also propose a subsampling procedure combined with harmonic regression as an efficient, reliable strategy to detect circadian genes in the single--cell setting.
Nuclear VANGL2 Inhibits Lactogenic Differentiation
Authors: Rubio Stefany , Molinuevo Rut , Sanz-Gomez Natalia , Zomorrodinia Talieh , Cockrum Chad S. , Luong Elina , Rivas Lucia , Cadle Kora , Menendez Julien , Hinck Lindsay
Published: December 2023

Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, PCP proteins are also trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in undifferentiated, but not differentiated, HC11 cells, which serve as a model for mammary lactogenic differentiation. Loss ofVangl2function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate direct binding of VANGL2 to specific DNA binding motifs, including one in theStat5apromoter. Knockdown (KD) ofVangl2in HC11 cells and primary mammary organoids results in upregulation ofStat5a,Ccnd1andCsn2, larger acini and organoids, and precocious differentiation; phenotypes rescued by overexpression ofVangl2, but notVangl2ΔNLS. Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.
Shaping contexts through entrepreneurship: a micro-historical analysis of Hongbang entrepreneurs in China (1896-1949)
Authors: Xu Cheng , Zhou Haibo , Fan Bohong , Sun Yanqi
Published: December 2023

Purpose

The purpose of this study is to address a significant gap in the understanding of entrepreneurship at the microfoundation level. It focuses on how individual entrepreneurs, specifically Hongbang entrepreneurs in China from 1896 to 1949, shape and transform their contexts. The aim is to provide a deeper understanding of the mechanisms that facilitate entrepreneurial success.

Design/methodology/approach

The study adopts a microhistorical approach, investigating the case of Hongbang entrepreneurs in China during 1896-1949. It involves an in-depth examination of historical records to explore the strategic interactions between these entrepreneurs and core stakeholders such as consumers, financial intermediaries, government regulators, and human resources. The research methodology emphasizes a process-oriented view, examining the evolution of personalized networks into extensive connections.

Findings

The research reveals that Hongbang entrepreneurs successfully reshaped their unfavorable embedded contexts by strategically collaborating with key stakeholders. They influenced consumer tastes, allied with financial intermediaries, negotiated with governments on regulation policies, and developed human resource stocks. The transformation was facilitated by the evolution of their networks from personalized to extensive connections. These findings highlight the localized strategies such as cronyism in resource acquisition within China’s private property development industry.

Originality/value

This study contributes to the field by offering insights into entrepreneurial contextualization and networking. It sheds light on the complex interplay between entrepreneurs and their contexts, providing a nuanced understanding of localized strategies in the Chinese context. The findings add value to the discourse on entrepreneurship by elucidating the strategic and processual acts through which entrepreneurs engage with stakeholders and reshape their environments.
Interactive effects of organizational resources on sustainable product design practices: a resource orchestration perspective
Authors: John-Mariadoss Babu , Pomirleanu Nadia , Chennamaneni Pavan R. , Ganesh Pillai Rajani , Zailani Suhaiza
Published: December 2023

Purpose

The purpose of this study is to investigate the interactive effects of a firm’s strategic sustainability orientation (SSO) and customer relationship capital (CRC) on sustainable product design practices (SPDP).

Design/methodology/approach

The authors examine the interactive effects of two firm resources, namely, SSO and CRC, as they relate to SPDP, using survey data from 132 manufacturers in Malaysia.

Findings

The findings show that the effect of SSO on SPDP is stronger when CRC is low, than otherwise. The authors also find that the interactive effects of the firm-level resources stated above are stronger when customer pressures (CPs) are higher than when they are low.

Research limitations/implications

The authors contribute to the literature by studying the effects of firm-level strategic resources and their interactions as they relate to SPDP. An important limitation of this research is the usage of single-source data and single-period data.

Practical implications

Managerially, this research provides new insights into how organizations should respond to CPs while understanding the counterintuitive but disabling effects of customer relationship assets.

Social implications

The findings are important to society because most of the environmental impact arising from the production, consumption and disposal of products is a direct consequence of decisions made at the product design stage and an unintended consequence of the marketing decision-making processes that underlie marketing strategy formulation that fails to recognize ecosystems impact as a standard decision influence.

Originality/value

To the best of the authors’ knowledge, this research is the first to study the effects of firm-level strategic resources and their interactions as they relate to SPDP.
After COVID-19 lockdown: an exploratory study about the influence of mindfulness-feelings toward an individual’s outdoor lifestyle and empowerment
Authors: Borges Ana Pinto , Vieira Elvira Pacheco , Rodrigues Paula , Lopes de Almeida António , Sousa Ana
Published: December 2023

Purpose

This study aimed to detect the relationships between mindfulness and events participation, and then between the later and psychological empowerment.

Design/methodology/approach

The proposed model's underlying hypotheses were empirically tested with data collected through an online survey addressed to a convenience sample of frequent leisure participants (n = 199). The authors applied the structural equation model (SEM) to confirm the aforementioned relationships. To assess the adequacy of the psychometric properties of the measures, the authors performed a confirmatory factor analysis of the measurement model, with a maximum likelihood estimation method.

Findings

Under the effects of the lockdown period environment, the results express a positive relationship between a mindful state of mind – related to observation/attention – and the yearnings and perceptions about the participation in events. This relationship for consistency was proven to be moderated by the perception of the participation importance to the individual subjective well-being/mental health. Due to participation insights, there was a positive effect on psychological empowerment, supporting the relationship that had been hypothesized.

Originality/value

The authors propose and test a new model that contributes to the theory and examines how mindfulness behavior can effect more alluring and intense participation in events and what are the anticipated outcomes in terms of psychological empowerment.
Validation of sustainability indicators in the energy sector considering their relationship with the UN SDGs: analysis of an emerging economy country using the Lawshe method
Authors: Marinho Samille Souza , Rego Neto Armando Gomes , Fernandes Reimison Moreira , Silva Melo André Cristiano , Lourenço Bastos Leonardo dos Santos , Martins Vitor William Batista
Published: December 2023

Purpose

This study aims to identify sustainability indicators in the energy sector through a literature review and validate them from the perspective and context of professionals working in the sector in an emerging economy country, Brazil, considering the relationship of these indicators with the achievement of the targets set by the United Nations sustainable development goals (UN SDGs).

Design/methodology/approach

To accomplish this, a literature review on sustainability indicators specific to the energy sector was conducted. Subsequently, a research instrument (questionnaire) based on the identified indicators was developed and a survey was administered to professionals in the field. The collected data were analyzed using the Lawshe method.

Findings

The results revealed 20 indicators, distributed across environmental, economic and social dimensions. Among these, nine indicators were validated, including global impacts, local impacts, renewable energy production as a percentage of total production, greenhouse gas emissions, access to electricity, investment in the energy sector, installed capacity in the electricity sector, energy prices in the end-use sector and energy distribution and conversion efficiency.

Originality/value

Consequently, it was possible to determine which SDGs are directly impacted and provide a foundation for future actions that can contribute to the sustainable advancement of the energy sector in emerging countries.
Awakening the giant within: turning SME’s survival strategy into improved performance
Authors: Yunus Erlinda N. , Ernawati Erni
Published: December 2023

Purpose

This study aims to examine the positive impact of strategies on the viability of small and medium-sized enterprises (SMEs) in times of crisis. Specifically, it investigates the influence of resource utilization as an initial survival strategy on innovation practices and SMEs’ performance. It further assesses the potential impact of government aid and partnerships on the relationship between resource utilization and innovation.

Design/methodology/approach

This study used a mixed-method approach that integrates phenomenology and quantitative research. This phenomenological study conducted in-depth interviews with 23 SME owners. Based on qualitative findings, a quantitative research design was developed, and this study surveyed 352 SMEs. Structural equation modeling was used for hypothesis testing.

Findings

Resource utilization as an initial survival strategy has a positive effect on increasing organizational innovation practices and ultimately affects business performance. Furthermore, government support and external partnerships significantly enhance the relationship between resource utilization and innovation.

Practical implications

The COVID-19 pandemic brought a crisis for businesses but has provided many positive transformations. SME entrepreneurs should sustain their survival strategies and seize external support to enhance their potential. Due to the pandemic, various efforts have created innovations, honed business resiliency and increased competitiveness.

Originality/value

SMEs struggled with the crisis and responded by utilizing many retrenchment strategies. This study is among the first to provide empirical evidence of an emergency response that has resulted in fruitful impacts. The findings can be generalized to represent the behavior of SMEs, especially in emerging countries.