bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression Mediates the Relationships between Hallucinations, Delusions, and Social Isolation in First-Episode Psychosis
Authors: Bornheimer Lindsay A , Li Verdugo Juliann , Thompson Sara
Published: October 2022

Social isolation is common among individuals with schizophrenia spectrum and other psychotic disorders. Research indicates that social isolation relates to poorer mental health outcomes, depression, and negative symptoms, with less known about its relationship with positive symptoms. This study examined depression as a mediator in the relationships between positive symptoms (i.e., hallucinations and delusions) and social isolation among an early treatment phase sample in the United States. Data were obtained from the Recovery After an Initial Schizophrenia Episode project of the National Institute of Mental Health’s Early Treatment Program. Participants (N = 404) included adults between ages 15 and 40 in a first episode of psychosis. Data were analyzed using structural equation modeling in Mplus (Version 8). The study showed that delusions (b = .095, SE = 0.04, p < .05) and hallucinations (b = .076, SE = 0.03, p < .01) were directly related to depression, and that both delusions (b = .129, SE = 0.06, p < .05) and depression (b = .254, SE = 0.09, p < .05) were directly related to social isolation. Findings of this study determined that depression functioned as a mediator in the relationships between positive symptoms and social isolation. Targeting psychosis symptomatology and depression in treatment, improving social skills and social support networks, and considering the role of stigma in social isolation are of great importance in the prevention of poorer mental health outcomes.
A safe breeding ground: genetically improved maritime pine for growth and stem form has more efficient but not more vulnerable xylem
Authors: Song Yanjun , Bouteiller Xavier Paul , Larter Maximilian , Plomion Christophe , Sin Fabrice , Delzon Sylvain
Published: October 2022

Through repeated cycles of selection and recombination, tree breeding programs deliver genetically improved varieties for a range of target characteristics such as biomass production, stem form, resistance to biotic stresses, wood properties, etc. However, in the context of increased drought and heat waves, it is not yet known whether growth performance will impede drought resistance. To address this question, we compared the hydraulic properties, such as hydraulic efficiency and hydraulic safety, in four varieties over successive varieties of genetically improved maritime pines (i.e., Pinus pinaster Aït.) for growth and stem form. We measured 22 functional traits related to hydraulic efficiency, hydraulic safety, xylem anatomy and wood density. We found that improved varieties presented higher hydraulic conductivity with larger tracheid lumen size and tracheid lumen fraction, and smaller wall thickness reinforcement and tracheid density, but not at the cost of reduced embolism resistance. The reported absence of trade-off between hydraulic conductivity and embolism resistance is a strong asset to improve biomass productivity, through increased hydraulic efficiency, without impacting drought resistance, and should enable new maritime pine varieties to cope with a drier climate. Our study is one of the first to reveal the hydraulic mechanisms over successive varieties of genetic improvement for tree growth. It provides guidelines for sustainable forest management through breeding for other forest tree species.
Tuberculosis prevalence, incidence and prevention in a south african cohort of children living with HIV
Authors: Anyalechi Gloria Ebelechukwu , Bain Rommel , Kindra Gurpreet , Mogashoa Mary , Sogaula Nonzwakazi , Mutiti Anthony , Arpadi Stephen , Rivadeneira Emilia , Abrams Elaine J , Teasdale Chloe A
Published: October 2022

Background

We describe tuberculosis (TB) disease among antiretroviral treatment (ART) eligible children living with HIV (CLHIV) in South Africa to highlight TB prevention opportunities.

Methods

In our secondary analysis among 0- to 12-year-old ART-eligible CLHIV in five Eastern Cape Province health facilities from 2012 to 2015, prevalent TB occurred 90 days before or after enrollment; incident TB occurred >90 days after enrollment. Characteristics associated with TB were assessed using logistic and Cox proportional hazards regression with generalized estimating equations.

Results

Of 397 enrolled children, 114 (28.7%) had prevalent TB. Higher-income proxy [adjusted odds ratio (aOR) 1.8 [95% confidence interval (CI) 1.3–2.6] for the highest, 1.6 (95% CI 1.6–1.7) for intermediate]; CD4+ cell count <350 cells/µl [aOR 1.6 (95% CI 1.1–2.2)]; and malnutrition [aOR 1.6 (95% CI 1.1–2.6)] were associated with prevalent TB. Incident TB was 5.2 per 100 person-years and was associated with delayed ART initiation [hazard ratio (HR) 4.7 (95% CI 2.3–9.4)], malnutrition [HR 1.8 (95% CI 1.1–2.7)] and absence of cotrimoxazole [HR 2.3 (95% CI 1.0–4.9)]. Among 362 children with data, 8.6% received TB preventive treatment.

Conclusions

Among these CLHIV, prevalent and incident TB were common. Early ART, cotrimoxazole and addressing malnutrition may prevent TB in these children.
A taxonomic reassessment of native and invasive species ofCorbiculaclams (Bivalvia: Cyrenidae) from the Russian Far East and Korea
Authors: Bespalaya Yulia V , Kropotin Alexander V , Kondakov Alexander V , Aksenova Olga V , Gofarov Mikhail Yu , Kim Sang Ki , Lee Jin Hee , Travina Oksana V , Vikhrev Ilya V , Vinarski Maxim V , Bolotov Ivan N
Published: October 2022

Currently, the validity of many nominal bivalve species of the genus Corbicula endemic to the Russian Far East and South Korea needs a critical reassessment. In this study, we clarify the taxonomic status of Corbicula species of this area based on a combination of molecular genetic, conchological and anatomical data. According to our results, four Corbicula lineages, corresponding to the nominal species Corbicula japonica, Corbicula elatior, Corbicula leana and Corbicula fluminea, can be delineated in samples collected in the Primorye and Khabarovsk regions of Russia and South Korea. Two species endemic to the Russian Far East (i.e. Corbicula finitima and Corbicula lindholmi) are considered here as junior synonyms of the species C. japonica, which is widely distributed in estuarine habitats around the Japanese Archipelago, Sakhalin Island, southern Kurile Islands, Primorye and Khabarovsk regions, Korean Peninsula and China. Three nominal species described from the Lower Amur basin (Corbicula amurensis, Corbicula nevelskoyi and Corbicula sirotskii) appeared to be synonyms of C. elatior, whose range covers the Korean Peninsula, Primorye and Khabarovsk regions and, perhaps, China. We delineated several colour morphs of C. fluminea and C. japonica. The distinctness between these colour morphs can be attributed to both heritable and environmental factors.
Refining Management of Apple Powdery Mildew in New York State with Weather-Based Fungicide Application Timing Programs
Authors: Strickland David A. , Ayer Katrin M. , Olmstead Daniel L. , Cox Kerik D.
Published: October 2022

In the absence of durable host resistance among commercial cultivars, chemical management continues to be an essential component of disease control in apple production. Apple powdery mildew, caused by the ascomycete Podosphaera leucotricha, is largely managed with regular fungicide applications from the host phenological stages of tight cluster to terminal bud growth set, with applications typically being made in a prophylactic manner irrespective of existing disease pressure. Here we evaluated two management programs that aligned fungicide applications to specific weather thresholds conducive to powdery mildew development using a rotation of single-site fungicides and sulfur. In three separate orchards among four cultivars, we compared powdery mildew disease progression over the growing season for each of the weather factor-based programs and a typical calendar-based application program. In each year of the trial, we found that management programs with weather-based fungicide applications provided levels of disease control similar to the calendar program but required 50 to 83.3% fewer mildew-specific fungicide applications throughout the growing season. Our results provide a framework with which to evaluate future weather-based management programs for apple powdery mildew management. This knowledge could be implemented in the creation of a powdery mildew disease management decision support system to better inform and aid fungicide application programs for continued sustainable apple production in the northeast United States.
Tomato Brown Rugose Fruit Virus Nextstrain Build Version 3: Rise of a Novel Clade
Authors: Botermans Marleen , de Koning Pier P. M. , Oplaat Carla , Fowkes Aimee R. , McGreig Sam , Skelton Anna , Adams Ian P. , Fox Adrian , De Jonghe Kris , Demers Jill E. , Roenhorst Johanna W. , Westenberg Marcel , van de Vossenberg Bart T. L. H.
Published: October 2022

In the Netherlands, tomato brown rugose fruit virus (ToBRFV; genus Tobamovirus) was first identified in tomato crops in 2019. Since then, the National Plant Protection Organization (NPPO-NL) has performed surveys to track and trace this regulated virus aiming for its eradication. To gain more insight in the epidemiology of ToBRFV, genomes were assembled from Illumina sequence data. Whole-genome phylogenetics was integrated with epidemiological metadata in a Nextstrain build. Two new clades were defined, one of which displayed a rapid increase in comparison to the previous version of the Nextstrain build. This rapid increase could be attributed to the unauthorized application of an isolate of ToBRFV as a cross-protection product. Further analysis of the test results of positive samples from tomato production sites suggests that both deliberate application and accidental introduction had occurred. This report introduces the inclusion of 61 new (near) complete ToBRFV genomes in version three of the Nextstrain build, available from https://nextstrain.nrcnvwa.nl/ToBRFV/20220412 .

[Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
Graphene oxide accelerates diabetic wound repair by inhibiting apoptosis of Ad‐MSCs via Linc00324/miR‐7977/STK4 pathway
Authors: Ji Zhe , Wang Jian , Yang Shuai , Tao Shengjun , Shen Caiqi , Wei Hanxiao , Li Qiang , Jin Peisheng
Published: October 2022

Many studies have shown that graphene oxide (GO) promotes proliferation and differentiation of a variety of stem cells. However, its effect on adipose‐derived mesenchymal stem cell (Ad‐MSCs) apoptosis is still unclear. Apoptosis is a significant factor affecting stem cell‐based treatment of diabetic wounds. Therefore, we explored the effect of GO on Ad‐MSC apoptosis and diabetic wound healing. In this study, qRT‐PCR was used to detect Ad‐MSC expression of LncRNAs, miRNAs, and mRNAs under high‐glucose environment. RNA immunoprecipitation (RIP), RNA pull‐down, and luciferase assays were used to detect interactions of specific lncRNAs, miRNAs, and mRNAs. The effects of GO on Ad‐MSC apoptosis were explored by flow cytometry, TUNEL assay, and Western blot. A diabetic wound model was used to explore the function of Linc00324 on Ad‐MSC reparative properties in vivo. As a result, GO inhibited high glucose‐induced apoptosis in Ad‐MSCs, and Linc00324 contributed to the anti‐apoptotic effect of GO. RIP and RNA pull‐down confirmed that Linc00324 directly interacted with miR‐7977, functioning as a miRNA sponge to regulate expression of the miR‐7977 target gene STK4 (MST1) and downstream signaling pathways. In addition, GO reduced the apoptosis of Ad‐MSCs in wounds and promoted wound healing. Taken together, these findings suggest GO may be a superior auxiliary material for Ad‐MSCs to facilitate diabetic wound healing via the Linc00324/miR‐7977/STK4 pathway.
Dual Application of Patient-Specific Occlusion-Based Positioning Guide and Fibular Cutting Guide for Accurate Reconstruction of Segmental Mandibular Defect
Authors: Choi Jong Woo , Kim Young Chul , Han Sung John , Jeong Woo Shik
Published: October 2022

In this study, the authors introduced a dual application of patient-specific occlusion-based positioning guide and fibular cutting guide to obtain ideal occlusal relationship and mandibular contour in patients undergoing mandibular reconstruction. A retrospective review was performed in 21 patients who underwent mandibular reconstruction with a fibular osteocutaneous free flap. Using computed tomography and intraoral scanning data, fibular cutting guide and occlusion-based positioning guide were simulated in a modeling software and 3-dimensionally printed. Both guides were applied in 9 patients, defined as dual guide group, while the fibular cutting guide was solely used in the remaining patients, defined as single guide group. Functional outcomes including occlusion status, trismus, presence of osseointegrated implant were assessed at 1-year postoperative period. To evaluate the accuracy of the reconstruction, the discrepancy between the planned simulation and actual surgical result was quantified by measuring mandibular deviation angle and volume conformity. Regarding the functional outcomes, all patients in dual guide group showed satisfactory occlusion and intact oral capacity at postoperative 1-year assessment, while 3 patients in single guide group had prolonged malocclusion. The dual guide group showed significantly decreased deviation angle in coronal (right side, 2.93°±1.98° vs. 7.02°±2.81°, P=0.003) and axial plane (right side, 3.20°±2.04° vs. 7.63°±3.40°, P=0.006). The mean volume conformity between the simulation and actual fibular object was significantly higher in the dual guide group (75.27%±6.12% vs. 59.06%±8.57%, P=0.001). In conclusion, the use of occlusion-based positioning guide combined with the fibular cutting guide can enhance the accuracy of mandible reconstruction and functional outcomes.
Deep characterization of cancer drugs mechanism of action by integrating large-scale genetic and drug screens
Authors: Sinha Sanju , Sinha Neelam , Ruppin Eytan
Published: October 2022

Knowing a drug’s mechanism of action (MOA) is essential for its clinical success by selecting the best indications, likely responders, and combinations. Yet knowledge of many drugs’ MOA remains lacking. Here we present DeepTarget, a computational tool for deep characterization of cancer drugs’ MOA by integrating existing large-scale genetic and drug screens. Spanning ∼1500 drugs across ∼18K possible target genes, DeepTarget predicts: (1) a drug’s primary target(s), (2) whether it specifically targets the wild-type or mutated target forms, and (3) the secondary target(s) that mediate its response when the primary target is not expressed. We first tested and successfully validated DeepTarget in a total of eleven unseen gold-standard datasets, with an average AUC of 0.82, 0.77, and 0.92 for the above three prediction abilities, respectively. We then proceed to use it in a wide range of applications: First, we find that DeepTarget’s predicted specificity of a drug to its target is strongly associated with its success in clinical trials and is higher in its FDA-approved indications. Second, DeepTarget predicts candidate drugs for targeting currently undruggable cancer oncogenes and their mutant forms. Finally, DeepTarget predicts new targets for drugs with unknown MOA and new secondary targets of approved drugs. Taken together, DeepTarget is a new computational framework for accelerating drug prioritization and its target discovery by leveraging large-scale genetic and drug screens.
Annotating and prioritizing human non-coding variants with RegulomeDB
Authors: Dong Shengcheng , Zhao Nanxiang , Spragins Emma , Kagda Meenakshi S. , Li Mingjie , Assis Pedro , Jolanki Otto , Luo Yunhai , Cherry J Michael , Boyle Alan P , Hitz Benjamin C
Published: October 2022

Nearly 90% of the disease risk-associated variants identified from genome-wide association studies (GWAS) are in non-coding regions of the genome. The annotations obtained from analyzing functional genomics assays can provide additional information to pinpoint causal variants, which are often not the lead variants identified from association studies. However, the lack of available annotation tools limits the use of such data.

To address the challenge, we have previously built the RegulomeDB database for prioritizing and annotating variants in non-coding regions1, which has been a highly utilized resource for the research community (Supplementary Fig. 1). RegulomeDB annotates a variant by intersecting its position with genomic intervals identified from functional genomic assays and computational approaches. It also incorporates those hits of a variant into a heuristic ranking score, representing its potential to be functional in regulatory elements.

Here we present a newer version of the RegulomeDB web server, RegulomeDB v2.1 (http://regulomedb.org). We improve and boost annotation power by incorporating thousands of newly processed data from functional genomic assays in GRCh38 assembly, and now include probabilistic scores from the SURF algorithm that was the top performing non-coding variant predictor in CAGI 52. We also provide interactive charts and genome browser views to allow users an easy way to perform exploratory analyses in different tissue contexts.
Granule cells affect dendritic tree selection in purkinje cells during cerebellar development
Authors: Kato Mizuki , Schutter Erik De
Published: October 2022

This study investigates the interrelationship between primary dendrite selection of Purkinje cells and migration of their pre-synaptic partner granule cells during cerebellar development. During development of the cerebellar cortex, each Purkinje cell grows more than three dendritic trees, from which a primary tree is selected to develop further, whereas the others completely retract. Experimental studies suggest that this selection process is coordinated by physical and synaptic interactions with granule cells. However, technical limitations hinder a continuous experimental observation of multiple populations. To reveal the mechanism underlying this selection process, we constructed a computational model of dendritic developments and granule cell migrations, using a new computational framework, NeuroDevSim. Comparisons of the resulting morphologies from the model demonstrate the roles of the selection stage in regulating the growth of the selected primary trees. The study presents the first computational model that simultaneously simulates growing Purkinje cells and the dynamics of granule cell migrations, revealing the role of physical and synaptic interactions upon dendritic selection. The model provides new insights about the distinct planar morphology of Purkinje cell dendrites and about roles of the dendritic selection process during the cerebellar development. The model also supports the hypothesis that synaptic interactions by granule cells are likely to be involved in the selection procedure.

Author Summary

The mature structure of a Purkinje cell, the main neuron of the cerebellum, is composed of a large flat dendritic tree composed of a single or sometimes 2 primary dendrites. However, this neuron has multiple similar trees during development, and retracts most of them to select its primary tree. We aim to explore roles of this developmental process as either an important step to attain optimal morphology or merely a redundant step to be eliminated by evolution in the future. We especially focused on environmental interactions on Purkinje cells as criteria to select the dendritic tree, hypothesizing that developing an efficient network with other neurons is one of the main goals of neuronal morphology. We constructed and used computational models to investigate detailed physical interactions and communications between Purkinje cells and their environment. Comparisons of models suggest the role of the selection stage is to obtain favorable growth of primary trees.
Profiling of the β-glucosidases identified in the genome ofPenicillium funiculosum: Insights from genomics, transcriptomics, proteomics and homology modelling studies
Authors: Okereke Omoaruemike Ebele , Gupta Mayank , Ogunyewo Olusola A. , Sharma Kanika , Yazdani Syed Shams
Published: October 2022

Enzymatic lignocellulosic biomass conversion to bioethanol is dependent on efficient enzyme systems with β-glucosidase as a key component. In this study, we performed in-depth profiling of the various β-glucosidases present in the genome of the hypercellulolytic fungus;Penicillium funiculosumusing genomics, transcriptomics, proteomics and molecular dynamics simulation approaches. Of the eight β-glucosidase genes identified in theP.funiculosumgenome, three were found to be extracellular, as evidenced by presence of signal peptides and mass spectrometry. Among the three secreted β-glucosidase, two belonged to the GH3 and one belonged to GH1 families. Modelled structures of these proteins predicted a deep and narrow active site for the GH3 β-glucosidases (PfBgl3A andPfBgl3B) and a shallow open active site for the GH1 β-glucosidase (PfBgl1A). The enzymatic assays indicated thatP. funiculosumsecretome showed high β-glucosidase activities with prominent bands on 4-methylumbelliferyl β-D-glucopyranoside (MUG) zymogram. To understand the contributory effect of each of the three secreted β-glucosidases (PfBgls), the corresponding gene was deleted separately and the effect of the deletion on β-glucosidase activity of the secretome was examined. Although not the most abundant β-glucosidase,PfBgl3A was found to be the most significant one as evidenced by a 42 % reduction in β-glucosidase activity in the ΔPfBgl3A strain. To improve the thermostability, two mutants ofPfBgl3A were designed with the help of molecular dynamics (MD) simulation and were expressed inPichia pastorisfor evaluation. ThePfBgl3A mutant (Mutant A) gave 1.4 fold increase in the half-life (T1/2) of the enzyme at 50°C.

IMPORTANCE

Commercially available cellulases are majorly produced fromTrichoderma reesei. However, external supplementation of the cellulase cocktail from this host with exogenous β-glucosidase is often required to achieve desired optimal saccharification of cellulosic feedstocks. This challenge has led to exploration of other cellulase-producing strains because of the importance of this class of enzymes in the cellulose deconstruction machinery. The non-model hypercellulolytic fungusPenicillium funiculosumhas been studied in recent times and identified as a promising source of industrial cellulases. Various genetic interventions targeted at strain improvement for cellulase production have been performed. However, the β-glucosidases of this strain have remained largely understudied. This study, therefore, reports profiling of all the eight β-glucosidases ofP. funiculosumvia molecular and computational approaches and enhancing thermostability of the most promising β-glucosidase via protein engineering. The results of this study set the background for future engineering strategies to transform the fungus into an industrial workhorse.
Brain tissue mechanics is governed by microscale relations of the tissue constituents
Authors: Sáez P. , Borau C. , Antonovaite N. , Franze K.
Published: October 2022

Local mechanical tissue properties are a critical regulator of cell function in the central nervous system (CNS) during development and disorder. However, we still don’t fully understand how the mechanical properties of individual tissue constituents, such as cell nuclei or myelin, determine tissue mechanics. Here we developed a model predicting local tissue mechanics, which induces non-affine deformations of the tissue components. Using the mouse hippocampus and cerebellum as model systems, we show that considering individual tissue components alone, as identified by immunohistochemistry, is not sufficient to reproduce the local mechanical properties of CNS tissue. Our results suggest that brain tissue shows a universal response to applied forces that depends not only on the amount and stiffness of the individual tissue constituents but also on the way how they assemble. Our model may unify current incongruences between the mechanics of soft biological tissues and the underlying constituents and facilitate the design of better biomedical materials and engineered tissues. To this end, we provide a freely-available platform to predict local tissue elasticity upon providing immunohistochemistry images and stiffness values for the constituents of the tissue.
Resource-aware construct design in mammalian cells
Authors: Roberto Di Blasi , Mara Pisani , Fabiana Tedeschi , Masue Marbiah , Karen Polizzi , Simone Furini , Velia Siciliano , Francesca Ceroni
Published: October 2022

Resource competition can be the cause of unintended coupling between co-expressed genetic constructs. Here we report quantification of the resource load imposed by different mammalian genetic components and identify construct designs with increased performance and reduced resource footprint. We use these to generate improved synthetic circuits and optimise the co-expression of co-transfected cassettes, shedding light on how this can be useful for bioproduction and biotherapeutic applications. This work provides the scientific community with a framework to take resource demand into consideration when designing mammalian constructs to achieve robust and optimised gene expression.
Sequencing and chromosome-scale assembly of the giantPleurodeles waltlgenome
Authors: Brown Thomas , Elewa Ahmed , Iarovenko Svetlana , Subramanian Elaiyaraja , Araus Alberto Joven , Petzold Andreas , Suzuki Miyuki , Suzuki Ken-ichi T. , Hayashi Toshinori , Toyoda Atsushi , Oliveira Catarina , Osipova Ekaterina , Leigh Nicholas D. , Simon Andras , Yun Maximina H.
Published: October 2022

The Iberian ribbed newt (Pleurodeles waltl) constitutes a central model for probing the basis of vertebrate regeneration. Here, we present the sequencing and chromosome-scale assembly of the 20.3GbP. waltlgenome, which exhibits the highest level of contiguity and completeness among giant genome assemblies. We uncover that DNA transposable elements are the major contributors to its expansion, with hAT transposons comprising a large portion of repeats. Several hATs are actively transcribed and differentially expressed during adultP. waltllimb regeneration, along with domesticated hAT transposons of the ZBED transcription factor family. Despite its size, syntenic relationships are conserved. As an example, we show the high degree of conservation of the regeneration-associated Tig1 locus with several neighbouring genes. Together, theP. waltlgenome provides a fundamental resource for the study of regenerative, developmental and evolutionary principles.
3D genome topologies distinguish pluripotent epiblast and primitive endoderm cells in the mouse blastocyst
Authors: Loof Gesa , Szabó Dominik , Garg Vidur , Kukalev Alexander , Zea-Redondo Luna , Kempfer Rieke , Sparks Thomas M. , Zhang Yingnan , Thieme Christoph J , Carvalho Sílvia , Weise Anja , Balachandran Milash , Liehr Thomas , Welch Lonnie R. , Hadjantonakis Anna-Katerina , Pombo Ana
Published: October 2022

The development of embryonic cell lineages is tightly controlled by transcription factors that regulate gene expression and chromatin organisation. To investigate the specialisation of 3D genome structure in pluripotent or extra-embryonic endoderm lineages, we applied Genome Architecture Mapping (GAM) in embryonic stem (ES) cells, extra-embryonic endoderm (XEN) stem cells, and in theirin vivocounterparts, the epiblast (Epi) and primitive endoderm (PrE) cells, respectively. We discover extensive differences in 3D genome topology including the formation domain boundaries that differ between Epi and PrE lineages, bothin vivoandin vitro, at lineage commitment genes. In ES cells,Sox2contacts other active regions enriched for NANOG and SOX2 binding sites. PrE-specific genes, such asLama1andGata6, form repressive chromatin hubs in ES cells.Lama1activation in XEN or PrE cells coincides with its extensive decondensation. Putative binding sites for OCT4 and SNAIL, or GATA4/6, distinguish chromatin contacts unique to embryonic or extra-embryonic lineages, respectively. Overall, 3D genome folding is highly specialised in early development, especially at genes encoding factors driving lineage identity.

Highlights

ES and XEN cells have specialised 3D genome structures

GAM applied in the blastocyst distinguishes Epi and PrE genome structures

Lineage specific genes establish cell-type specific chromatin contacts

Specific chromatin contacts feature putative bindings sites for GATA4/6 in XEN cells and SNAIL in ES cells
Bridging the gap between presynaptic hair cell function and neural sound encoding
Authors: Jaime Tobón Lina María , Moser Tobias
Published: October 2022

Neural diversity can expand the encoding capacity of a circuitry. A striking example of diverse structure and function is presented by the afferent synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in the cochlea. Presynaptic active zones at the pillar IHC side activate at lower IHC potentials than those of the modiolar side that have more presynaptic Ca2+-channels. The postsynaptic SGNs differ in their spontaneous firing rates, sound thresholds and operating ranges. While a causal relationship between synaptic heterogeneity and neural response diversity seems likely, experimental evidence linking synaptic and SGN physiology has remained difficult to obtain. Here, we aimed at bridging this gap byex vivopaired recordings of IHCs and postsynaptic SGN boutons with stimuli and conditions aimed to mimic those ofin vivoSGN-characterization. Synapses with high spontaneous rate of release (SR) were found predominantly on the pillar side of the IHC. These highSRsynapses had larger and more temporally compact spontaneous EPSCs, lower voltage-thresholds, tighter coupling of Ca2+channels and vesicular release sites, shorter response latencies and higher initial release rates. This study indicates that synaptic heterogeneity in IHCs directly contributes to the diversity of spontaneous and sound-evoked firing of SGNs.

Significance Statement

Sound encoding relies on spiral ganglion neurons (SGNs) with diverse spontaneous firing, sound thresholds of firing and sound-intensity range over which SGN firing rate changes. Such functional SGN diversity might originate from different input from afferent synapses with inner hair cells (IHCs). The present study addresses this hypothesis by using recordings from individual IHC-SGN synapses of hearing mice underex vivoconditions aimed to mimic cochlear physiology. The results provide evidence that synaptic heterogeneity in IHCs contributes to SGN firing diversity. Thus, the cochlea employs heterogeneous synapses to decompose sound information into different neural pathways that collectively inform the brain about sound intensity.
Structure of a G protein-coupled receptor with GRK2 and a biased ligand
Authors: Duan Jia , Liu Heng , Ji Yujie , Yuan Qingning , Li Xinzhu , Wu Kai , Gao Tianyu , Zhu Shengnan , Yin Wanchao , Jiang Yi , Xu H. Eric
Published: October 2022

Phosphorylation of G protein-coupled receptors (GPCR) by GPCR kinases (GRKs) desensitizes G protein signaling and promotes arrestin signaling, which is also modulated by biased ligands1–6. Molecular assembly of GRKs to GPCRs and the basis of GRK-mediated biased signaling remain largely unknown due to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gαq, and an arrestin-biased ligand, SBI-5537, at a resolution of 2.92 Å. The high-quality density map reveals the clear arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor TM6, analogous of the binding of G protein to the receptor. Strikingly, the arrestin-biased ligand is found at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of the biased ligand is compatible with arrestin binding but is clashed with the binding of a G protein, thus provide an unambiguous mechanism for its arrestin-biased signaling capability. Together, our structure provides a solid model for understanding the details of GPCR-GRK interactions and biased signaling.
Polymerization cycle of actin homolog MreB from a Gram-positive bacterium
Authors: Mao Wei , Renner Lars D. , Cornilleau Charlène , Li de la Sierra-Gallay Ines , Benlamara Sarah , Ah-Seng Yoan , Van Tilbeurgh Herman , Nessler Sylvie , Bertin Aurélie , Chastanet Arnaud , Carballido-López Rut
Published: October 2022

In most rod-shaped bacteria, the actin homologue MreB is an essential component of the protein complex effecting cell wall elongation. The polymerization cycle and filament properties of eukaryotic actin have studied for decades and are well characterized. However, purification andin vitrowork on MreB proteins have proven very difficult. Current knowledge of MreB biochemical and polymerization properties remains limited and is based on MreB proteins from Gram-negative species. In this study, we report the first observation of organized filaments and the first 3D-structure of MreB from a Gram-positive bacterium. We have purified MreB from the thermophilicGeobacillus stearothermophilusand shown that it forms straight pairs of protofilamentsin vitro, and that polymerization depends on the presence of both lipids and nucleotide triphosphate. Two spatially close short hydrophobic sequences mediate membrane anchoring. Importantly, we demonstrate that unlike eukaryotic actin, nucleotide hydrolysis is a prerequisite for MreB interaction with the membrane, and that binding to lipids then triggers polymerization. Based on our results, we propose a molecular model for the mechanism of MreB polymerization.
Dual Noncanonical Amino Acid Incorporation Enabling Chemoselective Protein Modification at Two Distinct Sites in Yeast
Authors: Lahiri Priyanka , Martin Meghan S. , Lino Briana R. , Scheck Rebecca A. , Van Deventer James A.
Published: October 2022

Incorporation of more than one non-canonical amino acid (ncAA) within a single protein endows the resulting construct with multiple useful features such as augmented molecular recognition or covalent crosslinking capabilities. Herein, for the first time, we demonstrate the incorporation of two chemically distinct ncAAs into proteins biosynthesized inSaccharomyces cerevisiae. To complement ncAA incorporation in response to the amber (TAG) stop codon in yeast, we evaluated opal (TGA) stop codon suppression using three distinct orthogonal translation systems. We observed selective TGA readthrough without detectable cross-reactivity from host translation components. Readthrough efficiency at TGA was modulated by factors including the local nucleotide environment, gene deletions related to the translation process, and the identity of the suppressor tRNA. These observations facilitated systematic investigation of dual ncAA incorporation in both intracellular and yeast-displayed protein constructs, where we observed efficiencies up to 6% of wildtype protein controls. The successful display of doubly-substituted proteins enabled the exploration of two critical applications on the yeast surface - A) antigen-binding functionality; and B) chemoselective modification with two distinct chemical probes through sequential application of two bioorthogonal click chemistry reactions. Lastly, by utilizing a soluble form of a doubly-substituted construct, we validated the dual incorporation system using mass spectrometry and demonstrated the feasibility conducting selective labeling of the two ncAAs sequentially using a ”single-pot” approach. Overall, our work facilitates the addition of a 22ndamino acid to the genetic code of yeast and expands the scope of applications of ncAAs for basic biological research and drug discovery.

Graphical Abstract

Herein we report the establishment of dual noncanonical amino acid incorporation in yeast to support expression and site-selective labelling of doubly substituted proteins in solution and on the yeast surface.
Structural basis of V-ATPase VOregion assembly by Vma12p, 21p, and 22p
Authors: Wang Hanlin , Bueler Stephanie A. , Rubinstein John L.
Published: October 2022

Vacuolar-type ATPases (V-ATPases) are rotary proton pumps that acidify specific intracellular compartments in almost all eukaryotic cells. These multi-subunit enzymes consist of a soluble catalytic V1region and a membrane-embedded proton-translocating VOregion. VOis assembled in the endoplasmic reticulum (ER) membrane and V1is assembled in the cytosol. However, V1binds VOonly after VOis transported to the Golgi membrane, thereby preventing acidification of the ER. We isolated VOcomplexes and subcomplexes fromSaccharomyces cerevisiaebound to V-ATPase assembly factors Vma12p, Vma21p, and Vma22p. Electron cryomicroscopy shows how the Vma12-22p complex recruits subunits a, e, and f to the rotor ring of VOwhile blocking premature binding of V1. Vma21p, which contains an ER-retrieval motif, binds the VO:Vma12-22p complex, ‘mature’ VO, and a complex that appears to contain a ring of loosely-packed rotor subunits and the proteins YAR027W and YAR028W. The structures suggest that Vma21p binds assembly intermediates that contain a rotor ring, and that activation of proton pumping following assembly of V1with VOremoves Vma21p, allowing V-ATPase to remain in the Golgi. Together, these structures show how Vma12-22p and Vma21p function in V-ATPase assembly and quality control, ensuring the enzyme acidifies only its intended cellular targets.
Putting AlphaFold models to work with phenix.process_predicted_model and ISOLDE
Authors: Oeffner Robert D. , Croll Tristan I. , Millán Claudia , Poon Billy K. , Schlicksup Christopher J. , Read Randy J. , Terwilliger Tom C.
Published: October 2022

AlphaFold has recently become an important tool in providing models for experimental structure determination by X-ray crystallography and cryo-EM. Large parts of the predicted models typically approach the accuracy of experimentally determined structures, although there are frequently local errors and errors in the relative orientations of domains. Importantly, residues in the model of a protein predicted by AlphaFold are tagged with a predicted local distance difference test score, informing users about which regions of the structure are predicted with less confidence. AlphaFold also produces a predicted aligned error matrix indicating its confidence in the relative positions of each pair of residues in the predicted model. The phenix.process_predicted_model tool downweights or removes low-confidence residues and can break a model into confidently predicted domains in preparation for molecular replacement or cryo-EM docking. These confidence metrics are further used in ISOLDE to weight torsion and atom–atom distance restraints, allowing the complete AlphaFold model to be interactively rearranged to match the docked fragments and reducing the need for the rebuilding of connecting regions.
Love or like: gender effects in emotional expression in online reviews
Authors: Abdul-Ghani Eathar , Kim Jungkeun , Kwon Junbum , Hyde Kenneth F. , Cui Yuanyuan (Gina)
Published: October 2022

Purpose

Given the socialisation of men and women to their gender roles and expression of emotion, this study aims to investigate whether there are gender differences in the use of emotive language in electronic word-of-mouth (eWOM), specifically in online reviews. The authors propose that female reviewers will use strong emotive terms, such as love, more frequently in online reviews than do male reviewers. The authors further propose that the gender of the reviewer influences audience responses to the reviewer’s use of emotive terms in online reviews.

Design/methodology/approach

The authors conducted secondary data analysis of restaurant reviews (Study 1) to provide evidence on whether the gender of the reviewer affects the frequency of use of emotive terms in an online review. In addition, three separate experiments (Studies 2–4) were conducted to test the theoretical arguments.

Findings

The results of the secondary data analysis indicated that female online reviewers used the term “love” much more frequently in their reviews than male reviewers, whereas there was no usage difference for the term “like”. The experimental studies further showed that an emotive review by a male reviewer containing the word “love” resulted in a higher evaluation of the restaurant being reviewed than a non-emotive review containing the word “like”. This difference was stronger when the overall rating was less salient and for consumers who believe (vs do not believe) that men and women use emotional language differently.

Research limitations/implications

First, the paper extends our understanding of gender differences in emotional expression within the domain of eWOM and online reviews as well as our understanding of consumer responses to these gender differences. Second, the authors identify a boundary condition for these gender effects, namely, the overall rating score. Third, the authors find that consumer beliefs regarding gender stereotypes in emotional expression provide an explanation for these effects.

Practical implications

The results of the research indicate that the electronic algorithms operating on review sites might be modified in terms of their criteria for selecting the reviews to display to consumers, as consumer decision-makers may find greater utility in reviews written by male reviewers that contain strongly positive emotive terms.

Originality/value

The research extends the knowledge on gender differences in emotional expression in online reviews by demonstrating the actual usage patterns and differing responses to the emotional expressions of each gender.
Embedding sustainability in university work experience placements: a De Montfort University model
Authors: Onyido Tochukwu Ben C. , Allman Zoe , Hardaker Pamela , Rughani Deepa , Letinov Allan
Published: October 2022

Purpose

The paper looks at the feasibility of university placements supporting small and medium-scale enterprises (SMEs) to operate in a sustainable manner. Due to size and resource constraints, many SMEs may regard sustainability more as a burden than a value-adding commercial strategy.

Design/methodology/approach

A two-year study was conducted on the sustainability-themed placements of 101 students of De Montfort University, United Kingdom, in SMEs. The placements were designed with the purpose of acting as a traditional work experience scheme while also equipping students with learning, skills and orientation with which to act as sustainability champions within companies. The study combined the use of students' reflections (via tools such as monthly logbooks) with interviews and questionnaire surveys of both employers and students, in order to evaluate the outcomes of the placements.

Findings

Students engaged with the sustainability aspect of their placements mainly by obtaining information on the sustainability performance of SMEs, with significant engagement also occurring in the areas of sustainability advocacy (e.g. proposing socio-environmental plans to companies) and initiatives/action.

Practical implications

Placements can potentially serve as a means of knowledge generation for universities while providing SMEs with cost-effective staff and innovation sustainability resources.

Originality/value

A circular approach to university placement programmes is proposed whereby the knowledge gained from previous placements about SMEs' sustainability performance is used to prepare later cohorts of placement students with a pragmatic understanding of challenges and opportunities related to the implementation of sustainability by SMEs.
Female superiority in accruals quality: some evidence from the Scandinavian region
Authors: Mnif Yosra , Cherif Imen
Published: October 2022

Purpose

The purpose of this paper is twofold. First, this study examines the relationship between the presence of a female (rather than a male) audit partner and the client firm’s accruals quality. Second, this study explores whether and how the female audit partners’ specific attributes influence the gendered auditor effect on the quality of the client firm’s accruals quality (if it exists).

Design/methodology/approach

Research hypotheses have been tested by conducting both univariate and multivariate empirical analyses based on a large sample of firm-year observations from the Swedish Corporation for the years 2010–2019. During the sample timeframe, the client firms have been audited by 56 female and 231 male audit partners.

Findings

The research findings first indicate that client firms of female audit partners are associated with downward earnings management, indicating a beneficial female auditor effect on client firm’s accruals quality. Results from the audit partner change analysis exhibit that the adverse female auditor effect on the client firm’s earnings management, and hence, the beneficial female auditor effect on the client firm’s accruals quality occurs from the first year of the assignment of a female audit partner to replace a male audit partner. When looking at how specific attributes of female audit partners influence accruals quality of their audited clients, this study reveals that the favorable female auditor effect on the client firm’s accruals quality holds constant for all the female audit partners’ specific attributes included in the researched models. This underscores that the mere presence of a female audit partner constrains earnings management and enhances, thereby, the client firm’s accruals quality.

Originality/value

This research supports regulators calling for the appointment of more women to the audit firms’ leading ranks (e.g. leadership).
The declining GAAP ETR trend over 1960-2016
Authors: Lu Yuzhu , Shao Liang , Zhang Yue
Published: October 2022

Purpose

This study aims to provide a comprehensive analysis on the reasons of the observed trend in the GAAP ETR over 1960–2016.

Design/methodology/approach

The authors use a linear tax function which allows for time-varying coefficients to track the trend in GAAP ETR over 1960–2016. This approach can decompose the ETR trend into the trends of the statutory tax rate, the propensity to recognize taxes, the tax-related firm characteristics and their coefficients. Thus, the authors can quantify the contribution of each factor in the tax function to the ETR trend.

Findings

Before 1988, the declining trend in tax expense is mainly driven by changes in the statutory tax rate; in contrast, after 1988, the trend is completely explained by firms’ decreasing propensity to recognize tax expense. While prevalent across different groups of firms, the decreasing propensity to recognize tax expense in the recent 30 years is more pronounced among firms that have higher needs for tax savings or greater tax-saving advantages.

Originality/value

To the best of the authors’ knowledge, this study is the first one that uses a trend analysis to examine the reasons for the downward trend in tax expense over a long period (1960–2016). The results show that, although the trend appears for the full sample period, it is driven by different forces between the first and second half of the time window. A decreasing propensity to recognize tax expense is the main reason for only the trend in recent years, which calls for attention from academia and policymakers. The results also show which firms have had faster trends in their propensity to recognize tax expense, suggesting targets for tax enforcement and tax researchers.