bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Iris Stiffness and Permeability in Primary Angle Closure Glaucoma
Authors: Panda Satish K. , Tan Royston K. Y. , Tun Tin A. , Buist Martin L. , Nongpiur Monisha , Baskaran Mani , Aung Tin , Girard Michaël J. A.
Published: May 2021

Purpose

To evaluate the biomechanical properties of the iris by evaluating iris movement during pupil constriction and to compare such properties between healthy and primary angle-closure glaucoma (PACG) subjects.

Methods

A total of 140 subjects were recruited for this study. In a dark room, the anterior segments of one eye per subject were scanned using anterior segment optical coherence tomography (AS-OCT, SS-1000 CASIA, Tomey Corporation, Nagoya, Japan) imaging during induced pupil constriction with an external white light source of 1700 lux. Using a custom segmentation code, we automatically isolated the iris segments from the AS-OCT images, which were then discretized and transformed into a three-dimensional point cloud. For each iris, a finite element (FE) mesh was constructed from the point cloud, and an inverse FE simulation was performed to match the clinically observed iris constriction in the AS-OCT images. Through this optimization process, we were able to identify the elastic modulus and permeability of each iris.

Results

For all 140 subjects (95 healthy and 45 PACG of Indian/Chinese ethnicity, Age: 60.2±8.7 for PACG subjects and 57.7±10.1 for healthy subjects), the simulated deformation pattern of the iris during pupil constriction matched well with OCT images. We found that the iris stiffness was higher in PACG than in healthy controls (24.5±8.4 kPa vs 17.1±6.6 kPa with 40 kPa of active stress specified in the sphincter region;p< 0.001), whereas iris permeability was lower (0.41±0.2 mm2/kPa.s vs 0.55±0.2 mm2/kPa.s;p= 0.142).

Conclusion

This study suggests that the biomechanical properties of the iris in PACG are different from those in healthy controls. An improved understanding of the biomechanical behavior of the iris may have implications for the understanding and management of angle-closure glaucoma.
Vacuole-specific lipid release for tracking intracellular lipid metabolism and transport inSaccharomyces cerevisiae
Authors: Girik Vladimir , Feng Suihan , Hariri Hanaa , Henne W Mike , Riezman Howard
Published: May 2021

Lipid metabolism is spatiotemporally regulated within cells, yet intervention into lipid functions at subcellular resolution remains difficult. Here we report a method that enables site-specific release of sphingolipids and cholesterol inside the vacuole inSaccharomyces cerevisiae. Using this approach, we monitored real-time sphingolipid metabolic flux out of the vacuole by mass spectrometry and found that the ER-vacuole tethering protein Mdm1 facilitated the metabolism of sphingoid bases into ceramides. In addition, we showed that cholesterol, once delivered into yeast using our method, could restore cell proliferation induced by ergosterol deprivation, overcoming the previously described sterol-uptake barrier under aerobic conditions. Together, these data define a new way to study intracellular lipid metabolism and transport from the vacuole in yeast.
Generation of lineage-resolved complete metagenome-assembled genomes by precision phasing
Authors: Bickhart Derek M. , Kolmogorov Mikhail , Tseng Elizabeth , Portik Daniel M. , Korobeynikov Anton , Tolstoganov Ivan , Uritskiy Gherman , Liachko Ivan , Sullivan Shawn T. , Shin Sung Bong , Zorea Alvah , Andreu Victòria Pascal , Panke-Buisse Kevin , Medema Marnix H. , Mizrahi Itzik , Pevzner Pavel A. , Smith Timothy P.L.
Published: May 2021

Microbial communities in many environments include distinct lineages of closely related organisms which have proved challenging to separate in metagenomic assembly, preventing generation of complete metagenome-assembled genomes (MAGs). The advent of long and accurate HiFi reads presents a possible means to address this challenge by generating complete MAGs for nearly all sufficiently abundant bacterial genomes in a microbial community. We present a metagenomic HiFi assembly of a complex microbial community from sheep fecal material that resulted in 428 high-quality MAGs from a single sample, the highest resolution achieved with metagenomic deconvolution to date. We applied a computational approach to separate distinct haplotype lineages and identified haplotypes of hundreds of variants across hundreds of kilobases of genomic sequence. Analysis of these haplotypes revealed 220 lineage-resolved complete MAGs, including 44 in single circular contigs, and demonstrated improvement in overall assembly compared to error-prone long reads. We report the characterization of multiple, closely-related microbes within a sample with potential to improve precision in assigning mobile genetic elements to host genomes within complex microbial communities.
Comparative Morphometric Analysis Of Captive Jaguars Vs. Wild Jaguars (Panthera onca) In Venezuela
Authors: Cañizales Israel
Published: May 2021

In Venezuela the oldest, although anecdotical, record known of a captive jaguar is a male in the city of Maracay between 1918 and 1935. Body measurements were made on 22 jaguars kept in Venezuelan zoos between 1996 and 2009 to provide data on external morphometrics and compare with the measurements of 25 free-living animals, published by Hoogesteijn and Mondolfi (1992) and determine whether there are significant differences in the morphology between sexes of captive and free-living animals. The evaluation of morphometric variation was focused on three body measurements and body weight: Head-and-body length (HBL) and Tail length (Tl). Total body length (TBL) was calculated by adding HBL and Tl. Body weight (BW) was determined using a clock scale to the nearest gramme/kilogram. To determine the values all animals were anesthetized. The sexes were analyzed separately. All data were used for the calculation of descriptive statistics. Student t-tests were used with a significance level α 0.05 to establish if there is a significant difference between the measurements and weights of the sexes. The TBL and HBL in captive males were observed to be 8.78% and 12.13%, respectively, less than that of free-living males. A principal components analysis made it possible to assess the variability between HBL, TBL, and BW between sexes and between free-living/wild and captive animals. This study showed no significant differences in the BW of captives and wild females. Some captive males’ jaguars in this study may be thinner than normal, because of their diet and others may be fatter because of the lack of physical activity imposed by captivity. Body mass index (BMI) was used to contrast the difference in the average mass of each sex in both captive and free-living animals. Simple linear regressions and correlation coefficients were used to determine the relationship between body mass and male/female size. According to correlation coefficients, the change in weight that can be attributed to the ratio of weight to body length is 8.55 % for males and 9.83 % for females.
A Discriminative Characterization of Heschl’s Gyrus Morphology using Spectral Graph Features
Authors: Maghsadhagh Sevil , Dalboni da Rocha Josué L. , Benner Jan , Schneider Peter , Golestani Narly , Behjat Hamid
Published: May 2021

Heschl’s Gyrus (HG), which hosts the primary auditory cortex, exhibits large variability not only in size but also in its gyrification patterns, within (i.e., between hemispheres) and between individuals. Conventional structural measures such as volume, surface area and thickness do not capture the full morphological complexity of HG, in particular, with regards to its shape. We present a method for characterizing the morphology of HG in terms of Laplacian eigenmodes of surface-based and volume-based graph representations of its structure, and derive a set of spectral graph features that can be used to discriminate HG subtypes. We applied this method to a dataset of 177 adults previously shown to display considerable variability in the shape of their HG, including data from amateur and professional musicians, as well as non-musicians. Results show the superiority of the proposed spectral graph features over conventional ones in differentiating HG subtypes, in particular, single HG versus Common Stem Duplications (CSDs). We anticipate the proposed shape features to be found beneficial in the domains of language, music and associated pathologies, in which variability of HG morphology has previously been established.
AZBA: A 3D Adult Zebrafish Brain Atlas for the Digital Age
Authors: Kenney Justin W. , Steadman Patrick E. , Young Olivia , Shi Meng Ting , Polanco Maris , Dubaishi Saba , Covert Kristopher , Mueller Thomas , Frankland Paul W.
Published: May 2021

Zebrafish have made significant contributions to our understanding of the vertebrate brain and the neural basis of behavior, earning a place as one of the most widely used model organisms in neuroscience. Their appeal arises from the marriage of low cost, early life transparency, and ease of genetic manipulation with a behavioral repertoire that becomes more sophisticated as animals transition from larvae to adults. To further enhance the use of adult zebrafish, we created the first fully segmented three-dimensional digitaladultzebrafishbrainatlas (AZBA). AZBA was built by combining tissue clearing, light-sheet fluorescence microscopy, and three-dimensional image registration of nuclear and antibody stains. These images were used to guide segmentation of the atlas into over 200 neuroanatomical regions comprising the entirety of the adult zebrafish brain. As an open source, onlineazba.wayne.edu), updatable digital resource, AZBA will significantly enhance the use of adult zebrafish in furthering our understanding of vertebrate brain function in both health and disease.
The Hypoxia Response Pathway Promotes PEP Carboxykinase Expression And Gluconeogenesis
Authors: Vora Mehul , Pyonteck Stephanie M. , Matlack Tarmie L. , Prashar Aparna , Kane Nanci S. , Shah Premal , Rongo Christopher
Published: May 2021

Actively dividing cells, including some cancers, rely on aerobic glycolysis rather than oxidative phosphorylation to generate energy, a phenomenon termed “the Warburg effect1.” Constitutive activation of the Hypoxia Inducible Factor (HIF-1), a transcription factor known for mediating an adaptive response to oxygen deprivation (hypoxia), is a hallmark of the Warburg effect2. HIF-1 is thought to promote glycolysis and suppress oxidative phosphorylation. Here, we show instead that HIF-1 can promote gluconeogenesis. Using a multiomics approach, we determined the genomic, transcriptomic, and metabolomic landscapes regulated by constitutively active HIF-1 inC. elegans. We performed RNA-seq and ChIP-seq under aerobic conditions in mutants lacking EGL-9, a key negative regulator of HIF-1, and then integrated these approaches to identify over a hundred genes directly and functionally upregulated by HIF-1. We show that HIF-1 directly promotes the expression of PCK-1, a PEP carboxykinase that is a rate-limiting mediator of gluconeogenesis3. This activation of PCK-1 by HIF-1 promotes survival in response to both oxidative and hypoxic stress. Our work is the first to identify functional direct targets of HIF-1in vivo, and it describes the first complete metabolome induced by constitutive HIF-1 activation in any organism.
Biphasic Control of Cell Expansion by Auxin Coordinates Etiolated Seedling Development
Authors: Du Minmin , Daher Firas Bou , Liu Yuanyuan , Steward Andrew , Tillmann Molly , Zhang Xiaoyue , Wong Jeh Haur , Ren Hong , Cohen Jerry D. , Li Chuanyou , Gray William M.
Published: May 2021

Seedling emergence is critical for food security. It requires rapid hypocotyl elongation and apical hook formation, both of which are mediated by regulated cell expansion. How these events are coordinated in etiolated seedlings is unclear. Here, we show that biphasic control of cell expansion by the phytohormone auxin underlies this process. Shortly after germination, high auxin levels restrain elongation. This provides a temporal window for apical hook formation, involving a gravity-induced auxin maximum on the eventual concave side of the hook, triggering PP2C.D1controlled asymmetrical H+-ATPase activity, resulting in differential cell elongation. Subsequently, auxin concentrations decline acropetally and switch from restraining to promoting elongation, driving hypocotyl elongation. Our findings elucidate how differential auxin concentrations throughout the hypocotyl coordinate etiolated development, leading to successful soil emergence.

One-Sentence Summary

Auxin concentration-dependent cell expansion coordinates hypocotyl elongation and apical hook development for soil emergence.
Cellular Bases of Olfactory Circuit Assembly Revealed by Systematic Time-lapse Imaging
Authors: Li Tongchao , Fu Tian-Ming , Li Hongjie , Xie Qijing , Luginbuhl David J. , Betzig Eric , Luo Liqun
Published: May 2021

Neural circuit assembly features simultaneous targeting of numerous neuronal processes from constituent neuron types, yet the dynamics is poorly understood. Here, we use theDrosophilaolfactory circuit to investigate dynamic cellular processes by which olfactory receptor neurons (ORNs) target axons precisely to specific glomeruli in the ipsi- and contralateral antennal lobes. Time-lapse imaging of individual axons from 28 ORN types revealed a rich diversity in extension speed, innervation timing, and ipsilateral branch locations, and identified that ipsilateral targeting occurs via stabilization of transient interstitial branches. Fast imaging using adaptive optics- corrected lattice light-sheet microscopy showed that upon approaching target, many ORN types exhibit “exploring branches” consisted of parallel microtubule-based terminal branches emanating from an F-actin-rich hub. Antennal nerve ablations uncovered essential roles for bilateral interactions in contralateral target selection, and for ORN axons to facilitate dendritic refinement of postsynaptic partner neurons. Altogether, these observations provide cellular bases for wiring specificity establishment.
Visualization of Arabidopsis root system architecture in 3D by refraction-contrast X-ray micro-computed tomography
Authors: Kurogane Tomofumi , Tamaoki Daisuke , Yano Sachiko , Tanigaki Fumiaki , Shimazu Toru , Kasahara Haruo , Yamauchi Daisuke , Uesugi Kentaro , Hoshino Masato , Kamisaka Seiichiro , Mineyuki Yoshinobu , Karahara Ichirou
Published: May 2021

Plant roots change their morphological traits in order to adapt themselves to different environmental conditions, resulting in alteration of the root system architecture. To understand this mechanism, it is essential to visualize morphology of the entire root system. To reveal effects of long-term alteration of gravity environment on root system development, we have performed an experiment in the International Space Station using Arabidopsis (Arabidopsis thaliana(L.) Heynh.) plants and obtained dried root systems grown in rockwool slabs (mineral wool substrate). X-ray computer tomography (CT) technique using an industrial X-ray scanner has been introduced for the purpose to visualize root system architecture of crop species grown in soil in 3D non-invasively. In the case of the present study, however, root system of Arabidopsis is composed of finer roots compared with typical crop plants and rockwool is also composed of fibers having similar dimension to that of the roots. A higher spatial resolution imaging method is required for distinguishing roots from rockwool. Therefore, in the present study, we tested refraction-contrast X-ray micro-CT using coherent X-ray optics available at the beamline BL20B2 of the synchrotron radiation facility SPring-8. Using this technique, both the primary and the secondary roots were successfully identified in the tomographic slices, clearly distinguished from the individual rockwool fibers and resulting in successful tracing of these roots from their basal regions. This newly-developed technique should contribute to elucidate the effect of microgravity on Arabidopsis root system architecture in space.
The human innate immune protein calprotectin elicits a multi-metal starvation response inPseudomonas aeruginosa
Authors: Nelson Cassandra E. , Huang Weilang , Zygiel Emily M. , Nolan Elizabeth M. , Kane Maureen A. , Oglesby Amanda G.
Published: May 2021

To combat infections, the mammalian host limits availability of essential transition metals such as iron (Fe), zinc (Zn), and manganese (Mn) in a strategy termed “nutritional immunity”. The innate immune protein calprotectin (CP) contributes to nutritional immunity by sequestering these metals to exert antimicrobial activity against a broad range of microbial pathogens. One such pathogen isPseudomonas aeruginosa, which causes opportunistic infections in vulnerable populations including individuals with cystic fibrosis. CP was previously shown to withhold Fe(II) and Zn(II) fromP. aeruginosaand induce Fe- and Zn-starvation responses in this pathogen. In this work, we performed quantitative, label-free proteomics to further elucidate how CP impacts metal homeostasis pathways inP. aeruginosa. We report that CP induces an incomplete Fe-starvation response, as many Fe-containing proteins that are repressed by Fe limitation are not affected by CP treatment. The Zn-starvation response elicited by CP seems to be more complete than the Fe-starvation response and includes increases in Zn transporters and Zn-independent proteins. CP also induces the expression of membrane-modifying proteins, and metal-depletion studies indicate this response results from the sequestration of multiple metals. Moreover, the increased expression of membrane-modifying enzymes upon CP treatment correlates with increased resistance to polymyxin B. Thus, response ofP. aeruginosato CP treatment includes both single and multi-metal starvation responses and includes many factors related to virulence potential, broadening our understanding of this pathogen’s interaction with the host.

Importance

Transition metals are critical for growth and infection by all pathogens, and the innate immune system withholds these metals from pathogens to limit their growth in a strategy termed “nutritional immunity”. While multi-metal depletion by the host is appreciated, the majority of metal depletion studies have focused on individual metald. Here we use the innate immune protein calprotectin (CP), which complexes with several metals including iron (Fe), zinc (Zn), and manganese (Mn), and the opportunistic pathogenPseudomonas aeruginosato investigate multi-metal starvation. Using an unbiased label-free proteomics response, we demonstrate that multi-metal withholding by CP induces a regulatory response that is not merely additive of individual metal starvation responses, including the induction of Lipid A modification enzymes.
The dengue virus NS1 protein conveys pro-inflammatory signals by docking onto human high-density lipoproteins
Authors: Benfrid Souheyla , Park Kyu-Ho , Dellarole Mariano , Voss James E. , Tamietti Carole , Pehau-Arnaudet Gérard , Raynal Bertrand , Brûlé Sébastien , England Patrick , Zhang Xiaokang , Mikhailova Anastassia , Ungeheuer Marie-Noëlle , Petres Stéphane , Biering Scott B. , Harris Eva , Sakunthabaï Anavaj , Buchy Philippe , Duong Veasna , Dussart Philippe , Coulibaly Fasséli , Bontems François , Rey Félix A. , Flamand Marie
Published: May 2021

The nonstructural NS1 protein is a virulence factor secreted by dengue virus (DENV)-infected cells. NS1 is known to alter the complement system, activate immune cells and perturb endothelial barriers. Here we show that pro-inflammatory signals are triggered by a high affinity complex formed between NS1 and human high-density lipoproteins (HDL). Electron microscopy images of the NS1-HDL complexes show spherical HDL particles with rod-shaped NS1 protrusions on their surface. These complexes are readily detectable in the plasma of hospitalized dengue patients using anti-apolipoprotein A-I (ApoA-I) antibodies specific of the HDL moiety. The functional reprogramming of HDL particles by the NS1 protein as a means to exacerbate systemic inflammation during DENV infection provides a new paradigm linking the human lipoprotein network to dengue pathogenesis.
Endoplasmic reticulum-targeting but not translation is required for mRNA balancing in trypanosomes
Authors: Aroko Erick O , Soale Majeed Bakari , Batram Christopher , Jones Nicola G , Engstler Markus
Published: May 2021

The cell surface of bloodstream form African trypanosomes is covered by a dense coat of immunogenic variant surface glycoproteins (VSGs). By continuously changing the expressed VSG antigen, the parasites can survive the host’s immune response. TheVSGis highly expressed inTrypanosoma brucei, accounting for approximately 10 – 20% of total mRNA. Depletion ofVSGmRNA is lethal, and a counterbalancing of the mRNA levels occurs when two or moreVSGsare simultaneously expressed. How the VSG expression levels are regulated is unknown. Here, by using inducible and constitutive systems for ectopic VSG expression, we have discovered that (i) the endogenousVSGmRNA level is downregulated only when the ectopicVSGis targeted to the ER, (ii) VSG translation is dispensable and in fact, (iii) the regulation ofVSGmRNA levels does not depend on aVSGopen reading frame. We propose that feedback elicited at the ER regulates theVSGmRNA amounts to avoid overshooting the secretory pathway capacity. In this way, VSG expression is quantitatively and qualitatively fine-tuned. Balancing the overall number of ER-targeted mRNAs could well be a general mechanism in cell biology. The trypanosome system with just one dominant mRNA species provides a versatile model for studying this phenomenon.
Virtual deep brain stimulation: Multiscale co-simulation of a spiking basal ganglia model and a whole-brain mean-field model with The Virtual Brain
Authors: Meier Jil M. , Perdikis Dionysios , Blickensdörfer André , Stefanovski Leon , Liu Qin , Maith Oliver , Ü. Dinkelbach Helge , Baladron Javier , Hamker Fred H. , Ritter Petra
Published: May 2021

Deep brain stimulation (DBS) has been successfully applied in various neurodegenerative diseases as an effective symptomatic treatment. However, its mechanisms of action within the brain network are still poorly understood. Many virtual DBS models analyze a subnetwork around the basal ganglia and its dynamics as a spiking network with their details validated by experimental data. However, connectomic evidence shows widespread effects of DBS affecting many different cortical and subcortical areas. From a clinical perspective, various effects of DBS besides the motoric impact have been demonstrated. The neuroinformatics platform The Virtual Brain (TVB) offers a modeling framework allowing us to virtually perform stimulation, including DBS, and forecast the outcome from a dynamic systems perspective prior to invasive surgery with DBS lead placement. For an accurate prediction of the effects of DBS, we implement a detailed spiking model of the basal ganglia, which we combine with TVB via our previously developed co-simulation environment. This multiscale co-simulation approach builds on the extensive previous literature of spiking models of the basal ganglia while simultaneously offering a whole-brain perspective on widespread effects of the stimulation going beyond the motor circuit. In the first demonstration of our model, we show that virtual DBS can move the firing rates of a Parkinson’s disease patient’s thalamus - basal ganglia network towards the healthy regime while, at the same time, altering the activity in distributed cortical regions with a pronounced effect in frontal regions. Thus, we provide proof of concept for virtual DBS in a co-simulation environment with TVB. The developed modeling approach has the potential to optimize DBS lead placement and configuration and forecast the success of DBS treatment for individual patients.

Highlights

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We implement and validate a co-simulation approach of a spiking network model for subcortical regions in and around the basal ganglia and interface it with mean-field network models for each cortical region.

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Our simulations are based on a normative connectome including detailed tracts between the cortex and the basal ganglia regions combined with subject-specific optimized weights for a healthy control and a patient with Parkinson’s disease.

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We provide proof of concept by demonstrating that the implemented model shows biologically plausible dynamics during resting state including decreased thalamic activity in the virtual patient and during virtual deep brain stimulation including normalized thalamic activity and distributed altered cortical activity predominantly in frontal regions.

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The presented co-simulation model can be used to tailor deep brain stimulation for individual patients.
Presynaptic Stochasticity Improves Energy Efficiency and Alleviates the Stability-Plasticity Dilemma
Authors: Schug Simon , Benzing Frederik , Steger Angelika
Published: May 2021

When an action potential arrives at a synapse there is a large probability that no neurotransmitter is released. Surprisingly, simple computational models suggest that these synaptic failures enable information processing at lower metabolic costs. However, these models only consider information transmission at single synapses ignoring the remainder of the neural network as well as its overall computational goal. Here, we investigate how synaptic failures affect the energy efficiency of models of entire neural networks that solve a goal-driven task. We find that presynaptic stochasticity and plasticity improve energy efficiency and show that the network allocates most energy to a sparse subset of important synapses. We demonstrate that stabilising these synapses helps to alleviate the stability-plasticity dilemma, thus connecting a presynaptic notion of importance to a computational role in lifelong learning. Overall, our findings present a set of hypotheses for how presynaptic plasticity and stochasticity contribute to sparsity, energy efficiency and improved trade-offs in the stability-plasticity dilemma.
Whole-genome duplication shapes the aneuploidy landscape of human cancers
Authors: Prasad Kavya , Bloomfield Mathew , Levi Hagai , Keuper Kristina , Bernhard Sara V. , Baudoin Nicolaas C. , Leor Gil , Giam Maybelline , Wong Cheng Kit , Rancati Giulia , Storchova Zuzana , Cimini Daniela , Ben-David Uri
Published: May 2021

Aneuploidy – a hallmark of cancer – has tissue-specific recurrence patterns suggesting it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on the cellular and genomic context in which it arises. Whole-genome duplication (WGD) is a common macro-evolutionary event that occurs in >25% of human tumors during the early stages of tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy than tumors that have not, it remains unknown whether WGD affects aneuploidy recurrence patterns in human cancers. Here we analyzed clinical tumor samples from 449 WGD- tumors and 157 WGD+ tumors across 22 tumor types. We found distinct recurrence patterns of aneuploidy in WGD- and WGD+ tumors. The relative prevalence of recurrent aneuploidies decreased in WGD+ tumors, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD- and WGD+ tumors, giving rise to distinct co-occurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy vs. arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation in WGD- and WGD+ tumors. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Lastly, we induced WGD in human colon cancer cell lines, and followed aneuploidy formation in the isogenic WGD+/WGD-cells under standard or selective conditions. These experiments validated key findings from the clinical tumor analysis, and revealed a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors, and propose that the interaction between WGD and aneuploidy is a major contributor to tumor evolution.
Rpl24Bstmutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K
Authors: Knight John R. P. , Vlahov Nikola , Gay David M. , Ridgway Rachel A. , Faller William J. , Proud Christopher G. , Mallucci Giovanna R. , von der Haar Tobias , Smales C. Mark , Willis Anne E. , Sansom Owen J.
Published: May 2021

Increased protein synthesis supports the rapid proliferation associated with cancer. TheRpl24Bstmutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here we show thatRpl24Bstalso suppresses tumorigenesis and proliferation in a model of colorectal cancer with two common patient mutations,ApcandKras. In contrast to previous reports,Rpl24Bstmutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation inRpl24Bstmutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for theRpl24Bstmutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in colorectal cancer, as well as other cancers where theRpl24Bstmutation has a tumour suppressive effect in mouse models.
Bromelain and Acetylcysteine (BromAc) alone and in combination with Gemcitabine inhibits subcutaneous deposits of pancreatic cancer after intraperitoneal injection
Authors: Mekkawy Ahmad H. , Pillai Krishna , Badar Samina , Akhter Javed , Képénékian Vahan , Ke Kevin , Valle Sarah J. , Morris David L.
Published: May 2021

Objective

Gemcitabine (GEM) is commonly chosen for treating pancreatic cancer. However, its use is limited by toxicity. Earlier in vitro studies with GEM in combination with Bromelain (Brom) and Acetylcysteine (Ac) indicated a substantial reduction in IC50. Here, we investigated the efficacy and safety of Brom and Ac (BromAc) in the pancreatic cancer model in vivo.

Design

Both low dose and high dose studies for safety and efficacy of BromAc and GEM were conducted in nude mice. Body weight, wellbeing and tumor volume were monitored. At autopsy, tumor weight, tumor density, percentage of tumor necrosis, expression of Ki67 antigen, and immunohistological evaluation of vital organs were compared between the treatment groups.

Results

The low and high doses of BromAc alone and with chemotherapy agents were safe. A very significant reduction in pancreatic tumor volume, weight, and ki67 were seen with BromAc therapy and was equal to treatment with GEM alone and better than treatment with 5-FU. In addition, tumor density was significantly reduced by BromAc.

Conclusion

These encouraging results are the firstin vivoevidence of the efficacy of BromAc in pancreatic cancer and provide some mechanistic leads.
Protective mitochondrial fission induced by stress responsive protein GJA1-20k
Authors: Shimura Daisuke , Nuebel Esther , Baum Rachel , Xiao Shaohua , Warren Junco S. , Hong TingTing , Rutter Jared , Shaw Robin M.
Published: May 2021

The Connexin43 gap junction geneGJA1has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound, and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 seconds of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin Related Protein 1 (DRP1). We find that GJA1-20k induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.
Magnitude-sensitive reaction times reveal non-linear time costs in multi-alternative decision-making
Authors: Marshall James A. R. , Reina Andreagiovanni , Hay Célia , Dussutour Audrey , Pirrone Angelo
Published: May 2021

Optimality analysis of value-based decisions in binary and multi-alternative choice settings predicts that reaction times should be sensitive only to differences in stimulus magnitudes, but not to overall absolute stimulus magnitude. Yet experimental work in the binary case has shown magnitude sensitive reaction times, and theory shows that this can be explained by switching from linear to geometric time costs, but also by nonlinear subjective utility. Thus disentangling explanations for observed magnitude sensitive reaction times is difficult. Here for the first time we extend the theoretical analysis of geometric time-discounting to ternary choices, and present novel experimental evidence for magnitude-sensitivity in such decisions, in both humans and slime moulds. We consider the optimal policies for all possible combinations of linear and geometric time costs, and linear and nonlinear utility; interestingly, geometric discounting emerges as the predominant explanation for magnitude sensitivity.
The role of a mega-sporting event in attracting domestic tourists: the case of Seoul
Authors: Jeong Yunduk , Kim Sukkyu
Published: May 2021

Purpose

Mega-sporting events reportedly can offer many tangible and intangible benefits to the host country and regions, such as job creation, image improvement, local pride enhancement, social overhead capital investment and tourism business development. However, a paucity of studies in the literature have developed integrative models or have explored domestic tourist behavior in a general, or the sports tourism, context. To address this gap, the present study investigates the relationships between event quality, personal involvement, destination image and destination loyalty in the context of event sports tourism in order to provide sporting destination managers with valuable information for sustainable sports tourism development.

Design/methodology/approach

The authors collected information from 365 domestic tourists who attended the 100th National Sports Festival held in Seoul, South Korea, in 2019. Construct validity of the measurement scale was verified by confirmatory factor analysis (CFA), factor loadings, average variance (AVE) extracted and construct reliability (CR). Reliability of the measurement scale was verified by Cronbach's alpha analysis. The authors utilized structural equation modeling (SEM) with maximum likelihood estimation to analyze the predicted relationships.

Findings

The findings display the positive impacts of (1) event quality on destination image, (2) personal involvement on destination image, (3) personal involvement on destination loyalty and (4) destination image on destination loyalty. The findings indicate the key roles for event quality and personal involvement in improving destination image and the important roles of personal involvement and destination image in building destination loyalty.

Originality/value

The present study (1) contributes to the recent debate in the sports tourism literature over the relationship between the destination image and destination loyalty and (2) shows that there is no mediating role of the destination image on the relationship between the event quality and destination loyalty, and personal involvement and destination loyalty.
Holistic and integrative review into the barriers to women’s advancement to the corporate top in Europe
Authors: van ’t Foort-Diepeveen Rosalien Alexandra , Argyrou Aikaterini , Lambooy Tineke
Published: May 2021

Purpose

This paper aims to analyze the barriers discussed in the extant literature as to why women are underrepresented in the corporate top and explains how these barriers interrelate. An understanding of the interrelatedness of the barriers can help develop suitable and effective measures to improve women’s representation.

Design/methodology/approach

The systematic review method was applied. The search resulted in 51 relevant academic articles from multiple disciplines which were used for the analysis.

Findings

Barriers identified include gender stereotypes, bias in recruitment and promotion, devaluation of women, masculine and long-hours organizational culture, work-family issues and the lack of professional support. The interrelatedness of these barriers is analyzed by means of a conceptual framework.

Research limitations/implications

The adopted method requires the use of search engines and search terms and consequently relevant articles may have been overlooked. The study is geographically demarcated to Europe and, hence is only applicable to developing suitable and effective measures in a European context. More research is needed into which measures are appropriate and effective to overcome the barriers identified.

Practical implications

The insights can be used by companies to foster gender equality and by companies and governments to develop appropriate and effective measures to overcome these barriers.

Originality/value

This review contributes to the literature by uncovering the interrelatedness of the barriers. Understanding the interrelatedness is crucial for developing appropriate measures to overcome the barriers and ultimately to achieve gender equality at the corporate top.
Change readiness in individuals experiencing homelessness and multiple complex needs
Authors: Lord Alex , Tickle Anna , Buckell Anna
Published: May 2021

Purpose

This study aims to understand how staff in homelessness services conceptualise readiness for change in the individuals they support and how this informs their decision-making in practice.

Design/methodology/approach

A qualitative design was used. Ten staff members participated in semi-structured interviews. Data were examined through inductive–deductive thematic analysis, using a social constructivist epistemological lens.

Findings

Five main themes were constructed: “multiple complex needs mean multiple complex changes”, “talk versus behaviour”, “change is not a linear trajectory”, “the role of consistent boundaried relationships” and “change is not solely within the individual’s control”.

Practical implications

This research challenges existing notions of “readiness for change” as located within individuals and a prerequisite for using support from services. It has implications for staff and services, particularly those which are time-limited and address only single problems; service users may not be ready for some changes, but it should not be assumed they are not ready for change in other areas of their life. The offer of supportive relationships may precede and contribute to readiness for positive changes. Support should be offered based not only an individual’s intra-psychic readiness for change but also how the system might actively work to promote hope that change can be achieved and maintained.

Originality/value

To the best of the authors’ knowledge, this is the first study to explore staff members’ conceptualisations of readiness to change in relation to individuals with multiple complex needs and how this might influence practice.
An agent-based model for simulating COVID-19 transmissions on university campus and its implications on mitigation interventions: a case study
Authors: Zhou Yuan , Li Lin , Ghasemi Yasaman , Kallagudde Rakshitha , Goyal Karan , Thakur Deependra
Published: May 2021

Purpose

Universities across the USA are facing challenging decision-making problems amid the COVID-19 pandemic. The purpose of this study is to facilitate universities in planning disease mitigation interventions as they respond to the pandemic.

Design/methodology/approach

An agent-based model is developed to mimic the virus transmission dynamics on campus. Scenario-based experiments are conducted to evaluate the effectiveness of various interventions including course modality shift (from face-to-face to online), social distancing, mask use and vaccination. A case study is performed for a typical US university.

Findings

With 10%, 30%, 50%, 70% and 90% course modality shift, the number of total cases can be reduced to 3.9%, 20.9%, 35.6%, 60.9% and 96.8%, respectively, comparing against the baseline scenario (no interventions). More than 99.9% of the total infections can be prevented when combined social distancing and mask use are implemented even without course modality shift. If vaccination is implemented without other interventions, the reductions are 57.1%, 90.6% and 99.6% with 80%, 85% and 90% vaccine efficacies, respectively. In contrast, more than 99% reductions are found with all three vaccine efficacies if mask use is combined.

Practical implications

This study provides useful implications for supporting universities in mitigating transmissions on campus and planning operations for the upcoming semesters.

Originality/value

An agent-based model is developed to investigate COVID-19 transmissions on campus and evaluate the effectiveness of various mitigation interventions.
Supervisor support and turnover intentions of yacht captains: the role of work–family conflict and psychological resilience during the COVID-19 pandemic
Authors: Yorulmaz Murat , Sevinc Figen
Published: May 2021

Purpose

The purpose of this study was to investigate work–family conflict’s (WFC) mediating role and psychological resilience’s (PR) moderating role on the perceived supervisor support (SS) of yacht captains and their turnover intentions (TI) during the COVID-19 pandemic.

Design/methodology/approach

The authors followed a quantitative approach and conducted a questionnaire survey of 320 Turkish yacht captains. The data were analyzed using SPSS 22 (Process macro v3.4) and AMOS 22 statistics package programs.

Findings

Perceived SS has direct and indirect effects on TI with WFC being the intermediate variable. WFC’s effect on TI varies according to the yacht captains’ levels of PR.

Practical implications

This study empirically uncovered the impact of supervisor support and PR levels, the most important factors for ensuring hospitality employees exhibit positive organizational attitudes and behaviors. This study shows that the success of yacht captains in this stressful work environment depends on positively perceived SS and PR levels. PR regulates the relationship between WFC and TIs. Thus, supervisors should prioritize meeting their employees’ expectations to effectively and efficiently manage their human resources, and supervisor support is essential for meeting these expectations.

Originality/value

According to the authors’ knowledge, this study is the first to assess the effect of supervisor support on TI, the mediating role of WFC and the moderating role of PR. In addition, the authors aimed to fill the research gaps on yacht captains, as a profession requiring expertise and field experience, and on PR in the tourism industry.
A sequential logic model between sales performance and salesperson satisfaction in B2B markets
Authors: Rodríguez Rocío , Høgevold Nils , Otero-Neira Carmen , Svensson Göran
Published: May 2021

Purpose

The purpose of this paper is to test the relationship between objective and subjective sales performance and salespeople’s economic and non-economic satisfaction in a sequential logic model.

Design/methodology/approach

Based on a questionnaire survey using a deductive approach. A total of 315 companies were ultimately selected for participation in the study, to represent a range of companies from different industries and company sizes in the product-oriented business sector of Norway. A total of 236 questionnaires were returned, generating a response rate of 74.9%.

Findings

The sequential logic of objective and subjective sales performance, in connection with salespeople’s economic and non-economic satisfaction, reveals an underlying structure that can link existing theory and previous studies on sales performance and salesperson satisfaction in business-to-business (B2B) settings.

Research limitations/implications

The results reported applying only to a B2B setting, to test whether the sequential logic model and mediating effects still hold in such setting. This study is also limited to product-oriented companies in Norway, which offers the opportunity for a future study to verify whether the refined research model also applies to service-oriented companies.

Practical implications

The results indicate that the constructs of objective and subjective sales performance and salespeoplés economic and non-economic satisfaction are intertwined in a B2B setting. Specifically, these constructs are related to one another sequentially.

Originality/value

Contributes to structuring in a B2B setting, the relationships between objective and subjective sales performance on the one hand and salespeoplés economic and non-economic satisfaction on the other. It also highlights two mediating effects, namely, subjective sales performance mediates the relationship effect between objective sales performance and salespeoplés economic satisfaction and salespeople economic’s satisfaction mediates the relationship effect between subjective sales performance and salespeople’s non-economic satisfaction.
The impact of COVID-19 on the construction industry in Ghana: the case of some selected firms
Authors: Agyekum Kofi , Kukah Augustine Senanu , Amudjie Judith
Published: May 2021

Purpose

With its impact already felt, the construction industry worldwide is gradually reviving following the lifting up of lockdowns amid the COVID-19 pandemic. Though some articles have been written regarding its impact on the construction industry in other countries, much is yet to be known concerning the current impact in Ghana. This study aims to examine the impact of COVID-19 on Ghana’s construction industry and assess how construction companies are contributing to the fight against COVID-19.

Design/methodology/approach

Semi-structured interviews with nine key professionals working with D1K1 firms currently working on projects of almost similar sizes within the confines of a reputable tertiary institution in Ghana were conducted over a span of three weeks. Thematic analysis was conducted with Nvivo 12 Pro Application software.

Findings

From the findings, the major impact includes: a decrease in work rate, delays in payments and an increase in the cost of materials arising from border closure. On the measures by construction companies in contributing to the fight against the pandemic, findings indicated: educating the workforce on the virus, the provision of PPEs, regular and effective checks on entry and exit from the site.

Practical implications

The study is significant, as knowledge of the impact posed by the pandemic will provide some idea of the measures to put in place to ensure the gradual to full recovery of the industry.

Originality/value

The originality of this study lies in the fact that it is a pioneering study on the impact of COVID-19 on the Ghanaian construction industry.