bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the prefrontal-supplementary motor network in obsessive-compulsive disorder with intensified electrical stimulation in two dosages: A randomized, controlled trial
Authors: Alizadehgoradel Jaber , Molaei Behnam , Jalali Khandan Barzegar , Pouresmali Asghar , Sharifi Kiomars , Hallajian Amir-Homayun , Nejati Vahid , Glinski Benedikt , Vicario Carmelo M , Nitsche Michael A. , Salehinejad Mohammad Ali
Published: December 2023

Obsessive-Compulsive Disorder (OCD) is associated with a high disease burden, and treatment options are limited. We used intensified electrical stimulation in two dosages to target a main circuitry associated with the pathophysiology of OCD, left dorsolateral prefrontal cortex (l- DLPFC) and supplementary motor area (SMA) and assessed clinical outcomes, neuropsychological performance and brain physiology. In a double-blind, randomized-controlled trial, thirty-nine patients with OCD were randomized to sham, 2-mA or 1-mA transcranial direct current stimulation (tDCS) targeting the l-DLPFC (F3) and SMA (FC2) with anodal and cathodal stimulation respectively. The treatment included 10 sessions of 20-minute stimulation delivered twice per day with 20-min between-session intervals. Outcome measures were reduction in OCD symptoms, anxiety and depressive states, performance on a neuropsychological test battery of response inhibition, working memory, attention, and oscillatory brain activities and functional connectivity. All outcome measures except EEG were examined at pre-intervention, post- intervention and 1-month follow-up times. The 2-mA protocol significantly reduced OCD symptoms, anxiety, depression states, and improved quality of life after the intervention up to 1- month follow-up compared to the sham group, while the 1-mA protocol reduced OCD symptoms only in the follow-up and depressive state immediately after and 1-month following the intervention. Both protocols partially improved response inhibition and the 2-mA protocol reduced attention bias to OCD-related stimuli and improved reaction time in working memory performance. Both protocols increased alpha oscillatory power and the 2-mA intensified protocol decreased delta power as well. Both protocols increased connectivity in higher frequency bands at frontal-central areas compared to the sham. Modulation of the prefrontal-supplementary motor network with intensified tDCS ameliorates OCD clinical symptoms and results in beneficial cognitive effects. The 2-mA intensified stimulation resulted in larger symptom reduction and improved more converging outcome variables related to therapeutic efficacy. These results support applying the intensified prefrontal-SMA tDCS in larger trials.
A Systematic Review and Dose-Response Meta-Analysis of the Association Between Nitrate & Nitrite intake and Gastroesophageal Cancer Risk: A Study Protocol
Authors: Ghasemi Mohammadreza , Bahrami koutenaei Mohammad , Ghasemi Alireza , Alizadeh-navaei Reza , Moosazadeh Mahmood
Published: December 2023

Objectives

The global burden of cancer underscores the necessity for evidence-based strategies to identify and manage risk factors. Nitrate and nitrite are inherent byproducts resulting from microbial-mediated nitrogen oxidation in plants, soil, or water. Fruits, vegetables, and combinations thereof are integral constituents of a nutritious diet. Despite the potential carcinogenicity of N-nitroso compounds (NOCs), certain epidemiological investigations have reported a lack of correlation between the dietary intake of nitrate, nitrite, and NOCs and the occurrence of cancer in human subjects.

Methods

PubMed/MEDLINE, Embase, WoS (Clarivate Analytics), Proquest, Scopus, and Google Scholar as electronic databases will be precisely searched for observational studies that assessed the relationship between nitrate/nitrite levels and gastric/esophageal cancer. In this study, an assessment will be conducted on studies spanning January 1, 1980, to October 30, 2023. The inclusion criteria will not restrict language. Discrepancies among the reviewers at various stages of the study, including screening, selection, quality assessment, and data extraction, will be resolved through consensus. In instances where disagreements persist unresolved, a third reviewer will decide. The combination method will be employed based on methodological similarities in the chosen articles, utilizing either the Random Effect Model or the Fixed Effect Model. Additionally, forest plots will be generated for the included articles. Statistical heterogeneity will be evaluated using the I2 statistic and the Q-statistic test. Furthermore, funnel plots will be employed to assess non-significant study effects and potential reporting bias. Eggers and Beggs tests will be executed, and the identification of publication bias will rely on significant findings (P < 0.05).

Conclusion

The findings of this study should be of benefit to governments and researchers in maintaining safe levels of nitrate and nitrite in drinking water as well as preventing Gastroesophageal cancers.
Aberration correction for deformable mirror based remote focusing enables high-accuracy whole-cell super-resolution imaging
Authors: Shi Wei , He Yingchuan , Wang Jianlin , Zhou Lulu , Chen Jianwei , Zhou Liwei , Xi Zeyu , Wang Zhen , Fang Ke , Li Yiming
Published: December 2023

Single-molecule localization microscopy (SMLM) enables three-dimensional (3D) investigation of nanoscale structures in biological samples, offering unique insights into their organization. However, traditional 3D super-resolution microscopy using high numerical aperture (NA) objectives is limited by imaging depth of field (DOF), restricting their practical application to relatively thin biological samples. Here, we developed a unified solution for thick sample super-resolution imaging using a deformable mirror (DM) which was served for fast remote focusing, optimized point spread function (PSF) engineering and accurate aberration correction. By effectively correcting the system aberrations introduced during remote focusing and sample aberrations at different imaging depths, we achieved high-accuracy, large DOF imaging of the whole-cell organelles [i.e. nuclear pore complex (NPC), microtubules, and mitochondria] with a nearly uniform resolution of approximately 30 nm across the entire cellular volume.
Structure, interaction, and nervous connectivity of beta cell primary cilia
Authors: Müller Andreas , Klena Nikolai , Pang Song , Galicia Garcia Leticia Elizabeth , Topcheva Oleksandra , Duran Solange Aurrecoechea , Sulaymankhil Davud , Seliskar Monika , Mziaut Hassan , Schöniger Eyke , Friedland Daniela , Kipke Nicole , Kretschmar Susanne , Münster Carla , Weitz Jürgen , Distler Marius , Kurth Thomas , Schmidt Deborah , Hess Harald F. , Xu C. Shan , Pigino Gaia , Solimena Michele
Published: December 2023

Primary cilia are sensory organelles present in many cell types. Based on an array of microtubules termed axoneme they form a specialized membrane compartment partaking in various signaling processes. Primary cilia of pancreatic islet beta cells play a role in autocrine and paracrine signaling and are linked to diabetes. Yet, the structural basis for their functions is unclear. We present three-dimensional reconstructions of complete mouse and human beta cell cilia, revealing a disorganized 9+0 axoneme structure. Within the islet, cilia are spatially confined within deep ciliary pockets or squeezed into narrow extracellular spaces between adjacent cells. Beta and alpha cell cilia physically interact with neighboring islet cells pushing and strongly bending their plasma membranes. Furthermore, beta cells can contain multiple cilia that can meet with other islet cell cilia in the extracellular space. Additionally, beta cell cilia establish connections with islet-projecting nerves. These findings highlight the pivotal role of beta cell primary cilia in islet cell connectivity, pointing at their potential functional role in integrating islet intrinsic and extrinsic signals. These novel insights contribute to understanding their significance in health and diabetes.
In-depth characterization of HINT1 pathogenic variants
Authors: Amor-Barris Silvia , Lazar Tamas , Peeters Kristien , Wodak Shoshana J. , Jordanova Albena
Published: December 2023

Loss-of-function variants in HINT1 were identified to cause axonal recessive peripheral neuropathy with neuromyotonia (NMAN). Patients suffer from motor-greater-than-sensory polyneuropathy with an age of onset, mainly within the first decade of life. Currently, nearly 30 NMAN disease-causing variants have been described, predominantly in sporadic cases and small families, most of them with limited functional evidence of pathogenicity. We systematically characterized all reported pathogenic missense mutations in HINT1, aiming to dissect their underlying loss-of-function mechanism. Individual variants were mapped onto the crystal structure of the HINT1 protein, and their potential effect on protein stability was computed. These variants were grouped into three main clusters: around the catalytic pocket, at the dimer interface, and in the β-sheet behind the catalytic pocket of the protein. The stability and functionality of the corresponding altered proteins were testedin vivousing HINT1 KO cells and a yeast model deficient for the orthologous gene (HNT1), providing insights into the structure-function relations. Our findings support the pathogenic character of most of the variants and uncover their differential effect on HINT1 function. Classifying the variants in three clusters sets the basis for patient stratification strategies for future therapeutic development.
PURA and GLUT1: Sweet partners for brain health
Authors: Colombo Rocío B. , Maxit Clarisa , Martinelli Diego , Anderson Mel , Masone Diego , Mayorga Lía
Published: December 2023

PURA, also known as Pur-alpha, is an evolutionarily conserved DNA/RNA-binding protein crucial for various cellular processes, including DNA replication, transcriptional regulation, and translational control. Comprising three PUR domains, it engages with nucleic acids and has a role in protein-protein interactions. The manifestation of PURA syndrome, arising from mutations in the PURA gene, presents neurologically with developmental delay, hypotonia, and seizures. In our prior work from 2018, we highlighted the unique case of a PURA patient displaying hypoglycorrhachia, suggesting a potential association with GLUT1 dysfunction in this syndrome.

In this current study, we expand the patient cohort with PURA mutations exhibiting hypoglycorrhachia and aim to unravel the molecular basis of this phenomenon. We established an in vitro model in HeLa cells to modulate PURA expression and investigated GLUT1 function and expression. Our findings indicate that PURA levels directly impact glucose uptake through the functioning of GLUT1, without influencing significantly GLUT1 expression. Moreover, our study reveals convincing evidence for a physical interaction between PURA and GLUT1, demonstrated by colocalization and co-immunoprecipitation of both proteins. Computational analyses, employing molecular dynamics, further corroborates these findings, demonstrating that PURA:GLUT1 interactions are plausible, and that the stability of the complex is altered when PURA is truncated and/or mutated.

In conclusion, our results suggest that PURA plays a pivotal role in driving the function of GLUT1 for glucose uptake, potentially forming a regulatory complex. Additional investigations are warranted to elucidate the precise mechanisms governing this complex and its significance in ensuring proper GLUT1 function.
Differential Effects of Posttranslational Modifications on the Membrane Interaction of Huntingtin Protein
Authors: Zhang Zhidian , Gehin Charlotte , Abriata Luciano A , Peraro Matteo Dal , Lashuel Hilal
Published: December 2023

Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine stretch near the N-terminus of the huntingtin (HTT) protein, rendering the protein more prone to aggregate. The first 17 residues in HTT (Nt17) interact with lipid membranes and harbor multiple posttranslational modifications (PTMs) that can modulate HTT conformation and aggregation. In this study, we used a combination of biophysical studies and molecular simulations to investigate the impact of PTMs on the helicity of Nt17 in the presence of various lipid membranes. We demonstrate that anionic lipids such as PI4P, PI(4,5)P2, and GM1 significantly enhance the helical structure of unmodified Nt17. This effect is attenuated by single acetylation events at K6, K9, or K15, whereas tri-acetylation at these sites abolishes Nt17 membrane interaction. Similarly, single phosphorylation at S13 and S16 decreased but did not abolish the POPG and PIP2-induced helicity, while dual phosphorylation at these sites markedly diminished Nt17 helicity, regardless of lipid composition. The helicity of Nt17 with phosphorylation at T3 is insensitive to the membrane environment. Oxidation at M8 variably affects membrane-induced helicity, highlighting a lipid-dependent modulation of Nt17 structure. Altogether, our findings reveal differential effects of PTMs and crosstalks between PTMs on membrane interaction and conformation of HTT. Intriguingly, the effects of phosphorylation at T3 or single acetylation at K6, K9, and K15 on Nt17 conformation in the presence of certain membranes do not mirror that observed in the absence of membranes. Our studies provide novel insight into the complex relationship between Nt17 structure, PTMs and membrane binding.

TOC figure
Multifrequency control of Faraday wave bioassembly for constructing multiscale hPSC-derived neuronal networks
Authors: Gu Longjun , Zhao Wen , Fan Yuhang , Shang Jia , Zhao Yang , Wang Jibo , Chen Tao , Liu Peidi , Chen Pu
Published: December 2023

Bioassembly is recently regarded as a critical alternative biofabrication technical route to bioprinting since it can directly manipulate millions of live cells to form multicellular structures with close intercellular proximity, improving contact-dependent cell communication and promoting the emergence of tissue-specific functions. However, acoustic bioassembly techniques are currently limited to generating cytoarchitecture with a single characteristic length which cannot faithfully mimic the multiscale cellular structures in native tissues. To overcome this challenge, herein we report a novel acoustic bioassembly technique that employs multifrequency control of Faraday waves to form multiscale cellular structures. By superimposing multiple sine wave signals with proper amplitude ratios, Faraday waves containing multiple wavelengths can be induced and enabled to generate multiscale structures in few seconds. Using this technique, we construct functional neuronal networks with multiscale connectivity that display spontaneous neuroelectrical activities. We anticipate this technique will find wide applications in tissue engineering and regenerative medicine.
Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitabilityviaoveractivation of neuronal GluN2C NMDA receptors
Authors: Pineau Louison , Buhler Emmanuelle , Tarhini Sarah , Bauer Sylvian , Crepel Valérie , Watrin Françoise , Cardoso Carlos , Represa Alfonso , Szepetowski Pierre , Burnashev Nail
Published: December 2023

Objective

Genetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C-containing glutamate- gated NMDA receptors (NMDARs) has been demonstrated for germline defects in theTSCgenes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II.

Methods

We used a rat model of FCD created byin uteroelectroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild-type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch-clamp whole-cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C- mediated currents.

Results

Neurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR-mediated spontaneous excitatory post-synaptic currents. GluN2C-dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time-window between postnatal days P9 and P20.

Significance

Somatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C-mediated NMDARs in neocortices of rat pups. The related and time- restricted hyperexcitability was sensitive to subunit GluN2C-specific blockade. Our study suggests that GluN2C-related pathomechanisms might be shared in common by mTOR pathway-related cortical dysplasia.

Key points

Excessive activation of GluN2C NMDAR-mediated currents in spiny stellate neurons expressing FCD-causing MTOR somatic variation

GluN2C-dependent increase in spontaneous spiking activity in rat somatosensory cortex containing mutant MTOR-expressing neurons

GluN2C-dependent excessive network activity is time-restricted to a critical period between P9 and P20
Differential development of antibiotic resistance and virulence betweenAcinetobacterspecies
Authors: Darby Elizabeth M. , Moran Robert A. , Holden Emma , Morris Theresa , Harrison Freya , Clough Barbara , McInnes Ross S. , Schneider Ludwig , Frickel Eva M. , Webber Mark A. , Blair Jessica M. A.
Published: December 2023

The two species that account for most cases ofAcinetobacter-associated bacteraemia in the UK areAcinetobacter lwoffii, often a commensal but also an emerging pathogen, andA. baumannii, a well-known antibiotic-resistant species. While these species both cause similar types of human infection and occupy the same niche,A. lwoffii(unlikeA. baumannii) has thus far remained susceptible to antibiotics. Comparatively little is known about the biology ofA. lwoffiiand this is the largest study on it conducted to date, providing valuable insights into its behaviour and potential threat to human health.

This study aimed to explain the antibiotic susceptibility, virulence, and fundamental biological differences between these two species. The relative susceptibility ofA. lwoffii, was explained as it encoded fewer antibiotic resistance and efflux pump genes thanA. baumannii(9 and 30 respectively). While both species had markers of horizontal gene transfer,A. lwoffiiencoded more DNA defence systems and harboured a far more restricted range of plasmids. Furthermore,A. lwoffiidisplayed a reduced ability to select for antibiotic resistance mutations, form biofilm and infect bothin vivoandin vitromodels of infection.

This study suggests that the emerging pathogenA. lwoffiihas remained susceptible to antibiotics because mechanisms exist to make it highly selective about the DNA it acquires, and we hypothesise that the fact that it only harbours a single RND system restricts the ability to select for resistance mutations. This provides valuable insights into how development of resistance can be constrained in Gram negative bacteria.

Importance

Acinetobacter lwoffiiis often a harmless commensal but is also an emerging pathogen and is the most common cause ofAcinetobacter-derived blood stream infections in England and Wales. In contrast to the well-studied, and often highly drug resistantA. baumannii,A. lwoffiihas remained susceptible to antibiotics. This study explains why this organism has not evolved resistance to antibiotics. These new insights are important to understand why and how some species develop antibiotic resistance, while others do not and could inform future novel treatment strategies.
Germline transformation of the West Nile Virus and avian malaria vectorCulex quinquefasciatusSay using the piggyBac transposon system
Authors: Nevard Katherine , Kaur Rajdeep , Harvey-Samuel Tim
Published: December 2023

Culex quinquefasciatusSay is a mosquito which acts as a vector for numerous diseases including West Nile Virus, lymphatic filariasis and avian malaria, over a broad geographical range. As the effectiveness of insecticidal mosquito control methods declines, the need has grown to develop genetic control methods to curb the spread of disease. The piggyBac transposon system - the most widely used genetic transformation tool in insects, including mosquitoes - generates quasi-random insertions of donor DNA into the host genome. However, despite the broad reported species range of piggyBac, previous attempts to use this tool to transformCulex quinquefasciatusmosquitoes have failed. Here we report the first successful transformation ofCulex quinquefasciatuswith the piggyBac transposon system. Using commercially synthesised piggyBac mRNA as a transposase source, we were able to generate three independent insertions of aZsGreenfluorescent marker gene, with transformation efficiencies of up to 5%. Through this work, we have expanded the genetic toolkit available for the genetic manipulation ofCulexmosquitoes and thus removed a barrier to developing novel genetic control methods in this important disease vector.
Inferring Disease Progressive Stages in Single-Cell Transcriptomics Using Weakly-Supervised Deep Learning Approach
Authors: Wehbe Fabien , Adams Levi , Yuen Samantha , Kim Yoon-Seong , Tanaka Yoshiaki
Published: December 2023

Background

Application of single-cell/nucleus genomic sequencing to patient-derived tissues offers potential solutions to delineate disease mechanisms in human. However, individual cells in patient-derived tissues are in different pathological stages, and hence such cellular variability impedes subsequent differential gene expression analyses.

Result

To overcome such heterogeneity issue, we present a novel deep learning approach, scIDST, that infers disease progressive levels of individual cells with weak supervision framework. The inferred disease progressive cells displayed significant differential expression of disease-relevant genes, which could not be detected by comparative analysis between patients and healthy donors. In addition, we demonstrated that pre-trained models by scIDST are applicable to multiple independent data resources, and advantageous to infer cells related to certain disease risks and comorbidities.

Conclusion

Taken together, scIDST offers a new strategy of single-cell sequencing analysis to identify bona fide disease-associated molecular features.
Spatial Relationships Matter: Kinesin-1 Molecular Motors Transport Liposome Cargo Through 3D Microtubule IntersectionsIn Vitro
Authors: Bensel Brandon M , Previs Samantha , Bookwalter Carol , Trybus Kathleen M , Walcott Sam , Warshaw David M
Published: December 2023

Kinesin-1 ensembles maneuver vesicular cargoes through intersections in the 3-dimensional (3D) intracellular microtubule (MT) network. To characterize directional outcomes (straight, turn, terminate) at MT intersections, we challenge 350 nm fluid-like liposomes transported by ∼10 constitutively active, truncated kinesin-1 KIF5B (K543) with perpendicular 2-dimensional (2D) and 3D intersectionsin vitro. Liposomes frequently pause at 2D and 3D intersections (∼2s), suggesting that motor teams can simultaneously engage each MT and undergo a tug-of-war. Once resolved, the directional outcomes at 2D MT intersections have a straight to turn ratio of 1.1; whereas at 3D MT intersections, liposomes more frequently go straight (straight to turn ratio of 1.8), highlighting that spatial relationships at intersections bias directional outcomes. Using 3D super-resolution microscopy (STORM), we define the gap between intersecting MTs and the liposome azimuthal approach angle heading into the intersection. We develop anin silicomodel in which kinesin-1 motors diffuse on the liposome surface, simultaneously engage the intersecting MTs, generate forces and detach from MTs governed by the motors’ mechanochemical cycle, and undergo a tug-of-war with the winning team determining the directional outcome in 3D. The model predicts that 1-3 motors typically engage the MT, consistent with optical trapping measurements. Modeled liposomes also predominantly go straight through 3D intersections over a range of intersection gaps and liposome approach angles, even when obstructed by the crossing MT. Our observations and modeling offer mechanistic insights into how cells might tune the MT cytoskeleton, cargo, and motors to modulate cargo transport.

Significance Statement

Kinesin-1 molecular motors transport vesicles containing essential cellular resources along the dense 3D microtubule (MT) cytoskeleton, with dysfunctions linked to neurodegenerative diseases such as Alzheimer’s. Despite its importance, the mechanism by which kinesin-1s maneuver intracellular cargoes through MT-MT intersections towards their destination remains unclear. Therefore, we developed a 3Din vitromodel transport system, which challenges kinesin-1 motor teams to maneuver vesicle-like liposomes through MT-MT intersections. Surprisingly, liposomes are biased to pass straight through 3D MT intersections rather than turn, even when the MT intersection presents as a physical barrier. A mechanistic model informs this observation, suggesting that spatial relationships between the cargo and MT intersection influence how molecular motors maneuver intracellular cargoes towards their destination to satisfy cellular demands.
Hemodynamics regulate spatiotemporal artery muscularization in the developing circle of Willis
Authors: Cheng Siyuan , Xia Ivan Fan , Wanner Renate , Abello Javier , Stratman Amber N. , Nicoli Stefania
Published: December 2023

Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries, playing a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular diseases and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating differentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on the zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that the arterial expression of CoW endothelial cells (ECs) occurs after their migration from the cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors upon recruitment to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity wall shear stress. Furthermore, pulsatile blood flow is required for differentiation of human brain pdgfrb+ mural cells into VSMCs as well as VSMC differentiation on zebrafish CoW arteries. Consistently, the flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, andklf2aknockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight the role of blood flow activation of endothelial klf2a as a mechanism regulating the initial VSMC differentiation on vertebrate brain arteries.
Getting there in one piece: The Rac pathway prevents cell fragmentation in a nonprotrusively migrating leader cell during organogenesis
Authors: Singh Noor , Li Karen Jian , Gordon Kacy Lynn
Published: December 2023

TheC. eleganshermaphrodite distal tip cell (DTC) leads gonadogenesis. Loss-of-function mutations in aC. elegansortholog of the Rac1 GTPase (ced-10) and its GEF complex (ced-5/DOCK180,ced-2/CrkII,ced-12/ELMO) cause gonad migration defects related to directional sensing; we discovered an additional defect class of gonad bifurcation in these mutants. Using genetic approaches, tissue-specific and whole-body RNAi, andin vivoimaging of endogenously tagged proteins and marked cells, we find that loss of Rac1 or its regulators causes the DTC to fragment as it migrates. Both products of fragmentation—the now-smaller DTC and the membranous patch of cellular material—localize important stem cell niche signaling (LAG-2/DSL ligand) and migration (INA-1/integrin subunit alpha) factors to their membranes, but only one retains the DTC nucleus and therefore the ability to maintain gene expression over time. The enucleate patch can lead a bifurcating branch off the gonad arm that grows through germ cell proliferation. Germ cells in this branch differentiate as the patch loses LAG-2 expression. While the nucleus is surprisingly dispensable for aspects of leader cell function, it is required for stem cell niche activity long-term. Prior work found thatRac1−/−;Rac2−/−mouse erythrocytes fragment; in this context, our new findings support the conclusion that maintaining a cohesive but deformable cell is a conserved function of this important cytoskeletal regulator.
Co-production revisited: from knowledge plurality to action for disaster risk reduction
Authors: Tran Minh , Kim Dayoon
Published: December 2023

Purpose

The authors revisit the notion of co-production, highlight more critical and re-politicized forms of co-production and introduce three principles for its operationalization. The paper’s viewpoint aims to find entry points for enabling more equitable disaster research and actions via co-production.

Design/methodology/approach

The authors draw insights from the authors’ reflections as climate and disaster researchers and literature on knowledge politics in the context of disaster and climate change, especially within critical disaster studies and feminist political ecology.

Findings

Disaster studies can better contribute to disaster risk reduction via political co-production and situating local and Indigenous knowledge at the center through three principles, i.e. ensuring knowledge plurality, surfacing norms and assumptions in knowledge production and driving actions that tackle existing knowledge (and broader sociopolitical) structures.

Originality/value

The authors draw out three principles to enable the political function of co-production based on firsthand experiences of working with local and Indigenous peoples and insights from a diverse set of co-production, feminist political ecology and critical disaster studies literature. Future research can observe how it can utilize these principles in its respective contexts.
Sustainable value creation through customization for smart PSS models: a multi-industry case study
Authors: Chang Yuan , Ming Xinguo , Liao Xiaoqiang , Bao Yuguang , Chen Zhihua , Song Wenyan
Published: December 2023

Purpose

This study is a reference for manufacturers who are promoting their product-service system (PSS) development. Currently, improvements in both digital customization and sustainability for various smart PSS categories have been considered rarely. This paper addresses this research gap by developing relevant models.

Design/methodology/approach

The development trends of customization-oriented PSS are described in a literature review. An in-depth multiple-case study methodology is adopted, and seven manufacturing companies are sampled. The goal is to identify digital customization measures that can be employed on representative smart PSS models and to explore how these models can create sustainable value.

Findings

This study provides valuable insights by uncovering a synthesis framework for achieving customization of the product/use/result-oriented smart PSSs, and the relevant representative smart functions are summarized. This identifies how digital customization capabilities can improve sustainability, including direct economic value for customers as well as additional social benefits and environmental improvements during customization.

Originality/value

Currently, the influence of digitalization on customized offerings and the relevant impact on sustainability development have not been fully addressed to date. This study provides comprehensive information with a reference value for digital customization transformation among the three main types of smart PSS.
Aging of stallion spermatozoa stored in vitro is delayed at 22°C using a 67 mm glucose–10 mm pyruvate‐based media
Authors: Becerro‐Rey Laura , Martín‐Cano Francisco Eduardo , Ferrusola Cristina Ortega , Rodríguez‐Martínez Heriberto , Gaitskell‐Phillips Gemma , da Silva‐Álvarez Eva , Silva‐Rodríguez Antonio , Gil María Cruz , Peña Fernando J.
Published: December 2023

Background

Most commerce of equine seminal doses is carried out using commercial extenders under refrigeration at 5°C.

Objectives

To determine if 10 mm pyruvate in a 67 mm glucose extender and storage at 22°C could be the basis of an alternative storage method to cooling to 5°C.

Material and methods

Stallion ejaculates were extendedin: INRA96 (67 mm glucose, non‐pyruvate control), modified Tyrode's (67 mm glucose–10 mm pyruvate), supplemented with 0, 10, 50, and 100 μM itaconate. As itaconate was vehiculated in DMSO, a control vehicle was also included. Sperm motility, viability, mitochondrial membrane potential, and production of reactive oxygen species were measured after collection and again after 48 and 96 h of storage at 22°C. To disclose molecular metabolic changes, spermatozoa were incubated up to 3 h in modified Tyrode's 67 mm glucose–10 mm pyruvate and modified Tyrode's 67 mm glucose, and metabolic analysis conducted.

Results

After 96 h of storage aliquots stored in the control, INRA96 had a very poor total motility of 5.6% ± 2.3%, while in the 67 mm glucose–10 mm pyruvate/10 μm itaconate extender, total motility was 34.7% ± 3.8% (p = 0.0066). After 96 h, viability was better in most pyruvate‐based media, and the mitochondrial membrane potential in spermatozoa extended in INRA96 was relatively lower (p < 0.0001). Metabolomics revealed that in the spermatozoa incubated in the high pyruvate media, there was an increase in the relative amounts of NAD+, pyruvate, lactate, and ATP.

Discussion and conclusions

Aliquots stored in a 67 mm glucose–10 mm pyruvate‐based medium supplemented with 10 μM itaconate, maintained a 35% total motility after 96 h of storage at 22°C, which is considered the minimum acceptable motility for commercialization. Improvements may be related to the conversion of pyruvate to lactate and regeneration of NAD+.
A comparative analysis of colour–emotion associations in 16–88‐year‐old adults from 31 countries
Authors: Jonauskaite Domicele , Epicoco Déborah , Al‐rasheed Abdulrahman S. , Aruta John Jamir Benzon R. , Bogushevskaya Victoria , Brederoo Sanne G. , Corona Violeta , Fomins Sergejs , Gizdic Alena , Griber Yulia A. , Havelka Jelena , Hirnstein Marco , John George , Jopp Daniela S. , Karlsson Bodil , Konstantinou Nikos , Laurent Éric , Marquardt Lynn , Mefoh Philip C. , Oberfeld Daniel , Papadatou‐Pastou Marietta , Perchtold‐Stefan Corinna M. , Spagnulo Giulia F. M. , Sultanova Aygun , Tanaka Takumi , Tengco‐Pacquing Ma. Criselda , Uusküla Mari , Wąsowicz Grażyna , Mohr Christine
Published: December 2023

As people age, they tend to spend more time indoors, and the colours in their surroundings may significantly impact their mood and overall well‐being. However, there is a lack of empirical evidence to provide informed guidance on colour choices, irrespective of age group. To work towards informed choices, we investigated whether the associations between colours and emotions observed in younger individuals also apply to older adults. We recruited 7393 participants, aged between 16 and 88 years and coming from 31 countries. Each participant associated 12 colour terms with 20 emotion concepts and rated the intensity of each associated emotion. Different age groups exhibited highly similar patterns of colour–emotion associations (average similarity coefficient of .97), with subtle yet meaningful age‐related differences. Adolescents associated the greatest number but the least positively biased emotions with colours. Older participants associated a smaller number but more intense and more positive emotions with all colour terms, displaying a positivity effect. Age also predicted arousal and power biases, varying by colour. Findings suggest parallels in colour–emotion associations between younger and older adults, with subtle but significant age‐related variations. Future studies should next assess whether colour–emotion associations reflect what people actually feel when exposed to colour.
Seven‐plus hours of daily sedentary time and the subsequent risk of breast cancer: Japan Multi‐Institutional Collaborative Cohort Study
Authors: Tomida Satomi , Koyama Teruhide , Ozaki Etsuko , Takashima Naoyuki , Morita Midori , Sakaguchi Koichi , Naoi Yasuto , Nishida Yuichiro , Hara Megumi , Hishida Asahi , Tamura Takashi , Okada Rieko , Kubo Yoko , Otonari Jun , Ikezaki Hiroaki , Nakamura Yohko , Kusakabe Miho , Tanoue Shiroh , Koriyama Chihaya , Koyanagi Yuriko N. , Ito Hidemi , Suzuki Sadao , Otani Takahiro , Miyagawa Naoko , Okami Yukiko , Arisawa Kokichi , Watanabe Takeshi , Kuriki Kiyonori , Wakai Kenji , Matsuo Keitaro
Published: December 2023

This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35–69 years from the Japan Multi‐Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure‐time metabolic equivalents (METs), frequency of leisure‐time physical activity, and daily walking time, were examined. During 315,189 person‐years of follow‐up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07–1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure‐time METs, ≥3 days/week of leisure‐time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11–2.25), 1.77 (95% CI, 1.20–2.61), and 1.42 (95% CI, 1.10–1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure‐time physical activity nor walking had a BC‐preventive effect in those with ≥7 h/d of sedentary time.
BRCA1/2 reversion mutations in a pan‐cancer cohort
Authors: Nakamura Kohei , Hayashi Hideyuki , Kawano Ryutaro , Ishikawa Marin , Aimono Eriko , Mizuno Takaaki , Kuroda Hajime , Kojima Yasuyuki , Niikura Naoki , Kawanishi Aya , Takeshita Kei , Suzuki Shinsuke , Ueno Shinichi , Okuwaki Kosuke , Sasaki Jiichiro , Yamaguchi Masatoshi , Masuda Kenta , Chiyoda Tatsuyuki , Yamagami Wataru , Okada Chihiro , Nohara Sachio , Tanishima Shigeki , Nishihara Hiroshi
Published: December 2023

Tumor sensitivity to platinum (Pt)‐based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency‐causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 (BRCA1/2) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan‐cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan‐cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell‐free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 (n = 3) and BRCA2 (n = 9) reversion mutations in breast (n = 4), ovarian/fallopian tube/peritoneal (n = 4), pancreatic (n = 2), prostate (n = 1), and gallbladder (n = 1) cancers. We identified 21 reversion events—BRCA1 (n = 3), BRCA2 (n = 18)—including eight pure deletions, one single‐nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology‐mediated end‐join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP‐inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt‐based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA‐associated cancers, our findings suggest that reversion mutations due to Pt‐chemotherapy might be correlated with BRCA1/2‐mediated tumorigenesis even in non‐BRCA‐associated histologies.
Younger, not older, children trust an inaccurate human informant more than an inaccurate robot informant
Authors: Li Xiaoqian , Yow W. Quin
Published: December 2023

This study examined preschoolers' trust toward accurate and inaccurate robot informants versus human informants. Singaporean children aged 3–5 years (N = 120, 57 girls, mostly Asian; data collected from 2017 to 2018) viewed either a robot or a human adult label familiar objects either accurately or inaccurately. Children's trust was assessed by examining their subsequent willingness to accept novel object labels provided by the same informant. Regardless of age, children trusted accurate robots to a similar extent as accurate humans. However, while older children (dis)trusted inaccurate robots and humans comparably, younger children trusted inaccurate robots less than inaccurate humans. The results indicate a developmental change in children's reliance on informants' characteristics to decide whom to trust.
Characterization of D4Z4 alleles and assessment of de novo cases in Facioscapulohumeral dystrophy (FSHD) in a cohort of Italian families
Authors: Strafella Claudia , Colantoni Luca , Megalizzi Domenica , Trastulli Giulia , Piorgo Emma Proietti , Primiano Guido , Sancricca Cristina , Ricci Giulia , Siciliano Gabriele , Caltagirone Carlo , Filosto Massimiliano , Tasca Giorgio , Ricci Enzo , Cascella Raffaella , Giardina Emiliano
Published: December 2023

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease, although 10%–30% of cases are sporadic. However, this percentage may include truly de novo patients (carrying a reduced D4Z4 allele that is not present in either of the parents) and patients with apparently sporadic disease resulting from mosaicism, non‐penetrance, or complex genetic situations in either patients or parents. In this study, we characterized the D4Z4 Reduced Alleles (DRA) and evaluated the frequency of truly de novo cases in FSHD1 in a cohort of DNA samples received consecutively for FSHD‐diagnostic from 100 Italian families. The D4Z4 testing revealed that 60 families reported a DRA compatible with FSHD1 (1–10 RU). The DRA co‐segregated with the disease in most cases. Five families with truly de novo cases were identified, suggesting that this condition may be slightly lower (8%) than previously reported. In addition, D4Z4 characterization in the investigated families showed 4% of mosaic cases and 2% with translocations. This study further highlighted the importance of performing family studies for clarifying apparently sporadic FSHD cases, with significant implications for genetic counseling, diagnosis, clinical management, and procreative choices for patients and families.
ONTbarcoder 2.0: rapid species discovery and identification with real‐time barcoding facilitated by Oxford Nanopore R10.4
Authors: Srivathsan Amrita , Feng Vivian , Suárez Daniel , Emerson Brent , Meier Rudolf
Published: December 2023

Most arthropod species are undescribed and hidden in specimen‐rich samples that are difficult to sort to species using morphological characters. For such samples, sorting to putative species with DNA barcodes is an attractive alternative, but needs cost‐effective techniques that are suitable for use in many laboratories around the world. Barcoding using the portable and inexpensive MinION sequencer produced by Oxford Nanopore Technologies (ONT) could be useful for presorting specimen‐rich samples with DNA barcodes because it requires little space and is inexpensive. However, similarly important is user‐friendly and reliable software for analysis of the ONT data. It is here provided in the form of ONTbarcoder 2.0 that is suitable for all commonly used operating systems and includes a Graphical User Interface (GUI). Compared with an earlier version, ONTbarcoder 2.0 has three key improvements related to the higher read quality obtained with ONT's latest flow cells (R10.4), chemistry (V14 kits) and basecalling model (super‐accuracy model). First, the improved read quality of ONT's latest flow cells (R10.4) allows for the use of primers with shorter indices than those previously needed (9 bp vs. 12–13 bp). This decreases the primer cost and can potentially improve PCR success rates. Second, ONTbarcoder now delivers real‐time barcoding to complement ONT's real‐time sequencing. This means that the first barcodes are obtained within minutes of starting a sequencing run; i.e. flow cell use can be optimized by terminating sequencing runs when most barcodes have already been obtained. The only input needed by ONTbarcoder 2.0 is a demultiplexing sheet and sequencing data (raw or basecalled) generated by either a Mk1B or a Mk1C. Thirdly, we demonstrate that the availability of R10.4 chemistry for the low‐cost Flongle flow cell is an attractive option for users who require only 200–250 barcodes at a time.
Additional Cover
Authors: Lyu Chunzi , Ni Tianxiang , Guo Yaqiu , Zhou Tingting , Chen Zi‐Jiang , Yan Junhao , Li Yan
Published: December 2023

The cover image is based on the Original Article Insufficient GDF15 expression predisposes women to unexplained recurrent pregnancy loss by impairing extravillous trophoblast invasion by Chunzi Lyu et al., https://doi.org/10.1111/cpr.13514.

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