bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic profiling of isolated immune synapses from primary mouse B cells
Authors: Cunha Diogo M. , Hernández-Pérez Sara , Awoniyi Luqman O. , Carisey Alexandre F. , Jacquemet Guillaume , Mattila Pieta K.
Published: February 2023

The immune synapse (IS) is a cell-cell interaction platform critical in lymphocyte activation by specific antigens. Despite of B cells being able to also respond to soluble antigens, in particular thein vivoimportance of the IS and surface-tethered antigen recognition has strongly emerged in the recent years. The IS serves as a dynamic hub for multiple cellular actions but the molecular details of these functions, especially beyond the B cell antigen receptor (BCR) signalling, remain poorly understood. Here, to address the lack in the systems level understanding of the IS, we setup methodology for comprehensive investigation of the composition of the primary mouse B cells’ IS at proteome level. Utilizing functionalized magnetic beads to mimic antigen presenting cells and trigger IS formation on them, we developed a method to specifically and robustly extract the cell adhesions on the beads, namely the IS or transferrin receptor mediated adhesion as a control. Our data revealed 661 proteins exclusively present in the IS at 15 minutes after BCR engagement, 13 exclusively in the control adhesions and 365 proteins shared between the samples. We got strong coverage of the known components of the IS as well as identified a plethora of unknown proteins and functional pathways with hitherto unknown roles in B cell IS. Thus, in this work, we validated the IS isolation method as a valuable tool to study early B cell activation by surface-bound antigens as well as unveil several novel proteins and pathways suggestive of new functional aspects in the IS.
GENEvaRX: A Novel AI-Driven Method and Web Tool Can Identify Critical Genes and Effective Drugs for Lichen Planus
Authors: Turki Turki , Taguchi Y-h.
Published: February 2023

Lichen planus (LP) is an autoimmune disorder diagnosed based on physical symptoms and lab tests. Examples of symptoms include flat bumps, and itchy and purplish skin, while lab tests include a shave biopsy of the lesion. When the pathology report shows consistency with LP and is negative for potential triggers for an allergy test and hepatitis C, a dermatologist typically prescribes corticosteroid in the form of pills or injection into the lesion to treat the symptoms. To understand the molecular mechanism of the disease and thereby overcome issues associated with disease treatment, there is a need to identify potential effective drugs, drug targets, and therapeutic targets associated the LP. Hence, we propose a novel computational framework based on new constrained optimization to support vector machines coupled with enrichment analysis. First, we downloaded three gene expression datasets (GSE63741, GSE193351, GSE52130) pertaining to healthy and LP patients from the gene expression omnibus (GEO) database. We then processed each dataset and entered it into our computational framework to select important genes. Finally, we performed enrichment analysis of selected genes, reporting the following results. Our methods outperformed baseline methods in terms of identifying disease and skin tissue. Moreover, we report 5 drugs (including, dexamethasone, retinoic acid, and quercetin), 45 unique genes (including PSMB8, KRT31, KRT16, KRT19, KRT17, COL3A1, LCE2D, LCE2A), and 23 unique TFs (including NFKB1, STAT1, STAT3) reportedly related to LP pathogenesis, treatments, and therapeutic targets. Our methods are publicly available in the GENEvaRX web server athttps://aibio.shinyapps.io/GENEvaRX/.
A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases in extracellular matrix abnormalities
Authors: Al-Thani Maha , Goodwin-Trotman Mary , Bell Steven , Patel Krushangi , Fleming Lauren K , Vilain Catheline , Abramowicz Marc , Allan Stuart M , Wang Tao , Cader Zameel , Horsburgh Karen , Van Agtmael Tom , Sinha Sanjay , Markus Hugh S , Granata Alessandra
Published: February 2023

Abstract/Summary

Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology but this remains poorly characterized.

To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients withCOL4A1/A2SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodelling and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cells tight junctions through paracrine actions.COL4A1/A2models also express high levels of matrix metalloproteinases (MMP) and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD.

Highlights

A novel human iPSC-derived model of genetic SVD due to collagen IV (COL4A1/A2) mutations is described

Mural cells expressingCOL4A1/A2mutations have prominent ECM abnormalities as seen in patients and mouse models and contribute to endothelial cells defects

ECM and endothelial cells abnormalities can be rescued by MMP inhibition in theCOL4A1/A2model
Statistical mining of triple-negative breast cancer-specific nanobodies among huge libraries from immunized alpacas
Authors: Maeda Ryota , Yamazaki Hiroyuki , Kobayashi Ryoga , Yamamoto Seishiro , Kasai Kazuki , Imura Akihiro
Published: February 2023

Breast cancer can be classified into several types according to the expression patterns of human epidermal growth factor receptor 2 (Her2), oestrogen receptor (ER), and progesterone receptor (PgR) proteins. The prognosis of patients with tumors showing low Her2 expression and no ER and PgR expression—categorized as triple-negative breast cancer (TNBC)—is worst among these groups. Due to the lack of specific antibodies for TNBC, curative treatments for TNBC remain limited. Antibodies targeting TNBC have potential as diagnostic and therapeutic tools. Here, we generate a panel of nanobodies targeting TNBC cell lines by immunizing alpacas and subsequently panning the resulting phage libraries with TNBC cell lines. We show that several clones exclusively stain Her2-negative cells in tissues of breast cancer patients, and a few clones stain both Her2-positive and Her2-negative regions in these tissues. These clones can be applied to patient-specific therapies using drug-conjugated antibodies, radiolabelled antibodies, chimaera antigen receptor T cells, or drug delivery components, as well as to TNBC diagnosis.
HilE represses the activity of HilD via a mechanism distinct from that of intestinal long-chain fatty acids
Authors: Joiner Joe D. , Steinchen Wieland , Kronenberger Thales , Bange Gert , Poso Antti , Wagner Samuel , Hartmann Marcus D.
Published: February 2023

The expression of virulence factors essential for the invasion of host cells bySalmonella entericais tightly controlled by a network of transcription regulators. The AraC/XylS transcription factor HilD is the main integration point of environmental signals into this regulatory network, with many factors affecting HilD activity. Long chain fatty acids (LCFAs), which are highly abundant throughout the host intestine directly bind to, and repress HilD, acting as environmental cues to coordinate virulence gene expression. The regulatory protein HilE also negatively regulates HilD activity, through a protein-protein interaction. Both of these regulators inhibit HilD dimerisation, preventing HilD from binding to target DNA. We investigated the structural basis of these mechanisms of HilD repression. LCFAs bind to a conserved pocket in HilD, in a comparable manner to that reported for other AraC/XylS regulators, whereas HilE forms a stable heterodimer with HilD by binding to the HilD dimerisation interface. Our results highlight two distinct mechanisms by which HilD activity is repressed, which could be exploited for the development of new antivirulence leads.
Dual-modality imaging of immunofluorescence and imaging mass cytometry for whole slide imaging with accurate single-cell segmentation
Authors: Kim Eun Na , Chen Phyllis Zixuan , Bressan Dario , Tripathi Monika , Miremadi Ahmad , di Pietro Massimiliano , Coussens Lisa M , Hannon Gregory J , Fitzgerald Rebecca C , Zhuang Lizhe , Chang Young Hwan
Published: February 2023

Imaging mass cytometry (IMC) is a powerful multiplexed tissue imaging technology that allows simultaneous detection of more than 30 makers on a single slide. It has been increasingly used for singlecell-based spatial phenotyping in a wide range of samples. However, it only acquires a small, rectangle field of view (FOV) with a low image resolution that hinders downstream analysis. Here, we reported a highly practical dual-modality imaging method that combines high-resolution immunofluorescence (IF) and high-dimensional IMC on the same tissue slide. Our computational pipeline uses the whole slide image (WSI) of IF as a spatial reference and integrates small FOVs IMC into a WSI of IMC. The high-resolution IF images enable accurate single-cell segmentation to extract robust high-dimensional IMC features for downstream analysis. We applied this method in esophageal adenocarcinoma of different stages, identified the single-cell pathology landscape via reconstruction of WSI IMC images, and demonstrated the advantage of the dual-modality imaging strategy.

Motivation

Highly multiplexed tissue imaging allows visualization of the spatially resolved expression of multiple proteins at the single-cell level. Although imaging mass cytometry (IMC) using metal isotope-conjugated antibodies has a significant advantage of low background signal and absence of autofluorescence or batch effect, it has a low resolution that hampers accurate cell segmentation and results in inaccurate feature extraction. In addition, IMC only acquires mm2-sized rectangle regions, which limits its application and efficiency when studying larger clinical samples with non-rectangle shapes. To maximize the research output of IMC, we developed the dual-modality imaging method based on a highly practical and technical improvement requiring no extra specialized equipment or agents and proposed a comprehensive computational pipeline that combines IF and IMC. The proposed method greatly improves the accuracy of cell segmentation and downstream analysis and is able to obtain whole slide image IMC to capture the comprehensive cellular landscape of large tissue sections.
Insulin B peptide-MHC class II-specific chimeric antigen receptor-Tregs prevent autoimmune diabetes
Authors: Spanier Justin A. , Fung Vivian , Wardell Christine M. , Alkhatib Mohannad H. , Chen Yixin , Swanson Linnea A. , Dwyer Alexander J. , Weno Matthew E. , Silva Nubia , Mitchell Jason S. , Orban Paul C. , Mojibian Majid , Verchere C. Bruce , Fife Brian T. , Levings Megan K.
Published: February 2023

Adoptive immunotherapy with Tregs is a promising approach for prevention or treatment of type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B-chain 10-23 peptide presented in the context of the IAg7MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g7 CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The InsB-g7 CAR re-directed NOD Treg specificity such that insulin B 10-23-peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Co-transfer of InsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In wild type NOD mice, InsB-g7 CAR Tregs stably expressed Foxp3 and prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor-like CAR is a promising new therapeutic approach for the prevention of autoimmune diabetes.

Brief Summary

Chimeric antigen receptor Tregs specific for an insulin B-chain peptide presented by MHC class II prevent autoimmune diabetes.
Human A2-CAR T cells reject HLA-A2+ human islets transplanted into mice without inducing graft versus host disease
Authors: Ellis Cara E. , Mojibian Majid , Ida Shogo , Fung Vivian C.W. , Skovsø Søs , McIver Emma , O’Dwyer Shannon , Webber Travis D. , Braam Mitchell J.S. , Saber Nelly , Kieffer Timothy J. , Levings Megan K.
Published: February 2023

Background

Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell mediated destruction of pancreatic beta-cells. Islet transplantation is an effective therapy, but its success is limited by islet quality and availability along with the need for immunosuppression. New approaches include use of stem cell-derived insulin-producing cells and immunomodulatory therapies, but a limitation is the paucity of reproducible animal models in which interactions between human immune cells and insulin-producing cells can be studied without the complication of xenogeneic graft-versus-host disease (xGVHD).

Methods

We expressed an HLA-A2-specific chimeric antigen receptor (A2-CAR) in human CD4+ and CD8+ T cells and tested their ability to reject HLA-A2+ islets transplanted under the kidney capsule or anterior chamber of the eye of immunodeficient mice. T cell engraftment, islet function and xGVHD were assessed longitudinally.

Results

The speed and consistency of A2-CAR T cells-mediated islet rejection varied depending on the number of A2-CAR T cells and the absence/presence of co-injected peripheral blood mononuclear cells (PBMCs). When <3 million A2-CAR T cells were injected, co-injection of PBMCs accelerated islet rejection but also induced xGVHD. In the absence of PBMCs, injection of 3 million A2-CAR T cells caused synchronous rejection of A2+ human islets within 1 week and without xGVHD for 12 weeks.

Conclusions

Injection of A2-CAR T cells can be used to study rejection of human insulin-producing cells without the complication of xGVHD. The rapidity and synchrony of rejection will facilitate in vivo screening of new therapies designed to improve the success of isletreplacement therapies.
Multiple sources of uncertainty confound inference of historical human generation times
Authors: Ragsdale Aaron P. , Thornton Kevin R.
Published: February 2023

Wanget al. (2023) recently proposed an approach to infer the history of human generation intervals from changes in mutation profiles over time. As the relative proportions of different mutation types depend on the ages of parents, binning variants by the time they arose allows for the inference of average paternal and maternal generation intervals over times. Applying this approach to published allele age estimates, Wanget al. (2023) inferred long-lasting sex differences in average generation times and surprisingly found that ancestral generation times of West African populations remained substantially higher than those of Eurasian populations extending tens of thousands of generations into the past. Here we argue that the results and interpretations in Wanget al. (2023) are primarily driven by noise and biases in input data and a lack of validation using independent approaches for estimating allele ages. With the recent development of methods to reconstruct genome-wide gene genealogies, coalescence times, and allele ages, we caution that downstream analyses may be strongly influenced by uncharacterized biases in their output.
Structural Analysis of Genomic and Proteomic Signatures Reveal Dynamic Expression of Intrinsically Disordered Regions in Breast Cancer and Tissue
Authors: Zatorski Nicole , Sun Yifei , Elmas Abdulkadir , Dallago Christian , Karl Timothy , Stein David , Rost Burkhard , Huang Kuan-Lin , Walsh Martin , Schlessinger Avner
Published: February 2023

Structural features of proteins capture underlying information about protein evolution and function, which enhances the analysis of proteomic and transcriptomic data. Here we developStructuralAnalysis ofGene and proteinExpressionSignatures (SAGES), a method that describes expression data using features calculated from sequence-based prediction methods and 3D structural models. We used SAGES, along with machine learning, to characterize tissues from healthy individuals and those with breast cancer. We analyzed gene expression data from 23 breast cancer patients and genetic mutation data from the COSMIC database as well as 17 breast tumor protein expression profiles. We identified prominent expression of intrinsically disordered regions in breast cancer proteins as well as relationships between drug perturbation signatures and breast cancer disease signatures. Our results suggest that SAGES is generally applicable to describe diverse biological phenomena including disease states and drug effects.
Desynapsis in potato is caused byStMSH4mutant alleles and leads to either highly uniform unreduced pollen or sterility
Authors: Clot Corentin R. , Klein Dennis , Koopman Joey , Schuit Cees , Engelen Christel J.M. , Hutten Ronald C.B. , Brouwer Matthijs , Visser Richard G.F. , Juranić Martina , van Eck Herman J.
Published: February 2023

The balanced segregation of homologous chromosomes during meiosis is essential for fertility and is mediated by crossovers. A strong reduction of crossovers leads to desynapsis, a process in which pairing of homologous chromosomes is abolished before metaphase I. This results in a random segregation of univalent and the production of unbalanced and sterile gametes. However, if desynapsis is combined with another meiotic alteration that restitutes the first meiotic division, then uniform and balanced unreduced gametes, essentially composed of non-recombinant homologs, are produced. This mitosis-like division is of interest to breeders because it transmits most of the parental heterozygosity to the gametes. In potato, desynapsis is a recessive trait that was tentatively mapped to chromosome8. In this article, we have fine-mapped the position of the desynapsis locus and identifiedStMSH4, an essential component of the class I crossover pathway, as the most likely candidate gene. A seven base-pair insertion in the second exon ofStMSH4was found to be associated with desynapsis in our mapping population. We also identified a second allele with a 3820 base-pair insertion and confirmed that both alleles cannot complement each other. Such non-functional alleles appeared to be common in potato cultivars. More than half of the varieties we tested are carriers of mutational load at theStMSH4locus. With this new information, breeders can choose to remove desynaptic alleles from their germplasm to improve fertility or to use them to produce highly uniform unreduced gametes in alternative breeding schemes.
Single cell and spatial alternative splicing analysis with long read sequencing
Authors: Fu Yuntian , Kim Heonseok , Adams Jenea I. , Grimes Susan M. , Huang Sijia , Lau Billy T. , Sathe Anuja , Hess Paul , Ji Hanlee P. , Zhang Nancy R.
Published: February 2023

Long-read sequencing has become a powerful tool for alternative splicing analysis. However, technical and computational challenges have limited our ability to explore alternative splicing at single cell and spatial resolution. The higher sequencing error of long reads, especially high indel rates, have limited the accuracy of cell barcode and unique molecular identifier (UMI) recovery. Read truncation and mapping errors, the latter exacerbated by the higher sequencing error rates, can cause the false detection of spurious new isoforms. Downstream, there is yet no rigorous statistical framework to quantify splicing variation within and between cells/spots. In light of these challenges, we developed Longcell, a statistical framework and computational pipeline for accurate isoform quantification for single cell and spatial spot barcoded long read sequencing data. Longcell performs computationally efficient cell/spot barcode extraction, UMI recovery, and UMI-based truncation- and mapping-error correction. Through a statistical model that accounts for varying read coverage across cells/spots, Longcell rigorously quantifies the level of inter-cell/spot versus intra-cell/ spot diversity in exon-usage and detects changes in splicing distributions between cell populations. Applying Longcell to single cell long-read data from multiple contexts, we found that intra-cell splicing heterogeneity, where multiple isoforms co-exist within the same cell, is ubiquitous for highly expressed genes. On matched single cell and Visium long read sequencing for a tissue of colorectal cancer metastasis to the liver, Longcell found concordant signals between the two data modalities. Finally, on a perturbation experiment for 9 splicing factors, Longcell identified regulatory targets that are validated by targeted sequencing.
The effects of inversion polymorphisms on patterns of neutral genetic diversity
Authors: Charlesworth Brian
Published: February 2023

The strong reduction in the frequency of recombination in heterozygotes for an inversion and a standard gene arrangement causes the arrangements to become partially isolated genetically, resulting in sequence divergence between them and changes in the levels of neutral variability at nucleotide sites within each arrangement class. Previous theoretical studies on the effects of inversions on neutral variability have either assumed that the population is panmictic or that it is divided into two populations subject to divergent selection. Here, the theory is extended to a model of an arbitrary number of demes connected by migration, using a finite island model with the inversion present at the same frequency in all demes. Recursion relations for mean pairwise coalescent times are used to obtain simple approximate expressions for diversity and divergence statistics for an inversion polymorphism at equilibrium under recombination and drift, and for the approach to equilibrium following the sweep of an inversion to a stable intermediate frequency. The effects of an inversion polymorphism on patterns of linkage disequilibrium are also examined. The reduction in effective recombination rate caused by population subdivision can have significant effects on these statistics. The theoretical results are discussed in relation to population genomic data on inversion polymorphisms, with an emphasis onDrosophila melanogaster. Methods are proposed for testing whether or not inversions are close to recombination-drift equilibrium, and for estimating the rate of recombinational exchange in heterozygotes for inversions; difficulties involved in estimating the ages of inversions are also discussed.
Polarimetric response of second harmonic generation in microscopy of chiral fibrillar structures
Authors: Alizadeh Mehdi , Habach Fayez , Maciulis Mykolas , Kontenis Lukas , Bagdonas Saulius , Krouglov Serguei , Baranauskas Vytautas , Bulotiene Danute , Karabanovas Vitalijus , Rotomskis Ricardas , Akens Margarete K. , Barzda Virginijus
Published: February 2023

Polarimetric second harmonic generation (SHG) microscopy is employed to study partially oriented fibrillar structures. The polarimetric SHG parameters are influenced by three-dimensional (3D) configuration of C6symmetry fibrilar structures in the focal volume (voxel) of a microscope. The achiral and chiral susceptibility tensor components ratios (R and C, respectively) are extracted from the linear polarization-in polarization-out (PIPO) measurements. The analytical derivations along with the polarimetric SHG microscopy results obtained from rat tail tendon, rabbit cornea, pig cartilage and meso-tetra (4-sulfonatophenyl) porphine (TPPS4) cylindrical aggregates demonstrate that SHG intensity is affected by parallel/antiparallel arrangements of the fibers, and R and C ratio values change by tilting the fibers out of image plane, as well as by crossing the fibers in 2D and 3D. The polarimetric microscopy results are consistent with the digital microscopy modeling of fibrillar structures. These results facilitate the interpretation of polarimetric SHG microscopy images in terms of 3D organization of fibrilar structures in each voxel of the samples.

Statement of Significance

Polarimetric second harmonic generation (SHG) microscopy is used to study partially oriented C6symmetry chiral fibrillar structures. The linear polarization-in polarization-out (PIPO) SHG imaging is performed on rat tail tendon, rabbit cornea, pig cartilage tissues and meso-tetra (4-sulfonatophenyl) porphine (TPPS4) cylindrical aggregates. The study demonstrates that SHG intensity is affected by parallel/antiparallel arrangements of the fibers, and the achiral and chiral susceptibility component ratio values change by tilting the fibers out of image plane, as well as by crossing the fibers in 2D and 3D. The polarimetric microscopy results are consistent with the digital microscopy modeling of fibrillar structures. These results facilitate the interpretation of polarimetric SHG microscopy images in terms of 3D organization of fibrillar structures in each voxel of the samples.
Synthetic Cooling Agent in Oral Nicotine Pouch Products Marketed as “Flavor-Ban Approved”
Authors: Jabba Sairam V. , Erythropel Hanno C , Woodrow Jackson G. , Anastas Paul T , O’Malley Stephanie S. , Krishnan-Sarin Suchitra , Zimmerman Julie B , Jordt Sven E.
Published: February 2023

Background

US sales of oral nicotine pouches (ONPs) have rapidly increased, with cool/mint-flavored ONPs the most popular. Restrictions on sales of flavored tobacco products have either been implemented or proposed by several US states and localities. Zyn, the most popular ONP brand, is marketing Zyn-”Chill” and Zyn-”Smooth” as “Flavor-Ban Approved”, probably to evade flavor bans. At present it is unclear whether these ONPs are indeed free of flavor additives that can impart pleasant sensations such as cooling.

Methods

Sensory cooling and irritant activities of “Flavor-Ban Approved” ONPs, Zyn-”Chill” and “Smooth”, along with “minty” varieties (Cool Mint, Peppermint, Spearmint, Menthol), were analyzed by Ca2+ microfluorimetry in HEK293 cells expressing the cold/menthol (TRPM8) or menthol/irritant receptor (TRPA1). Flavor chemical content of these ONPs was analyzed by GC/MS.

Results

Zyn-”Chill” ONP extracts robustly activated TRPM8, with much higher efficacy (39-53%) than the mint-flavored ONPs. In contrast, mint-flavored ONP extracts elicited stronger TRPA1 irritant receptor responses than Zyn-”Chill” extracts. Chemical analysis demonstrated the presence of WS-3, an odorless synthetic cooling agent, in Zyn-”Chill” and several other mint-flavored Zyn-ONPs

Conclusions

Synthetic cooling agents such as WS-3 found in ‘Flavor-Ban Approved’ Zyn-“Chill” can provide a robust cooling sensation with reduced sensory irritancy, thereby increasing product appeal and use. The label “Flavor-Ban Approved” is misleading and may implicate health benefits. Regulators need to develop effective strategies for the control of odorless sensory additives used by the industry to bypass flavor bans.
SEG: Segmentation Evaluation in absence of Ground truth labels
Authors: Sims Zachary , Strgar Luke , Thirumalaisamy Dharani , Heussner Robert , Thibault Guillaume , Chang Young Hwan
Published: February 2023

Identifying individual cells or nuclei is often the first step in the analysis of multiplex tissue imaging (MTI) data. Recent efforts to produce plug-and-play, end-to-end MTI analysis tools such as MCMICRO1– though groundbreaking in their usability and extensibility – are often unable to provide users guidance regarding the most appropriate models for their segmentation task among an endless proliferation of novel segmentation methods. Unfortunately, evaluating segmentation results on a user’s dataset without ground truth labels is either purely subjective or eventually amounts to the task of performing the original, time-intensive annotation. As a consequence, researchers rely on models pre-trained on other large datasets for their unique tasks. Here, we propose a methodological approach for evaluating MTI nuclei segmentation methods in absence of ground truth labels by scoring relatively to a larger ensemble of segmentations. To avoid potential sensitivity to collective bias from the ensemble approach, we refine the ensemble via weighted average across segmentation methods, which we derive from a systematic model ablation study. First, we demonstrate a proof-of-concept and the feasibility of the proposed approach to evaluate segmentation performance in a small dataset with ground truth annotation. To validate the ensemble and demonstrate the importance of our method-specific weighting, we compare the ensemble’s detection and pixel-level predictions – derived without supervision - with the data’s ground truth labels. Second, we apply the methodology to an unlabeled larger tissue microarray (TMA) dataset, which includes a diverse set of breast cancer phenotypes, and provides decision guidelines for the general user to more easily choose the most suitable segmentation methods for their own dataset by systematically evaluating the performance of individual segmentation approaches in the entire dataset.
Interplay between pollution and avian influenza virus in shorebirds and waterfowl
Authors: Ross Tobias A. , Zhang Junjie , Wille Michelle , Asimakopoulos Alexandros G. , Jaspers Veerle L. B. , Klaassen Marcel
Published: February 2023

Anthropogenic pollution may disrupt wildlife immune function and increase susceptibility to, and ability to withstand, infection. Of particular concern is avian influenza virus (AIV), which in its low-pathogenic form is endemic in many wild bird populations, notably waterfowl and shorebirds, and in its high-pathogenic form poses a threat to wildlife, livestock and people. Many pollutants have immunomodulative properties, yet little is known about how these pollutants affect AIV infection risk specifically. We examined concentrations of known immunomodulatory compounds, per- and polyfluoroalkyl substances (PFASs), and assessed their influence on AIV infection in three reservoir species, red-necked stint (Calidris ruficollis, n=121), pacific black duck (Anas superciliosa, n=57) and grey teal (Anas gracilis, n= 62). Using data on viral prevalence (cloacal/oropharyngeal swabs) and seroprevalence (AIV anti-nucleoprotein antibodies), we found no significant effect of PFASs pollution (total PFASs <0.01 – 470 ng/g in red-necked stint, <0.01 – 600 ng/g in pacific black duck and 0.3 – 200 ng/g in grey teal) on infection status in our three species. This may be due to relatively low pollutant concentrations, but we cannot rule out possible population culling through a synergy of pollution and infection stressors. We therefore recommend further studies on infection incidence in more polluted populations or species.
Exercise alters cortico-basal ganglia network functional connectivity: A mesoscopic level analysis informed by anatomic parcellation defined in the mouse brain connectome
Authors: Wang Zhuo , Donahue Erin K. , Guo Yumei , Renteln Michael , Petzinger Giselle M. , Jakowec Michael W. , Holschneider Daniel P.
Published: February 2023

The basal ganglia are important modulators of the cognitive and motor benefits of exercise. However, the neural networks underlying these benefits remain poorly understood. Our study systematically analyzed exercise-associated changes in functional connectivity in the cortico-basal ganglia-thalamic network during the performance of a new motor task, with regions-of-interest defined based on mesoscopic domains recently defined in the mouse brain structural connectome. Mice were trained on a motorized treadmill for six weeks or remained sedentary (control), thereafter undergoing [14C]-2-deoxyglucose metabolic brain mapping during wheel walking. Regional cerebral glucose uptake (rCGU) was analyzed in 3-dimensional brains reconstructed from autoradiographic brain sections using statistical parametric mapping. Functional connectivity was assessed by inter-regional correlation of rCGU. Compared to controls, exercised animals showed broad decreases in rCGU in motor areas, but increases in limbic areas, as well as the visual and association cortices. In addition, exercised animals showed (i) increased positive connectivity within and between the motor cortex and caudoputamen (CP), (ii) newly emerged negative connectivity of the substantia nigra pars reticulata with the globus pallidus externus, and CP, and (iii) reduced functional connectivity of the prefrontal cortex (PFC). Increased functional connectivity in the motor circuit in the absence of increases in rCGU strongly suggests greater network efficiency, which is also supported by the reduced involvement of PFC-mediated cognitive control during the performance of a new motor task. Our study delineates exercise-associated changes in functional circuitry at the subregional level and provides a framework for understanding the effects of exercise on new motor learning.
Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines
Authors: Dostálová Hana , Jorda Radek , Řezníčková Eva , Kryštof Vladimír
Published: February 2023

Small molecule Bruton’s tyrosine kinase (BTK) inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitors for anticancer therapy in 2013. Previous reports proved the receptor kinase human epidermal growth factor receptor 2 (HER2) to be a valid off-target kinase of ibrutinib and potentially other irreversible BTK inhibitors, as it possesses a druggable cysteine residue in the active site of the enzyme. These findings suggest ibrutinib as a candidate drug for repositioning in HER2-positive breast cancer (BCa). This subtype of breast cancer belongs to one of the most common classes of breast tumours, and its prognosis is characterized by a high rate of recurrence and tumour invasiveness. Based on their similar kinase selectivity profiles, we investigated the anticancer effect of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and sought to determine whether it is linked with targeting the epidermal growth factor receptor family (ERBB) pathway. We found that zanubrutinib is a potential inhibitor of the HER2 signalling pathway, displaying an antiproliferative effect in HER2-positive BCa cell lines. Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours.
Epigenetic regulation of innate immune genes and enhanced interleukin-10 expression underlie chronic subclinicalPlasmodium chabaudiinfection
Authors: de Souza Silva Leandro , Nguyen Yen Anh H. , Monks Brian G. , Forconi Catherine S. , Crabtree Juliet N. , Rodriguez Tomás , De Paula Tamburro Nelsy , Sontheimer Erik J. , Horvath Gabor L. , Abdullah Zeinab , Latz Eicke , Caffrey Daniel R. , Kurt-Jones Evelyn A. , Gazzinelli Ricardo T. , Fitzgerald Katherine A. , Golenbock Douglas T.
Published: February 2023

Subclinical (asymptomatic) parasitemia is very common amongstPlasmodium-infected individuals. The immunological mechanisms underlying subclinical parasitemia remain elusive. We investigated the immune regulatory mechanisms behind chronic asymptomaticPlasmodiuminfection using mice lacking humoral immunity (µMT−/−mice). µMT−/−mice became chronically infected, despite lacking outward signs of disease, and exhibited increased macrophage numbers, decreased dendritic and CD4 cells, massive hemozoin accumulation in the spleen and bone marrow, and inadequate hematopoiesis. These changes were accompanied by high circulating levels of interleukin-10 (IL-10), enhanced chromatin accessibility of the STAT3 promoter, and enhanced STAT3 binding to the IL-10 promoter in macrophages. Inhibition of IL-10 signaling, despite promoting parasite clearance, resulted in a proinflammatory response, weight loss, and mortality. These results suggest that epigenetic changes induced by chronicP. chabaudiinfection lead to high levels of circulating IL-10, protecting chronically infected mice against an excessive inflammatory response to high levels of blood-stage parasites.

Author summary

Malaria is a life-threatening disease with a range of symptoms, and it is induced in humans by infections with different species ofPlasmodium. Highly prevalent in endemic regions, asymptomaticPlasmodiuminfections are related to long-term exposure to the parasite due to multiple infections and have been demonstrated in human and mouse studies to be associated with elevated levels of IL-10. However, how IL-10 levels remain elevated in the circulation in individuals over the long term has not been determined. We used a mouse model of chronic asymptomaticPlasmodiuminfection to investigate the mechanisms by which IL-10 levels are elevated during chronic asymptomatic infection. Our results show that epigenetic changes in immune genes of myeloid origin could be responsible for the elevated levels of IL-10, and that IL-10 signaling protected chronically infected mice from a severe inflammatory response induced by the infection.
Not only age affects cardiovascular parameters, salivary biomarkers, and their correlation, but the level of physical conditioning changes this behavior in the elderly
Authors: Venâncio de Camargos Phabloo José de , Justino Allisson Benatti , Oliveira Gonçalves Luis Carlos , de Barros Rafael Joviano Souza , Sordi Bortolini Miguel Junior , Espindola Foued Salmen , de Magalhães Neto Aníbal Monteiro
Published: February 2023

To compare the physical conditioning, hemodynamic, and salivary biomarkers between elderly athletes and the physically active elderly. 14 men: EA (n = 8) and PAE (n = 6). Collection times (T0; TE; T5; T15). A negative correlation was found between SF and cardiovascular parameters, BL, and STP in both groups, but this was almost double among PAE. For HR and SBP, there was a faster recovery in EA. The EA increase was correlated with SBP, while for PAE it was correlated with HR. BL showed an increase in TE, reaching 481% in EA and 639% in PAE. SNO showed a similar increase for the groups at the TE, but at T5, while EA already showed a reduction, PAE saw a 94% increase, with a slower decay for this group at T15. The SF presented the negative Δ% was almost double in PAE, with a quick recovery already at T5 for EA and levels still negative at all times for PAE. For SIgA-s, there was an increase of 37% in EA and only 7% at the TE in PAE; 41% in EA and 15% in PAE for T5; and 26% in EA and 14% in PAE at T15. SA showed a higher peak in EA (TE) and less acute in PAE (T5) but there was a decrease among both at T15. STP increased by 126% in EA and 438% in PAE, already showing a return at T5 for EA, but increasing by 213% in PAE. Negative levels were reached at T15 for EA but levels remained high in PAE. Levels of physical conditioning affect cardiovascular parameters, salivary biomarkers, and their correlation within the over-60s.
Between consultation and control: how incubators perform a governance function for entrepreneurial firms
Authors: Flanschger Andreas , Heinzelmann Rafael , Messner Martin
Published: February 2023

Purpose

This paper examines the governance function that incubators perform for entrepreneurial firms. The authors demonstrate that this governance function has both a consultative and a control dimension and illustrate how these are enacted in the interactions between incubators and entrepreneurs. The authors also show how these interactions come into being and how entrepreneurs assess the value of the governance role played by incubators.

Design/methodology/approach

The paper is based on a cross-sectional interview study with entrepreneurs of 21 start-ups that were hosted by three different incubators. The start-ups are all early-stage technology firms. The analysis in the paper follows an inductive approach.

Findings

The authors find that the governance role of incubators is about both consultation and control. Consultative forms of governance include providing input and advice as well as questioning ideas and assumptions. Controlling forms of governance comprise setting targets and tracking progress as well as enforcing structures and documentation. The authors furthermore show that governance episodes are triggered either by the entrepreneurs themselves or by the incubator. In the former case, such episodes are mainly about consultation, while in the latter one, they often have a pronounced control element, which materializes particularly through regularly enforced meetings. Most entrepreneurs seem to appreciate this control element, acknowledging that, in its absence, they would lack the self-discipline of doing some things that need to be done.

Research limitations/implications

This study’s findings extend prior research on inter-organizational relationships and the types of governance mechanisms observed therein. The authors show that a strict separation between actors who offer consultation and those who exercise control is too simplistic. Incubators influence entrepreneurial firms both through consultative and controlling forms of governance. In terms of limitations, this study’s analysis focuses on the perspectives of entrepreneurs, and the authors did not include the perspectives of incubators nor did the authors directly observe meetings between these two parties.

Practical implications

This paper provides examples for how entrepreneurial firms can benefit from being part of an incubator.

Originality/value

This study contributes to the discussion of the governance of inter-organizational relationships by focusing on incubators. In so doing, the authors also complement extant literature on management control in entrepreneurial settings by showing how the incubator fulfills a control function for entrepreneurs before these implement control mechanisms themselves.
Innovation and SMEs performance: evidence from Vietnam
Authors: Le Danh Vinh , Le Huong Thi Thu , Pham Thanh Tien , Vo Lai Van
Published: February 2023

Purpose

The purpose of this paper is to examine the effect of innovation on the performance of small and medium-sized enterprises (SMEs) in Vietnam.

Design/methodology/approach

The paper uses data from the surveys on SMEs in Vietnam conducted by the Development Economics Research Group at the University of Copenhagen, the United Nations University’s World Institute for Development Economics Research, Central Institute for Economic Management and Institute of Labor Science and Social Affairs, and applies least squared regressions and 2SLS regressions to examine the effect of innovation on the performance of SMEs.

Findings

The authors find that SMEs with innovation tend to perform better than SMEs without innovation. The authors further show that the positive effect of innovation on firm performance mainly comes from the effect of improvement of existing products, an important type of innovation in SMEs. This result is persistent when the authors use propensity matching score and 2SLS regression with instrumental variable approaches. Overall, the results show the important role of innovation in enhancing the firm performance of SMEs, which sheds light on the literature on the controversial relation between innovation and SMEs performance in the world.

Research limitations/implications

The major limitation of the paper is the lack of data. Although the database used in the paper is widely used to analyze SMEs in Vietnam, it covers about 2,500 firms in only nine provinces/cities in Vietnam.

Practical implications

Policymakers should enact relevant policies to support SMEs with innovation activities, thereby increasing firm performance and their competitiveness. For instance, encouragement policies or financial incentives (tax reduction or subsidies) for innovative firms should be implemented and/or fostered.

Originality/value

To the best of the authors’ knowledge, this is the first paper to examine the effect of different types of innovation on the performance of SMEs in Vietnam.
Reliability assessment of grid-connected multi-inverter for renewable power generation sector
Authors: Abed Mohammed Jawad , Mhalla Anis
Published: February 2023

Purpose

The paper aims to present a grid-connected multi-inverter for solar photovoltaic (PV) systems to enhance reliability indices after selected the placement and level of PV solar.

Design/methodology/approach

In this study, the associated probability is calculated based on the solar power generation capacity levels and outages conditions. Then, based on this probability, dependability indices like average energy not supplied (AENS), expected energy not supplied and loss of load expectations (LOLE) are computed, also, another indices have been computed such as (customer average interruption duration index (CAIDI), system average interruption frequency index (SAIFI) and system average interruption duration index (SAIDI)) addressing by affected customers with distribution networks reliability assessment, including PV. On the basis of their dependability indices and active power flow, several PV solar modules installed in several places are analyzed. A mechanism for assessing the performance of the grid's integration of renewable energy sources is also under investigation.

Findings

The findings of this study based on data extracted form a PV power plant connected to the power network system in Diyala, Iraq 132 kV, attempts to identify the system's weakest points in order to improve the system's overall dependability. In addition, enhanced reliability indices are given for measuring solar PV systems performance connected to the grid and reviewed for the benefit of the customers.

Originality/value

The main contributions of this study are two methods for determining the reliability of PV generators taking into consideration the system component failure rates and the power electronic component defect rates in a PV system which depend on the power input and the power loss using electrical transient analysis program (ETAP) program.
Optimal error estimates of a linearized second-order BDF scheme for a nonlocal parabolic problem
Authors: Daoussa Haggar M.S. , Mbehou M.
Published: February 2023

Purpose

This paper focuses on the unconditionally optimal error estimates of a linearized second-order scheme for a nonlocal nonlinear parabolic problem. The first step of the scheme is based on Crank–Nicholson method while the second step is the second-order BDF method.

Design/methodology/approach

A rigorous error analysis is done, and optimal L2 error estimates are derived using the error splitting technique. Some numerical simulations are presented to confirm the study’s theoretical analysis.

Findings

Optimal L2 error estimates and energy norm.

Originality/value

The goal of this research article is to present and establish the unconditionally optimal error estimates of a linearized second-order BDF finite element scheme for the reaction-diffusion problem. An optimal error estimate for the proposed methods is derived by using the temporal-spatial error splitting techniques, which split the error between the exact solution and the numerical solution into two parts, that is, the temporal error and the spatial error. Since the spatial error is not dependent on the time step, the boundedness of the numerical solution in L∞-norm follows an inverse inequality immediately without any restriction on the grid mesh.