bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of CB2R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease
Authors: Kecheliev Vasil , Spinelli Francesco , Herde Adrienne , Haider Ahmed , Mu Linjing , Klohs Jan , Ametamey Simon M. , Ni Ruiqing 
Published: July 2022

AbstractNeuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease. The cannabinoid type 2 receptor (CB2R) is an emerging target for neuroinflammation and therapeutics of Alzheimer’s disease. Here, we aimed to assess the alterations in brain CB2R levels and evaluate novel CB2R imaging tracers in the arcAβ mouse model of Alzheimer’s disease amyloidosis. Immunohistochemical staining for Aβ deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB2R antibody was performed on brain slices from arcAβ mice 17 months of age. Autoradiography using the CB2R imaging probes [18F]RoSMA-18-d6, [11C]RSR-056 and [11C]RS-028 and mRNA analysis were performed in brain tissue from arcAβ and nontransgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB2R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAβ mice compared to NTL mice. CB2R immunofluorescence was higher in the glial cells inside 6E10-positive amyloid-β deposits than peri-plaque with a low background. Ex vivo autoradiography showed that the binding of [18F]RoSMA-18-d6 and [11C]RSR-056 was comparable in arcAβ and NTL mice at 6, 17 and 24 months. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAβ and NTL mice at 6, 17 or 24 months. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB2R expression levels in a model of AD-related cerebral amyloidosis/AD mouse model, emphasizing CB2R as a suitable target for imaging neuroinflammation.
Survival of Campylobacter jejuni in Acanthamoebae castellanii provides mechanistic insight into host pathogen interactions
Authors: Nasher Fauzy , Lehri Burhan , Horney Megan F , Stabler Richard A , Wren Brendan W 
Published: July 2022

AbstractCampylobacter jejuni is the leading cause of bacterial foodborne gastroenteritis world-wide but is rarely transferred between human hosts. Although a recognized microaerophile, C. jejuni is incapable of growing in an aerobic environment. The persistence and transmission of this pathogen outside its warm-blooded avian and mammalian hosts is poorly understood. Acanthamoebae species, are predatory protists and form an important ecological niche with several bacterial species. Here, we investigate the interaction of C. jejuni and Acanthamoebae castellanii at the single-cell level. We observe that a subpopulation of C. jejuni cells can resist killing by A. castellanii and non-digested bacteria are released into the environment where they can persist. In addition, we observe that A. castellanii can harbor C. jejuni even upon encystment. Transcriptome analyses of C. jejuni interactions revealed similar survival mechanisms when infecting both A. castellanii and warm-blooded hosts. In particular, nitrosative stress defense mechanisms and flagellum function are important as confirmed by mutational analyses. This study describes a new host-pathogen interaction for C. jejuni and confirms that amoebae are transient hosts for the persistence, adaptability and potential transmission of C. jejuni.
The PREGCARE study: Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation
Authors: Bernkopf Marie , Abdullah Ummi B. , Bush Stephen J. , Wood Katherine , Ghaffari Sahar , Giannoulatou Eleni , Koelling Nils , Maher Geoffrey J. , Thibault Loïc M. , Williams Jonathan , Blair Edward M. , Kelly Fiona Blanco , Bloss Angela , Burkitt-Wright Emma , Canham Natalie , Deng Alexander T. , Dixit Abhijit , Eason Jacqueline , Elmslie Frances , Gardham Alice , Hay Eleanor , Holder Muriel , Homfray Tessa , Hurst Jane A. , Johnson Diana , Jones Wendy D. , Kini Usha , Kivuva Emma , Kumar Ajith , Lees Melissa M. , Leitch Harry G. , Morton Jenny E. V. , Németh Andrea H. , Ramachandrappa Shwetha , Saunders Katherine , Shears Deborah J. , Side Lucy , Splitt Miranda , Stewart Alison , Stewart Helen , Suri Mohnish , Clouston Penny , Davies Robert W. , Wilkie Andrew O. M. , Goriely Anne 
Published: July 2022

AbstractNext-generation sequencing has led to a dramatic improvement in molecular diagnoses of serious pediatric disorders caused by apparently de novo mutations (DNMs); by contrast, clinicians’ ability to counsel the parents about the risk of recurrence in a future child has lagged behind. Owing to the possibility that one of the parents could be mosaic in their germline, a recurrence risk of 1-2% is frequently quoted, but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk stratification, by combining deep-sequencing of multiple tissues in the mother-father-child trio with haplotyping to determine the parental origin of the DNM. In the first 58 couples analysed (total of 59 DNMs in 49 different genes), the risk for 35 (59%) DNMs was decreased below 0.1% but for 6 (10%) couples it was increased owing to parental mosaicism - that could be quantified in semen (recurrence risks of 5.6-12.1%) for the paternal cases. Deep-sequencing of the DNM efficiently identifies couples at greatest risk for recurrence and may qualify them for additional reproductive technologies. Haplotyping can further reassure many other couples that their recurrence risk is very low, but its implementation is more technically challenging and will require better understanding of how couples respond to information that reduces their risks.
TGFβ−induced embryonic cell senescence at the origin of the Cornelia de Lange syndrome
Authors: Hachoud Céline , Chaabani Faten , Watrin Erwan , Wuelling Manuela , Peters Heiko , Cormier-Daire Valérie , Pucéat Michel 
Published: July 2022

AbstractCornelia de Lange Syndrome (CdLS) largely caused by mutation of the cohesin loader NIPBL is a rare developmental disorder affecting the formation of many organs. Besides a short body size and neurological defects, more than half of CdLS children feature various cardiac malformations.To mimic the disease and test a therapeutic strategy, we generated a C57/Bl6Nipbl+/-mouse model of the disease. These mice featured a severe delay in both embryonic and postnatal growth. TheNipbl-deficient embryonic and neonatal hearts developed ventricular hypertrophy, aortic and valve defects associated with a persistent truncus arteriosus and a ventricular septal defect. Muscles derived from the second heart field were deficient in theNipblhaplo-insufficient mouse embryos. The adult hearts then featured a severe aortic senescence phenotype and a stenosis resulting in an increase in aortic flux velocity and persistent left ventricular hypertrophy. Using proteomics and RNA-sequencing in embryos, we identified a dysregulated TGFβ pathway in the outflow tract of embryonic hearts as well as the presence of senescent cells as early as in E13.5Nipbl+/-embryonic hearts, limb primordium cartilage as well as in different post-natal tissues including muscle and brain cortex. Treatment of pregnantNipbl+/-mice with a TGFβR (ALK5) inhibitor from E9.5 to E13.5 prevented cell -senescence and rescued the cardiac phenotype as well as the body size of mice at birth.Altogether our data revealed that an exacerbated TGFβ pathway associated with cell senescence is at the origin of many defects in a CdL mouse model. This druggable pathway opens the path toward a potential preventive and/or therapeutic strategy for post-natal CdLS patients.
Neural integration and segregation revealed by a joint time-vertex connectome spectral analysis
Authors: Rué-Queralt Joan , Mancini Valentina , Rochas Vincent , Latrèche Caren , Uhlhaas Peter J , Michel Christoph M. , Plomp Gijs , Eliez Stephan , Hagmann Patric 
Published: July 2022

AbstractBrain oscillations are produced by the coordinated activity of large groups of neurons and different rhythms are thought to reflect different modes of information processing. These modes, in turn, are known to occur at different spatial scales. Nevertheless, how these rhythms support different modes of information processing at the brain scale is not yet fully understood. Here we present “Joint Time-Vertex Connectome Spectral Analysis”, a framework for characterizing the spectral content of brain activity both in time (temporal frequencies) and in space (spatial connectome harmonics). This method allows us to estimate the contribution of integration (global communication) and segregation (functional specialization) mechanisms at different temporal frequency bands in source-reconstructed M/EEG signals, thus providing a better understanding of the complex interplay between different information processing modes. We validated our method on two different datasets, an auditory steady-state response (ASSR) and a visual grating task. Our results suggest that different information processing mechanisms are carried out at different frequency channels: while integration seems to be a specific mechanism occurring at low temporal frequencies (alpha and theta), segregation is only observed at higher temporal frequencies (high and low gamma). Crucially, the estimated contribution of the integration and segregation mechanisms predicts performance in a behavioral task, demonstrating the neurophysiological relevance of this new framework.
Allosteric Regulation of a Synaptic Vesicle Glutamate Transporter
Authors: Li Fei , Eriksen Jacob , Oses-Prieto Juan A. , Gomez Yessica K. , Xu Hongfei , Finer-Moore Janet , Nguyen Phuong , Bowen Alisa , Nelson Andrew , Burlingame Alma , Grabe Michael , Stroud Robert M. , Edwards Robert H. 
Published: July 2022

AbstractConcentration of neurotransmitter inside synaptic vesicles (SVs) underlies the quantal nature of synaptic transmission. In contrast to many transporters, SV uptake of the principal excitatory neurotransmitter glutamate is driven by membrane potential. To prevent nonquantal efflux of glutamate after SV exocytosis, the vesicular glutamate transporters (VGLUTs) are allosterically inhibited by the neutral pH of the synaptic cleft. We have now determined high-resolution structures of VGLUT2 with a cyclic analog of glutamate bound that defines the mechanism of substrate recognition, a positively charged cytoplasmic vestibule that electrostatically attracts the negatively charged substrate, and modification by palmitoylation that promotes retrieval of the transporter after exocytosis. The structure also incorporates an extensive, cytoplasmic network of electrostatic interactions that acts as a gate. Functional analysis shows how this cytoplasmic gate confers the allosteric requirement for lumenal H+ required to restrict VGLUT activity to SVs.
Comparative genome-scale constraint-based metabolic modeling reveals key lifestyle features of plant-associated Pseudomonas spp
Authors: Poncheewin Wasin , van Diepeningen Anne D. , van der Lee Theo AJ , Schaap Peter J. , Martins dos⍰Santos Vitor A. P. , Suarez-Diez Maria 
Published: July 2022

AbstractPlant Growth Promoting Rhizobacteria (PGPR) dwell in the rhizosphere, the area surrounding the root of plants, and enhance growth of the host through different mechanisms: they can protect plants against pathogens, assist in nutrient gathering, and in increasing stress tolerance. Hence, developing strategies to enhance their performance is important to increase crop productivity. Specific solutions are necessary to enhance the performance of the beneficials while simultaneously avoiding nurturing of pathogens. This requires insights into the mechanisms underlying these microbials interactions. Pseudomonas is one of the most studied genera and contains both beneficials and pathogenic species. Hence, we used comparative genome-scale constraint-based metabolic modeling to reveal key features of both classes of Pseudomonads and which can provide leads for the possible interventions regarding these solutions. Models of 75 plant-growth promoting rhizosphere and 33 epiphytic pathogenic Pseudomonas strains were automatically reconstructed and validated using phenotype microarray (Biolog) data. The models were used for compositional analysis and 12 representative strains, 6 of each group, were further selected for extensive simulation. The analyses reveal differences in the potential for metabolite uptake and transport between these two distinct classes that suggest their nutrient preferences and their differences in, among other, D-ornithine acquisition mechanisms. The models enable simulation of metabolic state of root exudates. Simulations highlighted and summarized the differences in pathway utilization and intracellular states between two groups. The insights obtained will be very valuable to broader such studies of rhizobiome and to possibly develop strategies to improve crop productivity by supporting the beneficial microbiome while reducing pathogen activities.
Evaluating the capabilities and challenges of layer-fMRI VASO at 3T
Authors: Huber Laurentius (Renzo) , Kronbichler Lisa , Stirnberg Rüdiger , Ehses Philipp , Stöcker Tony , Fernández-Cabello Sara , Poser Benedikt A. , Kronbichler Martin 
Published: July 2022

AbstractSub-millimeter functional imaging has the potential to capture cortical layer-specific functional information flow within and across brain systems. Recent sequence advancements of fMRI signal readout and contrast generations resulted in wide adaptation of layer-fMRI protocols across the global ultra-high-field (UHF) neuroimaging community. However, most layer-fMRI applications are confined to one of ≈100 privileged UHF imaging centers, and sequence contrasts with unwanted sensitivity to large draining veins. In this work, we propose the application of vein-signal free vascular space occupancy (VASO) layerfMRI sequences at widely accessible 3T scanners. Specifically, we implement, characterize, and apply a cerebral blood volume (CBV)-sensitive VASO fMRI at a 3T scanner setup, as it is typically used in the majority of cognitive neuroscience and clinical neuroscience fMRI studies. We find that the longer , and stronger relative T1 contrast at 3T can account for some of the lower z-magnetization in the inversion-recovery VASO sequence compared to 7T and 9.4T. In the main series of experiments (N=16), we test the utility of this setup for motor tasks and find that-while being limited by thermal noise-3T layer-fMRI VASO is feasible within conventional scan durations. In a series of auxiliary studies, we furthermore explore the generalizability of the developed layer-fMRI protocols for a larger range of study designs including: visual stimulation, whole brain movie watching paradigms, and cognitive tasks with weaker effect sizes. We hope that the developed imaging protocols will help to increase accessibility of vein-signal free layer-fMRI imaging tools to a wider community of neuroimaging centers.Graphical abstract
APC and P53 mutations synergize to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer
Authors: Tian Yuhua , Wang Xin , Cramer Zvi , Rhoades Joshua , Estep Katrina N. , Ma Xianghui , Tzivelekidis Stephanie Adams , Katona Bryson W , Johnson F Brad , Yu Zhengquan , Blanco Mario Andres , Lengner Christopher , Li Ning 
Published: July 2022

AbstractColorectal cancer (CRC) is a leading cause of cancer-related deaths globally, with the majority of cases initiated by inactivation of the APC tumor suppressor. This results in the constitutive transcriptional activation of the canonical WNT signal transduction pathway effector β-Catenin, along with induction of WNT feedback inhibitors, including the extracellular palmitoleoyl-protein carboxylesterase NOTUM. Here, we show that NOTUM retains cell-autonomous tumor suppressive activity in APC-null adenomatous lesions despite constitutive β-Catenin activation. Strikingly, we find that NOTUM becomes an obligate oncogene upon subsequent P53 inactivation during the adenoma-adenocarcinoma transition, and that these phenotypes are WNT-independent, resulting from differential activity of NOTUM upon its enzymatic targets Glypican 1 and 4 in early vs. late-stage disease, respectively. Ultimately, preclinical mouse models of CRC and human tumoroid cultures demonstrate that pharmacological inhibition of NOTUM is highly effective in arresting primary adenocarcinoma growth and inhibiting metastatic colonization of distal organs. The finding that a single agent targeting an extracellular enzyme is effective in treating highly aggressive tumors make NOTUM a novel therapeutic vulnerability in advanced colorectal adenocarcinomas.
Integrated single-cell multiomic analysis of HIV latency reversal reveals novel regulators of viral reactivation
Authors: Manickam Ashokkumar , Peterson Jackson J , Harigaya Yuriko , Murdoch David M , Margolis David M , Oesterling Alex , Guo Zhicheng , Rudin Cynthia D , Jiang Yuchao , Browne Edward P 
Published: July 2022

AbstractDespite the success of antiretroviral therapy, HIV cannot be cured because of a reservoir of latently infected cells that evades therapy. To understand the mechanisms of HIV latency, we employed an integrated single-cell RNA-seq/ATAC-seq approach to simultaneously profile the transcriptomic and epigenomic characteristics of ~4000 latently infected cells after reactivation using three different latency-reversing agents (LRAs). Differentially expressed genes and differentially accessible motifs were used to examine transcriptional pathways and transcription factor (TF) activities across the cell population. We identify cellular transcripts and TFs whose expression/activity was correlated with viral reactivation and demonstrate that a machine learning model trained on these data was 68% accurate at predicting viral reactivation. Finally, we validate the role of a new candidate HIV-regulating factor, GATA3, in the viral response to prostratin stimulation. These data demonstrate the power of integrated multimodal single-cell analysis to uncover novel relationships between host cell factors and HIV latency.
Gluebodies improve crystal reliability and diversity through transferable nanobody mutations that introduce constitutive close contacts
Authors: Ye Mingda , Makola Mpho , Newman Joseph A. , Fairhead Michael , Maclean Elizabeth , Wright Nathan D. , Koekemoer Lizbé , Thompson Andrew , Bezerra Gustavo A. , Yi Gangshun , Li Huanyu , Rangel Victor L. , Mamalis Dimitrios , Aitkenhead Hazel , Davis Benjamin G. , Gilbert Robert J.C. , Duerr Katharina , Gileadi Opher , von Delft Frank 
Published: July 2022

AbstractThe design of proteins that may assemble in a manner that is transferable and modular remains an enduring challenge. In particular, obtaining well-diffracting protein crystals suitable for characterizing ligands or drug candidates and understanding different protein conformations remains a bottleneck for structural studies. Using nanobodies as crystallization chaperones is one strategy to address the problem, but its reliability is uncharacterized and, in this study, we observed it to have a limited success rate. Here we show that by exploring and testing the nanobody-nanobody interfaces predominant in >200 combinations of surface mutations in multiple iterations we can engineer robust crystallization behaviour into the nanobody scaffold. Strikingly, this survey yielded multiple polymorphs, all mediated by the same interface. The resulting ‘Gluebodies’ (Gbs) provide far superior resolution and reliability of diffraction and can be routinely generated for chaperone experiments. We furthermore show that Gbs cannot rescue intrinsically non-crystallizing proteins, but instead are a powerful approach to improve the packing and resolution limit of poorly diffracting crystals. The discovery of an engineered, preferred nanobody interface that arises under kinetic control - trapped here by irreversible crystallization - embodies a protein assembly strategy that could prove even more broadly useful for modular assembly trapped by other irreversible methods.
DREADD activation of the lateral septum alters prosocial and antisocial behaviors, but not partner preferences in male prairie voles
Authors: Sailer Lindsay L. , Park Ashley H. , Galvez Abigail , Ophir Alexander G. 
Published: July 2022

AbstractAlthough much has been written on the topic of social behavior, many terms referring to different aspects of social behavior have become inappropriately conflated and the specific mechanisms governing them remains unclear. It is therefore critical that we disentangle the pro- and anti-social elements associated with different forms of social behavior to fully understand the social brain. The lateral septum (LS) mediates social behaviors, emotional processes, and stress responses necessary for individuals to navigate day-to-day social interactions. The LS is particularly important in general and selective prosocial behavior (monogamy) but its role in how these two behavioral domains intersect is unclear. Here, we investigate the effects of chemogenetic-mediated LS activation on social responses in male prairie voles when they are 1) sex-naïve and generally affiliative and 2) after they become pair-bonded and display selective aggression. Amplifying neural activity in the LS augments same-sex social approach behaviors. Despite partner preference formation remaining unaltered, LS activation in pair-bonded males leads to reduced selective aggression while increasing social affiliative behaviors. These results suggest that LS activation alters behavior within certain social contexts, by increasing sex-naïve affiliative behaviors and reducing pair bonding-induced selective aggression with same-sex conspecifics, but not altering bonding with opposite-sex individuals.