bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Quality of Surgical Care Between the US Department of Veterans Affairs and Non-Veterans Affairs Settings: A Systematic Review
Authors: Blegen Mariah , Ko Jamie , Salzman Garrett , Begashaw Meron M , Ulloa Jesus G , Girgis Mark , Shekelle Paul , Maggard-Gibbons Melinda
Published: May 2023

In response to concerns about healthcare access and long wait times within the Veterans Health Administration (VA), Congress passed the Choice Act of 2014 and the Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act of 2018 to create a program for patients to receive care in non-VA sites of care, paid by VA. Questions remain about the quality of surgical care between these sites in specific and between VA and non-VA care in general. This review synthesizes recent evidence comparing surgical care between VA and non-VA delivered care across the domains of quality and safety, access, patient experience, and comparative cost/efficiency (2015 to 2021). Eighteen studies met the inclusion criteria. Of 13 studies reporting quality and safety outcomes, 11 reported that quality and safety of VA surgical care were as good as or better than non-VA sites of care. Six studies of access did not have a preponderance of evidence favoring care in either setting. One study of patient experience reported VA care as about equal to non-VA care. All 4 studies of cost/efficiency outcomes favored non-VA care. Based on limited data, these findings suggest that expanding eligibility for veterans to get care in the community may not provide benefits in terms of increasing access to surgical procedures, will not result in better quality, and may result in worse quality of care, but may reduce inpatient length of stay and perhaps cost less.
HIF-stabilizing Biomaterials: from Hypoxia-mimicking to Hypoxia-inducing
Authors: Colombani Thibault , Bhatt Khushbu , Epel Boris , Kotecha Mrignayani , Bencherif Sidi A.
Published: May 2023

Recent advances in our understanding of hypoxia and hypoxia-mediated mechanisms shed light on the critical implications of the hypoxic stress on cellular behavior. However, tools emulating hypoxic conditions (i.e., low oxygen tensions) for research are limited and often suffer from major shortcomings, such as lack of reliability and off-target effects, and they usually fail to recapitulate the complexity of the tissue microenvironment. Fortunately, the field of biomaterials is constantly evolving and has a central role to play in the development of new technologies for conducting hypoxia-related research in several aspects of biomedical research, including tissue engineering, cancer modeling, and modern drug screening. In this perspective, we provide an overview of several strategies that have been investigated in the design and implementation of biomaterials for simulating or inducing hypoxic conditions—a prerequisite in the stabilization of hypoxia-inducible factor (HIF), a master regulator of the cellular responses to low oxygen. To this end, we discuss various advanced biomaterials, from those that integrate hypoxia-mimetic agents to artificially induce hypoxia-like responses, to those that deplete oxygen and consequently create either transient (< 1 day) or sustained (> 1 day) hypoxic conditions. We also aim to highlight the advantages and limitations of these emerging biomaterials for biomedical applications, with an emphasis on cancer research.
Aird-ComboComp: A combinable compressor framework with a dynamic-decider for lossy mass spectrometry data compression
Authors: Lu Miaoshan , Tong Junjie , Wang Ruimin , An Shaowei , Wang Jinyin , Yu Changbin
Published: May 2023

Mass spectrum (MS) data volumes increase with an improved ion acquisition ratio and a highly accurate mass spectrometer. However, the most widely used data format, mzML, does not take advantage of compression methods and improved read performances. Several compression algorithms have been proposed in recent years, and they consider a number of factors, including, numerical precision, metadata read strategies and the compression performance. Due to limited compression ratio, the high-throughput MS data format is still quite large. High bandwidth and memory requirements severely limit the applicability of MS data analysis in cloud and mobile computing. ComboComp is a comprehensive improvement to the Aird data format. Instead of using the general-purpose compressor directly, ComboComp uses two integer-purpose compressors and four general-purpose compressors, and obtains the best compression combination with a dynamic decider, achieving the most balanced compression ratio among all the numerous varieties of compressors. ComboComp supports a seamless extension of the new integer and generic compressors, making it an evolving compression framework. The improvement of compression rate and decoding speed greatly reduces the cost of data exchange and real-time decompression, and effectively reduces the hardware requirements of MS data analysis. Analyzing mass spectrum data on IoT devices can be useful in real-time quality control, decentralized analysis, collaborative auditing, and other scenarios. We tested ComboComp on 11 datasets generated by commonly used MS instruments. Compared with Aird-ZDPD, the compression size can be reduced by an average of 12.9%. The decompression speed is increased by an average of 27.1%. The average compression time is almost the same as that of ZDPD. The high compression rate and decoding speed make the Aird format effective for data analysis on small memory devices. This will enable MS data to be processed normally even on IoT devices in the future. We provide SDKs in three languages, Java, C# and Python, which offer optimized interfaces for the various acquisition modes. All the SDKs can be found on Github:https://github.com/CSi-Studio/Aird-SDK.
A Machine Learning One-Class Logistic Regression Model to Predict Stemness in Single Cell Transcriptomics and Spatial Omics Datasets
Authors: Dezem Felipe Segato , Marção Maycon , Ben-Cheikh Bassem , Nikulina Nadya , Omotoso Ayodele , Burnett Destiny , Coelho Priscila , Badal Simone , Hurley Judith , Gomez Carmen , Phan-Everson Tien , Ong Giang , Martelotto Luciano , Lewis Zachary R. , George Sophia , Braubach Oliver , Malta Tathiane , Plummer Jasmine
Published: May 2023

Cell annotation is a crucial methodological component to interpreting single cell and spatial omics data. These approaches are often biased and manually curated. Here we harness an existing stemness model for assessing oncogenic states to transform its application to single cell and spatial omic datasets. This one-class logistic regression machine learning algorithm is used to extract transcriptomic or proteomic features from non-transformed stem cells to identify dedifferentiated cell states. We found this method identifies single cell states in metastatic tumor cell populations without the requirement of cell annotation. Finally these stemness indices are applicable across a variety of spatial transcriptomic and proteomic technologies for the identification of oncogenic cell types in the tumor microenvironment.

Graphical Abstract
The image-based ultrasonic cell shaking test
Authors: Ballard Miranda , Marek Aleksander , Pierron Fabrice
Published: May 2023

Mechanical signals play a vital role in cell biology and is a vast area of research. Thus, there is motivation to understand cell deformation and mechanobiological responses. However, the ability to controllably deform cells in the ultrasonic regime and test their response is a noted challenge throughout the literature. Quantifying and eliciting an appropriate stimulus has proven to be difficult, resulting in methods that are either too aggressive or oversimplified. Furthermore, the ability to gain a real-time insight into cell deformation and link this with the biological response is yet to be achieved. One application of this understanding is in ultrasonic surgical cutting, which is a promising alternative to traditional methods, but with little understanding of its effect on cells. Here we present the image based ultrasonic cell shaking test, a novel method that enables controllable loading of cells and quantification of their response to ultrasonic vibrations. Practically, this involves seeding cells on a substrate that resonates at ultrasonic frequencies and transfers the deformation to the cells. This is then incorporated into microscopic imaging techniques to obtain high-speed images of ultrasonic cell deformation that can be analysed using digital image correlation techniques. Cells can then be extracted after excitation to undergo analysis to understand the biological response to the deformation. This method could aid in understanding the effects of ultrasonic stimulation on cells and how activated mechanobiological pathways result in physical and biochemical responses.
Mortality surrogates in combined pulmonary fibrosis and emphysema
Authors: Zhao An , Gudmundsson Eyjolfur , Mogulkoc Nesrin , van Moorsel Coline , Corte Tamera J. , Romei Chiara , Chapman Robert , Wallis Tim J.M. , Denneny Emma , Goos Tinne , Savas Recep , Ahmed Asia , Brereton Christopher J. , van Es Hendrik W. , Jo Helen , De Liperi Annalisa , Duncan Mark , Pontoppidan Katarina , De Sadeleer Laurens J. , van Beek Frouke , Barnett Joseph , Cross Gary , Procter Alex , Veltkamp Marcel , Hopkins Peter , Moodley Yuben , Taliani Alessandro , Taylor Magali , Verleden Stijn , Tavanti Laura , Vermant Marie , Nair Arjun , Stewart Iain , Janes Sam M. , Young Alexandra L. , Barber David , Alexander Daniel C. , Porter Joanna C. , Wells Athol U. , Jones Mark G. , Wuyts Wim A. , Jacob Joseph
Published: May 2023

Background

Idiopathic pulmonary fibrosis (IPF) with co-existent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may be associated with reduced FVC decline compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts.

Methods

Visual emphysema extent (CPFE:non-CPFE: derivation cohort=317:183; replication cohort=358:152), scored on computed tomography imaging subgrouped CPFE patients using either a) 10%, or b) 15% visual emphysema threshold, or c) an unsupervised machine learning model considering emphysema and ILD extents. Baseline characteristics, 1-year forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLco) decline (linear mixed effects models), and their associations with mortality (multivariable Cox regression models) were compared across CPFE and non-CPFE subgroups.

Results

In both IPF cohorts, CPFE patients with >10% emphysema had a greater smoking history and lower baseline DLco compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with >10% emphysema, 1-year DLco decline was a better indicator of mortality than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials.

Results were replicated in the >15% emphysema population and using unsupervised machine learning. Importantly, the unsupervised machine learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines >5% and >10% showed comparable mortality associations.

Conclusion

When assessing disease progression in IPF, DLco decline should be considered in patients with >10% emphysema and a >5% 1-year FVC decline threshold considered in non-CPFE IPF patients.
Efficacy of Intrawound Vancomycin in Prevention of Periprosthetic Joint Infection After Primary Total Knee Arthroplasty
Authors: Mulpur Praharsha , Jayakumar Tarun , Yakkanti Ramakanth R , Apte Aditya , Hippalgaonkar Kushal , Annapareddy Adarsh , Masilamani A B Suhas , Gurava Reddy A V
Published: May 2023

Introduction

Peri-prosthetic Joint Infection (PJI) after total knee arthroplasty (TKA) is a devastating complication. Intra-wound vancomycin powder has been shown to reduce infection rates in spine surgery. Previous studies on the efficacy of local vancomycin powder in hip or knee arthroplasty are mostly retrospective case series. The aim of this prospective RCT was to evaluate the efficacy and safety of intrawound vancomycin in preventing PJI after primary TKA.

Methods

This study was a National Trial Registry-approved RCT of patients undergoing primary TKA. 1022 patients were randomized to the study group (n=507, received 2g intrawound vancomycin powder before arthrotomy closure) and control groups (n=515, no local vancomycin). The minimum follow-up was 12-months. The primary outcome was PJI rate. Secondary outcomes included surgical site infection (SSI) rates, incidence of revision for PJI/SSI, and incidence of wound complications. High-risk groups (Obesity and Diabetes) in both cohorts were also evaluated.

Results

The overall infection rate in 1022 patients was 0.66%. There was no significant difference in PJI rate in the study group (0.2%) versus the control group (0.58%), p=0.264. Reoperation rates in the study group (N=4;0.78%) and Control (N=5;0.97%) and SSI rates in the study (N=1;0.2%) and control groups (N=2;0.38%) were comparable. The Vancomycin cohort however demonstrated a significantly higher number of minor wound complications (n=67;13.9%) compared to the control group (n=39;8.4%, p<0.05). There was no difference in PJI/SSI rates or minor surgical complications among high-risk groups and no cases of nephrotoxicity were reported in the study.

Conclusion

Intra-wound vancomycin powder does not appear to reduce PJI/SSI rate in primary total knee arthroplasties, including high-risk groups. Although safe from a renal perspective, intra-wound vancomycin was associated with an increase in postoperative aseptic wound complications such as persistent wound drainage. Intra-wound vancomycin may not be effective in reducing the rate of PJI in primary TKA.
Dawnn: single-cell differential abundance with neural networks
Authors: Hall George T. , Castellano Sergi
Published: May 2023

Analysis of single-cell transcriptomes can identify cell populations more abundant in one sample or condition than another. However, existing methods to discover them suffer from either low discovery rates or high rates of false positives. We introduce Dawnn, a deep neural network able to find differential abundance with higher accuracy than current tools, both on simulated and biological datasets. Further, we demonstrate that Dawnn recovers published findings and discovers more cells in regions of differential abundance than existing methods, both in abundant and rare cell types, promising novel biological insights at single-cell resolution.
Deconvolution Of Hematopoietic Stem/Progenitor Cell Signaling Predicts Inflammatory Niche Remodeling To Be A Determinant Of Tissue Failure And Outcome In Human AML
Authors: Chen Lanpeng , Pronk Eline , van Dijk Claire , Bian Yujie , Feyen Jacqueline , van Tienhoven Tim , Yildirim Meltem , Pisterzi Paola , de Jong Madelon , Bastidas Alejandro , Hoogenboezem Remco , Wevers Chiel , Bindels Eric , Löwenberg Bob , Cupedo Tom , Sanders Mathijs A. , Raaijmakers Marc H.G.P.
Published: May 2023

Cancer initiation is orchestrated by interplay between tumor-initiating cells and their stromal/immune environment. Here, by adapted scRNAsequencing, we decipher the predicted signaling between tissue-resident hematopoietic stem/progenitor cells (HSPCs) and their neoplastic counterparts with their native niches in the human bone marrow. LEPR+stromal cells are identified as central regulators of hematopoiesis through predicted interactions with all cells in the marrow. Inflammatory niche remodeling and the resulting deprivation of critical HSPC regulatory factors is predicted to repress distinct high-output HSC subsets inNPM1-mutated AML, with relative resistance of clonal cells. Stromal gene signatures reflective of niche remodeling are associated with reduced relapse rates and favorable outcome after chemotherapy, across all genetic risk categories. Elucidation of the intercellular signaling defining human AML, thus, predicts that inflammatory remodeling of stem cell niches drives tissue repression and clonal selection, but may pose a vulnerability for relapse-initiating cells in the context of chemotherapeutic treatment.

statement of significance

Tumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcome in human AML.

Key points

A comprehensive taxonomy of the predicted interactions between LEPR+stromal niches, HSPCs and adaptive/innate immune cells in the human NBM.

Inflammation-associated decline of stromal niches in AML represses residual normal hematopoiesis with relative resistance of leukemic cells.

Inflammatory decline of stromal niches is associated with reduced relapse risk and favorable outcome.
NON-TOXIC ACID-FREE GLYOXAL FIXATIVE FOR VETERINARY HISTOPATHOLOGY, IMMUNOHISTOCHEMISTRY AND MOLECULAR ANALYSIS
Authors: Zappulli Valentina , Torrigiani Filippo , Moccia Valentina , Detillo Paolo , Gola Cecilia , Minoli Lucia , Morello Emanuela M. , Ferraris Erica I. , Rigillo Antonella , Caicci Federico , Rovere Giulia Dalla , De Biase Davide , Riccio Lorenzo , Rondena Marco , Iussich Selina , Bussolati Benedetta
Published: May 2023

Formaldehyde fixation is worldwide the most used system for histopathological examination. However, its toxicity is well known, and preservation of proteins and nucleic acids is not optimal. Alternative fixatives warranting similar morphological quality of tissues and costs, but lacking toxicity and allowing better preservation of proteins and nucleic acids would therefore increase both safety of operators and quality of molecular analysis in pathology.

This multi-institutional study aimed to compare the morphological, histochemical, immunohistochemical (IHC), and molecular analyses outcomes of a newly patented, non-toxic, acid-free Glyoxal (GAF) fixative with neutral buffered formaldehyde (NBF). Tissues from a total of 73 subjects were analyzed, including 13 necropsies.

Gross features were preserved after GAF fixation, with no tissue hardening or discoloration. Cellular ultrastructure was also better preserved with GAF and histology and histochemistry on GAF-fixed samples showed good results when compared to NBF-fixed samples, with the exception of loss of tinctorial affinity of erythrocytes and mast cell granules. IHC analyses also showed comparable results with only slight and rare protocol adjustment. DNA and RNA yields were higher from GAF-fixed samples (P<0.05) and the tested genes (p53andCOX1) were better amplified. RNA scope showed positive results forc-KITexpression in GAF-fixed mast cell tumors.

Based on these data, the non-toxic GAF fixative allows good macroscopical, histological and immunohistochemical analyses of tissue samples, including on-field application, and better molecular analyses when compared to NBF. This represents a promising possibility for teaching, diagnostic, and research in veterinary pathology.
Combinatorial Microgels for 3D ECM Screening and Heterogeneous Microenvironmental Culture of Primary Human Hepatic Stellate Cells
Authors: Ryoo Hyeon , Underhill Gregory H.
Published: May 2023

Non-alcoholic fatty liver disease affects 30% of the United States population and its progression can lead to non-alcoholic steatohepatitis (NASH), which can result in cirrhosis and hepatocellular carcinoma. NASH is characterized by a highly heterogeneous liver microenvironment created by the fibrotic activity of hepatic stellate cells (HSCs). While HSCs have been widely studied in 2D, further advancements in physiologically-relevant 3D culture platforms for the in vitro modeling of these heterogeneous environments are needed. In this study, we have demonstrated the use of stiffness-variable, ECM protein-conjugated polyethylene glycol microgels as 3D cell culture scaffolds to modulate HSC activation. We further employed these microgels as a high throughput ECM screening system to identify HSC matrix remodeling and metabolic activities in distinct heterogeneous microenvironmental conditions. In particular, 6 kPa fibronectin microgels were shown to significantly increase HSC matrix remodeling and metabolic activities in single or multiple component microenvironments. Overall, heterogeneous microenvironments consisting of multiple distinct ECM microgels promoted a decrease in HSC matrix remodeling and metabolic activities compared to homogeneous microenvironments. We envision this ECM screening platform being adapted to a broad number of cell types to aid the identification of ECM microenvironments that best recapitulate the desired phenotype, differentiation, or drug efficacy.
Computational design of DNA binding domain-retained fusion proteins and virtual screening against FDA-approved drugs
Authors: Kumar Himansu , Kim Pora
Published: May 2023

Even 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

Cbl-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

The 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

Hyperpolarization-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.

Highlights

A 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

Mentorship 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

Structural 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

tRNAs 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

Intracranial 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.
PLANT UNCOUPLING MITOCHONDRIAL PROTEIN 2 localizes to the Golgi
Authors: Fuchs Philippe , Feixes-Prats Elisenda , Arruda Paulo , Feitosa-Araújo Elias , Fernie Alisdair R. , Grefen Christopher , Lichtenauer Sophie , Linka Nicole , de Godoy Maia Ivan , Meyer Andreas J. , Schilasky Sören , Sweetlove Lee J. , Wege Stefanie , Weber Andreas P. , Millar A. Harvey , Keech Olivier , Florez Sarasa Igor , Barreto Pedro , Schwarzländer Markus
Published: May 2023

Mitochondria act as cellular hubs of energy transformation and metabolite conversion in most eukaryotes. Plant mitochondrial electron transport chains are particularly flexible, featuring alternative components, such as ALTERNATIVE NAD(P)H DEHYDROGENASES and ALTERNATIVE OXIDASES (AOXs), that can bypass proton translocation steps. PLANT UNCOUPLING MITOCHONDRIAL PROTEINS (named PUMPs or plant UCPs) have been identified in plants as homologues of mammalian Uncoupling Proteins (UCPs), and their biochemical and physiological roles have been investigated in the context of mitochondrial energy metabolism. To dissect UCP function in Arabidopsis, the two most conserved (UCP1 and UCP2) have been targeted in recent work by combining mutant lines to circumvent potential functional redundancyin vivo. Such approaches rely on the assumption that both proteins reside in the inner mitochondrial membrane as a prerequisite for functional redundancy. Yet, contradicting results have been reported on UCP2 localization in plants. Here we provide evidence that, conversely to UCP1, which is an abundant inner mitochondrial membrane protein, UCP2 localizes to the Golgi rather than to mitochondria. Based on multiple lines of new and prior evidence, we summarize the consensus view that we have reached and provide an example of how open, critical exchange within the research community is able to constructively address ambiguities. Our observations and considerations provide direction to the ongoing discussion about the functions of UCP proteins. They further offer new perspectives for the study of Golgi membrane transport and subcellular targeting principles of membrane proteins. Since 20 to 30 % of genes in plant genomes are predicted to encode transmembrane proteins and the function of most of those proteins has not been experimentally investigated, we highlight the importance of using independent evidence for localization as a prerequisite for understanding physiological function of membrane proteins.
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

Despite 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

Advanced 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

Spindle 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

Purpose

There 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.
A novel representation of electromagnetic field interaction with vertically stratified structures
Authors: Elkattan Mohamed , Kamel Aladin H.
Published: May 2023

Purpose

The purpose of this study is to develop an efficient model to solve the electromagnetic forward problem using a novel semi-analytical approach to compute the electromagnetic fields because of the presence of a scatterer.

Design/methodology/approach

The proposed model involves a novel formulation of a complete orthonormal set of radiating/nonradiating polarization currents. Furthermore, an integral equation-based representation is derived, and the appropriate boundary conditions are imposed to get the scattered electromagnetic field. An error term is introduced to evaluate the obtained results.

Findings

The proposed model was tested using several examples at different frequencies. The results of this study show that the novel representation exhibits fast convergence behavior and achieves highly accurate results, when compared to the results provided by the transmission line method.

Originality/value

The derived formulations presented in this study are significant in the electromagnetic forward modelling field because of the meaningful physical representation they provide. This is an important aspect that leads to precise calculation of electromagnetic fields for various applications.