bluuebunny/crossref_metadata_2025 huggingface dataset:
METTL17 is an Fe-S cluster checkpoint for mitochondrial translation
Authors: Ast Tslil , Itoh Yuzuru , Sadre Shayan , McCoy Jason G. , Namkoong Gil , Chicherin Ivan , Joshi Pallavi R. , Kamenski Piotr , Suess Daniel L. M. , Amunts Alexey , Mootha Vamsi K.
Published: November 2022

Abstract

Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN null cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.
Integration of optic flow into the sky compass network in the brain of the desert locust
Authors: Zittrell Frederick , Pabst Kathrin , Carlomagno Elena , Rosner Ronny , Pegel Uta , Endres Dominik M. , Homberg Uwe
Published: November 2022

Flexible orientation through any environment requires a sense of current relative heading that is updated based on self-motion. Global external cues originating from the sky or the earth’s magnetic field and local cues provide a reference frame for the sense of direction. Locally, optic flow may inform about turning maneuvers, travel speed and covered distance. The central complex in the insect brain is associated with orientation behavior and largely acts as a navigation center. Visual information from global celestial cues and local landmarks are integrated in the central complex to form an internal representation of current heading. However, it is largely unclear which neurons integrate optic flow in the central-complex network. We recorded intracellularly from neurons in the locust central complex while presenting lateral grating patterns that simulated translational and rotational motion to identify these sites of integration. Certain types of central-complex neurons were sensitive to visual self-motion independent of the type and direction of simulated motion. Columnar neurons innervating the noduli, paired central-complex substructures, were tuned to the direction of simulated horizontal turns. Modelling the connectivity of these neurons with a system of proposed compass neurons can account for rotation-direction specific shifts in the activity profile in the central complex corresponding to turn direction. Our model is similar but not identical to the mechanisms proposed for angular velocity integration in the navigation compass of the flyDrosophila.
Multiplexed selectivity screening of anti-GPCR antibodies
Authors: Dahl Leo , Kotliar Ilana B. , Bendes Annika , Dodig-Crnković Tea , Fromm Samuel , Elofsson Arne , Uhlén Mathias , Sakmar Thomas P. , Schwenk Jochen M.
Published: November 2022

G protein-coupled receptors (GPCRs) control critical cellular signaling pathways. Therapeutic agents, such as antibodies (Abs), are being developed to modulate GPCR signaling pathways. However, validating the selectivity of anti-GPCR Abs is challenging due to sequence similarities of individual receptors within GPCR subfamilies. To address this, we developed a multiplexed immunoassay to test >400 anti-GPCR Abs from the Human Protein Atlas targeting a customized library of 215 expressed and solubilized GPCRs representing all GPCR subfamilies. We found that ~61% of Abs were selective for their intended target, ~11% to bind off-target, and ~28% not to bind any GPCR. Antigens of on-target Abs were, on average, significantly longer, more disordered, and less likely to be buried in the interior of the GPCR protein than the other Abs. These results provide important insights into the immunogenicity of GPCR epitopes and form a basis for the design of therapeutic Abs and the detection of pathological auto-antibodies.

TEASER

A multiplexed library-to-library selectivity analysis of 400 anti-GPCR antibodies within subfamilies of 200 solubilized receptors.
3DProtDTA: the deep learning model for drug-target affinity prediction based on the residue-level protein graphs
Authors: Voitsitskyi Taras , Stratiichuk Roman , Koleiev Ihor , Popryho Leonid , Ostrovsky Zakhar , Henitsoi Pavel , Khropachev Ivan , Vozniak Volodymyr , Zhytar Roman , Nechepurenko Diana , Yesylevskyy Semen , Nafiev Alan , Starosyla Serhii
Published: November 2022

Accurate prediction of the drug-target affinity (DTA)in silicois of critical importance for modern drug discovery. Computational methods of DTA prediction, applied in the early stages of drug development, are able to speed it up and cut its cost significantly. A wide range of approaches based on machine learning was recently proposed for DTA assessment. The most promising of them are based on deep learning techniques and graph neural networks to encode molecular structures. The recent breakthrough in protein structure prediction made by AlphaFold made an unprecedented amount of proteins without experimentally defined structures accessible for computational DTA prediction. In this work, we propose a new deep learning DTA model 3DProtDTA, which utilises AlphaFold structure predictions in conjunction with the graph representation of proteins. The model is superior to its rivals on common benchmarking datasets and has a potential for further improvement.
SCALA: A web application for multimodal analysis of single cell next generation sequencing data
Authors: Tzaferis Christos , Karatzas Evangelos , Baltoumas Fotis A. , Pavlopoulos Georgios A. , Kollias George , Konstantopoulos Dimitris
Published: November 2022

Analysis and interpretation of high-throughput transcriptional and chromatin accessibility data at single cell resolution are still open challenges in the biomedical field. In this article, we present SCALA, a bioinformatics tool for analysis and visualization of single cell RNA sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) datasets. SCALA combines standard types of analysis by integrating multiple software packages varying from quality control to identification of distinct cell population and cell states. Additional analysis options enable functional enrichment, cellular trajectory inference, ligand-receptor analysis and regulatory network reconstruction. SCALA is fully parameterizable at every step of the analysis, presenting data in tabular format and produces publication-ready 2D and 3D visualizations including heatmaps, barcharts, scatter, violin and volcano plots. We demonstrate the functionality of SCALA through two use-cases related to TNF-driven arthritic mice, handling data from both scRNA-seq and scATAC-seq experiments. SCALA is mainly developed in R, Shiny and JavaScript and is available as a web application athttp://scala.pavlopouloslab.infoorhttps://scala.fleming.gr.
Mechanical wounding impacts the growth versus defence balance in tomato (Solanum lycopersicum)
Authors: Aparecida Cunha Ana Flavia , Duarte Rodrigues Pedro Henrique , Anghinoni Ana Clara , de Paiva Vinicius Juliani , da Silva Pinheiro Daniel Gonçalves , Campos Marcelo Lattarulo
Published: November 2022

Plants have evolved elaborate surveillance systems that allow them to perceive the attack by pests and pathogens and activate the appropriate defences. Mechanical stimulation, such as mechanical wounding, represents one of the most reliable cues for the perception of potential herbivore aggressors. Here we demonstrate that mechanical wounding disturbs the growth versus defence balance in tomato, a physiological condition where growth reduction arises as a pleiotropic consequence of the activation of defence responses (or vice-versa). We observed that consecutive lesions on tomato leaves impairs the formation of several growth-related traits, including shoot elongation, leaf expansion and time for flowering set, while concomitantly activating the production of defence responses such as trichome formation and the upregulation of defence-related genes. We also provide genetic evidence that this wound-induced growth repression is a consequence of tomato plants sensing the injuries via jasmonates (JAs), a class of plant hormones known to be master regulators of the plant growth versus defence balance. Besides providing a mechanistic explanation on how the growth and defence balance is shifted when plants are subjected to a specific type of mechanical stimulus, our results may offer a practical explanation for why tomato productivity is so negatively impacted by herbivore attack.

Highlight

Antagonism between growth and defence responses was observed in tomato plants subject to mechanical wounding, a treatment that hinders development while promoting the activation of anti-herbivore traits.
A meta-analysis of operational interactions between pinnipeds and fisheries
Authors: Jackson J , Arlidge W , Oyanedel R , Davis KJ
Published: November 2022

The global recovery of pinniped populations is a conservation success. However, pinniped population recovery has increased human-wildlife conflict with fisheries, an issue often reported and requiring management, but one that lacks global synthesis. We conduct a meta-analysis to estimate the impacts of operational interactions (specifically, lost catch) between pinnipeds and fisheries. Where quantifiable interactions are reported (n = 36), on average fishers have a 33.7% chance of interacting with pinnipeds on any given fishing day, and 13.8% lost catch. We find a large degree of heterogeneity between studies, with some fisheries experiencing much more negative interactions than others. Specifically, smaller-scale fisheries using nets are up to twice as likely to have negative interactions and lose up to five times more catch compared to large-scale fisheries. We conclude that pinniped-fishery conflict is a substantial global issue, but its impacts are not uniform. To successfully manage long-term coexistence between pinnipeds and humans, explicit data quantifying operational interactions is required. Population recoveries can have unintended consequences for fisheries, and management of ecological, social and economic outcomes is needed for long-term coexistence.

Teaser

Pinniped population recoveries have led to significant impacts on fisheries, but small-scale fisheries lose out most.
Developing best practices for genotyping-by-sequencing analysis in the construction of linkage maps
Authors: Taniguti Cristiane Hayumi , Taniguti Lucas Mitsuo , Amadeu Rodrigo Rampazo , Lau Jeekin , Gesteira Gabriel de Siqueira , Oliveira Thiago de Paula , Ferreira Getulio Caixeta , Pereira Guilherme da Silva , Byrne David , Mollinari Marcelo , Riera-Lizarazu Oscar , Garcia Antonio Augusto Franco
Published: November 2022

Background: Genotyping-by-Sequencing (GBS) provides affordable methods for genotyping hundreds of individuals using millions of markers. However, this challenges bioinformatic procedures that must overcome possible artifacts such as the bias generated by PCR duplicates and sequencing errors. Genotyping errors lead to data that deviate from what is expected from regular meiosis. This, in turn, leads to difficulties in grouping and ordering markers resulting in inflated and incorrect linkage maps. Therefore, genotyping errors can be easily detected by linkage map quality evaluations. Results: We developed and used the Reads2Map workflow to build linkage maps with simulated and empirical GBS data of diploid outcrossing populations. The workflows run GATK, Stacks, TASSEL, and Freebayes for SNP calling and updog, polyRAD, and SuperMASSA for genotype calling, and OneMap and GUSMap to build linkage maps. Using simulated data, we observed which genotype call software fails in identifying common errors in GBS sequencing data and proposed specific filters to better handle them. We tested whether it is possible to overcome errors in a linkage map using genotype probabilities from each software or global error rates to estimate genetic distances with an updated version of OneMap. We also evaluated the impact of segregation distortion, contaminant samples, and haplotype-based multiallelic markers in the final linkage maps. Through our evaluations, we observed that some of the approaches produce different results depending on the dataset (dataset-dependent) and others produce consistent advantageous results among them (dataset-independent). Conclusions: We set as default in the Reads2Map workflows the approaches that showed to be dataset-independent for GBS datasets according to our results. This reduces the number required of tests to identify optimal pipelines and parameters for other empirical datasets. Using Reads2Map, users can select the pipeline and parameters that best fit their data context. The Reads2MapApp shiny app provides a graphical representation of the results to facilitate their interpretation.
Syntheticin vivocompartmentalisation improves metabolic flux and modulates the product profile of promiscuous enzymes
Authors: Cheah Li Chen , Liu Lian , Plan Manuel R. , Peng Bingyin , Lu Zeyu , Schenk Gerhard , Vickers Claudia E. , Sainsbury Frank
Published: November 2022

Enzyme spatial organisation and compartmentalisation are naturally evolved mechanisms for facilitating multi-step biocatalysis. We explored the syntheticin vivoco-encapsulation of two different cargo proteins in yeast using a self-assembling virus-like particle. Co-encapsulation was verified using single particle techniques for both end-to-end fusion of the cargo proteins with the encapsulation anchor at one end, and coexpression of each cargo protein with their individual anchors. The co-encapsulation of a bifunctional geranyl diphosphate/farnesyl diphosphate synthase and a bifunctional linalool/nerolidol synthase delivered nerolidol titres up to 30 times that of an unorganised ‘free’ enzyme control, a remarkable improvement from a single engineering step. Interestingly, striking differences in the ratio of products (linalool and nerolidol) were observed with each spatial organisation approach. This work presents the largest reported titre fold increases fromin vivoenzyme compartmentalisation and suggests that enzyme spatial organisation could be used to modulate the product profile of promiscuous enzymes.
The impact of dance movement interventions on psychological health in older adults without dementia: A systematic review and meta-analysis
Authors: Podolski Odile , Whitfield Tim , Schaaf Leah , Cornaro Clara , Köbe Theresa , Koch Sabine , Wirth Miranka
Published: November 2022

Multimodal lifestyle-based interventions that integrate physical, mental and social stimulation could promote mental health and brain resilience against dementia. This meta-analysis examined the efficacy of dance movement interventions (DMI) on psychological health in older adults. Pre-registration was done with PROSPERO (CRD42021265112). PubMed, Web of Science and PsycInfo were searched for randomized controlled trials (RCT) evaluating the effects of DMI (>4 weeks’ duration) on measures of psychological health (primary outcome) and cognitive function (additional outcome) among older adults without dementia (≥55). Data of 13 primary RCT (n=943,n-DMI=474,n-control=469) were synthesized using a random effects meta-analysis with robust variance estimation. DMI had a small positive effect on overall psychological health (g=0.31;95% CI: [0.09,0.53];p=.01,I2=62.55) and a medium effect on general cognitive function (g=0.48;95% CI: [0.03,0.93],p=.04,I2=82.45) compared to comparators. None of the primary studies included measures of neuroplasticity. DMI may serve as a multimodal enrichment strategy to promote healthy mental aging. High-quality intervention studies are needed to expand evidence for psychological domains and identify the underlying neurophysiological correlates.
Visualization of Incrementally Learned Projection Trajectories for Longitudinal Data
Authors: Malepathirana Tamasha , Senanayake Damith , Gautam Vini , Engel Martin , Balez Rachelle , Lovelace Michael D. , Sundaram Gayathri , Heng Benjamin , Chow Sharron , Marquis Chris , Guillemin Gilles , Brew Bruce , Jagadish Chennupati , Ooi Lezanne , Halgamuge Saman
Published: November 2022

Longitudinal studies that continuously generate data enable the capture of temporal variations in experimentally observed parameters, facilitating the interpretation of results in a time-aware manner. We propose IL-VIS (Incrementally Learned Visualizer), a new machine learning pipeline that incrementally learns and visualizes a progression trajectory representing the longitudinal changes in longitudinal studies. At each sampling time point in an experiment, IL-VIS generates a snapshot of the longitudinal process on the data observed thus far, a new feature that is beyond the reach of classical static models. We first verify the utility and correctness of IL-VIS using simulated data, for which the true progression trajectories are known. We find that it accurately captures and visualizes the trends and (dis)similarities between high-dimensional progression trajectories. We then apply IL-VIS to longitudinal Multi-Electrode Array data from brain cortical organoids when exposed to different levels of Quinolinic Acid, a metabolite contributing to many neuroinflammatory diseases including Alzheimer’s disease, and its blocking antibody. We uncover valuable insights into the organoids’ electrophysiological maturation and response patterns over time under these conditions.
Fast actin disassembly and fimbrin mechanosensitivity support rapid turnover during clathrin-mediated endocytosis
Authors: Mousavi Sayed Iman , Lacy Michael M. , Li Xiaobai , Berro Julien
Published: November 2022

The actin cytoskeleton is central to force production in numerous cellular processes in eukaryotic cells. During clathrin-mediated endocytosis (CME), a dynamic actin meshwork is required to deform the membrane against high membrane tension or turgor pressure. Previous experimental work from our lab showed that several endocytic proteins, including actin and actin-interacting proteins, turn over several times during the formation of a vesicle during CME in yeast, and their dwell time distributions were reminiscent of Gamma distributions with a peak around 1 s (Lacy et al., 2019). However, the distribution for the filament crosslinking protein fimbrin contains a second peak around 0.5 s. To better understand the nature of these dwell time distributions, we developed a stochastic model for the dynamics of actin and its binding partners. Our model demonstrates that very fast actin filament disassembly is necessary to reproduce experimental dwell time distributions. Our model also predicts that actin-binding proteins bind rapidly to nascent filaments and filaments are fully decorated. Last, our model predicts that fimbrin detachment from actin endocytic structures is mechanosensitive to explain the extra peak observed in the dwell time distribution.
A compact-rigid multi-analyser for energy and angle filtering of high-resolution X-ray experiments. Part 1. Principles and implementation
Authors: Prat A. , Hodeau J.-L.
Published: November 2022

Diffraction and spectroscopy instruments using a filtering process with several analyser crystals have existed for about 30 years at synchrotron radiation sources, but they are difficult to use on laboratory sources. Several diffraction multi-filtering systems for powder diffraction experiments have been studied and optimized, in order to show the relevance, simplicity and efficiency of their implementation. Optical filter systems containing one or many diffracting elements, precisely positioned in a rigid manner on a logarithmic spiral surface and having a stability that allows high resolution and high sensitivity to powder diffraction experiments, have been developed. After having tested prototypes with various geometries, we present in particular the realization of a small rigid-compact multi-analyser comb that allows 20–50 measurements on synchrotron radiation sources to be filtered in parallel, but also and especially that can be adapted on laboratory X-ray sources (Ag Kα1) to increase by an order of magnitude the intensities and resolutions of the measurements. Such a rigid-compact multi-analyser block can advantageously be associated with `photon-counting' 1D and 2D detectors in order to drastically improve the detection thresholds of powder diffraction measurements to better than 0.1%, which allows the detection/quantification/analysis of minor phases in studies of `real' complex materials.
Analysing the marketing strategies that fish farming businesses in the UK can use to gain a competitive advantage
Authors: Olawunmi Christiana Adeola , Clarke Andrew Paul
Published: November 2022

Purpose

This study aims to explore marketing strategies that UK fish farming businesses can use to gain a competitive advantage. The marketing strategies examined include product branding and core competencies, sales promotion, market positioning and segmentation.

Design/methodology/approach

A survey through an online questionnaire was mailed to five randomly selected trade associations of UK fish farming businesses and distributed to their registered members, of which 200 responded. Both male and female genders with different age groups and levels of experience in the UK fish farming business participated. In addition, ten articles were sampled for a systematic review.

Findings

Results show that UK fish farming businesses could increase sales by using ecolabels in product branding to attract premium prices, build consumer confidence and using high-quality packages for fish products will keep fish fresh for a longer period.

Research limitations/implications

The scope of this research is limited to the UK. The findings cannot be generalised and used for other jurisdictions because of variable economic and market conditions.

Originality/value

A significant recommendation from this case study is that fish farming businesses need to be creative and innovative in ways such as leveraging branding, sales promotions and core competencies to win the trust and confidence of consumers. Most importantly, each fish farming business should know the specific marketing strategy that works for them; this case study shows that not all branding and sales promotion techniques enhance competitiveness. The scope of this research is limited to the UK. The findings cannot be generalised and used for other jurisdictions because of variable economic and market conditions.
Clinical course and outcomes of pemphigus vulgaris and foliaceus: A retrospective study using a nationwide database in Japan
Authors: Miyachi Hideaki , Konishi Takaaki , Hashimoto Yohei , Matsui Hiroki , Fushimi Kiyohide , Inozume Takashi , Yasunaga Hideo
Published: November 2022

Pemphigus is a life‐threatening autoimmune blistering disease. Patient characteristics, treatment courses, and outcomes remain unclear owing to its rarity. To describe the background, treatment, and outcomes of pemphigus, we identified 2598 patients with pemphigus vulgaris and 1186 patients with pemphigus foliaceus from a nationwide inpatient database in Japan. Patients with pemphigus vulgaris were younger (62 vs 72 years, P < 0.001), had fewer comorbidities, and were more likely to be admitted to high‐volume hospitals (38% vs 30%, P < 0.001) than those with pemphigus foliaceus. Patients with pemphigus vulgaris had undergone more aggressive treatment, including steroid pulse therapy, intravenous immunoglobulin, or plasmapheresis, compared with those with pemphigus foliaceus (48% vs 42%, P = 0.001); specifically, in patients aged <70 years, the pemphigus vulgaris group was more likely to undergo aggressive treatment than the pemphigus foliaceus group (52% vs 45%), whereas there was no significant difference in patients aged ≥70 years (40% vs 40%). Immunosuppressive agents (30% vs 26%, P = 0.015) and analgesics, including opioids (45% vs 36%, P < 0.001), were used more frequently, whereas topical corticosteroids were used less frequently (32% vs 48%, P < 0.001) in patients with pemphigus vulgaris compared with those with pemphigus foliaceus. In‐hospital mortality was lower in patients with pemphigus vulgaris than in those with pemphigus foliaceus (2.2% vs 4.0%, P = 0.002); in the comparison stratified by age, the mortality was equivalent among the two groups (0.6% in patients aged <70 years and 6.1% in those aged ≥70 years). Overall, patients with pemphigus vulgaris had a 10‐day longer hospitalization period and higher hospitalization costs than those with pemphigus foliaceus. Our findings provide useful information for understanding the current trends in the management of pemphigus in Japan.
Full waveform inversion based on inversion network reparameterized velocity
Authors: Jiang Peng , Wang Qingyang , Ren Yuxiao , Yang Senlin , Li Ningbo
Published: November 2022

Seismic velocity plays an important role in imaging and identifying underground geology. Conventional seismic velocity inversion methods, like full waveform inversion, directly update the velocity model based on the misfit between the observed and synthetic data. However, seismic velocity inversion is a highly nonlinear process, and the inversion effect greatly relies on the initial inversion model. In this paper, we propose a novel network‐domain full waveform inversion method. Different from the existing network‐domain full waveform inversion methods, which use random or fixed numbers as network input, we reparameterize the low‐dimensional acoustic velocity model in a high‐dimensional inversion network parameter domain with seismic observed data as the network input. In this way, the physical information within the observed data can be directly encoded into the inversion parameters, leading to a better inversion effect than the current network‐domain full waveform inversion method. Moreover, comparison experiments on the Society of Exploration Geophysicists and the European Association of Geoscientists and Engineers Overthrust model and the Marmousi model show the advantages of the proposed method over conventional full waveform inversion from the aspects of inversion accuracy, robustness to noisy data, and more complex geological structures. These advantages may benefit from the fact that reparameterization within the inversion network domain can empower the inversion process with the regularization ability of denoising and mitigating the cycle‐skipping issue. In the end, the potential of the proposed method in terms of network initialization is further discussed.
Inversion of self‐potential source based on particle swarm optimization
Authors: Luo Yijian , Du Xingzhong , Cui Yian , Guo Youjun , Xie Jing , Liu Jianxin
Published: November 2022

Particle swarm optimization is widely applied in self‐potential inversion, but most of these applications are limited to simple polarized bodies like inclined sheets and spheres. In this paper, two variants of particle swarm optimization are formed by introducing the resistivity constraint matrix and the damping factor and are then applied to two‐dimensional self‐potential source inversion. The two variants are combined to balance the exploration and exploitation capabilities in different situations, and the rationality of the parameter selection is validated through the stability analysis. To ensure both compactness and smoothness of the inversion results, we adopt an objective function based on L1–L2 norm regularization. Finally, we verify the effectiveness of the proposed algorithm through synthetic examples, the Cu–Fe model sandbox experiment and a field example. By imposing certain constraints, particle swarm optimization also shows great potential in high‐dimensional self‐potential source inversion, instead of being limited to the inversion of a few parameters.
Epidermal growth factor receptor tyrosine kinase inhibitors for non‐small cell lung cancer harboring uncommon EGFR mutations: Real‐world data from Taiwan
Authors: Chang John Wen‐Cheng , Huang Chen‐Yang , Fang Yueh‐Fu , Chang Ching‐Fu , Yang Cheng‐Ta , Kuo Chih‐Hsi Scott , Hsu Ping‐Chih , Wu Chiao‐En
Published: November 2022

Background

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) are the standard treatment for patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. This study aimed to evaluate the efficacy of EGFR‐TKIs and prognostic factors for patients with NSCLC harboring uncommon EGFR mutations, which account for 10% of EGFR mutations.

Methods

A total of 230 treatment‐naive patients with NSCLC harboring uncommon EGFR mutations treated with first‐line EGFR‐TKIs between 2011 and 2018 at four hospitals (belonging to four institutions, Linkou, Kaohsiung, Keelung, and Chiayi, of the Chang Gung Memorial Hospital) in Taiwan were retrospectively reviewed. Their clinicopathological characteristics, adverse events (AEs), objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), and overall survival (OS) were collected. Univariate and multivariate analyses were performed to identify potential prognostic factors for PFS.

Results

Overall, patients who received afatinib (n = 62) had better PFS (median: 6.4 vs. 5.9 months, p = 0.022) and OS (median: 13.4 vs. 13.0 months, p = 0.008) than those who received gefitinib/erlotinib (n = 124), although no significant differences were observed for ORR (46.8% vs. 35.5%, p = 0.137) or DCR (59.7% vs. 58.9%, p = 0.916). Patients who received afatinib showed significantly higher ORR (58.3% vs. 31.3%, p = 0.027) but not DCR compared with gefitinib/erlotinib for major uncommon mutations. Afatinib trended toward better PFS and OS for major uncommon mutations and compound mutations. No EGFR‐TKIs were effective for most NSCLC patients with exon 20 insertions. Performance status, metastasis of the liver and pleura, and dose reduction were independent prognostic factors for PFS.

Conclusion

Afatinib demonstrated better survival outcomes than gefitinib/erlotinib for NSCLC patients harboring major EGFR uncommon mutations and compound mutations. Performance status and metastatic sites may be useful for predicting PFS for major uncommon mutations and compound mutations.
Follicle‐stimulating hormone effectiveness in male idiopathic infertility: What happens in daily practice?
Authors: Romeo Marilina , Spaggiari Giorgia , Nuzzo Federico , Granata Antonio R. M. , Simoni Manuela , Santi Daniele
Published: November 2022

Objectives

To assess the effectiveness of follicle‐stimulating hormone (FSH) administration in male idiopathic infertility in a clinical setting.

Methods

A retrospective real‐world study was carried out, including all consecutive FSH‐treated infertile men attending the Andrology Unit of Modena (Italy) from June 2015 to May 2022. Medical history, physical and andrological examinations, hormonal and seminal parameters, therapeutic management and pregnancy data were collected. The primary endpoint was the number of pregnancies obtained after FSH administration, whereas semen parameters change was the secondary outcome.

Results

A total of 194 of 362 (53.6%) infertile men, eligible according to the Italian Health System regulations, were treated with FSH (mean age 37.9 ± 6.1 years). Following FSH administration (mean therapy duration 9.1 ± 7.1 months), 43 pregnancies were recorded (27.6%), of which 22 occurred naturally and 21 after assisted reproduction. A significant increase in sperm concentration (9.9 ± 12.2 vs. 18.9 ± 38.9 million/mL, p = 0.045) was detected after treatment, together with a significant increase in normozoospermia (from 1.0% to 5.1%, p = .044) and a reduction in azoospermia rate (from 9.8% to 7%, p = 0.044). Dividing the cohort in FSH‐responders and non‐responders, in terms of pregnancy achieved, higher sperm concentrations (15.7 ± 26.6 vs. 22.2 ± 25.7 million/mL, p = 0.033) and progressive sperm motility (18.0 ± 18.2 vs. 27.3 ± 11.3, p = 0.044) were found in pregnancy group.

Conclusion

Our experience suggests that FSH, empirically administered to men with idiopathic infertility, leads to pregnancy in one out of four patients and increases sperm concentration. Although the expected limits because of a real‐world data study, the number of FSH‐treated patients required to achieve one pregnancy seems to be lower in clinical setting if compared to previously published data.
A critical review of the precautionary approach of the IUCN impact classification for non‐native taxa
Authors: Cassini Marcelo H.
Published: November 2022

The International Union for the Conservation of Nature (IUCN) proposes the use of the Environmental Impact Classification for Alien Taxa to standardize the classification of introduced species (IS) based on their environmental impact. The IUCN invoked the precautionary principle (PP) via 2 rules: the impact assigned to a taxon must be the maximum recorded impact across different impact assessments, and when the main driver of environmental damage is unclear, it must be assumed to be caused by the IS. The validity of PP is conditioned on the degree of emergency that warrants urgent decisions and on the scientific evidence demonstrating the advantages of applying a preventive measure. The application of an impact classification system does not arise in the context of an emergency that requires management; it occurs before the decision‐making phase. Thus, PP should not be used in early steps of the risk analysis process. The IUCN also did not provide enough scientific basis to justify the use of PP. Instead, the PP rules appear to be rooted primarily in the ethical value system underlying conservation science. Conservationists assign intrinsic value to native species by virtue of their roles and relationships within ecological and evolutionary systems and processes; thus, individuals introduced in new environments not only cease to have value because they are no longer part of that natural diversity and lack those links with the rest of the ecosystem, but they become a threat to what conservationists value most. The consequence of this belief is that all introduced taxa will have an impact at some level, suggesting that values justify the PP rules.
Burden of migraine in Brazil: A cross‐sectional real‐world study
Authors: Souza Marcio Nattan Portes , Cohen Joshua M. , Piha Tony , Ribalov Rinat , Lengil Tamar , van der Laan Andressa , Calderaro Marcelo , Lee Lulu K.
Published: November 2022

Objective

To assess the burden and consequences of migraine in Brazil in terms of health‐related quality of life (HRQoL), work productivity and daily activities, and healthcare resource utilization (HRU).

Background

Despite existing data on how migraine affects populations worldwide, there are limited data on the burden of migraine in Latin America.

Methods

This cross‐sectional study used patient‐reported data from the 2018 Brazil National Health and Wellness Survey. HRQoL scores (EuroQol 5‐dimension 5‐level [EQ‐5D‐5L]; 36‐item Short Form Health Survey, version 2 [SF‐36v2]; and Short Form 6‐dimension [SF‐6D]), impairments to work productivity and daily activities (Work Productivity and Activity Impairment questionnaire), and all‐cause HRU were compared between migraine respondents and matched non‐migraine controls.

Results

Of the 12,000 total respondents in the survey database, 1643 self‐reported a physician diagnosis of migraine and were propensity score matched 1:1 with controls without migraine. HRQoL was lower in patients with migraine versus non‐migraine controls, with significantly lower SF‐36v2 physical (mean [± SD] 50.3 [7.5] vs. 52.0 [7.6]) and mental component (mean [± SD] 42.9 [10.2] vs. 46.0 [9.9]) summary scores and SF‐6D (mean [± SD] 0.7 [0.1] vs. 0.7 [0.1]) and EQ‐5D‐5L (mean [± SD] 0.7 [0.2] vs. 0.8 [0.2]) utility scores (all p < 0.001). Patients with migraine reported higher levels of work productivity loss (mean [± SD], 40.6% [31.4%] vs. 28.6% [30.9%], including absenteeism 12.8% [19.1%] vs. 8.4% [17.1%] and presenteeism 35.0% [28.7%] vs. 24.8% [28.0%]; all p < 0.001); activity impairment (mean [± SD] 36.0% [28.8%] vs. 25.5% [28.1%]; p < 0.001); and significantly higher HRU in the past 6 months (healthcare provider and emergency department visits [mean [± SD] 7.2 [9.5] vs. 4.5 [6.3] and 1.7 [3.8] vs. 0.9 [2.2]; both p < 0.001] and hospitalizations [mean [± SD] 0.4 [2.7] vs. 0.2 [1.1]; p = 0.002]) than controls.

Conclusion

Migraine is associated with poorer HRQoL, higher all‐cause HRU, and greater activity impairment and work productivity loss versus non‐migraine controls in Brazil.
B4C reinforced NiTi‐based composites: Microstructure and wear performance
Authors: Velayatipour Omid , Nikzad Leila , Farvizi Mohammad
Published: November 2022

In this study, NiTi–x wt.% B4C (x = 0, 2, and 4) composites were consolidated with spark plasma sintering method, and the effects of boron carbide reinforcement addition on the microstructure and wear behavior of samples were investigated. Identification of the constituent phases of samples by the X‐ray diffraction method plus Rietveld analysis revealed that the stability of the martensite phase increased in the composite samples because of mismatch stresses between the NiTi matrix phase and the reinforcing particles, which increases the density of the dislocations and facilitates the diffusion process that subsequently leads to the formation of stable intermetallics. The results of hardness test indicated that the hardness value increased from 3.67 GPa for pure NiTi to 10.99 GPa for NiTi–4 wt.% B4C. Results of wear test revealed that boron carbide reinforced composite specimens had higher wear resistance, whereas wear rate of NiTi sample was 3.6 × 10−3 mm3/N m, and it reached to .21 × 10−3 mm3/N m for NiTi–4 wt.% B4C. Investigation of microstructure by scanning electron microscopy images and EDS analysis revealed that the wear mechanism in NiTi samples was abrasive and the addition of B4C to NiTi changed the wear mechanisms from abrasive to a combination of oxidation, adhesive, and delamination mechanisms.
Chromosomal rearrangements and the first indication of an ♀X1X1X2X2/♂X1X2Y sex chromosome system in Rineloricaria fishes (Teleostei: Siluriformes)
Authors: Marajó Leandro , Viana Patrik Ferreira , Ferreira Alex Matheus Viana , Py‐Daniel Lúcia Helena Rapp , Cioffi Marcelo de Bello , Sember Alexandr , Feldberg Eliana
Published: November 2022

Rineloricaria is the most diverse genus within the freshwater fish subfamily Loricariinae, and it is widely distributed in the Neotropical region. Despite limited cytogenetic data, records from southern and south‐eastern Brazil suggest a high rate of chromosomal rearrangements in this genus, mirrored in remarkable inter‐ and intraspecific karyotype variability. In the present work, we investigated the karyotype features of Rineloricaria teffeana, an endemic representative from northern Brazil, using both conventional and molecular cytogenetic techniques. We revealed different diploid chromosome numbers (2n) between sexes (33♂/34♀), which suggests the presence of an ♀X1X1X2X2/♂X1X2Y multiple sex chromosome system. The male‐limited Y chromosome was the largest and the only biarmed element in the karyotype, implying Y‐autosome fusion as the most probable mechanism behind its origination. C‐banding revealed low amounts of constitutive heterochromatin, mostly confined to the (peri)centromeric regions of most chromosomes (including the X2 and the Y) but also occupying the distal regions of a few chromosomal pairs. The chromosomal localization of the 18S ribosomal DNA (rDNA) clusters revealed a single site on chromosome pair 4, which was adjacent to the 5S rDNA cluster. Additional 5S rDNA loci were present on the autosome pair 8, X1 chromosome, and in the presumed fusion point on the Y chromosome. The probe for telomeric repeat motif (TTAGGG)n revealed signals of variable intensities at the ends of all chromosomes except for the Y chromosome, where no detectable signals were evidenced. Male‐to‐female comparative genomic hybridization revealed no sex‐specific or sex‐biased repetitive DNA accumulations, suggesting a presumably low level of neo‐Y chromosome differentiation. We provide evidence that rDNA sites might have played a role in the formation of this putative multiple sex chromosome system and that chromosome fusions originate through different mechanisms among different Rineloricaria species.
Sensitivity of canine hematological cancers to BH3 mimetics
Authors: Jegatheeson Selvi , Cannon Claire , Mansfield Caroline , Devlin Joanne , Roberts Andrew
Published: November 2022

Background

Inhibition of antiapoptotic B‐cell lymphoma 2 (BCL2) proteins by small molecule Bcl‐2 homology 3 (BH3) mimetics causes rapid induction of apoptosis of human hematological cancers in vitro and in vivo.

Objectives

Assess in vitro sensitivity of non‐neoplastic lymphocytes and primary hematological cancer cells from dogs to venetoclax (VEN) or the dual BCL2/ B‐cell lymphoma‐extra‐large (BCLxL) inhibitor, navitoclax (NAV), and evaluate the association between BCL2 protein expression and VEN sensitivity.

Animals

Nine client‐owned dogs without cancer and 18 client‐owned dogs with hematological cancer.

Methods

Prospective, nonrandomized noncontrolled study. Lymphocytes isolated from peripheral blood, lymph node, or bone marrow from dogs were incubated with BH3 mimetics for 24 hours. Viable cells were counted using flow cytometry and half maximal effective concentration (EC50) was calculated. BCL2 protein from whole cell lysates was assessed via immunoblots.

Results

Nodal B and T lymphocytes were more sensitive to VEN than circulating lymphocytes (P = .02). Neoplastic T lymphocytes were sensitive to VEN (mean EC50 ± SD = 0.023 ± 0.018 μM), whereas most non‐indolent B cell cancers were resistant to killing by VEN (mean EC50 ± SD = 288 ± 700 μM). Unclassified leukemias showed variable sensitivity to VEN (mean EC50 ± SD = 0.49 ± 0.66 μM). Detection of BCL2 protein was not associated with VEN sensitivity.

Conclusion and Clinical Importance

Neoplastic canine T lymphocytes are sensitive to VEN in vitro. Quantification of BCL2 protein alone is insufficient to predict sensitivity to VEN.
Well‐defined multispecies probiotic and enzyme combination outperforms traditional fermented probiotic applications in an intensive Pacific white shrimp, Litopenaeus vannamei (Boone, 1931), culture system
Authors: Novriadi Romi , Prihadi Tri Heru , Saragih Hartati Sri Devi , Kesselring Jutta , Standen Benedict
Published: November 2022

A series of treatments were designed to evaluate the efficacy of feeding commercial multispecies probiotics feeding with enzymes and fermentation process on the growth parameters and culture environment of Pacific white shrimp, Litopenaeus vannamei (Boone, 1931), in an intensive culture system. Commercial multispecies probiotics and enzymes (PEs) were continuously applied in three different doses, namely (i) 0.2, (ii) 0.4, and (iii) 0.6 mg L−1 and designated as 0.2, 0.4, and 0.6 PE during the first 30 days of intensive culture of Pacific white shrimp, L. vannamei (Boone, 1931). The probiotics were continually applied every alternate day, while the enzymes were added every sixth day throughout the trial period. The PE dose for all treated tanks was increased by 0.2 ppm after 30 days of culture and another 0.2 ppm after day 60. Meanwhile, fermentation technique, which has become the common method applied in Indonesia in the control treatment, was added on the same day with the PE group with increasing dosage, following the same trend with the 0.6 PE group. Results showed that the group receiving 0.6 PE showed higher final biomass, higher mean weight, and protein retention efficiency as well as a lower feed conversion ratio compared with the control treatment. Abundance of Vibrio spp. remained below 103 cfu mL−1 throughout the trial. Water quality indicators TAN, NO2N and NO3N peaked in weeks 3–5 and then declined after that until the end of the culture period in all tanks. This decline was significantly faster in PE‐treated tanks. Multispecies PEs have potential applications in controlling Vibrio spp., maintaining proper water quality condition, and enhancing the growth of shrimp in intensive culture system.
The Sakhnin/Misgav Land Dispute: Using 3‐D Negotiation Strategies to Analyze Conflict Resolution in Israel
Authors: Tarabeih Hussein , Gilad Shula , Sheffield Jennifer
Published: November 2022

This article discusses a bitter land dispute in Israel between a Palestinian municipality and a Jewish municipality, analyzing the game‐changing moves made by local civil society organizations to shift their relationship from adversaries to allies for regional cooperation. The article explores the origins of the conflict between Sakhnin Municipality and the neighboring Misgav Regional Council. We explain their failed attempts to negotiate agreements to end a local dispute that can be described as a microcosm of the Israeli–Palestinian geopolitical conflict. Using Lax and Sebenius's 3‐D Negotiation Framework and William Ury's Third Side concept as lenses, we analyze the strategy and activities employed by civil society actors, who embody a Third Side role and succeed in breaking the stalemate, reaching agreements, and transforming relationships. Through conducting interviews and reviewing media articles, emails, protocols, letters, and other documents in Sakhnin's archives and on official governmental websites, we reconstruct the negotiation process and demonstrate how the Third Side was able to restore relationships, trust, and communication and develop creative options—away from the negotiating table. We suggest that this case can serve as a model to resolve other conflicts, particularly local disputes with power disparities that are intertwined with high politics.
An NBS‐LRR protein in the Rpp1 locus negates the dominance of Rpp1‐mediated resistance against Phakopsora pachyrhizi in soybean
Authors: Wei Wei , Wu Xing , Garcia Alexandre , McCoppin Nancy , Viana João Paulo Gomes , Murad Praerona S. , Walker David R. , Hartman Glen L. , Domier Leslie L. , Hudson Matthew E. , Clough Steven J.
Published: November 2022

The soybean Rpp1 locus confers resistance to Phakopsora pachyrhizi, causal agent of rust, and resistance is usually dominant over susceptibility. However, dominance of Rpp1‐mediated resistance is lost when a resistant genotype (Rpp1 or Rpp1b) is crossed with susceptible line TMG06_0011, and the mechanism of this dominant susceptibility (DS) is unknown. Sequencing the Rpp1 region reveals that the TMG06_0011 Rpp1 locus has a single nucleotide‐binding site leucine‐rich repeat (NBS‐LRR) gene (DS‐R), whereas resistant PI 594760B (Rpp1b) is similar to PI 200492 (Rpp1) and has three NBS‐LRR resistance gene candidates. Evidence that DS‐R is the cause of DS was reflected in virus‐induced gene silencing of DS‐R in Rpp1b/DS‐R or Rpp1/DS‐R heterozygous plants with resistance partially restored. In heterozygous Rpp1b/DS‐R plants, expression of Rpp1b candidate genes was not significantly altered, indicating no effect of DS‐R on transcription. Physical interaction of the DS‐R protein with candidate Rpp1b resistance proteins was supported by yeast two‐hybrid studies and in silico modeling. Thus, we conclude that suppression of resistance most likely does not occur at the transcript level, but instead probably at the protein level, possibly with Rpp1 function inhibited by binding to the DS‐R protein. The DS‐R gene was found in other soybean lines, with an estimated allele frequency of 6% in a diverse population, and also found in wild soybean (Glycine soja). The identification of a dominant susceptible NBS‐LRR gene provides insight into the behavior of NBS‐LRR proteins and serves as a reminder to breeders that the dominance of an R gene can be influenced by a susceptibility allele.