bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational design of DNA binding domain-retained fusion proteins and virtual screening against FDA-approved drugs
Authors: Kumar Himansu , Kim Pora 
Published: May 2023

ABSTRACTEven though the transcription factors (TFs) are not regarded as good drug targets, mutated or dysregulated TFs can be a unique class of drug targets. Specifically, the TF fusion protein, which is the translated structural variants including TFs may affect downstream to promote tumorigenesis. To date, we lack the fusion protein sequence information and 3D structure information in identifying the potential drugs of fusion proteins. In this study, we predicted the 3D structures of 732 transcription factor fusion proteins (TFFPs). For the top five most frequent TFFPs, we performed the virtual screening across the FDA-approved drugs. Our study will provide an initial platform to develop novel therapeutic targets in the transcription factor fusion proteins.
Probing the mechanism of Cbl-b inhibition by a small-molecule inhibitor
Authors: Kimani Serah , Perveen Sumera , Szewezyk Magdalena , Zeng Hong , Dong Aiping , Li Fengling , Ghiabi Pegah , Li Yanjun , Chau Irene , Arrowsmith Cheryl , Barsyte-Lovejoy Dalia , Santhakumar Vijayaratnam , Vedadi Masoud , Halabelian Levon 
Published: May 2023

ABSTRACTCbl-b is a RING-type E3 ubiquitin ligase that is expressed in several immune cell lineages, where it negatively regulates the activity of immune cells. Cbl-b has specifically been identified as an attractive target for cancer immunotherapy due to its role in promoting an immunosuppressive tumor environment, and Nx-1607, is in phase I clinical trials for advanced solid tumor malignancies. Using a suite of biophysical and cellular assays, we confirmed potent binding of C7683 (an analogue of Nx-1607) to the full-length Cbl-b and its N-terminal fragment containing the TKBD-LHR-RING domains. To further elucidate its mechanism of inhibition, we determined the co-crystal structure of Cbl-b with C7683, revealing compound interaction with both the TKBD and LHR, but not the ring domain. Here, we provide structural insights into a novel mechanism of Cbl-b inhibition by a small-molecule inhibitor that locks the protein in an inactive conformation by acting as an intramolecular glue.
Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease
Authors: Jullienne Amandine , Szu Jenny I. , Quan Ryan , Trinh Michelle V. , Norouzi Tannoz , Noarbe Brenda P. , Bedwell Amanda A. , Eldridge Kierra , Persohn Scott C. , Territo Paul R. , Obenaus Andre 
Published: May 2023

AbstractThe 5xFAD mouse model is a popular model of familial Alzheimer’s Disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Male and female 5xFAD and WT littermates underwentin vivo18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter. With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced18F-FDG uptake compared to WT across their lifespan. While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of the motor and visual cortex and increased vessel lengths alongside decreased collaterals coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.
Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish
Authors: Doldur-Balli Fusun , Smieszek Sandra , Keenan Brendan T. , Zimmerman Amber J. , Veatch Olivia J. , Polymeropoulos Christos M. , Birznieks Gunther , Polymeropoulos Mihael H. 
Published: May 2023

AbstractHyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels generate electrical rhythmicity in various tissues although primarily heart, retina and brain. The HCN channel blocker compound, Ivabradine (Corlanor), is approved by the US Food and Drug Administration (FDA) as a medication to lower heart rate by blocking hyperpolarization activated inward current in the sinoatrial node. In addition, a growing body of evidence suggests a role for HCN channels in regulation of sleep/wake behavior. Zebrafish larvae are ideal model organisms for high throughput drug screening, drug repurposing and behavioral phenotyping studies. We leveraged this model system to investigate effects of three HCN channel blockers (Ivabradine, Zatebradine Hydrochloride and ZD7288) at multiple doses on sleep/wake behavior in wild type zebrafish. Results of interest included shorter latency to day time sleep at 0.1 μM dose of Ivabradine (ANOVA, p:0.02), moderate reductions in average activity at 30 μM dose of Zatebradine Hydrochloride (ANOVA, p:0.024) in daytime, and increased nighttime sleep at 4.5 μM dose of ZD7288 (ANOVA, p:0.036). These differences support the hypothesis that compounds blocking HCN channels decreases wakefulness.HighlightsA drug screening study in which effects of HCN channel blocker compounds were tested displayed decreased wakefulwness in zebrafish.There was modest evidence of these drugs on sleep and wake phenotypes including shorter latency to sleep, moderate reductions in average activity and increased sleep at different doses of three compounds compared to DMSO.While several specific doses of Ivabradine, Zatebradine hydrochloride or ZD7288 demonstrated some differences compared to DMSO, effects of these compounds was smaller than the effect of melatonin, a positive control.
Insights from a survey of mentorship experiences by graduate and postdoctoral researchers
Authors: Sarabipour Sarvenaz , Niemi Natalie M , Burgess Steven J , Smith Christopher T , Bisson Filho Alexandre W , Ibrahim Ahmed , Clark Kelly 
Published: May 2023

AbstractMentorship is vital for early career researchers in training positions, allowing them to navigate the challenges of work and life in research environments. However, the quality of mentorship received by trainees can vary by investigator and by institution. One challenge faced by those hoping to improve trainee mentorship is that the extent to which mentorship is offered to and experienced by research trainees is not well characterized. To address this knowledge gap, we conducted a survey to examine the quality of mentorship received by trainees in research environments, to identify characteristics of positive and negative mentorship, and to highlight best practices to improve trainee mentorship. We received 2,114 responses from researchers at graduate and postdoctoral career stages worldwide. Quantitative analysis showed that at least ∼25-45% of respondents were dissatisfied with some aspects of their mentorship. Qualitative responses revealed that common issues in mentorship include unclear expectations in research and mentoring interactions, lack of guidance, and inadequate support of trainee independence and career goals. Our findings also identified key mentorship elements desired by trainee mentees. Based on trainee suggestions, we describe strategies for individual mentors, departments, and institutions to improve the training experience for graduate and postdoctoral researchers.
PDBminer to Find and Annotate Protein Structures for Computational Analysis
Authors: Degn Kristine , Beltrame Ludovica , Tiberti Matteo , Papaleo Elena 
Published: May 2023

AbstractStructural bioinformatics and molecular modeling of proteins strongly depend on the protein structure selected for investigation. The choice of protein structure relies on direct application from the Protein Data Bank (PDB), homology- or de-novo modeling. Recent de-novo models, such as AlphaFold2, require little preprocessing and omit the need to navigate the many parameters of choosing an experimentally determined model. Yet, the experimentally determined structure still has much to offer, why it should be of interest to the community to ease the choice of experimentally determined models. We provide an open-source software package, PDBminer, to mine both the AlphaFold Database (AlphaFoldDB) and the PDB based on search criteria set by the user. This tool provides an up-to-date, quality-ranked table of structures applicable for further research. PDBminer provides an overview of the available protein structures to one or more input proteins, parallelizing the runs if multiple cores are specified. The output table reports the coverage of the protein structures aligned to the UniProt sequence, overcoming numbering differences in PDB structures, and providing information regarding model quality, protein complexes, ligands, and nucleotide binding. The PDBminer2coverage and PDBminer2network tools assist in visualizing the results. We suggest that PDBminer can be applied to overcome the tedious task of choosing a PDB structure without losing the wealth of additional information available in the PDB. As developers, we will guarantee the introduction of new functionalities, assistance, training of new contributors, and package maintenance. The package is available athttp://github.com/ELELAB/PDBminer.
tRNASeroverexpression induces adaptive mutations in NSCLC tumors
Authors: Ferreira Marta , Pinheiro Miguel , Reis Andreia , André Ana , Rocha Sara , Santos Manel A. S. , Santos Mafalda , Oliveira Carla 
Published: May 2023

AbstracttRNAs are a driving force of genome evolution in Yeast and Bacteria. Their deregulation is frequently observed in tumors with Serine tRNAs being often overexpressed. This has important functional consequences, such as increased metabolism and tumor growth. In yeast, time and chemical stimulus boost alterations in the genome driven by tRNA deregulation. Therefore, we hypothesized that tRNA deregulation may contribute to the increased genome instability observed in tumors. To study the effect of tRNA deregulation in tumors, we overexpressed tRNA-Ser-AGA-2-1 in a NSCLC cell line, H460. This cell line and a Mock (control) were xenografted in nude mice and collected at 3 timepoints: T1-Naïve; T2-Treated once with cisplatin/vehicle and; T3) treated twice with cisplatin/vehicle. These tumors were characterized by WES, RNAseq and Mass Spectrometry and the data obtained was integrated. The tumor mutation burden was increased in T3 tRNASerOE tumors, regardless of treatment. Although in T1 Mock and tRNASer tumors have a similar number of variants, in T2&3, tRNASerOE tumors display two times more variants than Mock tumors regardless of treatment. Interestingly, tRNASerOE exclusive variants favor proliferation and therapy resistance, which is in line with the phenotypes observed and supported by RNAseq and proteomics data. In conclusion, tRNASerOE increases the tumor mutation burden and the variants detected favor tumor growth, proving tRNA deregulation is enough to induce adaptive mutations in the genome.
Neural response properties predict perceived contents and locations elicited by intracranial electrical stimulation of human auditory cortex
Authors: Wang Qian , Luo Lu , Xu Na , Wang Jing , Yang Ruolin , Chen Guanpeng , Ren Jie , Luan Guoming , Fang Fang 
Published: May 2023

AbstractIntracranial electrical stimulation (iES) of auditory cortex can elicit sound experiences with a variety of perceived contents (hallucination or illusion) and locations (contralateral or bilateral side), independent of actual acoustic inputs. However, the neural mechanisms underlying this elicitation heterogeneity remain undiscovered. Here, we collected subjective reports following iES at 3062 intracranial sites in 28 patients and identified 113 auditory cortical sites with iES-elicited sound experiences. We then decomposed the sound-induced intracranial electroencephalogram (iEEG) signals recorded from all 113 sites into time-frequency features. We found that the iES-elicited perceived contents can be predicted by the early high-γ features extract from sound-induced iEEG. In contrast, the perceived locations elicited by stimulating hallucination sites and illusion sites are determined by the late high-γ and long-lasting α features, respectively. Our study unveils the crucial neural signatures of iES-elicited sound experiences in human and presents a new strategy to hearing restoration for individuals suffering from deafness.
Targeted neutralizing IgY antibodies against SGLT1 glucose transporter reduce glucose uptake and improve glycemic profile in vivo
Authors: Saxena Uday , Meher Kranti , Reddy RN Arpitha , Saranya K , Kadiyala Gopi , Iyer Subramanian , Vangala Subrahmanyam , Chandran Satish 
Published: May 2023

SummaryDespite the use of several drugs available to treat type 2 diabetes, many patients are unable to reach their target fasting plasma glucose and HbA1c levels. SGLT1 is the major intestinal transport transmembrane protein which functions in uptake of dietary glucose. If we antagonise the binding of dietary glucose to this transport protein, it is expected that blood glucose lowering will follow. We designed specific inhibitory avian antibodies (IgY) against the extracellular glucose binding domain of SGLT1 and tested their potential in glucose lowering. We demonstrate here the antibodies block uptake of glucose and improve the glycemic profile in vivo and represent a novel approach to inhibiting dietary glucose absorption as treatment for diabetes.
The Interplay between Mutagenesis and Extrachromosomal DNA Shapes Urothelial Cancer Evolution
Authors: Nguyen Duy D. , Hooper William F. , Chu Timothy R. , Geiger Heather , Shelton Jennifer M. , Shah Minita , Goldstein Zoe R. , Winterkorn Lara , Sigouros Michael , Manohar Jyothi , Moyer Jenna , Wilkes David , Singh Rahul R. , Liu Weisi , Sboner Andrea , Tagawa Scott T. , Nanus David M. , Nauseef Jones T. , Sternberg Cora N. , Molina Ana M. , Scherr Douglas , Inghirami Giorgio , Mosquera Juan Miguel , Elemento Olivier , Robine Nicolas , Faltas Bishoy M. 
Published: May 2023

AbstractAdvanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity. In this study, we investigate the evolution of the genomic signatures caused by endogenous and external mutagenic stimuli and their interplay with complex structural variants. We superimposed mutational signatures and phylogenetic analyses of matched serial tumors from patients with urothelial cancer to define the evolutionary patterns of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas mutational bursts comprising hundreds of late subclonal mutations are induced by chemotherapy. Using a novel genome graph computational paradigm, we observed frequent circular high copy-number amplicons characteristic of extrachromosomal DNA (ecDNA) involving double-minutes, breakage-fusion-bridge, and tyfonas events. We characterized the distinct temporal patterns of APOBEC3 mutations and chemotherapy-induced mutations within ecDNA, gaining new insights into the timing of these events relative to ecDNA biogenesis. Finally, we discovered that mostCCND1amplifications in urothelial cancer arise within circular ecDNA amplicons. TheseCCND1ecDNA amplification events persisted and increased in complexity incorporating additional DNA segments potentially contributing selective fitness advantage to the evolution of treatment resistance. Our findings define fundamental mechanisms driving urothelial cancer evolution and have therapeutic implications for treating this disease.
Site-Specific Phosphorylation of ZYG-1 Regulates ZYG-1 Stability and Centrosome Number
Authors: Medley Jeffrey C. , Yim Nahyun , DiPanni Joseph , Sebou Brandon , Shaffou Blake , Cramer Evan , Wu Colin , Kabara Megan , Song Mi Hye 
Published: May 2023

SummarySpindle bipolarity is critical for genomic integrity. Given that centrosome number often dictates mitotic bipolarity, tight control of centrosome assembly is vital for the fidelity of cell division. The kinase ZYG-1/Plk4 is a master centrosome factor that is integral for controlling centrosome number and is modulated by protein phosphorylation. While autophosphorylation of Plk4 has been extensively studied in other systems, the mechanism of ZYG-1 phosphorylation inC. elegansremains largely unexplored. InC. elegans, Casein Kinase II (CK2) negatively regulates centrosome duplication by controlling centrosome-associated ZYG-1 levels. In this study, we investigated ZYG-1 as a potential substrate of CK2 and the functional impact of ZYG-1 phosphorylation on centrosome assembly. First, we show that CK2 directly phosphorylates ZYG-1in vitroand physically interacts with ZYG-1in vivo.Intriguingly, depleting CK2 or blocking ZYG-1 phosphorylation at putative CK2 target sites leads to centrosome amplification. In the non-phosphorylatable (NP)-ZYG-1 mutant embryo, the overall levels of ZYG-1 are elevated, leading to an increase in centrosomal ZYG-1 and downstream factors, providing a possible mechanism of the NP-ZYG-1 mutation to drive centrosome amplification. Moreover, inhibiting the 26S proteasome blocks degradation of the phospho-mimetic (PM)-ZYG-1, while the NP-ZYG-1 mutant shows partial resistance to proteasomal degradation. Our findings suggest that site-specific phosphorylation of ZYG-1, partly mediated by CK2, controls ZYG-1 levels via proteasomal degradation, limiting centrosome number. We provide a mechanism linking CK2 kinase activity to centrosome duplication through direct phosphorylation of ZYG-1, which is critical for the integrity of centrosome number.
Effect of pitting corrosion on the mechanical properties and fracture model of steel wires for bridge cable
Authors: Kang Zhuangsu , Zhang Zongxing , Song Shenyou , Cheng Qian , Tao Siyu , Ni Ya 
Published: May 2023

Purpose
This paper aims to investigate the effect of characteristic parameters of pits on the mechanical properties and fracture model of cable steel wires.

Design/methodology/approach
The tensile test and finite element analysis of steel wires with corrosion damage were carried out. The stress development of corroded steel wire under corrosion morphology was studied by the 3D reverse reconstruction technology. The internal relationship between the stress triaxiality, equivalent plastic strain and pit depth, depth-width ratio of corroded steel wire was discussed.

Findings
With the increase of corrosion degree, the neck shrinkage phenomenon of steel wire was not significant, and the crack originated near the pit bottom and expanded to the section inside of specimen. The fiber area of corroded steel wire decreased while the radiation area increased, and the ductile fracture gradually changed to brittle fracture. The pit size significantly changed the triaxial degree and distribution of stress and accelerated the initiation and propagation of internal cracks at the neck shrinkage stage.

Originality/value
The proposed fracture model based on the void growth model could accurately simulate the fracture behavior of steel wires with corrosion damage.
Eye movement desensitisation and reprocessing as a treatment for PTSD, trauma, and trauma related symptoms in children with intellectual disabilities: a general review
Authors: Williamson Chloe Louise , Rayner-Smith Kelly 
Published: May 2023

Purpose
This paper aims to discuss the utility of eye movement desensitization and reprocessing (EMDR) therapy as a treatment for children with intellectual disabilities (ID) who have experienced trauma.

Design/methodology/approach
Relevant National Institute for Health and Care Excellence (NICE) guidance and literature were reviewed to provide support for the use of EMDR as a treatment for trauma in children with ID.

Findings
There is a growing body of evidence which demonstrates that EMDR therapy is successful for the treatment of trauma in adults and children. However, for children with ID, the research is limited despite those with ID being more likely than non-disabled peers to experience trauma such as abuse or neglect.

Practical implications
EMDR can only be facilitated by trained mental health nurses, psychiatrists, psychologists (clinical, forensic, counselling or educational) or occupational therapists or social workers with additional training. Finally, general practitioners who are experienced in psychotherapy or psychological trauma and have accreditation. Therefore, this highlights that there may be a lack of trained staff to facilitate this intervention and that those who are generally working with the client closely and long term such as learning disability nurses are not able to conduct this intervention.

Originality/value
This paper presents an account of NICE guidance and evidence of the efficacy of EMDR as a treatment for adults, children and those with ID.
The role of social media in consumers’ intentions to buy green food: evidence from Türkiye
Authors: Armutcu Barış , Ramadani Veland , Zeqiri Jusuf , Dana Leo-Paul 
Published: May 2023

PurposeThere is limited research examining the relationship between social media and green food purchasing behaviour. In the current study, we examine the factors that affect consumers’ green food purchasing behaviour in Türkiye.Design/methodology/approach Data collected from the participants by survey method were analysed using Smart PLS 4.0 with IBM SPSS 26 and PLS to run SEM.Findings Our findings have revealed that from all the structural elements in the theory of planned behaviour (TPB), only attitude and perceived behavioural control contribute to consumers’ green food purchasing behaviour, while subjective norms do not contribute to consumers’ green food purchasing behaviour. Additionally, it was found that social media usage (SMU) and digital marketing interactions (DMI) have a positive and significant effect on green food purchasing behaviour. More information, experiences, opinions and recommendations on green foods in social media channels can encourage consumers to buy more green food.Originality/value This study first evaluates the applicability of the TPB model in explaining green food purchasing behaviour. This study is extended with two new factors included in the original framework of the TPB model, namely, SMU and DMI.