bluuebunny/crossref_metadata_2025 huggingface dataset:
Laws of genome nucleotide composition
Authors: Zhang Zhang
Published: September 2023

Genome nucleotide composition is of fundamental significance in molecular evolution, genome organization and synthetic biology. Albeit studied for decades, it remains unclear whether there is any theoretical law underlying variable genome nucleotide composition across different species. From the mathematical viewpoint, here we propose three laws of genome nucleotide composition and validate their effectiveness on a large collection of empirical genome sequences across three domains of life. The three laws together provide a unifying framework that is able to unravel the mystery of genome-wide nucleotide composition variation across diverse species, paving the way towards a new era with quantitative insights for deciphering basic principles of life and further advancing theoretical biology.

One-Sentence Summary

The three laws of genome nucleotide composition provide a fundamental framework for molecular evolution, genome organization and synthetic biology.
Protocol for primary human lung organoid-derived air-liquid interfacein vitromodel to study response to SARS-CoV-2
Authors: Castaneda Diana Cadena , Jangra Sonia , Yurieva Marina , Martinek Jan , Callender Megan , Coxe Matthew , Choi Angela , Diego Juan García-Bernalt , Wu Te-Chia , Marches Florentina , Chaussabel Damien , García-Sastre Adolfo , Schotsaert Michael , Williams Adam , Palucka Karolina
Published: September 2023

This article presents a comprehensive protocol for establishing primary human lung organoid-derived air-liquid interface (ALI) cultures from cryopreserved human lung tissue. These cultures serve as a physiologically relevant model to study human airway epitheliumin vitro. The protocol encompasses lung tissue cryostorage, tissue dissociation, lung epithelial organoid generation, and ALI culture differentiation. It also demonstrates SARS-CoV-2 infection in these cultures as an example of their utility. Quality control steps, ALI characterization, and technical readouts for monitoring virus response are included in the study.

For additional details on the use and execution of this protocol, please refer to Diana Cadena Castaneda et al (https://doi.org/10.1016/j.isci.2023.107374).

Highlights

Human lung tissue dissection, embedding in OCT blocks, and tissue cryopreservation.

Thawing & lung tissue dissociation for lung epithelium organoid generation.

Organoid-derived air-liquid-interface cultures for the study of viral infection.

Bulk RNA-Seq, flow cytometry, viral titer, and imaging to follow response to virus.

Graphical abstract
A biobank-scale test of marginal epistasis reveals genome-wide signals of polygenic epistasis
Authors: Fu Boyang , Pazokitoroudi Ali , Xue Albert , Anand Aakarsh , Anand Prateek , Zaitlen Noah , Sankararaman Sriram
Published: September 2023

The contribution of epistasis (interactions among genes or genetic variants) to human complex trait variation remains poorly understood. Methods that aim to explicitly identify pairs of genetic variants, usually single nucleotide polymorphisms (SNPs), associated with a trait suffer from low power due to the large number of hypotheses tested while also having to deal with the computational problem of searching over a potentially large number of candidate pairs. An alternate approach involves testing whether a single SNP modulates variation in a trait against a polygenic background. While overcoming the limitation of low power, such tests of polygenic or marginal epistasis (ME) are infeasible on Biobank-scale data where hundreds of thousands of individuals are genotyped over millions of SNPs.

We present a method to test for ME of a SNP on a trait that is applicable to biobank-scale data. We performed extensive simulations to show that our method provides calibrated tests of ME. We applied our method to test for ME at SNPs that are associated with 53 quantitative traits across ≈ 300 K unrelated white British individuals in the UK Biobank (UKBB). Testing 15, 601 trait-loci associations that were significant in GWAS, we identified 16 trait-loci pairs across 12 traits that demonstrate strong evidence of ME signals (p-value). We further partitioned the significant ME signals across the genome to identify 6 trait-loci pairs with evidence of local (within-chromosome) ME while 15 show evidence of distal (cross-chromosome) ME. Across the 16 trait-loci pairs, we document that the proportion of trait variance explained by ME is about 12x as large as that explained by the GWAS effects on average (range: 0.59 to 43.89). Our results show, for the first time, evidence of interaction effects between individual genetic variants and overall polygenic background modulating complex trait variation.
A scoping review of the unmet needs of patients diagnosed with idiopathic pulmonary fibrosis (IPF)
Authors: Bramhill Carita , Langan Donna , Mulryan Helen , Eustace-Cook Jessica , Russell Anne-Marie , Brady Anne-Marie
Published: September 2023

Title

A scoping review of the unmet needs of patients diagnosed with idiopathic pulmonary fibrosis (IPF).

Aims

Patients diagnosed with IPF have a high symptom burden and numerous needs that remain largely unaddressed despite advances in available treatment options. There is a need to comprehensively identify patients’ needs and create opportunities to address them. This scoping review aimed to synthesise the available evidence and identify gaps in the literature regarding the unmet needs of patients diagnosed with IPF.

Methods

The protocol for the review was registered with Open Science Framework (DOI 10.17605/OSF.IO/SY4KM). A systematic search was performed in March 2022, in CINAHL, MEDLINE, Embase, PsyhcoInfo, Web of Science Core Collection and ASSIA Applied Social Science Index. A comprehensive review of grey literature was also completed. Inclusion criteria included patients diagnosed with IPF or PF; English language only and date range 2011-2022. A range of review types were included. Data was extracted using a data extraction form. Data was analysed using descriptive and thematic analysis. A total of 884 citations were reviewed. Ethical approval was not required.

Results

52 citations were selected for final inclusion. Five themes were identified: psychological impact of an IPF diagnosis; adequate information and education: at the right time and in the right way; high symptom burden support needs; referral to palliative care and advanced care planning (ACP) and health service provision-a systems approach.

Conclusion

This review highlights the myriad of needs patients with IPF have and highlights the urgent need for a systems approach to care, underpinned by an appropriately resourced multi-disciplinary team. The range of needs experienced by patients with IPF are broad and varied and require a holistic approach to care including targeted research, coupled with the continuing development of patient-focused services and development of a clinical care programme.
Epidermal barrier dysregulation in atopic skin predisposes for excessive growth of the allergy-associated yeastMalassezia
Authors: Ruchti Fiorella , Zwicky Pascale , Becher Burkhard , Dubrac Sandrine , LeibundGut-Landmann Salomé
Published: September 2023

The skin barrier is vital for protection against environmental threats including insults caused by skin-resident microbes. Dysregulation of the barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While sensitisation toMalassezia, the most abundant commensal fungus of the skin, is common in AD, its relevance for pathogenesis remains unclear. Here we show that in barrier-disrupted skin,Malasseziaacquires enhanced fitness. This is not a consequence of the dysregulated allergic immune status characteristic for AD but is rather explained by structural and metabolic changes in the cutaneous niche that provide increased accessibility and a favourable lipid profile, to which the lipid-dependent yeast adapts for enhanced nutrient assimilation. These findings reveal fundamental insights into the role of the mycobiota in the pathogenesis of common skin barrier disorders.
Targeting monocytic Occludin impairs monocyte transmigration and HIV neuroinvasion
Authors: Brychka Diana , Ayala-Nunez Nilda Vanesa , Bare Yonis , Dupas Amandine , Partiot Emma , Mittelheisser Vincent , Lucansky Vincent , Goetz Jacky G. , Osmani Nael , Gaudin Raphael
Published: September 2023

Transmigration of circulating monocytes from the bloodstream toward the central nervous system (CNS) represents a hallmark of neuroinflammation and plays an important role during viral encephalitis and HIV-associated neurocognitive disorders (HAND). The molecular mechanisms involved in monocyte transmigration through endothelia has been extensively studied, but how monocytes locally unzip tight junction-associated proteins (TJAPs) of the endothelium composing the neurovascular unit (NVU) to reach the CNS remains poorly understood. Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through cerebral microvessel endothelial cells. Silencing monocytic OCLN (mOCLN) impairs monocyte transmigration, while mOCLN overexpression increases transmigration. Using high-resolution live cell imaging, we observed that mOCLN clusters at the monocyte-endothelium interface during the transmigration process, forming a transient ring of mOCLN at the site of diapedesis. Furthermore, we designed OCLN-derived peptides targeting its extracellular loop (EL) 1 or 2 to prevent potential trans-homotypic interactions of mOCLN with endothelial OCLN. We found that transmigration of human monocytes was significantly inhibited upon treatment with the EL2 peptidein vitroand in zebrafish embryos, while preserving vascular integrity. Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and here, we showed that the treatment of transmigrating monocytes with the EL2 peptide prevents the dissemination of HIV to cerebral organoids. In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent HIV neuroinvasion.
The intervening influence of the quality of health-care administrative process on the relationship between facilities management service quality and patients’ health-care experience in Ghana
Authors: Amankwah Oti , Choong Weng Wai , Boakye-Agyeman Naana Amakie , Afrane Ebenezer
Published: September 2023

Purpose

Patient-centred strategies should be applied in health-care facilities management (HcFM) to guarantee service quality to meet patients’ needs and ensure quality patient health-care experience. This paper aims to examine the intervening influence of the quality of health-care administrative process (QAP) on the association between health-care facilities service quality and patients’ experiences with medical care.

Design/methodology/approach

A quantitative technique was used for this cross-sectional study in three Ghanaian teaching hospitals. A total of 622 relevant questionnaires were used for the analysis of the study using SEM-PLS.

Findings

The intervening influence of the QAP on the relationship between HcFM service quality (empathy and tangibility) and patients’ health-care experience (PHcE) were reinforced whilst that of reliability, responsiveness and assurance were not reinforced. The association between the QAP and PHcE was also established.

Research limitations/implications

A high-quality health-care workforce (both core and supporting) and quality work environment provided by the FM department and QAP are essential during quality-of-care delivery, to reduce threats to patient safety to achieve exceptional PHcE. The constraint on the study is that information was gathered from only Ghana. Hence, the generalisation of the findings will be a challenge. Thus, in future, it is proposed that a comparative study across a developed country and a developing country can be conducted. Future research can assess the influence of the health-care internal appearance on patients’ satisfaction.

Practical implications

Practically, the administrative system can be improved by reducing patients overall waiting time. Steps must also be taken to reduce the problem of needless administrative tasks and practices to simplify administrative practices and improve patients’ total health-care experience (core health-care delivery and HcFM), as this influence patients’ total health-care experience.

Originality/value

To the best of the authors’ knowledge, this empirical validation is one of the initial studies in service quality and FM to examine how health-care administrative process quality affects the relationship between FM service quality and patients’ experiences with medical care. This framework can be adapted for research in different countries to extend knowledge.
Study on (3+1)-dimensional nonlocal Boussinesq equation: multiple soliton solutions
Authors: Wazwaz Abdul-Majid , Alshehri Mansoor , El-Tantawy Samir A.
Published: September 2023

Purpose

This study aims to explore novel solitary wave solutions of a new (3 + 1)-dimensional nonlocal Boussinesq equation that illustrates nonlinear water dynamics.

Design/methodology/approach

The authors use the Painlevé analysis to study its complete integrability in the Painlevé sense.

Findings

The Painlevé analysis demonstrates the compatibility condition for the model integrability with the addition of new extra terms.

Research limitations/implications

The phase shifts, phase variables and Hirota’s bilinear algorithm are used to furnish multiple soliton solutions.

Practical implications

The authors also furnish a variety of numerous periodic solutions, kink solutions and singular solutions.

Social implications

The work formally furnishes algorithms for investigating several physical systems, including plasma physics, optical communications and oceans and seas, among others.

Originality/value

This paper presents an original work using a newly developed Painlevé integrable model, as well as novel and insightful findings.
A train timetable rescheduling approach based on multi-train tracking optimization of high-speed railways
Authors: Wang Rongsheng , Zhang Tao , Yuan Zhiming , Ding Shuxin , Zhang Qi
Published: September 2023

Purpose

This paper aims to propose a train timetable rescheduling (TTR) approach from the perspective of multi-train tracking optimization based on the mutual spatiotemporal information in the high-speed railway signaling system.

Design/methodology/approach

Firstly, a single-train trajectory optimization (STTO) model is constructed based on train dynamics and operating conditions. The train kinematics parameters, including acceleration, speed and time at each position, are calculated to predict the arrival times in the train timetable. A STTO algorithm is developed to optimize a single-train time-efficient driving strategy. Then, a TTR approach based on multi-train tracking optimization (TTR-MTTO) is proposed with mutual information. The constraints of temporary speed restriction (TSR) and end of authority are decoupled to calculate the tracking trajectory of the backward tracking train. The multi-train trajectories at each position are optimized to generate a time-efficient train timetable.

Findings

The numerical experiment is performed on the Beijing-Tianjin high-speed railway line and CR400AF. The STTO algorithm predicts the train’s planned arrival time to calculate the total train delay (TTD). As for the TSR scenario, the proposed TTR-MTTO can reduce TTD by 60.60% compared with the traditional TTR approach with dispatchers’ experience. Moreover, TTR-MTTO can optimize a time-efficient train timetable to help dispatchers reschedule trains more reasonably.

Originality/value

With the cooperative relationship and mutual information between train rescheduling and control, the proposed TTR-MTTO approach can automatically generate a time-efficient train timetable to reduce the total train delay and the work intensity of dispatchers.
Does CSR digitalization improve the sustainable competitive performance of SMEs? Evidence from an emerging economy
Authors: Ahmad Maqsood , Wu Qiang , Ahmed Shakeel
Published: September 2023

Purpose

This study aims to investigate the influence of the digitalization of corporate social responsibility (CSR) on the sustainable competitive performance (SCP) of small- and medium-sized enterprises (SMEs) in an emerging economy and to examine the moderating effect of digital organizational culture on this relationship.

Design/methodology/approach

Data collection was conducted through a survey completed by 311 owners and top managers operating in service, trading and manufacturing sector SMEs positioned within the twin cities of Pakistan. A convenient purposively sampling technique and snowball method were used for data collection, and structural equation modeling was used for data analysis.

Findings

The results of this study suggest that CSR digitalization has a markedly positive influence on the SCP. Digital organizational culture appears to moderate these relationships.

Practical implications

This study highlights the importance of considering CSR digitalization and fostering a digital organizational culture for SMEs to achieve SCP. The findings provide valuable insights for strategic decision-makers, including owners, CEOs and senior management of SMEs, to enhance their knowledge concerning how and why a digital organizational culture makes it easier to digitalize CSR activities, with the ultimate objective of ensuring SCP and SME growth. Overall, the findings of this study have practical implications for policymakers and managers in SMEs as they can promote the adoption of digital technologies in CSR initiatives and develop a digital organizational culture within the organization. This would contribute to enhancing the SCP of SMEs. Thus, this research is beneficial for business actors, policymakers and researchers seeking to enhance SMEs’ SCP.

Social implications

This study provides valuable guidance to the senior management of SMEs regarding successfully adopting and integrating digital technologies into their CSR practices. This integration can lead to increased social and environmental benefits, which positively impact both business and society. Policymakers can use these findings to develop policies and initiatives to encourage CSR digitalization among SMEs. By providing support and incentives for digital transformation, policymakers can help SMEs adopt digital tools to improve their CSR performance, contributing to economic growth and sustainability.

Originality/value

This study pioneers research on the links between CSR digitalization, digital organizational culture and the SCP of SMEs. This study contributes to the literature by defining CSR digitalization as an antecedent to the SCP of SMEs. In addition, this study underlines the significance of CSR digitalization for the achievement of SMEs’ SCP of SMEs with the moderating role of digital organizational culture. Overall, this study enriches the resource base view literature through empirical evidence.
Cu-Cu joint with Sn-58Bi/Porous Cu/Sn-58Bi transient liquid phase bonding under formic acid atmosphere
Authors: Xiong Bifu , He Siliang , Ge Jinguo , Li Quantong , Hu Chuan , Yan Haidong , Shen Yu-An
Published: September 2023

Purpose

This paper aims to examine the effects of bonding temperature, bonding time, bonding pressure and the presence of a Pt catalyst on the bonding strength of Cu/SB/P-Cu/SB/Cu joints by transient liquid phase bonding (TLPB).

Design/methodology/approach

TLPB is promising to assemble die-attaching packaging for power devices. In this study, porous Cu (P-Cu) foil with a distinctive porous structure and Sn-58Bi solder (SB) serve as the bonding materials for TLPB under a formic acid atmosphere (FA). The high surface area of P-Cu enables efficient diffusion of the liquid phase of SB, stimulating the wetting, spreading and formation of intermetallic compounds (IMCs).

Findings

The higher bonding temperature decreased strength due to the coarsening of IMCs. The longer bonding time reduced the bonding strength owing to the coarsened Bi and thickened IMC. Applying optimal bonding pressure improved bonding strength, whereas excessive pressure caused damage. The presence of a Pt catalyst enhanced bonding efficiency and strength by facilitating reduction–oxidation reactions and oxide film removal.

Originality/value

Overall, this study demonstrates the feasibility of low-temperature TLPB for Cu/SB/P-Cu/SB/Cu joints and provides insights into optimizing bonding strength for the interconnecting materials in the applications of power devices.
Effect of autochthonous starter and non‐starter cultures on the physicochemical, microbiological and sensorial characteristics of Castellano cheese
Authors: Abarquero Daniel , Bodelón Raquel , Manso Catalina , Rivero Pablo , Fresno José María , Tornadijo María Eugenia
Published: September 2023

The effect of different combinations of starter and non‐starter lactic acid bacteria on the physicochemical, colour, microbiological and sensory characteristics of Castellano cheese was investigated. Five batches of Castellano cheese were produced from pasteurised sheep's milk. Significant differences in pH, titratable acidity, microbial counts and sensory attributes between the cheese batches made with different starter cultures were found. In conclusion, the incorporation of autochthonous non‐starter lactic acid bacteria strains gave cheeses made with pasteurised milk better flavour and aroma characteristics than the batch made only with commercial starter culture.
An innovative method for human height estimation combining video images and 3D laser scanning
Authors: Ciampini Claudio , Petrillo Antonella , Zomparelli Federico , Groutas Stefano
Published: September 2023

Digitalization has increased the number of video surveillance systems that sometimes capture crime images. Traditional methods of human height estimation use projective geometry. However, sometimes they cannot be used because the video camera surveillance system is not available or has been moved and there are no reference lines on the frame. Scientific studies have developed a new method for human height estimation using 3D laser scanning. This model necessarily requires a series of approximations, which increase the final measurement error. To overcome this problem, in the present study, images of a subject are projected directly on the 3D model, estimating the height of the subject. This article describes the methodological approach adopted through the analysis of a real case study in a controlled environment executed by Carabinieri Forensic Investigation Department (Italy). The aim is to obtain a human anthropometric measure derived from frames extracted from the videos associated with the digital survey of the framed area obtained with 3D laser scanning and point cloud analysis. The result is the height estimation of five subjects filmed by a camera obtained through the combination of 2D images extracted by a DVR/surveillance systems with 3D laser scanning. Results show that most estimated measurements are less than the real measurement of the subject; it also depends on the posture of the subject while walking. Furthermore, results shows the differences between the real height and the estimated height with a statistical approach.
Eco‐parcel: An approach to identify and describe attractions to support adapting nature‐based tourism destinations to climate‐change impacts
Authors: Kilungu Halima , Munishi Pantaleo K.
Published: September 2023

Informing climate‐change adaptation measures for nature‐based tourism destinations is contingent on understanding how individual attractions respond to the impact of climate change. There is, however, no evidence of the existence of specific approaches for linking individual attractions to climate change. The eco‐parcel approach is therefore devised to address the gap. The approach follows three simple steps: (1) identifying and defining individual tourist attractions (2) describing and creating a link between individual attractions and their supporting ecosystems using land cover as a proxy; (3) assessing the importance of discrete landscape patches (eco‐parcels) for tourism. The three steps employ literature reviews, tourists' preference surveys and GIS data collection techniques. The operationalisation of the approach in Tanzanian Serengeti and Kilimanjaro National parks case studies shows that the approach is capable of establishing a list of attractions that a destination has and creating spatial–temporal links between attractions and their supporting ecosystems. In conclusion, the eco‐parcel approach allows accurate assessment of the likely losses or gains of individual attractions in the event of climate change, providing information on destination‐specific climate adaptation strategies and, thus, a useful tool for adapting NBT to climate‐change impacts.
Differentiation of human primary testicular cells in the presence of SCF using the organoid culture system
Authors: Nikmahzar Aghbibi , Koruji Morteza , Jahanshahi Mehrdad , Khadivi Farnaz , Shabani Maryam , Dehghani Sanaz , Forouzesh Mehdi , Jabari Ayob , Feizollahi Narjes , Salem Maryam , Ghanami Gashti Nasrin , Abbasi Yasaman , Abbasi Mehdi
Published: September 2023

Purpose

Development of organoids using human primary testicular cells has remained a challenge due to the complexity of the mammalian testicular cytoarchitecture and culture methods. In this study, we generated testicular organoids derived from human primary testicular cells. Then, we evaluated the effect of stem cell factor (SCF) on cell differentiation and apoptosis in the testicular organoid model.

Methods

The testicular cells were harvested from the three brain‐dead donors. Human spermatogonial stem cells (SSCs) were characterized using immunocytochemistry (ICC), RT‐PCR and flow cytometry. Testicular organoids were generated from primary testicular cells by hanging drop culture method and were cultured in three groups: control group, experimental group 1 (treated FSH and retinoic acid (RA)), and experimental group 2 (treated FSH, RA and SCF), for five weeks. We assessed the expression of SCP3 (Synaptonemal Complex Protein 3) as a meiotic gene, PRM2 (Protamine 2) as a post‐meiotic marker and apoptotic genes of Bax (BCL2‐Associated X Protein) and Bcl‐2 (B‐cell lymphoma 2), respectively by using RT‐qPCR. In addition, we identified the expression of PRM2 by immunohistochemistry (IHC).

Results

Relative expression of SCP3, PRM2 and Bcl‐2 were highest in group 2 after five weeks of culture. In contrast, BAX expression level was lower in experimental group 2 in comparison with other groups. IHC analyses indicated the highest expression of PRM2 as a postmeiotic marker in group 2 in comparison to 2D culture and control groups but not find significant differences between experimental group 1 and experimental group 2 groups. Morphological evaluations revealed that organoids are compact spherical structures and in the peripheral region composed of uncharacterized elongated fibroblast‐like cells.

Conclusion

Our findings revealed that the testicular organoid culture system promote the spermatogonial stem cell (SSC) differentiation, especially in presence of SCF. Developed organoids are capable of recapitulating many important properties of a stem cell niche.
When DNA can't help: The osteobiographical profile and stable isotope analysis as auxiliary tools for refining genealogical relationships, on the example of the Swéerts‐Sporck family
Authors: Cvrček Jan , Drtikolová Kaupová Sylva , Vytlačil Zdeněk , Zazvonilová Eliška , Velemínský Petr
Published: September 2023

Research into the family of the Counts Swéerts‐Sporck raised doubts regarding their biographical data, particularly concerning a child who died in 1817, later identified as Philipp Swéerts‐Sporck, and his siblings Joseph and Barbara. These were alleged to include a pair of dizygotic twins, but DNA could not be used to clarify their relationships. Carbon and nitrogen isotopes were therefore measured in their first permanent molars, whereas Philipp's biological age was estimated based on his skeleton. Philipp died at an older age than the written sources claim; an isotopic similarity was found between Joseph and Barbara, but Philipp differed.
Pharmacological characterization of SAGE‐718, a novel positive allosteric modulator of N‐methyl‐d‐aspartate receptors
Authors: Beckley Jacob T. , Aman Teresa K. , Ackley Michael A. , Kazdoba Tatiana M. , Lewis Michael C. , Smith Anne C. , Farley Brandon J. , Dai Jing , Deats Wayne , Hoffmann Ethan , Robichaud Albert J. , Doherty James J. , Quirk Michael C.
Published: September 2023

Background and Purpose

Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)‐hydroxycholesterol (24(S)‐HC), which is an N‐methyl‐d‐aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction.

Experimental Approach

Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE‐718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile.

Key Results

SAGE‐718 potentiated GluN1/GluN2A‐D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE‐718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine‐evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE‐718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)‐HC depletion caused by 7‐dehydrocholesterol reductase inhibition. Finally, SAGE‐718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing.

Conclusions and Implications

These findings provide strong evidence that SAGE‐718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction.
Debate: Better use of existing services, not more new pathways, is required for psychosis prevention in young people – Commentary on Salazar de Pablo and Arango: ‘Prevention of psychosis in adolescents: doesCAMHShave a role?’
Authors: Tiffin Paul A. , Northover Guy
Published: September 2023

Background

There has been much academic interest in ‘the clinical high‐risk state for psychosis’ (CHR‐P) concept. Whilst early intervention in psychosis (EIP) services have offered input to individuals meeting the CHR‐P criteria the involvement of CAMHS clinicians in supporting young people with ideational and perceptual disturbance has been more inconsistent and uncertain.

Method

We bring together our relevant lived experience, empirical evidence and clinical and research expertise to write this commentary.

Results

We assert that the CHR‐P paradigm needs to be revised. This should reflect the low transition rates to psychosis and the prevalent general, impairing psychopathology in individuals meeting these criteria. Nevertheless, it is clear that both CAMHS and EIP services have potential roles in meeting the needs of young people affected by distressing ideational and perceptual disturbance.

Conclusions

We suggest that new care pathways and services are not required for young people affected by distressing psychosis‐like experiences. Rather more effective joint working between CAMHS, EIP, crisis services and other agencies could meet the needs of these young people more comprehensively.
Local heterogeneity of coral reef diversity and environmental stress provides opportunities for small‐scale conservation
Authors: McClanahan T. R.
Published: September 2023

Aim

Strong social‐ecological trade‐offs between resource extraction and protection have created challenges for large, protected area management in natural resource‐dependent countries. Therefore, local governments and community conservation activities are becoming common and information about low environmental exposure and high biodiversity can provide for planning localized conservation activities.

Location

The western Indian Ocean.

Methods

Coral reef sites were evaluated for local‐scale environmental and species richness to elucidate local patterns in spatial heterogeneity. Local coral and fish taxonomic richness and coral community susceptibility to stress were normalized to partially account for common and heterogenous disturbances to coral cover and fish biomass. Residuals of these three response variables were evaluated for local geographic patterns and specific relationships with 21 environmental variables using machine learning methods.

Results

Richness was highly variable at local geographies and had a double‐peaked shape with latitudes. Thirteen of the 21 examined variables were selected and indicated complex, spatially heterogeneous and weak cumulative predictive relationships with specific environmental and human influences. For example, each selected variable contributed 7% to 25% of the variance but with different relationships for the three responses. Coral fish richness and coral community susceptibility correlations were positive but weak and therefore produced different local spatial patterns. Nevertheless, these spatial patterns exhibited some coarse‐scale similarities indicating locations with shared positive community attributes and potential climate refugia. Shared richness variables included depth and wave energy, temperature variables of SST skewness, excess heat and rate of rise. Human influences of distance to shore, human populations and cities were also selected for richness and community susceptibility responses.

Main Conclusions

Planning to include local stress and richness patterns variability could contribute to species persistence. From these specific data, sites in the Pemba Channel between the Tanzanian mainland and Pemba Island, and northern Mozambique and Madagascar fit refugia characteristics.
Endoscopic ultrasound‐guided drainage of perforated gallbladder in patients with hilar cholangiocarcinoma postbiliary uncovered self‐expandable metal stent placement
Authors: Chavan Radhika , Gandhi Chaiti , Rajput Sanjay
Published: September 2023

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Export‐platform foreign direct investment and trade policy uncertainty: Evidence from brexit
Authors: Tamberi Nicolò
Published: September 2023

This paper analyses the effect of trade policy uncertainty in a customs union on export‐platform foreign direct investment (FDI). First, I develop a partial equilibrium framework with heterogeneous firms based on the proximity–concentration trade‐off that involves trade policy uncertainty about trade costs inside a customs union. Second, I derive an empirical equation that I test by exploiting the 2016 Brexit referendum as a natural experiment and using data on manufacturing greenfield FDI projects. The results show that trade policy uncertainty impacted negatively the decisions of firms to invest in export‐platform activities in the UK following the Brexit referendum. Moreover, I find that extra‐EU manufacturing firms preferred EU countries as opposed to the UK for new investments after the 2016 referendum.
L‘évolution de l‘écart salarial entre hommes et femmes en Europe: le rôle du prix des compétences professionnelles
Authors: KAYA Ezgi
Published: September 2023

Dans cette analyse sur l'évolution de l'écart salarial entre hommes et femmes, l'autrice évalue le rôle de la variation du rendement salarial des compé‐tences professionnelles «cérébrales» (cognitives et interpersonnelles) et «physiques» (compétences motrices et force musculaire). Utilisant une série harmonisée sur six pays européens et des données comparables sur les États‐Unis, elle montre que l'effet du prix des compétences professionnelles est très variable selon les pays. Toutefois, dans tous les pays de l'échantillon, une proportion considérable de l'évo‐lution de l'écart de rémunération entre hommes et femmes reste inexpliquée par l'évolution de ce prix.
Tendencias de la brecha salarial de género en Europa. Análisis de factores asociados a los precios de las calificaciones
Authors: KAYA Ezgi
Published: September 2023

En este artículo se examinan las tendencias de la brecha salarial de género desde la perspectiva de la evolución de los rendimientos salariales de las competencias intelectuales (cognitivas e interpersonales) y físicas (fuerza y capa‐cidad motora). Tras analizar datos armonizados de seis países europeos y datos comparables de los Estados Unidos, se observan variaciones sustanciales en cuanto a la influencia de los precios de las calificaciones profesionales en la brecha salarial. Sin embargo, en todos los países de la muestra, una parte considerable de la variación de la disparidad salarial no puede explicarse por la evolución de los precios de las calificaciones.
Sindicatos y desigualdad de ingresos en una selección de países europeos
Authors: MONTEBELLO Roberta , SPITERI Jonathan , VON BROCKDORFF Philip
Published: September 2023

La relación entre la actividad sindical y la creciente desigualdad de ingresos observada en las economías avanzadas, a pesar de su ambigüedad teórica, se ha pasado por alto en los estudios empíricos. En este artículo se estima un modelo empírico para 26 países europeos entre 2005 y 2018, especificando la desigualdad de ingresos como una función de la tasa de densidad sindical, su valor al cuadrado y un conjunto de variables de control. El modelo se amplía con la inclusión de otras instituciones del mercado de trabajo para evaluar los efectos distributivos de la densidad sindical en toda la estructura institucional. Se observa una relación significativa y persistente, en forma de U invertida, entre densidad sindical y desigualdad de ingresos.
Comprehensive modular analyses of scar subtypes illuminate underlying molecular mechanisms and potential therapeutic targets
Authors: Liu Liang , Lu Lantian , Qiu Min , Han Ning , Dai Shijie , Shi Shuiping , He Shanshan , Zhang Jing , Yan Qingfeng , Chen Shuqing
Published: September 2023

Pathological scarring resulting from traumas and wounds, such as hypertrophic scars and keloids, pose significant aesthetic, functional and psychological challenges. This study provides a comprehensive transcriptomic analysis of these conditions, aiming to illuminate underlying molecular mechanisms and potential therapeutic targets. We employed a co‐expression and module analysis tool to identify significant gene clusters associated with distinct pathophysiological processes and mechanisms, notably lipid metabolism, sebum production, cellular energy metabolism and skin barrier function. This examination yielded critical insights into several skin conditions including folliculitis, skin fibrosis, fibrosarcoma and congenital ichthyosis. Particular attention was paid to Module Cluster (MCluster) 3, encompassing genes like BLK, TRPV1 and GABRD, all displaying high expression and potential implications in immune modulation. Preliminary immunohistochemistry validation supported these findings, showing elevated expression of these genes in non‐fibrotic samples rich in immune activity. The complex interplay of different cell types in scar formation, such as fibroblasts, myofibroblasts, keratinocytes and mast cells, was also explored, revealing promising therapeutic strategies. This study underscores the promise of targeted gene therapy for pathological scars, paving the way for more personalised therapeutic approaches. The results necessitate further research to fully ascertain the roles of these identified genes and pathways in skin disease pathogenesis and potential therapeutics. Nonetheless, our work forms a strong foundation for a new era of personalised medicine for patients suffering from pathological scarring.
Making Art Explicit: Knowledge, Reason and Art History in the Art and Design Curriculum
Authors: Walton Neil
Published: September 2023

Different and competing conceptions of knowledge have recently been the focus of debate in education, especially art education. The cognitive science conception of knowledge as information processing and storage in long‐term memory is especially prominent in educational policy. By contrast, within writing that is directly about art education, discussion of knowledge has often been framed in negative, terms, as reductive, as entailing the imposition of rigid subject content and as antithetical to art. Taking issue with both these contrasting views, and using a non‐empirical, philosophical approach, this article puts forward a case for the centrality of knowledge and reasoning within the art and design curriculum. Specifically, the article draws on inferentialism, a theory that has not previously been applied to art education. The argument presented understands art as discursive and rational, as concept using and reason sensitive, as essentially a disjunctive set of historical‐social practices. Art education is then best thought of as a rational‐critical introduction to knowing those practices, as making explicit their proprieties, entailments and contradictions and the choices that are thereby made possible. This view emphasises learning in art and design as developing increasing levels of responsibility and commitment by integrating concepts in practice and theory.
A Green Manifesto for Art, Craft and Design Education
Authors: Hall Emese
Published: September 2023

In the challenging – and frightening – times in which we now live, education is seen as playing a key role in making change for the better. However, the Department for Education's (2022) strategy on education for sustainability and climate change, applicable to schools in England, is lacking in many areas and fails to address students’, teachers’, and teacher educators’ priorities. Crucially, the environment and climate emergency greatly concerns many children and young people and these issues should be addressed across the whole curriculum, not just in geography and science. Further, there needs to be more focus on emotions rather than facts, wellbeing rather than the economy. So, the question is: How can we ‘green’ art, craft and design education to ensure it is both effective and affective? Art can change the world because it is ‘homeless, endless, and edgeless’ – this sounds exciting but does not aid teachers in curriculum design. In this paper I will share an emergent manifesto for an environmentally responsible art, craft and design (ACD) curriculum…
Comparative interaction patterns of groups in an open network environment: The role of facilitators in collaborative learning
Authors: Zhang Wenmei , Wang Cixiao
Published: September 2023

Background

Collaborative learning can effectively promote the development of higher‐order competencies, where learners collaborate via social interactions to explore and solve complex problems. It has been found that the effective occurrence of collaborative learning requires appropriate external guidance and support. In particular, collaborative interactions in open learning environments are more complex and difficult, which makes it important to provide dynamic interventions for learners according to different collaborative situations. However, the role of facilitators and the characteristics and mechanisms of their interventions have yet to be thoroughly investigated.

Objectives

The study aims to uncover the characteristics and patterns of interaction among groups with different collaborative performance and facilitator performance in an open learning environment, and to explore the differentiated role of facilitators in this process.

Method

Groups are categorised as high or low based on their collaborative performance and facilitator performance. This study used lag sequential analysis (LSA) and content analysis to explore the interaction patterns of groups with different collaborative performance and facilitator performance. Also, the different roles of facilitators were analysed by comparing the differences in interaction patterns of different collaborative performance groups.

Results

The study found that groups with different collaborative performances and facilitator performances showed significant differences in interaction patterns, and the two had crossover effects. There is also variability in the role of facilitators in groups with different collaborative performance profiles. Patterns of transition between different layers of interaction can indicate the level of groups' collaborative engagement. Specific interaction patterns exist that are conducive to enhancing collaborative learning.

Conclusions

The results of the study pointed out that groups with different collaborative performance and facilitator performance showed different characteristics of interaction patterns. The role of the facilitator in online collaborative learning is characterised by compensatory and merit‐promoting. High‐quality online collaboration is the result of multiple factors, including learners and facilitators working together. This study has practical implications for the design of instructional interventions for group collaboration in online learning communities.
RALF22 promotes plant immunity and amplifies the Pep3 immune signal
Authors: He Yu‐Han , Chen Song‐Yu , Chen Xing‐Yan , Xu You‐Ping , Liang Yan , Cai Xin‐Zhong
Published: September 2023

Rapid alkalinization factors (RALFs) in plants have been reported to dampen pathogen‐associated molecular pattern (PAMP)‐triggered immunity via suppressing PAMP‐induced complex formation between the pattern recognition receptor (PRR) and its co‐receptor BAK1. However, the direct and positive role of RALFs in plant immunity remains largely unknown. Herein, we report the direct and positive roles of a typical RALF, RALF22, in plant immunity. RALF22 alone directly elicited a variety of typical immune responses and triggered resistance against the devastating necrotrophic fungal pathogen Sclerotinia sclerotiorum in a FERONIA (FER)‐dependent manner. LORELEI (LRE)‐like glycosylphosphatidylinositol (GPI)‐anchored protein 1 (LLG1) and NADPH oxidase RBOHD were required for RALF22‐elicited reactive oxygen species (ROS) generation. The mutation of cysteines conserved in the C terminus of RALFs abolished, while the constitutive formation of two disulfide bridges between these cysteines promoted the RALF22‐elicited ROS production and resistance against S. sclerotiorum, demonstrating the requirement of these cysteines in the functions of RALF22 in plant immunity. Furthermore, RALF22 amplified the Pep3‐induced immune signal by dramatically increasing the abundance of PROPEP3 transcript and protein. Supply with RALF22 induced resistance against S. sclerotiorum in Brassica crop plants. Collectively, our results reveal that RALF22 triggers immune responses and augments the Pep3‐induced immune signal in a FER‐dependent manner, and exhibits the potential to be exploited as an immune elicitor in crop protection.