bluuebunny/crossref_metadata_2025_split huggingface dataset:
Group BStreptococcusCas9 variants provide insight into programmable gene repression and CRISPR-Cas transcriptional effects
Authors: Gopalakrishna Kathyayini P , Hillebrand Gideon H , Bhavana Venkata H , Elder Jordan L , D’Mello Adonis , Tettelin Hervé , Hooven Thomas A 
Published: May 2023

AbstractGroup BStreptococcus(GBS;S. agalactiae) causes chorioamnionitis, neonatal sepsis, and can also cause disease in healthy or immunocompromised adults. GBS possesses a type II-A CRISPR-Cas9 system, which defends against foreign DNA within the bacterial cell. Several recent publications have shown that GBS Cas9 influences genome-wide transcription through a mechanism uncoupled from its function as a specific, RNA-programmable endonuclease. We examine GBS Cas9 effects on genome-wide transcription through generation of several isogenic variants with specific functional defects. We compare whole-genome RNA-seq from Δcas9GBS with a full-length Cas9 gene deletion;dcas9defective in its ability to cleave DNA but still able to bind to frequently occurring protospacer adjacent motifs; andscas9that retains its catalytic domains but is unable to bind protospacer adjacent motifs. Comparingscas9GBS to the other variants, we identify nonspecific protospacer adjacent motif binding as a driver of genome-wide, Cas9 transcriptional effects in GBS. We also show that Cas9 transcriptional effects from nonspecific scanning tend to influence genes involved in bacterial defense and nucleotide or carbohydrate transport and metabolism. While genome-wide transcription effects are detectable by analysis of next-generation sequencing, they do not result in virulence changes in a mouse model of sepsis. We also demonstrate that catalytically inactive dCas9 expressed from the GBS chromosome can be used with a straightforward, plasmid-based, single guide RNA expression system to suppress transcription of specific GBS genes without potentially confounding off-target effects. We anticipate that this system will be useful for study of nonessential and essential gene roles in GBS physiology and pathogenesis.
Modelling the effect of matrix metalloproteinases in dermal wound healing
Authors: Dari Sonia , Fadai Nabil T. , O’Dea Reuben D. 
Published: May 2023

AbstractWith over 2 million people in the UK suffering from chronic wounds, understanding the biochemistry and pharmacology that underpins these wounds and wound healing is of high importance. Chronic wounds are characterised by high levels of matrix metalloproteinases (MMPs), which are necessary for the modification of healthy tissue in the healing process. Overexposure of MMPs, however, adversely affects healing of the wound by causing further destruction of the surrounding extracellular matrix. In this work, we propose a mathematical model that focuses on the interaction of MMPs with dermal cells using a system of partial differential equations. Using biologically realistic parameter values, this model gives rise to travelling waves corresponding to a front of healthy cells invading a wound. From the arising travelling wave analysis, we observe that deregulated apoptosis results in the emergence of chronic wounds, characterised by elevated MMP concentrations. We also observe hysteresis effects when both the apoptotic rate and MMP production rate are varied, providing further insight into the management (and potential reversal) of chronic wounds.
RAPSYN-Mediated Neddylation of BCR-ABL Alternatively Determines the Fate of Philadelphia Chromosome-positive Leukemia
Authors: Zhao Mengya , Dai Beiying , Li Xiaodong , Zhang Yixin , Qiao Chun , Qin Yaru , Li Zhao , Li Qingmei , Wang Shuzhen , Yang Yong , Chen Yijun 
Published: May 2023

AbstractPhiladelphia chromosome-positive (Ph+) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKI) have achieved remarkable success in prolonging patient survival, intolerance, relapse and TKI resistance remain serious issues for patients with Ph+leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph+leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast toin vivoineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph+leukemia.
Neural correlates of object identity and reward outcome in the corticohippocampal hierarchy: double dissociation between perirhinal and secondary visual cortex
Authors: Fiorilli J. , Marchesi P. , Ruikes T. , Huis in ‘t Veld G. , Buckton R. , Duque Quintero M. , Reiten I. , Bjaalie J. , Pennartz C.M.A. 
Published: May 2023

AbstractNeural circuits support behavioral adaptations by integrating sensory and motor information with reward and error-driven learning signals, but it remains poorly understood how these signals are distributed across different levels of the corticohippocampal hierarchy. We trained rats on a multisensory object-recognition task and compared visual and tactile responses of simultaneously recorded neuronal ensembles in somatosensory cortex, secondary visual cortex, perirhinal cortex and hippocampus. The sensory regions primarily represented unisensory information, while hippocampus was modulated by both vision and touch. Surprisingly, secondary visual cortex but not perirhinal neurons coded object-specific information, whereas perirhinal but not visual cortical neurons signaled trial outcome. A majority of outcome-related perirhinal cells responded to a negative outcome (reward omission), whereas a minority of other cells coded positive outcome (reward delivery). Our results support a distributed neural coding of multisensory variables in the cortico-hippocampal hierarchy, with a double dissociation between higher visual cortex and perirhinal cortex in coding of object identity versus feedback on trial outcome.
IL-36/IL-36R Signaling Promotes CD4+ T Cell-Dependent Colitis via Pro-Inflammatory Cytokine Production
Authors: Maarouf Maya , Kuczma Michal , Denning Timothy L. 
Published: May 2023

AbstractInflammatory bowel disease (IBD) is a multifactorial, chronic disease that affects approximately 1.5 million people in the United States [1]. It presents with inflammation of the intestine with unknown etiology and its two main forms are Crohn’s disease (CD) and ulcerative colitis (UC). Several important factors are implicated in the pathogenesis of IBD, one being dysregulation of the immune system resulting in the accumulation and stimulation of innate and adaptive immune cells and subsequent release of soluble factors, including pro-inflammatory cytokines. One of these cytokines is a member of the IL-36 cytokine family, IL-36γ, which is overexpressed in human IBD and experimental mouse models of colitis. In this study, we explored the role of IL-36γ in promoting CD4+T cell activation and cytokine secretion. We found that IL-36γ stimulation of naïve CD4+T cells significantly induced IFNγ expressionin vitroand was associated with augmented intestinal inflammationin vivousing naive CD4+cell transfer model of colitis. Using IFNγ-/- CD4+cells, we observed a dramatic decrease in the ability of TNFα production and delayed colitis. This data not only suggests that IL-36γ is a master regulator of a pro-inflammatory cytokine network involving IFNγ and TNFα, but also highlights the importance of targeting IL-36γ and IFNγ as therapeutic approaches. Our studies have broad implications in relation to targeting specific cytokines in human IBD.
The novel spore-specific regulator SscA governsAspergillusconidiogenesis
Authors: Son Ye-Eun , Yu Jae-Hyuk , Park Hee-Soo 
Published: May 2023

AbstractA major group of fungi produces asexual spores (conidia) for propagation and infection. Despite the critical role of conidia, the underlying mechanism of spore formation, integrity, and viability is not fully elucidated. In this study, we have identified and investigated the role of the spore-specific transcription factor (TF) SscA in three representativeAspergillusspecies. Comparative transcriptomic analyses have revealed that 25 TF encoding genes showed higher mRNA levels in conidia than in hyphae in three species. Functional and transcriptomic analyses of the 25 genes have identified SscA as a key TF for conidial formation, maturation, germination, integrity, amino acid production, and secondary metabolism inAspergillus nidulansconidia. Importantly, the roles of SscA are conserved in otherAspergillusspecies. Altogether, our study demonstrates that SscA is a novel spore-specific TF that governs production of intact and functional conidial formation inAspergillusspecies.ImportanceFilamentous fungi produce myriads of asexual spores are main reproductive particles and act as infectious or allergenic agents. Although the serial of asexual sporogenesis is coordinated by various genetic regulators, there remain uncharacterized transcription factors inAspergillus. To understand the underlying mechanism of spore formation, integrity, and viability, we have performed comparative transcriptomic analyses on three representativeAspergillusspecies and found a novel spore-specific transcription factor, SscA. SscA has a major role in conidial formation, maturation and dormancy, and germination inAspergillus nidulans. Transcriptomic data indicate that SscA coordinates conidial wall integrity, amino acid production, and secondary metabolism inA. nidulansconidia. Furthermore, the roles of SscA are conserved in otherAspergillusspecies. Our findings that the novel SscA has broad functions inAspergillusconidia will help to understand conidiogenesis ofAspergillusspecies.
Single Cell Spatial Analysis and Biomarker Discovery in Hodgkin Lymphoma
Authors: Xu Alexander M , Jiang Aixiang , Aoki Tomohiro , Gamboa Alicia , Chong Lauren , Colombo Anthony , Yin Yifan , Lownik Joseph , Takata Katsuyoshi , Hav Monirath , Steidl Christian , Merchant Akil 
Published: May 2023

ABSTRACTThe biology of tumors is suffused with spatial interactions, such as tumor-immune signaling through localized cytokine/ligand secretion, cell-cell contacts, and checkpoint ligand/receptor signaling. Hodgkin Lymphoma (HL) can serve as a study paradigm for tumor microenvironment (TME) architecture as the defining pathological feature is the scarcity of the malignant Hodgkin and Reed Sternberg (HRS) cells, leaving a diverse and predominantly immune cell rich tumor microenvironment (TME) with complex tumor-immune interactions. Previous studies have identified TME features that are prognostic and predictive, however these studies did not consider the entirety of TME cellular ecosystems, including precisely defined immune cell subsets with opposing inflammatory and immune-suppressive effects, as a determinant for differential clinical course of HL patients. Here we use Imaging Mass Cytometry (IMC) with 42 antibody markers to profile tumors from 93 patients with HL. Our cohort consists of relapsed/refractory HL with matched diagnostic and relapsed biopsies, and we present a bioinformatic pipeline to profile 10 major cell lineages and their subtypes including spatial interaction mapping. Our pipeline identifies putative biomarker candidates with a focus on “rosettes” – local aggregates of immune cells around single tumor cells. In addition to validating existing biomarkers centered on CD68+ macrophages, GranzymeB+CD8+ T cells, and others in HL, we propose new biomarkers based on localized interactions between HRS cells and aggregating CD4+ and CD8+ T cells and macrophages involving the immune checkpoints PD1/PDL1, LAG3, and Galectin9. This study serves as a broad tissue imaging resource for multi-timepoint biopsies in HL, and a computational resource and pipeline for users of IMC and other multiplexed imaging studies to perform tissue analysis and biomarker candidate testing with any tissue type.
A mechanistically novel peptide agonist of the IL-7 receptor that addresses limitations of IL-7 cytokine therapy
Authors: Dower William J. , Park Angie Inkyung , Bakker Alice V. , Cwirla Steven E. , Pongtornpipat Praechompoo , Williams Blake M. , Joshi Prarthana , Baxter Bryan A. , Needels Michael C. , Barrett Ronald W. 
Published: May 2023

AbstractInterleukin (IL)-7 is broadly active on T-cell populations, and modified versions have been clinically evaluated for a variety of therapeutic applications, including cancer, lymphopenia and infectious diseases; and found to be relatively well-tolerated and biologically active. Here we describe novel IL-7R agonists that are unrelated in structure to IL-7, bind to the receptor subunits differently from IL-7, but closely emulate IL-7 biology. The small size, low structural complexity, and the natural amino acid composition of the pharmacologically active peptide MDK1472 allows facile incorporation into protein structures, such as the IgG2-Fc fusion MDK-703. This molecule possesses properties potentially better suited to therapeutic applications than native IL-7 or its derivatives. We compared these compounds with IL-7 for immune cell selectivity, induction of IL-7R signaling, receptor-mediated internalization, proliferation, and generation of immune cell phenotypes in human and non-human primate (NHP) peripheral blood cells in vitro; and found them to be similar in biological activity to IL-7.In cynomolgus macaques, MDK-703 exhibits a circulating half-life of 46 hr, and produces sustained T-cell expansion characteristic of IL-7 treatment. In the huCD34+-engrafted NSG mouse model of the human immune system, MDK-703 induces an immune cell profile very similar to that generated by IL-7-derived compounds; including the pronounced expansion of memory T-cells, particularly the population of stem-like memory T-cells (Tscm), which may be important for anti-tumor activities reported with IL-7 treatment.Clinical administration of IL-7 and modified variants has been reported to induce anti-drug antibodies (ADAs), including IL-7 neutralizing antibodies. The novel peptide agonist reported here scores very low in predicted immunogenicity, and because the peptide lacks sequence similarity with IL-7, the problematic immunogenic neutralization of endogenous cytokine should not occur.
Primacy of vision shapes behavioral strategies and neural substrates of spatial navigation in the hippocampus of the common marmoset
Authors: Piza Diego B. , Corrigan Benjamin W. , Gulli Roberto A. , Carmo Sonia Do , Cuello A. Claudio , Muller Lyle , Martinez-Trujillo Julio 
Published: May 2023

AbstractThe mammalian hippocampus has been compared to a Global Positioning System (GPS) that enables spatial navigation. This notion has been primarily drawn from studies conducted in nocturnal mammals, such as rats; that lack many adaptations to daylight vision compared to diurnal primates. Here we demonstrate that during foraging in a 3D maze, the common marmoset, a new world diurnal primate with foveal, stereo-color vision, predominantly uses rapid head-gaze shifts to visually explore their surroundings while remaining stationary, and then minimizes head movements to navigate towards goals. On the other hand, rats, mainly move their head at low velocities while locomoting to explore the environment using their whiskers. These differences in exploration-navigation strategies reflect the species’ sensory adaptations to different ecological niches. In the marmoset hippocampus CA3/CA1 regions putative pyramidal neurons show selectivity for 3D view, head direction, and less for place, but mainly mixed selectivity for combinations of these variables. Despite weak place selectivity, the spatial position of the animal in the maze can be decoded from the activity of small ensembles of mixed selective neurons. Inhibitory interneurons are tuned to 3D angular head velocity and translation speed, with most cells showing mixed selectivity for both variables. Finally, marmosets lack the rhythmic theta oscillations of local field potentials seen during locomotion in rats. Instead, they show resetting of theta oscillations triggered by head-gaze shifts that co-occurred with the activation of inhibitory interneurons, followed by various modulations in the activity of pyramidal cells. Our results show that the marmoset visual exploration/navigation strategies and the hippocampal neuronal specializations supporting them diverge from those observed in rats, reflecting the far-sensing capabilities of the marmoset visual system adapted to diurnal lifestyle.
Macrophage Receptor with collagenous structure (MARCO) recognizes the cellular protein corona formed on environmental particles
Authors: Hirano Seishiro , Kanno Sanae 
Published: May 2023

AbstractSeveral difficulties hamper the toxicological evaluation of particulate substancesin vitro. One of the most serious difficulties is that most particles are insoluble in water, and easily agglomerate during the assay. Albumin and some detergents have been used to disperse the particles in the culture medium. However, effects of these additives on the cellular uptake of particles and the following biological consequences are unknown. The first event when phagocytic cells encounter particulate substances is an association of the plasma membrane with the particle surface. Macrophage receptor with collagenous structure (MARCO) has been identified as a receptor for environmental particles such as titanium dioxide (TiO2) and carbonaceous particles. However, it remained to be revealed how MARCO recognizes the unopsonized particles. While investigating the particle surface-cell membrane interaction using GFP-tagged MARCO-expressing cells, we found that cytosolic proteins were released from the cells and rapidly adsorbed on the surface of TiO2particles. The GFP-tagged MARCO-overexpressing cells were further engineered to express RFP-tagged LC3 (cytosolic protein) to visualize adsorption of proteins on the surface of titanium dioxide (TiO2) particles. We found that cytosolic proteins including LC3 were released in the culture medium from intact cells and adsorbed on the particle surface quickly in the cell culture system. These results indicate that MARCO probably recognizes adsorbed intracellular proteins rather than the uncoated inorganic surface of environmental particles.
Genetic profiling andin silicosequence analysis ofCSN2(β-casein) andCSN3(κ-casein) genes in the indian buffalo (Bubalus bubalis)
Authors: Mehra Vinay Kumar , Kumar Satish 
Published: May 2023

AbstractBuffalo rank second for milk production in the world and play important role in Indian economy. There are four types of caseins α-S1-casein, α-S2-casein, β-casein and κ-casein in milk. The major function of the casein protein in milk is to chelate colloidal calcium phosphate and serves as a major source of amino acids, calcium and phosphate. In buffalo milk all four casein proteins (αs1, αs2, β and κ) are encoded by four closely linked autosomal genes (CSN1S1, CSN1S2, CSN2 and CSN3 respectively) that are present on chromosome 7. Bovine CSN2 (β-casein) gene is 8.5 kb long and contains nine exons and CSN3 (κ-casein) is ∼ 13 kb long. The aim of the study was to characterize CSN2 and CSN3 genes,In-silicoanalysis of β-casein and κ-casein protein and evolutionary relationship with other species. Buffalo mammary gland tissue was collected from local slaughterhouse (New Delhi, India) and total RNA was isolated from Buffalo Mammary Epithelial Cells. The ORF region of CSN2 and CSN3 genes were amplified and sequenced for characterization. Physiochemical properties showed that both buffalo β-casein (Bu_CSN2) and κ-casein (Bu_CSN3) proteins are stable and hydrophobic in nature.The presence of high phosphorylated residues in both β-casein and κ-casein proteins residues suggested that they are involved in signal transduction processes, cell growth and metabolism. The N-glycosylation result showed that both proteins are less in foldable state. The presence of methylation and acetylation sites in both protein revealed that they are involved in different cellular process. The evolutionary analysis showed that both buffalo genes more closely toBos grunniens (yak).
Vaccination withHelicobacter pyloriattachment proteins protects against gastric cancer
Authors: Bugaytsova Jeanna A. , Piddubnyi Artem , Tkachenko Iryna , Rakhimova Lena , Edlund Johan Olofsson , Thorell Kaisa , Marcotte Harold , Lundquist Anders , Schön Karin , Lycke Nils , Suerbaum Sebastian , Schulz Christian , Malfertheiner Peter , Hansen Lori M. , Solnick Jay V. , Moskalenko Roman , Hammarström Lennart , Borén Thomas 
Published: May 2023

SUMMARYMost cases of gastric cancer are caused by chronicHelicobacter pyloriinfection, but the lack of early onco-diagnostics and a high risk for antibiotic resistance hampers early intervention through eradication ofH. pyloriinfection by antibiotics. We reported on a protective mechanism whereH. pylorigastric mucosal attachment can be reduced by natural antibodies that block the binding of its attachment protein BabA. Here we show that challenge infection withH. pyloriinduced response of such blocking antibodies in both human volunteers and in rhesus macaques, that mucosal vaccination with BabA protein antigen induced blocking antibodies in rhesus macaques, and that vaccination in a mouse model induced blocking antibodies that reduced gastric mucosal inflammation, preserved the gastric juice acidity, and fully protected the mice from gastric cancer caused byH. pylori.
Combining Low toxic dose Tramadol and smoking is relatively safe unless you stop them: An Animal model evidence of Endoplasmic reticulum stress
Authors: Ghorab Doaa , Abuelrub Ejlal M. , Gharaibeh Mohamed Hamdi , Yehya Alaa , Khasawneh Ramada R , Matalgah Laila M , Helaly Ahmed Mohamed 
Published: May 2023

AbstractLow toxic doses of tramadol induced animal brain cortex apoptosis and hippocampus injury. Adding nicotine reverted hippocampus pathological changes without triggering brain injury. The expression of CHOP protein in real-time PCR showed mild Endoplasmic reticulum stress (ER) in rats’ brains. Histological, immunohistochemical, and western blotting analysis of CHOP and BIP chaperones demonstrated Endoplasmic reticulum stress in brain and liver tissue samples. Furthermore, the levels of apoptosis and autophagy markers demonstrated a mild increase. Adding Nicotine relatively decreasedbrain and liver ER stress. The combined profile was considerably protective in comparison to administering each drug separately. Mild ER stress is essential for normal cell functions. The blood level of serotonin was high in all study groups with a marked increase in its level when tramadol and nicotine were combined. Low toxic doses of tramadol in combination with nicotine were safe at the reproductive system level which was evaluated by histological examination and animal blood androgen assay. Generally, combining low-dose tramadol with smoking was found to be safe in various animal tissues and organs, however, the high serotonin level in the blood can be critical and associated with a high risk of serious withdrawal and pathological consequences. Serotonin receptor blockers such as olanzapine may increase systemic serotonin levels and need further investigation to utterly pinpoint their roles in managing mood disorders.