bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nanoparticle Enrichment Mass-Spectrometry Proteomics Identifies Protein Altering Variants for Precise pQTL Mapping
Authors: Suhre Karsten , Venkataraman Guhan Ram , Guturu Harendra , Halama Anna , Stephan Nisha , Thareja Gaurav , Sarwath Hina , Motamedchaboki Khatereh , Donovan Margaret , Siddiqui Asim , Batzoglou Serafim , Schmidt Frank 
Published: April 2023

ABSTRACTGenome-wide association studies (GWAS) with proteomics generate hypotheses on protein function and offer genetic evidence for drug target prioritization. Although most protein quantitative loci (pQTLs) have so far been identified by high-throughput affinity proteomics platforms, these methods also have some limitations, such as uncertainty about target identity, non-specific binding of aptamers, and inability to handle epitope-modifying variants that affect affinity binding. Mass spectrometry (MS) proteomics has the potential to overcome these challenges and broaden the scope of pQTL studies. Here, we employ the recently developed MS-based Proteograph™ workflow (Seer, Inc.) to quantify over 18,000 unique peptides from almost 3,000 proteins in more than 320 blood samples from a multi-ethnic cohort. We implement a bottom-up MS-proteomics approach for the detection and quantification of blood-circulating proteins in the presence of protein altering variants (PAVs). We identify 184 PAVs located in 137 genes that are significantly associated with their corresponding variant peptides in MS data (MS-PAVs). Half of these MS-PAVs (94) overlap withcis-pQTLs previously identified by affinity proteomics pQTL studies, thus confirming the target specificity of the affinity binders. An additional 54 MS-PAVs overlap withtrans-pQTLs (and notcis-pQTLs) in affinity proteomics studies, thus identifying the putatively causalcis-encoded protein and providing experimental evidence for its presence in blood. The remaining 36 MS-PAVs have not been previously reported and include proteins that may be inaccessible to affinity proteomics, such as a variant in the incretin pro-peptide (GIP) that associates with type 2 diabetes and cardiovascular disease. Overall, our study introduces a novel approach for analyzing MS-based proteomics data within the GWAS context, provides new insights relevant to genetics-based drug discovery, and highlights the potential of MS-proteomics technologies when applied at population scale.HighlightsThis is the first pQTL study that uses the Proteograph™(Seer Inc.) mass spectrometry-based proteomics workflow.We introduce a novel bottom-up proteomics approach that accounts for protein altering variants in the detection of pQTLs.We confirm the target and potential epitope effects of affinity binders forcis-pQTLs from affinity proteomics studies.We establish putatively causal proteins for known affinity proteomicstrans-pQTLs and confirm their presence in blood.We identify novel protein altering variants in proteins of clinical relevance that may not be accessible to affinity proteomics.Graphical abstract
Neural patterns of conscious visual awareness in the Riddoch syndrome
Authors: Beyh Ahmad , Rasche Samuel E , Leff Alexander , ffytche Dominic , Zeki Semir 
Published: April 2023

SummaryThe Riddoch syndrome is one in which patients blinded by lesions to their primary visual cortex can consciously perceive visual motion in their blind field, an ability that correlates with activity in motion area V5. Our assessment of the characteristics of this syndrome in patient ST, using multimodal MRI, showed that: 1. ST’s V5 is intact, receives direct subcortical input, and decodable neural patterns emerge in it only during the conscious perception of visual motion; 2. moving stimuli activate medial visual areas but, unless associated with decodable V5 activity, they remain unperceived; 3. ST’s high confidence ratings when discriminating motion at chance levels, is associated with inferior frontal gyrus activity. Finally, we report that ST’s Riddoch Syndrome results in hallucinatory motion with hippocampal activity as a correlate. Our results shed new light on perceptual experiences associated with this syndrome and on the neural determinants of conscious visual experience.
Bayesian inference of spike-timing dependent plasticity learning rules from single neuron recordings in humans
Authors: Hem Ingeborg , Ledergerber Debora , Battistin Claudia , Dunn Benjamin 
Published: April 2023

AbstractSpike-timing dependent plasticity (STDP) learning rules are popular in both neuroscience and artificial neural networks due to their ability to capture the change in neural connections arising from the correlated activity of neurons. Recent technological advances have made large neural recordings common, substantially increasing the probability that two connected neurons are simultaneously observed, which we can use to infer functional connectivity and associated learning rules. We use a Bayesian framework and assume neural spike recordings follow a binary data model to infer the connections and their evolution over time from data using STDP rules. We test the resulting method on simulated and real data, where the real case study consists of human electrophysiological recordings. The simulated case study allows validation of the model, and the real case study shows that we are able to infer learning rules from awake human data.
Metabolic Reprogramming via targeting ACOD1 promotes polarization and anti-tumor activity of human CAR-iMACs in solid tumors
Authors: Wang Xudong , Su Siyu , Zhu Yuqing , Cheng Xiaolong , Cheng Chen , Chen Leilei , Lei Anhua , Zhang Li , Xu Yuyan , Li Wei , Zhang Yi , Ye Dan , Zhang Jin 
Published: April 2023

AbstractThe pro-inflammatory state of macrophages is crucial in conferring its role in combating tumor cells. That state is closely associated with metabolic reprogramming. Here we identified key metabolic genes regulating macrophage pro-inflammatory activation in a pooled metabolic gene knockout CRISPR screen. We found thatKEAP1 andACOD1are strong regulators of the pro-inflammatory state, and therefore developed humanACOD1knockout macrophages with our induced pluripotent stem cell-derived CAR-macrophage (CAR-iMAC) platform. The engineered iMACs showed stronger and more persistent polarization toward the pro-inflammatory state, more ROS production, and more potent phagocytosis and cytotoxic functions against cancer cellsin vitro. Upon transplantation to ovarian or pancreatic cancer mouse models,ACOD1depleted CAR-iMACs exhibited enhanced capacity in repressing tumorsin vivoand prolonged the lifespan of mice. In addition, combiningACOD1-depleted CAR-iMACs with immune check point inhibitors (ICIs), such as the anti-CD47 antibody or anti-PD1 antibody resulted in stronger tumor suppressing effect. Mechanistically, the depletion of ACOD1 reduced the immunometabolite itaconate, allowing KEAP1 to prevent NRF2 from entering the nucleus to activate the anti-inflammatory program. This study demonstrates that ACOD1 is a new myeloid target for cancer immunotherapy and metabolically engineered human iPSC-derived CAR-iMACs exhibit enhanced polarization and anti-tumor functions in adoptive cell transfer therapies.
Early-life stress exposure impacts the hippocampal synaptic proteome in a mouse model of Alzheimer’s disease: age- and pathology-dependent effects on mitochondrial proteins
Authors: Kotah Janssen M. , Kater Mandy S.J. , Hoeijmakers Lianne , Brosens Niek , Lesuis Sylvie L. , Tandari Roberta , Marchetto Luca , Yusaf Ella , Smit August B. , Lucassen Paul J. , Krugers Harm , Verheijen Mark H.G. , Korosi Aniko 
Published: April 2023

AbstractEpidemiological evidence indicates that early life stress (ES) exposure increases the risk for later-life diseases, such as Alzheimer’s disease (AD). Accordingly, we and others have shown that ES aggravates the development of, and response to, amyloid-beta (Aβ) pathology in animal models. Moreover, ES-exposed transgenic APP/PS1 mice display deficits in both cognitive flexibility and synaptic function. As the mechanisms behind these changes were unclear, we here investigated how exposure to ES, using the limited nesting and bedding model, affects the synaptic proteome across 2 different ages in both wildtype and APP/PS1 transgenic mice.We found that, compared to wildtype mice, the hippocampal synaptosomes of APP/PS1 mice at an early pathological stage (4 months) showed a higher abundance of mitochondrial proteins and lower levels of proteins involved in actin dynamics. Interestingly, ES exposure in wildtype mice had similar effects on the level of mitochondrial and actin-related synaptosomal proteins at this age, whereas ES exposure had no additional effect on the synaptosomal proteome of early-stage APP/PS1 mice. Accordingly, ultrastructural analysis of the synapse using electron microscopy in a follow-up cohort showed fewer mitochondria in pre- and post-synaptic compartments of APP/PS1 and ES-exposed mice, respectively.At a later pathological stage (10 months), the hippocampal synaptic proteome of APP/PS1 mice revealed an upregulation of proteins related to Aβ processing, that was accompanied by a downregulation of proteins related to postsynaptic receptor endocytosis. ES exposure no longer affected the synaptic proteome of wildtype animals by this age, whereas it affected the expression of astrocytic proteins involved in lipid metabolism in APP/PS1 mice. We confirmed a dysregulation of astrocyte protein expression in a separate cohort of 12-month-old mice, by immunostaining for the alpha subunit of the mitochondrial trifunctional protein and fatty acid synthase in astrocytes.In conclusion, our data suggest that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and astrocytic lipid metabolism. These pathways might be underlying contributors to the long-term aggravation of the APP/PS1 phenotype by ES, as well as to the ES-associated risk for AD progression.These data are publicly accessible online as a web app viahttps://amsterdamstudygroup.shinyapps.io/ES_Synaptosome_Proteomics_Visualizer/.
Altered X-chromosome inactivation predisposes to autoimmunity
Authors: Huret Christophe , Férrayé Léa , David Antoine , Mohamed Myriame , Valentin Nicolas , Charlotte Frédéric , Savignac Magali , Goodhardt Michele , Guéry Jean-Charles , Rougeulle Claire , Morey Céline 
Published: April 2023

AbstractIn mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism that ensures the silencing of one X in females, may participate in these sex-biases. Here, we perturbed the expression of the trigger of XCI, the non-coding RNAXist,in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signalling pathway, in monocyte/macrophages, dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti-nucleic acid autoantibodies, increased frequencies of age-associated and germinal centre B cells and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signalling is dysregulated in macrophages, which leads to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity.TeaserThe reason why autoimmunity mostly affects women is unclear. Here, we show that aberrant expression of genes on the X induces signs of lupus in female mice.
The ultrastructural nature of human oocytes’ cytoplasmatic abnormalities and the role of cytoskeleton dysfunction
Authors: Tatíčková Martina , Trebichalská Zuzana , Kyjovská Drahomíra , Otevřel Pavel , Kloudová Soňa , Holubcová Zuzana 
Published: April 2023

ABSTRACTBackgroundEgg quality is a limiting factor of female fertility and assisted reproductive technology (ART) success. Oocytes recovered from hyperstimulated ovaries often display morphological anomalies suspected to compromise their fertilization and developmental potential. Knowledge of (ab)normal oocyte’s intracellular organization is vital to establish reliable criteria for morphological evaluation of oocytes intended for in vitro fertilization (IVF).MethodsTransmission electron microscopy (TEM) was used to investigate the fine morphology of 22 dysmorphic IVF eggs exhibiting different types of cytoplasmic irregularities, namely (1) refractile bodies, (2) centrally-located cytoplasmic granularity (CLCG), (3) smooth endoplasmic reticulum (SER) disc, and (4) vacuoles. The cytoskeleton targeting compounds were employed to address the causative mechanism behind the anomalous cytoplasmic architecture observed in abnormal egg samples. A total of 133 immature oocytes were exposed to chemical inhibitors/control conditions, and their morphology was examined by fluorescent and electron microscopy.ResultsTEM exposed the structural basis of the common oocyte aberrations and revealed that the underlying cause of two of the studied morphotypes was excessive organelle clustering. Inhibition experiments showed that disruption of actin, not microtubules, allows inordinate aggregation of subcellular structures resembling the ultrastructural pattern seen in morphologically abnormal eggs retrieved in IVF cycles. These results imply that actin serves as a regulator of organelle distribution during human oocyte maturation.ConclusionsThe ultrastructural analogy between dysmorphic eggs and oocytes, in which actin network integrity was perturbed, suggests that malfunction of the actin cytoskeleton might be implicated in generating common cytoplasmic aberrations. Knowledge of human oocytes’ inner workings and the origin of morphological abnormalities is a step forward to more objective egg quality assessment in clinical practice.
The genome ofTalinum fruticosum
Authors: Brilhaus Dominik , Denton Alisandra K. , Maleckova Eva , Reichel-Deland Vanessa , Weber Andreas P. M. 
Published: April 2023

AbstractResearch on crassulacean acid metabolism (CAM) has in recent years focused on obligate CAM species, such asKalanchoë fedtschenkoiand pineapple (Ananas comosus). To fully understand the plasticity of the CAM pathway, its evolutionary trajectory and regulation, genomic resources of additional species, including facultative CAM species are desirable. To this end, we sequenced the genome and full-length transcripts (Iso-Seq) of the facultative CAM dicotTalinum fruticosum.The provided resources may aid in CAM engineering as an approach to improving crop water-use efficiency.
Nociception in chicken embryos, Part III: Analysis of movements before and after application of a noxious stimulus
Authors: Süß Stephanie C. , Werner Julia , Saller Anna M. , Weiss Larissa , Reiser Judith , Ondracek Janie M. , Zablotski Yury , Kollmansperger Sandra , Anders Malte , Schusser Benjamin , Fenzl Thomas , Baumgartner Christine 
Published: April 2023

AbstractMany potentially noxious interventions are performed on chicken embryos in research and in the poultry industry. It is therefore in the interest of animal welfare to define the point at which a chicken embryo is capable of nociception. The present part III of a comprehensive study examined the movements of developing chicken embryos with the aim of identifying behavioral responses to aww noxious stimulus. For this purpose, a noxious mechanical stimulus and a control stimulus were applied. The recorded movements of the embryos were evaluated using the markerless pose estimation software DeepLabCut and manual observations. After the application of the noxious stimulus, a significant increase in beak movement was identified in 15- to 18-day-old embryos. In younger embryos, no behavioral changes related to the noxious stimulus were observed. The results indicate that noxious stimuli at the beak base evoke a nocifensive reaction in chicken embryos starting at embryonic day 15.
Gaze-centered gating and reactivation of value encoding in orbitofrontal cortex
Authors: Ferro Demetrio , Cash-Padgett Tyler , Wang Maya Zhe , Hayden Benjamin , Moreno-Bote Rubén 
Published: April 2023

SummaryDuring economic choice, we often consider options in alternation, until we commit to one. Nonetheless, neuroeconomics typically ignores the dynamic aspects of deliberation. We trained macaques to perform a value-based decision-making task where two risky offers were presented in sequence at different locations of the visual field, each followed by a delay epoch where offers were invisible. Subjects looked at the offers in sequence, as expected. Surprisingly, during the delay epochs, we found that subjects still tend to look at empty locations where the visual offers were formerly presented; and, moreover, longer fixation to given empty location increases the probability of choosing the associated offer, even after controlling for the offer values. We show that activity in orbitofrontal cortex (OFC) reflects the value of the gazed offer, but also the value of the offer associated to the gazed spatial location, even if it is not the most recently viewed. This reactivation reflects a reevaluation process, as fluctuations in neural spiking during offer stimuli presentation and delays correlate with upcoming choice. Our results suggest that look-at-nothing gazing triggers the reactivation of a previously seen offer for further reevaluation, revealing novel aspects of deliberation.
Biophysical characterization and analysis of a mesophilic chorismate mutase fromB. pumilus
Authors: Wilkins Ryan Scott , Lund Bjarte Aarmo , Isaksen Geir Villy , Åqvist Johan , Brandsdal Bjørn Olav 
Published: April 2023

AbstractChorismate mutases have extensively been used as computational benchmarking systems for enzyme catalysis, yet the roles entropy and enthalpy play in catalysis are still not fully understood. Thus, it is important to better understand these enzymes for potential research or industrial applications. Here, we report the first crystal structure and kinetic characterization of a chorismate mutase fromBacillus pumilus. This enzyme exhibits a high degree of similarity to a known mesophilic chorismate mutase fromBacillus subtilis. Using this crystal structure, we further employ EVB/MD simulations to construct Arrhenius plots, allowing us to extract thermodynamic activation parameters. Overall, this study provides new insights into the structural and functional features of theB. pumiluschorismate mutase and highlights its potential as a valuable enzyme for biocatalytic and biotechnological applications.
Establishment of a screening platform based on human coronavirus OC43 for the identification of microbial natural products with antiviral activity
Authors: Martínez-Arribas Blanca , Annang Frederick , Díaz-González Rosario , Pérez-Moreno Guiomar , Martín Jesús , Mackenzie Thomas A. , Castillo Francisco , Reyes Fernando , Genilloud Olga , Ruiz-Pérez Luis Miguel , Vicente Francisca , Ramos María C. , González-Pacanowska Dolores 
Published: April 2023

ABSTRACTHuman coronaviruses (HCoVs) cause respiratory tract infections and are of great importance due to the recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Human betacoronavirus OC43 (HCoV-OC43) is an adequate surrogate for SARS-CoV-2 because it infects the human respiratory system, presents a comparable biology, and is transmitted in a similar way. Its use is advantageous since it only requires biosafety level (BSL)-2 infrastructure which minimizes costs and biosafety associated limitations. In this report, we describe a high-throughput screening (HTS) platform to identify compounds that inhibit the propagation of HCoV-OC43. Optimization of assays based on inhibition of the cytopathic effect and virus immunodetection with a specific antibody, has provided a robust methodology for the screening of a selection of microbial natural product extracts from the Fundación MEDINA collection. Using this approach, a subset of 1280 extracts has been explored. Of these, upon hit confirmation and early LC-MS dereplication, 10 extracts were identified that contain potential new compounds. In addition, we report on the novel antiviral activity of some previously described natural products whose presence in bioactive extracts was confirmed by LC/MS analysis.IMPORTANCEThe COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production. The implementation of a high-throughput screening platform using the betacoronavirus OC43 in a human cell line infection model has provided proof of concept of the approach and has allowed for the rapid and efficient evaluation of 1280 microbial extracts. The identification of several active compounds validates the potential of the platform for the search for new compounds with antiviral capacity.
replicAnt: A pipeline for generating annotated images of animals in complex environments using Unreal Engine
Authors: Plum Fabian , Bulla René , Beck Hendrik K. , Imirzian Natalie , Labonte David 
Published: April 2023

AbstractDeep learning-based computer vision methods are transforming animal behavioural research. Transfer learning has enabled work in non-model species, but still requires hand-annotation of example footage, and is only performant in well-defined conditions. To overcome these limitations, here we presentreplicAnt, a configurable pipeline implemented in Unreal Engine 5 and Python, designed to generate large and variable training datasets on consumer-grade hardware.replicAntplaces 3D animal models into complex, procedurally generated environments, from which automatically annotated images can be exported. We demonstrate that synthetic data generated withreplicAntcan significantly reduce the hand-annotation required to achieve benchmark performance in common applications such as animal detection, tracking, pose-estimation, and semantic segmentation. We also show that it increases the subject-specificity and domain-invariance of the trained networks, thereby conferring robustness. In some applications,replicAntmay even remove the need for hand-annotation altogether. It thus represents a significant step towards porting deep learning-based computer vision tools to the field.