bluuebunny/crossref_metadata_2025_split huggingface dataset:
WWOX promotes osteosarcoma development via upregulation of Myc
Authors: Akkawi Rania , Hidmi Osama , Yehya Ameen Haji , Monin Jonathon , Diment Judith , Drier Yotam , Stein Gary S. , Aqeilan Rami I. 
Published: March 2023

AbstractOsteosarcoma is an aggressive bone tumor that primarily affects children and adolescents. This malignancy is highly aggressive, associated with poor clinical outcomes, and primarily metastasizes to the lungs. Due to its rarity and biological heterogeneity, limited studies on its molecular basis exist, hindering the development of effective therapies. The WW domain-containing oxidoreductase (WWOX) is frequently altered in human osteosarcoma. Combined deletion ofWwoxandTrp53usingOsterix1-Cretransgenic mice has been shown to accelerate osteosarcoma development. In this study, we generated a traceable osteosarcoma mouse model harboring the deletion of Trp53 alone (single-knockout) or combined deletion of Wwox/Trp53 (double-knockout) and expressing a tdTomato reporter. By tracking Tomato expression at different time points, we detected the early presence of tdTomato-positive cells in the bone marrow mesenchymal stem cells of non-osteosarcoma-bearing mice (young BM). We found that double-knockout young BM cells, but not single-knockout young BM cells, exhibited tumorigenic traits both in vitro and in vivo. Molecular and cellular characterization of these double-knockout young BM cells revealed their resemblance to osteosarcoma tumor cells. Interestingly, one of the observed significant transcriptomic changes in double-knockout young BM cells was the upregulation of Myc and its target genes compared to single-knockout young BM cells. Intriguingly, Myc-chromatin immunoprecipitation sequencing revealed its increased enrichment on Myc targets, which were upregulated in double-knockout young BM cells. Restoration of WWOX in double-knockout young BM cells reduced Myc protein levels. As a prototype target, we demonstrated the upregulation of MCM7, a known Myc target, in double-knockout young BM relative to single-knockout young BM cells. Inhibition of MCM7 expression using simvastatin resulted in reduced proliferation and tumor cell growth of double-knockout young BM cells. Our findings reveal BM mesenchymal stem cells as a platform to study osteosarcoma and Myc and its targets as WWOX effectors and early molecular events during osteosarcomagenesis.
SpatialScope: A unified approach for integrating spatial and single-cell transcriptomics data using deep generative models
Authors: Wan Xiaomeng , Xiao Jiashun , Tam Sindy Sing Ting , Cai Mingxuan , Sugimura Ryohichi , Wang Yang , Wan Xiang , Lin Zhixiang , Wu Angela Ruohao , Yang Can 
Published: March 2023

AbstractThe rapid emergence of spatial transcriptomics (ST) technologies are revolutionizing our under-standing of tissue spatial architecture and their biology. Current ST technologies based on either next generation sequencing (seq-based approaches) or fluorescence in situ hybridization (image-based approaches), while providing hugely informative insights, remain unable to provide spatial characterization at transcriptome-wide single-cell resolution, limiting their usage in resolving detailed tissue structure and detecting cellular communications. To overcome these limitations, we developed SpatialScope, a unified approach to integrating scRNA-seq reference data and ST data that leverages deep generative models. With innovation in model and algorithm designs, SpatialScope not only enhances seq-based ST data to achieve single-cell resolution, but also accurately infers transcriptome-wide expression levels for image-based ST data. We demonstrate the utility of SpatialScope through comprehensive simulation studies and then apply it to real data from both seq-based and image-based ST approaches. SpatialScope provides a spatial characterization of tissue structures at transcriptome-wide single-cell resolution, greatly facilitating the downstream analysis of ST data, such as detection of cellular communication by identifying ligand-receptor interactions from seq-based ST data, localization of cellular subtypes, and detection of spatially differently expressed genes.
Lifespan Neurodegeneration Of The Human Brain In Multiple Sclerosis
Authors: Coupé Pierrick , Planche Vincent , Mansencal Boris , Kamroui Reda A. , Koubiyr Ismail , Manjon José V. , Tourdias Thomas 
Published: March 2023

AbstractBackgroundAtrophy related to Multiple Sclerosis (MS) has been found at the early stages of the disease. However, the archetype dynamic trajectories of the neurodegenerative process, even prior to clinical diagnosis, remain unknown.MethodsWe modeled the volumetric trajectories of brain structures across the entire lifespan using 40944 subjects (38295 healthy controls and 2649 MS patients). Then, we estimated the chronological progression of MS by assessing the divergence of lifespan trajectories between normal brain charts and MS brain charts.ResultsChronologically, the first affected structure was the thalamus, then the putamen and the pallidum (3 years later), followed by the ventral diencephalon (7 years after thalamus) and finally the brainstem (9 years after thalamus). To a lesser extent, the anterior cingulate gyrus, insular cortex, occipital pole, caudate and hippocampus were impacted. Finally, the precuneus and accumbens nuclei exhibited a limited atrophy pattern.ConclusionSubcortical atrophy was more pronounced than cortical atrophy. The thalamus was the most impacted structure with a very early divergence in life. It paves the way toward utilization of these lifespan models for future preclinical/prodromal prognosis and monitoring of MS.
Identification of potential selective autophagy receptors from protein-content profiling of autophagosomes
Authors: Cristiani Alberto , Dutta Arghya , Poveda-Cuevas Sergio Alejandro , Kern Andreas , Bhaskara Ramachandra M. 
Published: March 2023

AbstractSelective autophagy receptors (SARs) are central to cellular homeostatic and organellar recycling pathways. Over the last two decades, more than 30 SARs have been discovered and validated using a variety of experimental approaches ranging from cell biology to biochemistry, including high-throughput imaging and screening methods. Yet, the extent of selective autophagy pathways operating under various cellular contexts e.g., under basal and starvation conditions, remains unresolved. Currently, our knowledge of all known SARs and their associated cargo components is fragmentary and limited by experimental data with varying degrees of resolution. Here, we use classical predictive and modeling approaches to integrate high-quality autophagosome content profiling data with disparate datasets. We identify a global set of potential SARs and their associated cargo components active under basal autophagy, starvation-induced, and proteasome-inhibition conditions. We provide a detailed account of cellular components, biochemical pathways, and molecular processes that are degraded via autophagy. Our analysis yields a catalog of new potential SARs that satisfy the characteristics of bonafide, well-characterized SARs. We categorize them by the subcellular compartments they emerge from and classify them based on their likely mode of action. Our structural modeling validates a large subset of predicted interactions with the human ATG8 family of proteins and shows characteristic, conserved LC3-interacting region (LIR)–LIR-docking site (LDS) and Ubiquitin-interacting motif (UIM)–UIM-docking site (UDS) binding modes. Our analysis also revealed the most abundant cargo molecules targeted by these new SARs. Our findings expand the repertoire of SARs and provide unprecedented details into the global autophagic state of HeLa cells. Taken together, our findings provide motivation for the design of new experiments, testing the role of these novel factors in selective autophagy.
Perception of near-threshold visual stimuli is influenced by pre-stimulus alpha-band amplitude but not by alpha phase
Authors: Melcón María , Stern Enrique , Kessel Dominique , Arana Lydia , Poch Claudia , Campo Pablo , Capilla Almudena 
Published: March 2023

AbstractOngoing brain activity preceding visual stimulation has been suggested to shape conscious perception. The underlying mechanisms are still under debate, although alpha oscillations have been pointed out as the main explanatory candidate. According to the pulsed-inhibition framework, bouts of functional inhibition arise in each alpha cycle, allowing information to be processed in a pulsatile manner. Consequently, it has been hypothesized that perceptual outcome can be influenced by the specific phase of alpha oscillations prior to the stimulus onset, although empirical findings are controversial. In this study, we aimed to shed light on the role of pre-stimulus alpha oscillations in visual perception. To this end, we recorded electroencephalographic (EEG) activity while participants performed three near-threshold visual detection tasks with different attentional involvement: a no-cue task, a non-informative cue task (50% cue validity), and an informative cue task (100% cue validity). Cluster-based permutation statistics were complemented with Bayesian analyses to test the effect of pre-stimulus oscillatory amplitude and phase on visual awareness. We additionally examined whether these effects differed on trials with low and high oscillatory amplitude, as expected from the pulsed-inhibition theory. Our results show a clear effect of pre-stimulus alpha amplitude on conscious perception, but only when alpha fluctuated spontaneously and was not modulated by attention, supporting the notion that alpha-band power indexes neural excitability. In contrast, we did not find any evidence that pre-stimulus alpha phase influences the perceptual outcome, not even when differentiating between low and high amplitude trials. Furthermore, Bayesian analysis provided moderate evidence in favor of the absence of phase effects. Taken together, our results challenge the central theoretical predictions of the pulsed-inhibition framework, at least for the particular experimental conditions used here.
Engineering the biological conversion of formate into crotonate inCupriavidus necator
Authors: Collas Florent , Dronsella Beau B. , Kubis Armin , Schann Karin , Binder Sebastian , Arto Nils , Claassens Nico J. , Kensy Frank , Orsi Enrico 
Published: March 2023

AbstractTo advance the sustainability of the biobased economy, our society needs to develop novel bioprocesses based on truly renewable resources. The C1-molecule formate is increasingly proposed as carbon and energy source for microbial fermentations, as it can be efficiently generated electrochemically from CO2and renewable energy. Yet, its biotechnological conversion into value-added compounds has been limited to a handful of examples. In this work, we engineered the natural formatotrophic bacteriumC. necatoras cell factory to enable biological conversion of formate into crotonate, a platform short-chain unsaturated carboxylic acid of biotechnological relevance. First, we developed a small-scale (150-mL working volume) cultivation setup for growingC. necatorin minimal medium using formate as only carbon and energy source. By using a fed-batch strategy with automatic feeding of formic acid, we could increase final biomass concentrations 15-fold compared to batch cultivations in flasks. Then, we engineered a heterologous crotonate pathway in the bacteriumviaa modular approach, where each pathway section was assessed using multiple candidates. The best performing modules included a malonyl-CoA bypass for increasing the thermodynamic drive towards the intermediate acetoacetyl-CoA and subsequent conversion to crotonyl-CoA through partial reverse β-oxidation. This pathway architecture was then tested for formate-based biosynthesis in our fed-batch setup, resulting in a two-fold higher titer, three-fold higher productivity, and five-fold higher yield compared to the strain not harboring the bypass. Eventually, we reached a maximum product titer of 148.0 ± 6.8 mg/L. Altogether, this work consists in a proof-of-principle integrating bioprocess and metabolic engineering approaches for the biological upgrading of formate into a value-added platform chemical.
Topography of inputs into the hippocampal formation of a food-caching bird
Authors: Applegate Marissa C. , Gutnichenko Konstantin S. , Aronov Dmitriy 
Published: March 2023

AbstractThe mammalian hippocampal formation (HF) is organized into domains associated with different functions. These differences are driven in part by the pattern of input along the hippocampal long axis, such as visual input to the septal hippocampus and amygdalar input to temporal hippocampus. HF is also organized along the transverse axis, with different patterns of neural activity in the hippocampus and the entorhinal cortex. In some birds, a similar organization has been observed along both of these axes. However, it is not known what role inputs play in this organization. We used retrograde tracing to map inputs into HF of a food-caching bird, the black-capped chickadee. We first compared two locations along the transverse axis: the hippocampus and the dorsolateral hippocampal area (DL), which is analogous to the entorhinal cortex. We found that pallial regions predominantly targeted DL, while some subcortical regions like the lateral hypothalamus (LHy) preferentially targeted the hippocampus. We then examined the hippocampal long axis and found that almost all inputs were topographic along this direction. For example, the anterior hippocampus was preferentially innervated by thalamic regions, while posterior hippocampus received more amygdalar input. Some of the topographies we found bear resemblance to those described in the mammalian brain, revealing a remarkable anatomical similarity of phylogenetically distant animals. More generally, our work establishes the pattern of inputs to HF in chickadees. Some of these patterns may be unique to chickadees, laying the groundwork for studying the anatomical basis of these birds’exceptional hippocampal memory.
Hem25p is a mitochondrial IPP transporter
Authors: Tai Jonathan , Guerra Rachel M. , Rogers Sean W. , Fang Zixiang , Muehlbauer Laura K. , Shishkova Evgenia , Overmyer Katherine A. , Coon Joshua J. , Pagliarini David J. 
Published: March 2023

AbstractCoenzyme Q (CoQ, ubiquinone) is an essential cellular cofactor comprised of a redox-active quinone head group and a long hydrophobic polyisoprene tail. How mitochondria access cytosolic isoprenoids for CoQ biosynthesis is a longstanding mystery. Here, via a combination of genetic screening, metabolic tracing, and targeted uptake assays, we reveal that Hem25p—a mitochondrial glycine transporter required for heme biosynthesis—doubles as an isopentenyl pyrophosphate (IPP) transporter inSaccharomyces cerevisiae. Mitochondria lacking Hem25p fail to efficiently incorporate IPP into early CoQ precursors, leading to loss of CoQ and turnover of CoQ biosynthetic proteins. Expression of Hem25p inEscherichia colienables robust IPP uptake demonstrating that Hem25p is sufficient for IPP transport. Collectively, our work reveals that Hem25p drives the bulk of mitochondrial isoprenoid transport for CoQ biosynthesis in yeast.
Determine transposable genes when the orders of genes are different
Authors: Wang Yue 
Published: March 2023

AbstractCertain nucleotide sequences in DNA can change their positions. Such nucleotide sequences might be shorter than a general gene. When we restrict to nucleotide sequences that form complete genes, we can still find genes that change their relative locations in a genome. Thus for different individuals of the same species, the orders of genes might be different. Such spatial difference of gene orders might be affected by temporal difference of gene (mutation) orders, and can be used to explain the order of mutation problem in myeloproliferative neoplasm. A practical problem is to determine such transposable genes in given gene sequences. Through an intuitive rule, we transform the biological problem of determining transposable genes into a rigorous mathematical problem of determining the longest common subsequence. Given several number sequences, determining the longest common subsequence is a classical problem in computer science. Depending on whether the gene sequence is linear or circular, and whether genes have multiple copies, we classify the problem of determining transposable genes into different scenarios and design corresponding algorithms. Specifically, we study the situation where the longest common subsequence is not unique.
A Novel Transcription Factor Combination for Direct Reprogramming to a Spontaneously Contracting Human Cardiomyocyte-like State
Authors: Romero-Tejeda Marisol , Fonoudi Hananeh , Weddle Carly J. , DeKeyser Jean-Marc , Lenny Brian , Fetterman K. Ashley , Magdy Tarek , Sapkota Yadav , Epting Conrad , Burridge Paul W. 
Published: March 2023

ABSTRACTThe reprogramming of somatic cells to a spontaneously contracting cardiomyocyte-like state using defined transcription factors has proven successful in mouse fibroblasts. However, this process has been less successful in human cells, thus limiting the potential clinical applicability of this technology in regenerative medicine. We hypothesized that this issue is due to a lack of cross-species concordance between the required transcription factor combinations for mouse and human cells. To address this issue, we identified novel transcription factor candidates to induce cell conversion between human fibroblasts and cardiomyocytes, using the network-based algorithm Mogrify. We developed an automated, high-throughput method for screening transcription factor, small molecule, and growth factor combinations, utilizing acoustic liquid handling and high-content kinetic imaging cytometry. Using this high-throughput platform, we screened the effect of 4,960 unique transcription factor combinations on direct conversion of 24 patient-specific primary human cardiac fibroblast samples to cardiomyocytes. Our screen revealed the combination ofMYOCD,SMAD6, andTBX20(MST) as the most successful direct reprogramming combination, which consistently produced up to 40% TNNT2+cells in just 25 days. Addition of FGF2 and XAV939 to the MST cocktail resulted in reprogrammed cells with spontaneous contraction and cardiomyocyte-like calcium transients. Gene expression profiling of the reprogrammed cells also revealed the expression of cardiomyocyte associated genes. Together, these findings indicate that cardiac direct reprogramming in human cells can be achieved at similar levels to those attained in mouse fibroblasts. This progress represents a step forward towards the clinical application of the cardiac direct reprogramming approach.GRAPHICAL ABSTRACTHIGHLIGHTSUsing network-based algorithm Mogrify, acoustic liquid handling, and high-content kinetic imaging cytometry we screened the effect of 4,960 unique transcription factor combinations.Using 24 patient-specific human fibroblast samples we identified the combination ofMYOCD,SMAD6, andTBX20(MST) as the most successful direct reprogramming combination.MST cocktail results in reprogrammed cells with spontaneous contraction, cardiomyocyte-like calcium transients, and expression of cardiomyocyte associated genes.
Phosphorylation barcodes direct biased chemokine signaling at CXCR3
Authors: Eiger Dylan S. , Smith Jeffrey S. , Shi Tujin , Stepniewski Tomasz Maciej , Tsai Chia-Feng , Honeycutt Christopher , Boldizsar Noelia , Gardner Julia , Nicora Carrie D. , Moghieb Ahmed M. , Kawakami Kouki , Choi Issac , Zheng Kevin , Warman Anmol , Alagesan Priya , Knape Nicole M. , Huang Ouwen , Silverman Justin D. , Smith Richard D. , Inoue Asuka , Selent Jana , Jacobs Jon M. , Rajagopal Sudarshan 
Published: March 2023

SUMMARYG protein-coupled receptor (GPCR) biased agonism, the activation of some signaling pathways over others, is thought to largely be due to differential receptor phosphorylation, or “phosphorylation barcodes.” At chemokine receptors, ligands act as “biased agonists” with complex signaling profiles, which contributes to the limited success in pharmacologically targeting these receptors. Here, mass spectrometry-based global phosphoproteomics revealed that CXCR3 chemokines generate different phosphorylation barcodes associated with differential transducer activation. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of CXCR3 phosphosites altered β-arrestin conformation in cellular assays and was confirmed by molecular dynamics simulations. T cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles. Our results demonstrate that CXCR3 chemokines are non-redundant and act as biased agonists through differential encoding of phosphorylation barcodes and lead to distinct physiological processes.
Speed-dependent optimization of gravity effects for motor control
Authors: Poirier Gabriel , Mourey France , Sirandre Cyril , Papaxanthis Charalambos , Gaveau Jeremie 
Published: March 2023

AbstractSeveral sensorimotor control studies have provided evidence supporting that the central nervous system optimizes gravity’s effects to minimize muscle effort. Recently, this hypothesis has been supported by the consistent observation of direction-specific negative epochs in the phasic electromyographic signal of antigravity muscles during vertical arm movements. This suggests that gravity torque is harvested to produce some of the arm’s motion. However, further investigation is needed to more finely understand how the CNS integrates gravity effects into muscle commands. Here, we aimed to analyze the phasic muscular activity across varying movement speeds during horizontal and vertical arm movements. We quantified the amount of negativity during acceleration and deceleration phases for all movement directions during fast, natural, and slow movements. We found that the negativity was more important during the acceleration phase of downward movements and during the deceleration phase of upward movements, resulting in diminished phasic activity compared to horizontal movements. Concomitantly, we found direction-specific effects of movement speed on phasic EMG activity of gravity muscles. This resulted in altered EMG to kinematics relationships in vertical movements compared to horizontal ones. These results support theEffort-minimization hypothesisand confirm that the negativity of phasic EMG is an important aspect of the motor command. Furthermore, the present results reveal that the CNS finely tunes this feature across a range of movement speeds and directions.