bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dogs and cats are less susceptible to the omicron variant of concern of SARS-CoV-2 – a field study
Authors: Klein Constantin , Michelitsch Anna , Allendorf Valerie , Conraths Franz Josef , Beer Martin , Denzin Nicolai , Wernike Kerstin 
Published: February 2023

SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic of unprecedented extent. Beside humans, a number of animal species can be infected, however, in some species differing susceptibilities were observed depending on the virus variant. Here, we serologically investigated cats and dogs living in households with human COVID-19 patients. The study was conducted during the transition period from delta as the dominating variant of concern (VOC) to omicron (BA.1/BA.2) to investigate the frequency of virus transmission of both VOCs from infected owners to their pets. The animal sera were tested by surrogate virus neutralization tests (sVNT) using either the original receptor-binding domain (RBD), enabling the detection of antibodies against the delta variant, or an omicron-specific RBD. Of the 290 canine samples, 20 tested positive by sVNT, but there were marked differences between the sampling time, and, related thereto, the virus variants, the dogs had contact to. While in November 2021 infected owners led to 50% seropositive dogs (18/36), only 0.8% (2/254) of animals with household contacts to SARS-CoV-2 between December 2021 and April 2022 tested positive. In all cases, the positive reaction was recorded against the original RBD. For cats, a similar pattern was seen, as in November 2021 38.1% (16/42) tested positive and between December 2021 and March 2022 only 5.0% (10/199). The markedly reduced ratio of seropositive animals during the period of omicron circulation suggests a considerably lower susceptibility of dogs and cats to this VOC.To examine the effect of BA.2, BA.4 and BA.5 omicron subvariants, sera taken in the second and third quarter of 2022 from randomly selected cats were investigated. 2.3% (11/372) tested seropositive and all of them showed a stronger reaction against the original RBD, further supporting the assumption of a lower susceptibility of companion animals to the omicron VOC.
Paclitaxel- and vincristine-induced neurotoxicity and drug transport in sensory neurons
Authors: Mortensen Christina , Chua Katherina C. , Hammer Helen S. , Nielsen Flemming , Pötz Oliver , Svenningsen Åsa Fex , Kroetz Deanna L. , Stage Tore Bjerregaard 
Published: February 2023

AbstractChemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and the lack of therapies for treatment and prevention. Patients with CIPN primarily present with sensory symptoms, such as sensory disturbances that may progress to neuropathic pain in hands and feet. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. We utilized a model of human sensory neurons derived from induced pluripotent stem cells (iPSC-SNs) to provide mechanistic understanding of CIPN caused by paclitaxel and vincristine. The morphological phenotype of iPSC-SNs following paclitaxel exposure was characterized by retraction and thickening of axons while vincristine caused fragmentation and abolishment of axons. Both agents increased the mRNA expression of the pain receptor, transient receptor potential vanilloid (TRPV1), and highly induced neuronal damage, as measured by activating transcription factor 3 (ATF3) mRNA. iPSC-SNs express the efflux transporters, P-glycoprotein (P-gp, encoded byABCB1) and multidrug resistance-associated protein 1 (MPR1, encoded byABCC1). Inhibition of P-gp and MRP1 in iPSC-SNs exacerbated neurotoxicity of paclitaxel and vincristine respectively. We further show that pre-treatment with the P-gp inducer rifampicin alleviated chemotherapy-induced structural and transcriptional alterations in iPSC-SNs. iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters play a critical role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system.
Avirulent ME49Δgra5Protecting Hosts AgainstToxoplasma gondiiInfection and Breast Tumors
Authors: Chen Min , Yang Pei , Xin Zixuan , Chen Jiating , Zou Weihao , Zhou Lijuan , Yang Lili , Peng Jiao , Peng Hongjuan 
Published: February 2023

AbstractToxoplasma gondiiis the causative agent of toxoplasmosis, a zoonotic disease that poses a threat to human health and a considerable loss to livestock farming. At present, clinical therapeutic drugs mainly targetT. gondiitachyzoites and fail to eradicate bradyzoites. Developing a safe and effective vaccine against toxoplasmosis is urgent and important.T. gondiipossesses dense granule organelles that secrete immunogenic dense granule proteins (GRAs). GRA5 localizes to the parasitophorous vacuole membrane (PVM) in the tachyzoite stage and to the cyst wall in the bradyzoite stage. Here we report thatgra5knockoutT. gondiistrain is avirulent and fails to form cysts, but stimulates sero-conversion in mice. We next investigated the protective efficacy of ME49Δgra5vaccination againstT. gondiiinfection. All the immunized mice survived the challenge infection with either wild-type RH, ME49, VEG tachyzoites or ME49 cysts. Remarkably, ME49Δgra5tachyzoites inoculationin situattenuated the growth of murine breast tumor (4T1) in mice and prevented 4T1’s lung metastasis. ME49Δgra5inoculation might upregulate the levels of Th1 cytokines and tumor-infiltrating T cells in tumor microenvironment (TME) and trigger anti-tumor responses by increasing the number of NK, B, T cells, macrophages, and dendritic cells (DCs) in spleen. Collectively, the results support the potential of ME49Δgra5as attenuated live vaccine againstT. gondiiinfection and breast cancer.Author summaryThe zoonotic toxoplasmosis poses a great disease burden to humans and big loss to livestock farming. At present, clinical therapeutic drugs mainly targetT. gondiitachyzoites but have no effect on bradyzoites. A safe and effective vaccine against toxoplasmosis is urgent and important. Dense granule proteins (GRAs) are a group of immunoactive proteins secreted byT. gondiidense granule organelles. GRA5 is located on the parasitophorous vacuole membrane (PVM) at the tachyzoite stage and on the cyst wall at the bradyzoite stage. We discovered that thegra5knockoutT. gondiistrain became avirulent and failed to form cysts in mice. ME49Δgra5immunized mice survived the challenge infection of wild-type RH, ME49, and VEG tachyzoites, and ME49 cysts. Meanwhile, ME49Δgra5tachyzoites inoculationin situremarkably attenuated the growth of murine breast tumor (4T1) in mice including the injected and distant tumors, as well as prevented 4T1’s lung metastasis. This results support the potential of ME49Δgra5as attenuated live vaccine againstT. gondiiinfection and breast cancer.
GLI1 facilitates rheumatoid arthritis by collaborative regulation of DNA methyltransferases
Authors: Ge Gaoran , Guo Qianping , Zhou Ying , Li Wenming , Zhang Wei , Bai Jiaxiang , Wang Qing , Tao Huaqiang , Wang Wei , Wang Zhen , Gan Minfeng , Xu Yaozeng , Yang Huilin , Li Bin , Geng Dechun 
Published: February 2023

AbstractRheumatoid arthritis (RA) is characterized by joint synovitis and bone destruction, the etiology of which remains to be explored. Overactivation of M1 macrophages and osteoclasts has been thought a direct cause of joint inflammation and bone destruction. Glioma-associated oncogene homolog 1 (GLI1) has been revealed to be closely linked to bone metabolism. In this study, GLI1-expression in synovial tissue of RA patients showed to be positively correlated with RA-related scores and was highly expressed in collagen-induced arthritis (CIA) mouse articular macrophage-like cells. The decreased expression and inhibition of nuclear transfer of GLI1 downregulated macrophage M1 polarization and osteoclast activation, the effect of which was achieved by modulation of DNA methyltransferases (DNMTs) via transcriptional regulation and protein interaction ways. By pharmacological inhibition of GLI1, the proportion of proinflammatory macrophages and the number of osteoclasts were significantly reduced, and the joint inflammatory response and bone destruction in CIA mice were alleviated. This study clarified the mechanism of GLI1 in macrophage phenotypic changes and activation of osteoclasts, suggesting potential applications of GLI1 inhibitor in the clinical treatment of RA.
Transcranial direct current stimulation elevates the baseline activity while sharpening the spatial tuning of the human visual cortex
Authors: Ahn Jeongyeol , Ryu Juhyoung , Lee Sangjun , Lee Chany , Im Chang-Hwan , Lee Sang-Hun 
Published: February 2023

AbstractBackgroundAlthough transcranial direct current stimulation (tDCS) is widely used to affect various kinds of human cognition, behavioral studies on humans have produced highly inconsistent results. This requires a clear understanding of how tDCS impacts the system-level neural activity, a prerequisite for the principled application of tDCS to human cognition.ObjectiveHere, we aim to gain such understanding by probing the spatial and temporal cortical activity of the human early visual cortex (EVC) in diverse aspects while controlling the polarity and presence of tDCS. We target EVC to capitalize on its well-established anatomical and functional architecture that is readily accessible with non-invasive quantitative neuroimaging methods.MethodsTo create an electric field in EVC precisely and effectively, we tailored high-definition stimulation montages for 15 individual brains by running electric field simulations. We then conducted an fMRI (functional magnetic neuroimaging)-tDCS experiment on each brain with a sham-controlled crossover design over multiple days. We quantified tDCS effects with eight measures, tested their significance with mixed ANOVA, and further validated their robustness to across-voxel and across-subject variability.ResultsThe anodal application of tDCS gradually elevated EVC’s baseline BOLD activity and sharpened its spatial tuning by augmenting surround suppression without affecting its evoked activity.ConclusionsComparisons of our and previous findings suggest the fundamental differences in tDCS effects between the visual and motor cortices, inhibitory and excitatory effects predominant in the former and latter, respectively. This calls for considering the differences in the excitatory-inhibitory recurrent network between brain regions in predicting or interpreting tDCS effects.
Rapid, activity-dependent intrinsic plasticity in the developing zebra finch auditory cortex
Authors: Lu Yao , Sciaccotta Francesca , Kiely Leah , Bellanger Benjamin , Erisir Alev , Meliza C Daniel 
Published: February 2023

AbstractThe acoustic environment an animal experiences early in life shapes the structure and function of its auditory system. This process of experience-dependent development is thought to be primarily orchestrated by potentiation and depression of synapses, but plasticity of intrinsic voltage dynamics may also contribute. Here we show that at the peak of the critical period for song memorization, neurons in the zebra finch caudal mesopallium, a cortical-level auditory area, can rapidly change their firing dynamics. This plasticity was only observed in birds that were reared in a complex acoustic and social environment, which also caused increased expression of the low-threshold potassium channel Kv1.1 in the plasma membrane and endoplasmic reticulum. Intrinsic plasticity depended on activity, was reversed by blocking low-threshold potassium currents, and was prevented by blocking intracellular calcium signaling. Taken together, these results suggest that Kv1.1 is rapidly mobilized to the plasma membrane by activity-dependent elevation of intracellular calcium. This produces a shift in the excitability and temporal integration of CM neurons that may be permissive for auditory learning in complex acoustic environments during a crucial period for the development of vocal perception and production.
LIM-HD transcription factors are required for regeneration of neuronal and intestinal cell subtypes in planarians
Authors: Molina M. Dolores , Abduljabbar Dema , Fraguas Susanna , Cebrià Francesc 
Published: February 2023

ABSTRACTAdult planarians can regenerate the gut, eyes, and even a functional brain in just a few days after injury. Proper regeneration of these complex structures requires that signals guide and restrict the commitment of their adult stem cells and ensure the identity and patterning of the newly formed structures. During embryogenesis of both vertebrates and invertebrates, LIM Homeodomain (LIM-HD) transcription factors act in a combinatorial ‘LIM code’ that controls crucial aspects of cell fate determination and cell differentiation, including specification of neuronal cell type identity and axonal guidance. So far, however, our understanding about the role these genes may play during regeneration is limited. Here, we report the identification and functional characterization of the full repertoire of LIM-HD genes inSchmidtea mediterranea. We found that theselim homeobox genes(lhx) appear mainly expressed in complementary patterns along the cephalic ganglia and digestive system of the planarian. By functional RNAi based analysis we have identified that severalSmed-lhxgenes (islet1,lhx1/5-1,lhx2/9-3,lhx6/8,lmx1a/b-2andlmx1a/b-3) are essential to pattern and size the planarian brain as well as for correct regeneration of specific subpopulations of dopaminergic, serotonergic, GABAergic and cholinergic neurons, while others (Smed-lhx1/5.2andSmed-lhx2/9.2) are required for the proper expression of diverse intestinal cell type markers, specifically the goblet subtype. LIM-HD are also involved in the control of axonal pathfinding (lhx6/8), axial patterning (islet1andlmx1a/b-3), head/body proportions (islet2) and stem cell proliferation (lhx3/4,lhx2/9-3,lmx1a/b-2andlmx1a/b-3) in planarians. Altogether, our results suggest that planarian LIM-HD could provide a combinatorial LIM code to control axial patterning, axonal growing as well as to specify distinct neuronal and intestinal cell identities during regeneration.
Subdural CMOS optical probe (SCOPe) for bidirectional neural interfacing
Authors: Pollmann Eric H. , Yin Heyu , Uguz Ilke , Dubey Agrita , Wingel Katie Elizabeth , Choi John S , Moazeni Sajjad , Gilhotra Yatin , Pavlovsky Victoria A. , Banees Adam , Boominathan Vivek , Robinson Jacob , Veeraraghavan Ashok , Pieribone Vincent A. , Pesaran Bijan , Shepard Kenneth L. 
Published: February 2023

AbstractOptical neurotechnologies use light to interface with neurons and can monitor and manipulate neural activity with high spatial-temporal precision over large cortical extents. While there has been significant progress in miniaturizing microscope for head-mounted configurations, these existing devices are still very bulky and could never be fully implanted. Any viable translation of these technologies to human use will require a much more noninvasive, fully implantable form factor. Here, we leverage advances in microelectronics and heterogeneous optoelectronic packaging to develop a transformative, ultrathin, miniaturized device for bidirectional optical stimulation and recording: the subdural CMOS Optical Probe (SCOPe). By being thin enough to lie entirely within the subdural space of the primate brain, SCOPe defines a path for the eventual human translation of a new generation of brain-machine interfaces based on light.
MGAdeletion leads to Richter’s transformation via modulation of mitochondrial OXPHOS
Authors: Iyer Prajish , Zhang Bo , Liu Tingting , Jin Meiling , Hart Kevyn , Zhang Jibin , Song Joo , Chan Wing C. , Siddiqi Tanya , Rosen Steven T. , Danilov Alexey , Wang Lili 
Published: February 2023

AbstractRichter’s transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma.MGA(Max gene associated), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms ofMGAdeletion driving CLL to RT remain elusive. We established a novel RT mouse model by knockout ofMgain theSf3b1/MdrCLL model via CRISPR-Cas9 to determine the role ofMgain RT. Murine RT cells exhibit mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). We identifiedNme1(Nucleoside diphosphate kinase) as aMgatarget through RNA sequencing and functional characterization, which drives RT by modulating OXPHOS. AsNME1is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and ETC complex II significantly prolongs the survival of RT micein vivo. Our results suggest thatMga-Nme1axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a novel therapeutic avenue for RT.Statement of SignificanceWe established a murine RT model through knockout ofMgain an existing CLL model based on co-expression ofSf3b1-K700E anddel(13q). We determined that theMGA/NME1regulatory axis is essential to the CLL-to-RT transition via modulation of mitochondrial OXPHOS, highlighting this pathway as a novel target for RT treatment.
mRNA trans-splicing dual AAV vectors for (epi)genome editing and gene therapy
Authors: Riedmayr Lisa Maria , Hinrichsmeyer Klara Sonnie , Thalhammer Stefan Bernhard , Karguth Nina , Böhm Sybille , Mittas David Manuel , Weber Valentin Johannes , Otify Dina , Splith Victoria , Brümmer Manuela , Boon Nanda , Wijnholds Jan , Mehlfeld Verena , Michalakis Stylianos , Fenske Stefanie , Biel Martin , Becirovic Elvir 
Published: February 2023

AbstractLarge genes including several CRISPR-Cas modules, such as gene activators (CRISPRa), require dual adeno-associated viral (AAV) vectors for an efficientin vivodelivery and expression. Current dual AAV vector approaches have important limitations, e.g., low reconstitution efficiency, production of alien proteins, or low flexibility in split site selection. Here, we present a dual AAV vector technology based onreconstitutionvia mRNA trans-splicing (REVeRT). REVeRT is flexible in split site selection and can efficiently reconstitute different split genes in numerousin vitromodels, in human organoids, andin vivo. Furthermore, REVeRT can functionally reconstitute a CRISPRa module targeting genes in various mouse tissues and organs in single or multiplexed approaches upon different routes of administration. Finally, intravitreal supplementation ofABCA4via REVeRT improves retinal degeneration and function in a mouse model of Stargardt disease. Due to its flexibility and efficiency REVeRT harbors great potential for basic research and clinical applications.
Detection of Activated Receptor Tyrosine Kinases in Human Lung Squamous Cell Carcinoma
Authors: Kendrick Nancy , Hoelter Matt , Koll Andrew , Darie Costel C. , Johansen Jon 
Published: February 2023

AbstractLung squamous cell carcinoma (LSCC) has a high mutational burden and poor prognosis, even with immunotherapy. In the Lux-Lung 8 trial, afatinib, an epidermal growth factor receptor (EGFR) inhibitor, showed a long-term benefit in 5.3% of patients with LSCC. Because activating mutations of EGFR are rare in LSCC, the response was likely due to wild-type EGFR being activated by an unknown mechanism. All receptor tyrosine kinase (RTK) proteins, both wild-type and mutated, are activated by phosphorylation of specific tyrosines which serve as binding sites for various SH2 proteins. The aim of this feasibility study was to determine whether enhanced chemiluminescent western blotting (WB) with a phosphotyrosine (pTyr) antibody is sufficiently sensitive to detect pTyr-RTK proteins in human LSCC tissues. We performed WB analysis on 25 resected human lung tissue samples, including 12 LSCC, two adenocarcinomas (LADC), and 11 control (non-tumor) lung samples. The analysis showed ∼220 kDa pTyr-protein bands in two LSCC samples that were much more abundant than the corresponding bands in controls or LADC samples. To identify pTyr-RTKs, pTyr WB patterns of the two samples were compared to those of five RTK candidates: EGFR, platelet-derived growth factor receptor beta (PDGFRB), vascular endothelial growth factor receptor, anaplastic lymphoma receptor, and mesenchymal-epithelial transition factor. The strong pTyr signal in one sample matched EGFR, whereas the other matched a combination of EGFR and PDGFRB. We conclude that pTyr WB is sufficiently sensitive to detect pTyr-RTK drivers in flash-frozen tumor tissues and might identify LSCC patient subsets responsive to RTK inhibitors.
Genome-wide mapping of theEscherichia coliPhoB regulon reveals many transcriptionally inert, intragenic binding sites
Authors: Fitzgerald Devon , Stringer Anne , Smith Carol , Lapierre Pascal , Wade Joseph T. 
Published: February 2023

ABSTRACTGenome-scale analyses have revealed many transcription factor binding sites within, rather than upstream of genes, raising questions as to the function of these binding sites. Here, we use complementary approaches to map the regulon of theEscherichia colitranscription factor PhoB, a response regulator that controls transcription of genes involved in phosphate homeostasis. Strikingly, the majority of PhoB binding sites are located within genes, but these intragenic sites are not associated with detectable transcription regulation and are not evolutionarily conserved. Many intragenic PhoB sites are located in regions bound by H-NS, likely due to shared sequence preferences of PhoB and H-NS. However, these PhoB binding sites are not associated with transcription regulation even in the absence of H-NS. We propose that for many transcription factors, including PhoB, binding sites not associated with promoter sequences are transcriptionally inert, and hence are tolerated as genomic “noise”.IMPORTANCERecent studies have revealed large numbers of transcription factor binding sites within the genes of bacteria. The function, if any, of the vast majority of these binding sites has not been investigated. Here, we map the binding of the transcription factor PhoB across theEscherichia coligenome, revealing that the majority of PhoB binding sites are within genes. We show that PhoB binding sites within genes are not associated with regulation of the overlapping genes. Indeed, our data suggest that bacteria tolerate the presence of large numbers of non-regulatory, intragenic binding sites for transcription factors, and that these binding sites are not under selective pressure.
Peer’s Presence Reverses Escalated Cocaine Intake in Rats
Authors: Vielle Cassandre , Tiran-Cappello Alix , Vignal Lucie , Maurice Nicolas , Degoulet Mickael , Brocard Cécile , Pelletier Florence , Pelloux Yann , Baunez Christelle 
Published: February 2023

AbstractThe immediate social context at the time of drug consumption is critical at modulating it. The neurobiological substrate of such an influence is however poorly documented. The presence of a stranger peer, naïve to the drug, has been shown to reduce recreational cocaine intake in rats with similar results in human cocaine users. Here we assessed its influence in rats having previously lost their control over drug consumption. The subthalamic nucleus (STN) has been shown to play a critical role in cocaine motivation, escalation and re-escalation, as well as compulsive drug seeking. We show here that after escalation of cocaine intake, the presence of a stranger peer drastically reduced cocaine intake. The same effect was observed after both optogenetic inhibition and high-frequency stimulation of the STN in absence of a peer. We further show that the beneficial influence of social presence is mediated via the STN.One Sentence SummaryThe presence of a stranger peer drastically decreases cocaine intake after drug escalation, as does a subthalamic optogenetic modulation.