bluuebunny/crossref_metadata_2025_split huggingface dataset:
HeberFERON distinctively targets Cell Cycle in the glioblastoma-derived cell line U-87MG
Authors: Miranda Jamilet , Vázquez-Blomquist Dania , Bringas Ricardo , Fernández-de-Cossio Jorge , Palenzuela Daniel , Novoa Lidia I. , Bello-Rivero Iraldo 
Published: September 2022

AbstractBackgroundHeberFERON is a co-formulation of α2b and γ interferons, based on their synergism, that have shown its clinical superiority over individual interferons in basal cell carcinomas. In Glioblastoma (GBM), HeberFERON has shown promising preclinical and clinical results. This motivated us to design a microarray experiment aimed to identify the molecular mechanisms involved into the distinctive effect of HeberFERON compared with individual interferons.MethodsTranscriptional expression profiling including a control (untreated) and three groups receiving α2b-interferon, γ-interferon and HeberFERON was performed using an Illumina HT-12 microarray platform. Unsupervised methods for gene and sample grouping, identification of differentially expressed genes, functional enrichment and network analysis computational biology methods were applied to identify distinctive patterns of HeberFERON action. Validation of most distinctive genes was performed by qPCR. Cell Cycle analysis of cell treated by HeberFERON for 24h, 48h and 72h was carried out by flow cytometry.ResultsThe three treatments show different behavior based on the gene expression profiles. Enrichment analysis identified several Mitotic Cell Cycle related events, in particular from Prometaphase to Anaphase, that are exclusively targeted by HeberFERON. FOXM1 transcription factor network which is involved in several Cell Cycle phases and is highly expressed in GBMs is significantly down regulated by HeberFERON. Flow cytometry experiments corroborated the action of HeberFERON over Cell Cycle in a dose and time dependent manner with a clear cellular arrest since 24h post-treatment. Despite the fact that p53 was not down-regulated by HeberFERON several genes involved in its regulatory activity were functionally enriched. Network analysis also revealed a strong relation of p53 with genes targeted by HeberFERON. We propose a mechanistic model to explain HeberFERON distinctive action, based on the simultaneous activation of PKR and ATF3, p53 phosphorylation changes as well as its reduced MDM2 mediated ubiquitination and export from nucleus to cytoplasm. PLK1, AURKB, BIRC5 and CCNB1 genes, all regulated by FOXM1, also play central roles in this model. These and other interactions could explain a G2/M arrest and the effect of HeberFERON over the proliferation of U-87MG.ConclusionsWe proposed molecular mechanisms underlying the distinctive behavior of HeberFERON compared to individual interferon treatments, where Cell Cycle related events showed the highest relevance.
The Effect of Bottleneck Size on Evolution in Nested Darwinian Populations
Authors: Nitschke Matthew C. , Black Andrew J. , Bourrat Pierrick , Rainey Paul B. 
Published: September 2022

AbstractPrevious work has shown how a minimal ecological structure consisting of patchily distributed resources and recurrent dispersal between patches can scaffold Darwinian properties onto collections of cells. When the timescale of dispersal is long compared with the time to consume resources, patches evolve such that their size increases, but at the expense of cells whose growth rate decreases within patches. This creates the conditions that initiate evolutionary transitions in individuality. A key assumption of this scaffolding is that a bottleneck is created during dispersal, so patches are founded by single cells. The bottleneck decreases competition within patches and hence creates a strong hereditary link at the level of patches. Here we construct a fully stochastic model of nested Darwinian populations and investigate how larger bottlenecks affect the evolutionary dynamics at both cell and collective levels. It is shown that, up to a point, larger bottlenecks simply slow the dynamics, but at some point, which depends on the parameters of the within-patch model, the direction of evolution toward the equilibrium is reversed. Introducing random bottleneck sizes with some positive probability of smaller sizes can counteract this, even if the probability of smaller bottlenecks is small.
Conformable neural interface based on off-stoichiometry thiol-ene-epoxy thermosets
Authors: Borda Eleonora , Airaghi Leccardi Marta Jole Ildelfonsa , Medagoda Danashi Imani , Zollinger Elodie Geneviève , Ghezzi Diego 
Published: September 2022

AbstractOff-stoichiometry thiol-ene-epoxy (OSTE+) thermosets have recently gained attention for the rapid prototyping of microfluidic chips because they show low permeability to gases and little absorption of dissolved molecules, they allow direct low-temperature dry bonding without surface treatments, they have a low Young’s modulus, and they can be manufactured via UV polymerisation. The compatibility with standard clean-room processes and the outstanding mechanical properties make OSTE+ an excellent candidate as a novel material for neural implants. Here we exploit OSTE+ to manufacture a conformable multilayer micro-electrocorticography array with 16 platinum electrodes coated with platinum black. The mechanical properties allow device conformability to curved surfaces such as the brain. The low permeability and strong adhesion between layers improve the stability of the device. Acute experiments in mice show the multimodal capacity of the array to record and stimulate the neural tissue by smoothly conforming to the mouse cortex. Devices are not cytotoxic, and immunohistochemistry stainings reveal only modest foreign body reaction after two and six weeks of implantation. This work introduces OSTE+ as a promising material in the field of implantable neural interfaces.
Exploitation of ATP-sensitive potassium ion (KATP) channels by HPV promotes cervical cancer cell proliferation by contributing to MAPK/AP-1 signalling
Authors: Scarth James A. , Wasson Christopher W. , Patterson Molly R. , Evans Debra , Barba-Moreno Diego , Carden Holli , Whitehouse Adrian , Mankouri Jamel , Samson Adel , Morgan Ethan L. , Macdonald Andrew 
Published: September 2022

AbstractPersistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (KATP) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or KATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of KATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of KATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer.
Fibroblast activation during decidualization: Embryo-derived TNFα induction of PGI2-PPARδ-ACTIVIN A pathway through luminal epithelium
Authors: Chen Si-Ting , Shi Wen-Wen , Lin Yu-Qian , Yang Zhen-Shang , Wang Ying , Li Meng-Yuan , Li Yue , Liu Ai-Xia , Hu Yali , Yang Zeng-Ming 
Published: September 2022

ABSTRACTObjectivesHuman endometrium undergoes cyclical shedding and bleeding, scar-free repair and regeneration in subsequent cycles. Fibroblast activation has been shown to play a key role during normal tissue repair and scar formation. Abnormal fibroblast activation leads to fibrosis. Fibrosis is the main cause of intrauterine adhesion, uterine scaring, and thin endometrium. Endometrial decidualization is a critical step during early pregnancy. There are 75% of pregnancy failures pointed to decidualization defects. Because fibroblast activation and decidualization share similar markers, we assumed that fibroblast activation should be involved in decidualization.Materials and MethodsBoth pregnant and pseudopregnant ICR mice were used in this study. Immunofluorescence and immunohistochemistry were applied to examine fibroblast activation-related markers in mouse uteri. Western blotting was used to identify the impact on decidualization. Western blot and RT were used to show how arachidonic acid and its downstream product prostaglandin activate fibroblasts. Additionally, embryo-derived TNFα was shown to stimulate the secretion of arachidonic acid by immunofluorescence, western blot, and ELASA. The aborted decidual tissues with fetal trisomy 16 were compared with control tissues. GraphPad Prism5.0 Student’s t test was used to compare differences between control and treatment groupsResultsFibroblast activation-related markers are obviously detected in pregnant decidua and under in vitro decidualization. ACTIVIN A secreted under fibroblast activation promotes in vitro decidualization. We showed that arachidonic acid released from uterine luminal epithelium can induce fibroblast activation and decidualization through PGI2and its nuclear receptor PPAR-δ. Based on the significant difference of fibroblast activation-related markers between pregnant and pseudopregnant mice, we found that embryo-derived TNFα promotes cPLA2αphosphorylation and arachidonic acid release from luminal epithelium. Fibroblast activation is also detected under human in vitro decidualization. Similar arachidonic acid-PGI2-PPARδ-ACTIVIN A pathway is conserved in human endometrium. Compared to controls, fibroblast activation is obviously compromised in human decidual tissues with fetal trisomy 16.ConclusionsEmbryo-derived TNFα promotes cPLA2α phosphorylation and arachidonic acid release from luminal epithelium to induce fibroblast activation and decidualization.Graphic abstract
A Drosophila model of diabetic neuropathy reveals a crucial role of proteasome activity in the glia
Authors: Suzuki Mari , Kuromi Hiroshi , Shindo Mayumi , Sakata Nozomi , Niimi Naoko , Fukui Koji , Saitoe Minoru , Sango Kazunori 
Published: September 2022

SUMMARYDiabetic peripheral neuropathy (DPN) is the most common chronic, progressive complication of diabetes mellitus. The main symptom is sensory loss; the molecular mechanisms are not fully understood. We found that Drosophila fed a high-sugar diet, which induces diabetes-like phenotypes, exhibit impairment of noxious heat avoidance. The impairment of heat avoidance was associated with shrinkage of the leg neurons expressing the Drosophila transient receptor potential channel Painless. Using a candidate genetic screening approach, we identified proteasome modulator 9 as one of the modulators of impairment of heat avoidance. We further showed that proteasome inhibition in the glia reversed the impairment of noxious heat avoidance, and heat-shock proteins and exosome secretion in the glia mediated the effect of proteasome inhibition. Our results establish Drosophila as a useful system for exploring molecular mechanisms of diet-induced peripheral neuropathy and propose that the glial proteasome is one of the candidate therapeutic targets for DPN.
A high-resolution, nanopore-based artificial intelligence assay for DNA replication stress in human cancer cells
Authors: Jones Mathew J.K. , Rai Subash Kumar , Pfuderer Pauline L. , Bonfim-Melo Alexis , Pagan Julia K. , Clarke Paul R. , McClelland Sarah E. , Boemo Michael A. 
Published: September 2022

AbstractDNA replication stress is a hallmark of cancer that is exploited by chemotherapies. Current assays for replication stress have low throughput and poor resolution whilst being unable to map the movement of replication forks genome-wide. We present a new method that uses nanopore sequencing and artificial intelligence to map forks and measure their rates of movement and stalling in melanoma and colon cancer cells treated with chemotherapies. Our method can differentiate between fork slowing and fork stalling in cells treated with hydroxyurea, as well as inhibitors of ATR, WEE1, and PARP1. These different therapies yield different characteristic signatures of replication stress. We assess the role of the intra-S-phase checkpoint on fork slowing and stalling and show that replication stress dynamically changes over S-phase. This method requires sequencing on only a single nanopore flow cell, and the cost-effectiveness and high throughput enables functional screens to determine how human cancers respond to replication-targeted therapies.
Deletion of Tac1 gene impact kinase phosphorylation involved in signaling pathways associated with pain
Authors: Ben Salem Jennifer , Zhang Ji , Beaudry Francis 
Published: September 2022

AbstractPain in elderly persons is often not adequately treated, and current treatments may lead to poor outcomes. Therefore, new treatment strategies need to be developed based on a better understanding of the mechanisms underlying the development of chronic pain. Recent studies have shown that Tac1-/-mice display a significant decrease in nociceptive pain responses to moderate or intense stimuli but present no phenotypic changes following light or nonpainful stimuli. Moreover, the deletion of the Tac1 gene led to a deficit of opioid peptides, which are essential to endogenous pain control mechanisms. Thus, we investigated whether Tac1-/-mice show defective pain modulatory pathways by specifically profiling protein kinases in mice spinal cord using phosphoproteomics and bioinformatics. Protein phosphorylation is a key feature of the cellular regulatory mechanism, and phosphorylation status is related to the regulation and modulation of protein–protein binding. Bioinformatics analysis revealed that MAPK, tyrosine kinase, senescence, interleukin signaling, and TCR signaling are modulated in Tac1-/-mice. Interestingly, these processes are intimately linked with inflammatory responses leading to the release of cytokines and chemokines implicated in the interactions and communications between cells. They are key players involved in the initiation and persistence of pathologic pain. The absence of the Tac1 gene products may trigger a much wider cell response to compensate for the lack of important components of the nociceptive pain transmission system.
ESCRT-dependent STING degradation curtails steady-state and cGAMP-induced signaling
Authors: Gentili Matteo , Liu Bingxu , Papanastasiou Malvina , Dele-Oni Deborah , Schwartz Marc A , Carlson Rebecca J. , Al’Khafaji Aziz , Krug Karsten , Brown Adam , Doench John G , Carr Steven A , Hacohen Nir 
Published: September 2022

AbstractSTING is an intracellular sensor of cyclic di-nucleotides involved in response to pathogen- or self-derived DNA that induces protective immunity, or if dysregulated, autoimmunity. STING trafficking is tightly linked to its activity. We aimed to systematically characterize genes regulating STING trafficking and to define their impact on STING responses. Based on proximity-ligation proteomics and genetic screens, an ESCRT complex containing HGS, VPS37A and UBAP1 was found to be required for STING degradation and signaling shutdown. Analogous to phosphorylated STING creating a platform for IRF3 recruitment, oligomerization-driven STING ubiquitination by UBE2N formed a platform for ESCRT recruitment at the endosome, responsible for STING signaling shutdown. A UBAP1 mutant that underlies human spastic paraplegia and disrupts ESCRT function led to STING-dependent type I IFN responses at the steady-state, defining ESCRT as a homeostatic regulator of STING signaling.
Deciphering bacteriophage T5 host recognition mechanism and infection trigger
Authors: Degroux Séraphine , Effantin Grégory , Linares Romain , Schoehn Guy , Breyton Cécile 
Published: September 2022

AbstractBacteriophages, viruses infecting bacteria, recognise their host with high specificity, either binding to saccharide motifs or proteins of the cell wall of their host. In the majority of bacteriophages, this host recognition is performed by Receptor Binding Proteins (RBPs) located at the extremity of a tail. Interaction between the RBPs and the host is the trigger for bacteriophage infection, but the molecular details of the mechanisms are unknown for the majority of bacteriophages. Here, we present the electron cryo-microscopy structure of bacteriophage T5 RBPpb5 in complex with its E. coli receptor, the iron ferrichrome transporter FhuA. Monomeric RBPpb5 is located at the extremity of T5 long flexible tail, and its irreversible binding to FhuA commits T5 to infection. Analysis of RBPpb5 structure within the complex, comparison with its AlphaFold2 predicted structure, and its fit into a previously determined map of T5 tail tip in complex with FhuA allow us to propose a mechanism of transmission of RBPpb5 receptor binding to the straight fibre, initiating the cascade of events that commits T5 to DNA ejection.
In-silico analysis of cyanobacteriochrome architectures and spectral diversity
Authors: Mihnev Aleksandar , Amtmann Anna 
Published: September 2022

ABSTRACTThe cyanobacteriochrome GAF domains represent a trove of spectral diversity. These proteins are endemic to cyanobacteria and sense the color and power of light. Multiple mechanisms are used to tune the natural absorbance spectrum of the bound bilin chromophore. In practice, these are difficult to identify from the predicted amino acid sequence. Their individual presence rarely yields a consistent and predictable outcome. The absorbance characteristics of the GAF domain are a complex function of many such tuning mechanisms. This implies that a more combinatoric approach to characterizing the diversity of GAF domains would better to predict spectral tunes. We reviewed the literature and constructed a dataset of predicted/confirmed cyanobacteriochrome GAF domains. This dataset was subjected to multiple sequence alignments and 18 GAF domain families were defined. The amino acid sequence similarity correlated well with known spectral characteristics but there were exceptions. A second approach to predict chromotype involved using Principal Component Analysis to characterize the whole domain architectures of cyanobacteriochrome. This approach identified 7 conserved domain architectures, with some variations. These also offered a correlation to the spectral tune of the GAF domains therein, in addition to the 18 GAF families. The three-dimensional structures of 98 spectrally characterized GAF domains were predicted using Phyre2. Subsequent grouping based on distance maps offered an insight into how the general spectral position of the domain is set. Finer tuning is likely to be achieved by means of six key residues within the binding pocket. Taken together, these insights allowed us to carry out a Multiple Correlation Analysis serving as a mathematical summary of the diversity of cyanobacteriochrome GAF domains. This summary or “cyanobacteriochrome atlas” can be used to make spectral predictions on uncharacterized GAF domains.
Prediction of Biopharmaceutical Characteristics of PROTACs using the ANDROMEDA by Prosilico Software
Authors: Fagerholm Urban , Hellberg Sven , Alvarsson Jonathan , Spjuth Ola 
Published: September 2022

ABSTRACTBackgroundPROTACs are comparably large and flexible compounds with limited solubility (S) and permeability (Pe). It is crucial to better understand, predict and optimize their human clinical pharmacokinetics (PK).MethodsThe main objective was to use the ANDROMEDA by Prosilico software to predict the human clinicalin vivodissolution potential (fdiss) and fraction absorbed (fa) of 23 PROTACs at a dose level of 50 mg and to explore whether there is any relationship betweenin vitroS andin silicopredictedin vivofdiss.ResultsIn silicopredictions showed that the PROTACs are effluxed by intestinal transporters and have limited fdiss(34 to 98 %), permeability and fa(13 to 58 %) in man. For some PROTACs this may be a major obstacle and jeopardize the clinical development programs, especially in cases of required high oral dose. A modest relationship betweenin vitroS and predictedin vivofdisswas demonstrated (R2=0.26). Predicted human fa(27 %) and oral bioavailability (20 %) of ARV-110 (a PROTAC with some availablein vivoPK data in rodents and man) were consistent with data obtained in rodents (estimated faapproximately 30-40 %; measured oral bioavailability 27-38 %). Laboratories were unable to quantify S for 7 (30 %) of the PROTACs. In contrast, ANDROMEDA could predict parameters for all.ConclusionANDROMEDA predicted fdissand fafor all the chosen PROTACs and showed limited fdiss, Peand faand dose-dependent fdissand fa. One available example shows promise for the applicability of ANDROMEDA for predicting biopharmaceutics of PROTACsin vivoin man. Weak to modest correlations between S and fdissand a considerable portion of compounds with non-quantifiable S limit the use of S-data to predict the uptake of PROTACs.
A data-driven investigation of human action representations
Authors: Dima Diana C. , Hebart Martin N. , Isik Leyla 
Published: September 2022

AbstractUnderstanding actions performed by others requires us to integrate different types of information about people, scenes, objects, and their interactions. What organizing dimensions does the mind use to make sense of this complex action space? To address this question, we collected intuitive similarity judgments across two large-scale sets of naturalistic videos depicting everyday actions. We used cross-validated sparse non-negative matrix factorization (NMF) to identify the structure underlying action similarity judgments. A low-dimensional representation, consisting of nine to ten dimensions, was sufficient to accurately reconstruct human similarity judgments. The dimensions were robust to stimulus set perturbations and reproducible in a separate odd-one-out experiment. Human labels mapped these dimensions onto semantic axes relating to food, work, and home life; social axes relating to people and emotions; and one visual axis related to scene setting. While highly interpretable, these dimensions did not share a clear one-to-one correspondence with prior hypotheses of action-relevant dimensions. Together, our results reveal a low-dimensional set of robust and interpretable dimensions that organize intuitive action similarity judgments and highlight the importance of data-driven investigations of behavioral representations.