bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathogenic mis-splicing of CPEB4 in schizophrenia
Authors: Ollà Ivana , Pardiñas Antonio F. , Parras Alberto , Hernández Ivó H. , Santos-Galindo María , Picó Sara , Callado Luis F. , Elorza Ainara , Fernández-Miranda Gonzalo , Belloc Eulàlia , Walters James T.R. , O’Donovan Michael C. , Toma Claudio , Méndez Raúl , Meana J. Javier , Owen Michael J. , Lucas José J.
Published: September 2022

Schizophrenia (SCZ) is caused by a complex interplay of polygenic risk and environmental factors, which might alter regulators of gene expression leading to pathogenic mis-expression of SCZ risk genes. The RNA binding protein family CPEB (CPEB1, CPEB2, CPEB3, CPEB4) regulates the translation of target RNAs bearing CPE sequences in their 3’UTR (approximately 40% of overall genes). We previously identified CPEB4 as a key dysregulated translational regulator in autism spectrum disorder (ASD), proving that its neuronal-specific microexon (exon 4) is mis-spliced in brains of ASD probands, leading to concerted underexpression of a plethora of high confidence ASD-risk genes. The genetic and pathogenic mechanisms shared between SCZ and ASD make it plausible that mis-splicing of CPEB4 might occur also in SCZ patients, leading to downstream altered brain expression of multiple SCZ-related genes. In this study, we first analyzed Psychiatric Genomics Consortium GWAS data and found significant enrichment of SCZ-associated genes for CPEB4-binder transcripts. We also found decreased inclusion of CPEB4 microexon in postmortem prefrontal cortex of SCZ probands. This mis-splicing is associated with decreased protein levels of SCZ-associated genes that are targets of CPEB4. Interestingly, this happens specifically in individuals with low exposure to antipsychotic medication. Finally, we show that mild overexpression of a CPEB4 transcript lacking exon 4 (CPEB4Δ4) in mice suffices to induce decreased protein levels of SCZ genes targeted by CPEB4; these mice are also characterized by SCZ-linked behaviors. In summary, this study identifies aberrant CPEB4 splicing and downstream mis-expression of SCZ-risk genes as a novel etiological mechanism in SCZ.
Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain
Authors: Cermak Samantha , Centeno Maria Virginia , Jabakhanji Rami , Vigotsky Andrew , Cox Julia , Brink Andrew , Apkarian Apkar Vania
Published: September 2022

We studied the behavioral consequences of fentanyl vapor self-administration (SA) in mice with and without chronic neuropathic pain (one month after spared-nerve injury(SNI) model or sham injury). We assessed fentanyl consumption, motivation, and seeking during as well as anxiety, hyperactivity, immobility, and pain for two regimens of fentanyl SA: 1) Dose escalation, where over a 3-week period mice are exposed (daily 2-hour sessions) to escalating numbers of fentanyl puffs per active nosepoke (from 1 puff/active nosepoke for first 3 days, up to 6 puffs/active nosepoke in days 16-18). 2) Effort escalation, where over a 3-week period (daily 2-hour sessions) mice need to increase effort to acquire the same amount of fentanyl (fixed ratio 1 (FR) = 1 active nosepoke results in 1 fentanyl puff, while second and third week we use FR5 and FR10). We observe sex-, injury- and regimen-dependent differences in outcomes. Importantly the dose escalation regimen resulted in higher seeking behavior (post forced abstinence, context and cue driven nosepoking in the absence of fentanyl delivery), long lasting increased anxiety, immobility, and hyperactivity, as well as transient but full pain relief in SNI mice. Therefore, this regimen seems a better rodent model for translating outcomes to human chronic pain patients managed with opioids.
Pharmacological inhibition of bromodomain and extra-terminal proteins induces NRF-2-mediated inhibition of SARS-CoV-2 replication and is subject to viral antagonism
Authors: Mhlekude Baxolele , Postmus Dylan , Weiner January , Stenzel Saskia , Zapatero-Belinchón Francisco J. , Olmer Ruth , Jansen Jenny , Richter Anja , Heinze Julian , Heinemann Nicolas , Mühlemann Barbara , Schroeder Simon , Jones Terry C. , Müller Marcel Alexander , Drosten Christian , Pich Andreas , Thiel Volker , Martin Ulrich , Niemeyer Daniela , Gerold Gisa , Beule Dieter , Goffinet Christine
Published: September 2022

Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of ACE2 expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions on their clinical suitability in the context of COVID-19.
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

Background

HeberFERON 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.

Methods

Transcriptional 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.

Results

The 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.

Conclusions

We 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

Previous 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

Off-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

Persistent 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

Objectives

Human 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 Methods

Both 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 groups

Results

Fibroblast 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.

Conclusions

Embryo-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

Diabetic 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

DNA 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

Pain 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

STING 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

Bacteriophages, 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

The 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

Background

PROTACs 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).

Methods

The 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.

Results

In 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.

Conclusion

ANDROMEDA 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

Understanding 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.
CLASP2 facilitates dynamic actin filament organization along the microtubule lattice
Authors: Rodgers NC , Lawrence EJ , Sawant AV , Efimova N , Gonzalez-Vasquez G , Hickman TT , Kaverina I , Zanic M
Published: September 2022

Coordination between the microtubule and actin networks is essential for cell motility, neuronal growth cone guidance, and wound healing. Members of the CLASP (Cytoplasmic Linker-Associated Protein) family of proteins have been implicated in the cytoskeletal crosstalk between microtubules and actin networks, however, the molecular mechanisms underlying CLASPs role in cytoskeletal coordination are unclear. Here, we investigate CLASP2α’s crosslinking function with microtubules and F-actin. Our results demonstrate that CLASP2α crosslinks F-actin to the microtubule lattice in vitro. We find that the crosslinking ability is retained by L-TOG2-S, a minimal construct containing the TOG2 domain and serine-arginine rich region of CLASP2α. Furthermore, CLASP2α promotes the accumulation of multiple actin filaments along the microtubule, supporting up to 11 F-actin landing events on a single microtubule lattice region. CLASP2α also facilitates dynamic organization of polymerizing actin filaments templated by the microtubule network, with F-actin forming bridges between individual microtubules. Finally, we find that depletion of CLASPs in vascular smooth muscle cells results in disorganized actin fibers and reduced co-alignment of actin fibers with microtubules, suggesting that CLASP and microtubules contribute to higher-order actin structures. Taken together, our results indicate that CLASP2α can directly crosslink F-actin to microtubules, and that this microtubule-CLASP-actin interaction may influence overall cytoskeletal organization in cells.
Generation and functional analysis of defective viral genomes during SARS-CoV-2 infection
Authors: Zhou Terry , Gilliam Nora J. , Li Sizhen , Spaudau Simone , Osborn Raven M. , Anderson Christopher S. , Mariani Thomas J. , Thakar Juilee , Dewhurst Stephen , Mathews David H. , Huang Liang , Sun Yan
Published: September 2022

Defective viral genomes (DVGs) have been identified in many RNA viruses as a major factor influencing antiviral immune response and viral pathogenesis. However, the generation and function of DVGs in SARS-CoV-2 infection are less known. In this study, we elucidated DVG generation in SARS-CoV-2 and its relationship with host antiviral immune response. We observed DVGs ubiquitously from RNA-seq datasets ofin vitroinfections and autopsy lung tissues of COVID-19 patients. Four genomic hotspots were identified for DVG recombination and RNA secondary structures were suggested to mediate DVG formation. Functionally, bulk and single cell RNA-seq analysis indicated the IFN stimulation of SARS-CoV-2 DVGs. We further applied our criteria to the NGS dataset from a published cohort study and observed significantly higher DVG amount and frequency in symptomatic patients than that in asymptomatic patients. Finally, we observed unusually high DVG frequency in one immunosuppressive patient up to 140 days after admitted to hospital due to COVID-19, first-time suggesting an association between DVGs and persistent viral infections in SARS-CoV-2. Together, our findings strongly suggest a critical role of DVGs in modulating host IFN responses and symptom development, calling for further inquiry into the mechanisms of DVG generation and how DVGs modulate host responses and infection outcome during SARS-CoV-2 infection.

Importance

Defective viral genomes (DVGs) are ubiquitously generated in many RNA viruses, including SARS-CoV-2. Their interference activity to full-length viruses and IFN stimulation provide them the potential for novel antiviral therapies and vaccine development. SARS-CoV-2 DVGs are generated through the recombination of two discontinuous genomic fragments by viral polymerase complex and the recombination is also one of the major mechanisms for the emergence of new coronaviruses. Focusing on the generation and function of SARS-CoV-2 DVGs, these studies identify new hotspots for non-homologous recombination and strongly suggest that the secondary structures within viral genomes mediate the recombination. Furthermore, these studies provide the first evidence for IFN stimulation activity ofde novoDVGs during natural SARS-CoV-2 infection. These findings set up the foundation for further mechanism studies of SARS-CoV-2 recombination and provide the evidence to harness DVGs’ immunostimulatory potential in the development of vaccine and antivirals for SARS-CoV-2.
Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms
Authors: Nagasaka Kota , Davidson Iain F. , Stocsits Roman R. , Tang Wen , Wutz Gordana , Betty Paul , Panarotto Melanie , Litos Gabriele , Schleiffer Alexander , Gerlich Daniel Wolfram , Peters Jan-Michael
Published: September 2022

Cohesin connects CTCF binding sites and other genomic loci in cis to form chromatin loops, and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here we describe a cohesin hinge mutant, which can extrude DNA into loops but is unable to mediate cohesion. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesin’s cohesion and loop extrusion activities can be separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wildtype cohesin. This suggests that cohesion establishment and cohesin’s interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.
Drug repurposing for Cystic Fibrosis: identification of drugs that induce CFTR-independent fluid secretion in nasal organoids
Authors: Rodenburg Lisa W. , Delpiano Livia , Railean Violeta , Centeio Raquel , Pinto Madalena C. , Smits Shannon M.A. , van der Windt Isabelle S. , van Hugten Casper F.J. , van Beuningen Sam F.B. , Rodenburg Remco N.P. , van der Ent Cornelis K. , Amaral Margarida D. , Kunzelmann Karl , Gray Michael A. , Beekman Jeffrey M. , Amatngalim Gimano D.
Published: September 2022

Individuals with Cystic Fibrosis (CF) suffer from severe respiratory disease due to a genetic defect in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene, which impairs airway epithelial ion and fluid secretion. New CFTR modulators that restore mutant CFTR function have been recently approved for a large group of people with CF (pwCF), but ∼19% of pwCF cannot benefit from CFTR modulators [1]. Restoration of epithelial fluid secretion through non-CFTR pathways might be an effective treatment for all pwCF. Here we developed a medium-throughput 384-wells screening assay using nasal CF airway epithelial organoids, with the aim to repurpose FDA-approved drugs as modulators of non-CFTR dependent epithelial fluid secretion. From a ∼1400 FDA-approved drug library, we identified and validated 12 FDA-approved drugs that induced CFTR-independent fluid secretion. Among the hits were several cAMP-mediating drugs, including β2-adrenergic agonists. The hits displayed no effects on chloride conductance measured in Ussing chamber, and fluid secretion was not affected by TMEM16A as demonstrated by knockout (KO) experiments in primary nasal epithelial cells. Altogether, our results demonstrate the use of primary nasal airway cells for mediumscale drug screening, target validation with a highly efficient protocol for generating CRISPR-Cas9 KO cells and identification of compounds which induce fluid secretion in a CFTR- and TMEM16A-indepent manner.
Multifaceted modes of γ-tubulin complex recruitment and microtubule nucleation at mitotic centrosomes
Authors: Zhu Zihan , Becam Isabelle , Tovey Corinne A. , Yen Eugenie C. , Bernard Fred , Guichet Antoine , Conduit Paul T.
Published: September 2022

Microtubule nucleation is mediated by γ-tubulin ring complexes (γ-TuRCs). In most eukaryotes, a GCP4/5/4/6 “core” complex promotes γ-tubulin small complex (γ-TuSC) association to generate cytosolic γ-TuRCs. Unlike γ-TuSCs, however, this core complex is non-essential in various species and absent from budding yeasts. InDrosophila, Spindle defective-2 (Spd-2) and Centrosomin (Cnn) redundantly recruit γ-tubulin complexes to mitotic centrosomes. Here we show that Spd-2 recruits γ-TuRCs formed via the GCP4/5/4/6 core, but that Cnn can recruit γ-TuSCs directly via its well-conserved CM1 domain, similar to its homologues in budding yeast. When centrosomes fail to recruit γ-tubulin complexes, they still nucleate microtubules via the TOG domain protein Mini-spindles (Msps), but these microtubules have different dynamic properties. Our data therefore help explain the dispensability of the GCP4/5/4/6 core and highlight the robustness of centrosomes as microtubule organising centres. They also suggest that the dynamic properties of microtubules are influenced by how they were nucleated.
IRF7 impacts on prostate cancer cell survival in response to radiation
Authors: Pickard Adam , Amoroso Francesca , McCulloch Kelsey , Erickson Andrew , Sachdeva Ashwin , Steele Rebecca , Mukherjee Debayan , Dellett Margaret , McComb Jonathan , McCaffery Laura , Hart Claire A. , Brown Michael D. , McDade Simon , Waugh David , Clarke Noel , Butterworth Karl , Illidge Tim , Mirtti Tuomas , Overton Ian M. , Mills Ian G.
Published: September 2022

Understanding the impact of radiotherapy on the evolution of treatment resistant prostate cancer is critical for selecting effective treatment combinations. Whilst activation of Type 1 interferon signalling is a hallmark of how cells respond to viral infection, in cancer cells, multiple stresses are known to activate this same response. In this study we have evaluated for the first time the changes in the interferon response induced by culturing prostate cancer cells under sphere- forming conditions and following irradiation. We report a conserved upregulated transcript profile for both conditions that is strongly associated with therapeutic resistance and cell survival in vitro and in vivo. The profile includes and is regulated by the Type 1 interferon master regulator IRF7 which, when depleted, delays tumour re-growth following irradiation. We immuno-stained two independent prostate cohorts for IRF7 and found that increased expression, particularly in cases with low PTEN expression, correlated with poor prognosis. To more comprehensively characterise the impact of IRF7 and radiation on cells, RNA-Seq was performed on IRF7 knockdown cells at different radiation doses. We identified a number of biological processes that were IRF7-dependent, including the formation of stem-like cell populations and also therapeutic vulnerabilities. For example, irradiation sensitised surviving cells to either a combination of an IKKε/TBK1 and a MEK inhibitor or treatment with an inhibitor of IDO1, an IRF7- dependent gene. Translationally our work suggests that IRF7 expression can be used to stratify patients who may not benefit from receiving radiotherapy alone but rather may benefit from treatment combinations. In two cohorts treated with radical intent, strong IRF7 staining was associated with disease-specific death implicating this pathway as a convergence point for therapeutic resistance in prostate and potentially other cancer types.
Board characteristics and demand for audit quality: a meta-analysis
Authors: Kalia Deepali , Basu Debarati , Kundu Sayantan
Published: September 2022

Purpose

The study explores extant knowledge on the nature of the relationship between internal and external corporate governance mechanisms, particularly board characteristics and audit quality, respectively, while also investigating how the relationship varies across geographies.

Design/methodology/approach

The extant knowledge is synthesized using a meta-analysis, which is conducted using a sample of 56 empirical studies from publications of varying grades. The studies span over 25 years (1996–2021) and cover 147 empirical samples (343,787 firm-year observations) across more than 20 countries. The dependent variable is audit fees, and the independent variable captures 12 different measures of board characteristics.

Findings

Overall, the results reveal a positive association between board characteristics and audit fees, indicating complementarity between governance mechanisms. Effect size analysis shows board characteristics, like size and independence, are positively associated with audit fees. However, heterogeneity is noted for some characteristics, and further analysis by geography (developed vs emerging countries) explains the heterogeneity.

Practical implications

This study helps multiple stakeholders like firms, shareholders, boards, regulators and policymakers in designing and strengthening governance frameworks.

Social implications

Both governance and auditing literature benefit from identifying specific board characteristics that drive audit quality consistently across different institutional settings and samples. Heterogeneity analysis helps improve the understanding of contradictions documented in prior literature.

Originality/value

This meta-analysis is the first to explore the interplay between internal and external corporate governance mechanisms, with a focus on board characteristics and audit quality. The study provides valuable insights on how different governance mechanisms influence each other while highlighting, for the first time, how the interaction between governance mechanisms varies by a country's level of development.
The innovation potential of Islamic crowdfunding platforms in contributing to sustainable development
Authors: Testa Stefania , Atawna Thaer , Baldi Gino , Cincotti Silvano
Published: September 2022

Purpose

This paper aims at explaining variances in the contribution of Islamic crowdfunding platforms (ICFPs) to sustainable development (SD), by adopting an institutional logic perspective (ILP). ICFPs represent a dual institutional overlap between two logics (the Western-mainstream and the Islamic logic) which have an impact on corporate social responsibility (CSR) interpretations, practices, and decisions and whose conflicts are mitigated by choosing different resolution strategies. The authors aim at showing that this choice affects SD differently.

Design/methodology/approach

The authors develop a conceptual typology through the following steps: (1) choice of variables and identification of corresponding variable domains, through literature review. Variables chosen are the elemental CSR dimensions related to various social and environmental corporate responsibilities to whom diverse meaning and emphasis are given under the Western-mainstream and Islamic logics. (2) Identification of three distinct ideal types of ICFPs, building on different resolution strategies to mitigate conflicts between logics; (3) development, for each ideal type, of a set of implications related to SD; (4) implementation of a first test aiming at assigning real cases to each ideal type.

Findings

The authors identify Western-mimicking (platforms adopting as resolution strategy decoupling or compartmentalizing strategies), Islamic-driven (platforms focusing on one prevailing logic) and Syncretism-inspired (platforms adopting hybridizing practices) ideal-types.

Originality/value

It is the first paper suggesting ILP to explain variances in crowdfunding platforms' role in addressing SD. It focuses on a specific type of CF platforms till now neglected.
Enhancement of turbulent thermal convection in a circular tube with a slotted twisted tape
Authors: Perng Shiang-Wuu , Wu Horng Wen , Kelana Nugroho Putra , Guo Yi-Ling , Yang Chen-Jui
Published: September 2022

Purpose

The purpose of this paper, computational fluid dynamics (CFD) work, is to promote turbulent thermal convection in a heated circular tube using a passive scheme of a slotted twisted sheet.

Design/methodology/approach

The inventive design uses square-cut and conjugate triangular perforations to diversify the twisted tape for better thermal convection. The current novel passive scheme methodology is accomplished by carving the same square cuts and slitting various sizes of equilateral triangle perforations (side length varies between 8 and 16 mm). The re-normalisation group turbulence model and the semi-implicit method for pressure-linked equation method examine the turbulent thermal convection aspects of all simulations at different Reynolds numbers (6,000, 10,000 and 14,000).

Findings

The analyses of simulations exhibit that the placement of a twisted tape with triangle perforations and equidistant square cuts can effectually promote thermal convection in a circular tube. A larger-sized triangle perforation can increase the thermal convection enhancement and thermal performance factor, but an enlarged perforation may decrease the thermal convection enhancement and thermal performance factor. As a result, compared with the smooth circular tube, the circular tube with the slotted twisted sheet slit by a 10 mm equilateral triangle brings about the maximum improvement ratio of the mean Nusselt number of about 2.8 at Re = 6,000. Under weighing the friction through the circular tube, the tube with the slotted twisted sheet slit by a 10 mm equilateral triangle gains the best thermal performance factor of about 1.36 at Re = 6,000.

Research limitations/implications

The working fluid is water and its physical features are assumed to be constant. In addition, the fluid is considered a steady flow in this CFD work.

Practical implications

These CFD predictions will benefit the development of heat exchanger tubes equipped with a slotted twisted sheet to acquire preferable thermal convection enhancement.

Social implications

Higher thermal performance achieved by placing a slotted twisted tape in a heated tube will benefit society in lower energy consumption, machinery maintenance costs and impact on the environment.

Originality/value

This study combined triangle perforations and square cuts on the twisted sheet. This combination can induce the fluid flow across the sheet to disturb the swirling flow and then promote the fluid mixing to increase thermal convection. Therefore, this modified tape can be a profitable passive device for designing a heat exchanger.