bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolutionary constraint genes implicated in autism spectrum disorder across 2,054 nonhuman primate genomes
Authors: Kikuchi Yukiko , Uddin Mohammed , Veltman Joris A. , Wells Sara , Woodbury-Smith Marc 
Published: November 2023

AbstractBackgroundSignificant progress has been made in elucidating the genetic underpinning of Autism Spectrum Disorder (ASD). This childhood-onset chronic disorder of cognition, communication and behaviour ranks among the most severe from a public health perspective, and it is therefore hoped that new discoveries will lead to better therapeutic options. However, there are still significant gaps in our understanding of the link between genomics, neurobiology and clinical phenotype in scientific discovery. New models are therefore needed to address these gaps. Rhesus macaques (Macaca mulatta) have been extensively used for preclinical neurobiological research because of remarkable similarities to humans across biology and behaviour that cannot be captured by other experimental animals.MethodsWe used the macaque Genotype and Phenotype (mGAP) resource (v2.0) consisting of 2,054 macaque genomes to examine patterns of evolutionary constraint in known human neurodevelopmental genes. Residual variation intolerance scores (RVIS) were calculated for all annotated autosomal genes (N = 18,168) and Gene Set Enrichment Analysis (GSEA) was used to examine patterns of constraint across ASD genes and related neurodevelopmental genes.ResultsWe demonstrated that patterns of constraint across autosomal genes are correlated in humans and macaques, and that ASD-implicated genes exhibit significant constraint in macaques (p= 9.4 x 10-27). Among macaques, many key ASD genes were observed to harbour predicted damaging mutations. A small number of key ASD genes that are highly intolerant to mutation in humans, however, showed no evidence of similar intolerance in macaques (CACNA1D,CNTNAP2,MBD5,AUTS2andNRXN1). Constraint was also observed across genes implicated in intellectual disability (p= 1.1 x 10-46), epilepsy (p= 2.1 x 10-33) and schizophrenia (p= 4.2 x 10-45), and for an overlapping neurodevelopmental gene set (p= 4.0 x 10-10)LimitationsThe lack of behavioural phenotypes among the macaques whose genotypes were studied means that we are unable to further investigate whether genetic variants have similar phenotypic consequences among nonhuman primates.ConclusionThe presence of pathological mutations in ASD genes among macaques, and the evidence of similar constraints in these genes to humans, provide a strong rationale for further investigation of genotype-phenotype relationships in nonhuman primates. This highlights the importance of identifying phenotypic behaviours associated with clinical symptoms, elucidating the neurobiological underpinnings of ASD, and developing primate models for translational research to advance approaches for precision medicine and therapeutic interventions.
Combinatorial CRISPR screen revealsFYNandKDM4as targets for synergistic drug combination for treating triple negative breast cancer
Authors: Kim Tackhoon , Park Byung-Sun , Heo Soobeen , Jeon Heeju , Kim Jaeyeal , Kim Donghwa , Lee Sang Kook , Jung So-Youn , Kong Sun-Young , Lu Timothy K. 
Published: November 2023

AbstractTyrosine kinases play a crucial role in cell proliferation and survival and are extensively investigated as targets for cancer treatment. However, the efficacy of most tyrosine kinase inhibitors (TKIs) in cancer therapy is limited due to resistance. In this study, we identify a synergistic combination therapy involving TKIs for the treatment of triple negative breast cancer. By employing pairwise tyrosine kinase knockout CRISPR screens, we identifyFYNandKDM4as critical targets whose inhibition enhances the effectiveness of TKIs, such as NVP-ADW742 (IGF-1R inhibitor), gefitinib (EGFR inhibitor), and imatinib (ABL inhibitor) bothin vitroandin vivo. Mechanistically, treatment with TKIs upregulates the transcription ofKDM4, which in turn demethylates H3K9me3 atFYNenhancer forFYNtranscription. This compensatory activation ofFYNandKDM4contributes to the resistance against TKIs.FYNexpression is associated with therapy resistance and persistence by demonstrating its upregulation in various experimental models of drug-tolerant persisters and residual disease following targeted therapy, chemotherapy, and radiotherapy. Collectively, our study provides novel targets and mechanistic insights that can guide the development of effective combinatorial targeted therapies, thus maximizing the therapeutic benefits of TKIs.
Cohesin complex oligomerization maintains end-tethering at DNA double-strand breaks
Authors: Phipps Jamie , Toulouze Mathias , Ducrot Cécile , Costa Rafaël , Brocas Clémentine , Dubrana Karine 
Published: November 2023

AbstractDNA double-strand breaks (DSB) must be repaired to ensure genome stability. Crucially, DSB ends must be kept together for timely repair. InSaccharomyces cerevisiae, two poorly understood pathways mediate DSB end-tethering. One employs the Mre11-Rad50-Xrs2 (MRX) complex to physically bridge DSB ends. Another requires the conversion of DSB ends into single-strand DNA (ssDNA) by Exo1, but the bridging proteins are unknown. We uncover that cohesin, its loader and Smc5/6 act with Exo1 to tether DSB ends. Remarkably, cohesin specifically impaired in oligomerization fails to tether DSB ends, revealing a new function for cohesin oligomerization. In addition to the known importance of sister chromatid cohesion, microscopy-based microfluidic experiments unveil a new role for cohesin in repair by ensuring DSB end-tethering. Altogether, our findings demonstrate that oligomerization of cohesin prevents DSB end separation and promotes DSB repair, revealing a novel mode of action and role for cohesin in safeguarding genome integrity.
A BCG Skin Challenge Model for Assessing TB Vaccines
Authors: Krishnan Nitya , Priestman Miles , Uhía Iria , Charitakis Natalie , Glegola-Madejska Izabella T , Baer Thomas M. , Tranberg Albin , Faraj Alan , Simonsson Ulrika SH , Robertson Brian D. 
Published: November 2023

AbstractControlled Human infection models (CHIM) are valuable tools for assessing relevant biological activity in vaccine candidates, with the potential to accelerate Tuberculosis vaccine development into the clinic. Tuberculosis infection poses significant constraints on the design of a CHIM using the causative agentMycobacterium tuberculosis. As a safer alternative, we propose a challenge model using the attenuated vaccine agentMycobacterium bovisBCG as a surrogate forMycobacterium tuberculosis,and intradermal (skin) challenge as an alternative to pulmonary infection. We have developed a unique non-invasive imaging system based on fluorescent reporters to quantitatively measure bacterial load over time, thereby determining a relevant biological vaccine effect. We assessed the utility of this model to measure the effectiveness of two TB vaccines: the currently licenced BCG and a novel subunit vaccine candidate. To assess the efficacy of the skin challenge model a pharmacometric model was built describing the decline of fluorescence over time. The results show that vaccination is a statistically significant factor which reduced the fluorescence readout of both fluorophores. The higher decline in vaccinated mice correlated with bacterial burden in the lungs. This supports the fluorescence output from the skin as a reflection of vaccine induced functional pulmonary immune responses. This novel non-invasive approach allows for repeated measurements from the challenge site, providing a dynamic readout of vaccine induced responses over time. This BCG skin challenge model represents an important contribution to the ongoing development of controlled challenge models for Tuberculosis.
APC/C prevents non-canonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest
Authors: Mouery Brandon L , Baker Eliyambuya M , Mills Christine A , Herring Laura E , Fleifel Dalia , Cook Jeanette Gowen 
Published: November 2023

AbstractRegulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase APC/C (anaphase promoting complex/cyclosome), although the APC/C substrates whose degradation restrains G1-S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear if APC/C maintains all types of arrest. Here by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological CDK4/6 inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves cyclin-dependent kinases acting in an atypical order to inactivate RB-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability.SignificanceAppropriate stable cell cycle arrest is critical to prevent cancer. However, it is not well-understood how cells maintain arrest. It is known that arrest requires repressing proliferation-stimulating genes, but the role of targeted protein degradation is unclear. This work demonstrates that continuous degradation of cyclin A through the action of the anaphase promoting complex/cyclosome (APC/C) is required to maintain arrest induced by a cancer drug that blocks cell cycle kinase enzymes. APC/C activity is required to prevent cell cycle re-entry. Impaired APC/C activity causes arrest bypass, inefficient DNA replication, and ultimately long-term proliferation defects. These results suggest that the activity level of the APC/C in tumors may profoundly influence the response to drugs that target cell cycle kinases.
Detecting skewed pricing in tenders for public-sector projects
Authors: Hyari Khaled Hesham , Thneibat Mujahed 
Published: November 2023

Purpose
Skewed pricing is a typical tactic used by tenderers in unit price projects to gain additional advantages at the expense of the owner or other competing tenderers. This paper aims to describe the development of a model for detecting skewed pricing in competitive tendering for unit price contracts.

Design/methodology/approach
The model evaluates how much the offered unit rates for work items deviate from the reasonable rate identified from the item’s submitted unit rates. Item rate deviations are integrated into a total deviation score for each submitted tender based on the relative weight of the work item to the total project amount. The model allows for assigning higher weights to work items that are more prone to skewed pricing, such as those that are performed early and those that are expected to experience quantity fluctuations.

Findings
The paper presents a detection model that uses only the submitted prices of the competing tenderers to perform the needed calculations, which reduces subjectivity in identifying skewed tenders. Two examples are given to demonstrate how the model may be used to detect skewed tenders.

Originality/value
The model supports tendering officials in the challenging task of identifying skewed tenders, which is required by rules and regulations governing public procurement. The model’s ease of use is expected to make it more widely used as a decision-support tool during the tender evaluation stage of real-world projects.
Advancing “no natural disasters” with care: risks and strategies to address disasters as political phenomena in conflict zones
Authors: Mena Rodrigo 
Published: November 2023

PurposeThe notion that disasters are not natural is longstanding, leading to a growing number of campaigns aimed at countering the use of the term “natural disaster.” Whilst these efforts are crucial, critical perspectives regarding the potential risks associated with this process are lacking, particularly in places affected by violent conflict. This paper aims to present a critical analysis of these efforts, highlighting the need to approach them with care.Design/methodology/approachThe author draws upon insights and discussions accumulated over a decade of research into the relationship between disasters and conflict. The article includes a critical literature review on the disaster–conflict relationship and literature specifically addressing the idea that disasters are not natural. The analysis of field notes led to a second literature review covering topics such as (de) politicisation, instrumentalisation, disaster diplomacy, ethics, humanitarian principles, disaster risk reduction, peacebuilding and conflict sensitivity.FindingsThis analysis underscores the importance of advocating that disasters are not natural, especially in conflict-affected areas. However, an uncritical approach could lead to unintended consequences, such as exacerbating social conflicts or obstructing disaster-related actions. The article also presents alternatives to advance the understanding that disasters are not natural whilst mitigating risks, such as embracing a “do-no-harm” approach or conflict-sensitive analyses.Originality/valueThe author offers an innovative critical approach to advancing the understanding that disasters are not natural but socio-political. This perspective is advocated, especially in conflict-affected contexts, to address the root causes of both disasters and conflicts. The author also invites their peers and practitioners to prioritise reflective scholarship and practices, aiming to prevent the unintentional exacerbation of suffering whilst working towards its reduction.
An approach for the estimation of lateral track irregularity using axle-box acceleration
Authors: Xu Xiaodi , Sun Shanchao , Fei Yang , Niu Liubin , Tian Xinyu , Ke Zaitian , Dai Peng , Liang Zhiming 
Published: November 2023

PurposeThis article aims to predict the rapid track geometry change in the short term with a higher detection frequency, and realize the monitoring and maintenance of the railway state.Design/methodology/approachFirstly, the ABA data needs to be filtered to remove the DC component to reduce the drift due to integration. Secondly, the quadratic integration in frequency domain for concern components of the vertical and lateral ABA needs to be done. Thirdly, the displacement in lateral of the wheelset to rail needs to be calculated. Then the track alignment irregularity needs to be calculated by the integration of lateral ABA and the lateral displacement of the wheelset to rail.FindingsBy comparing with a commercial track geometry measurement system, the high-speed railway application results in different conditions, after removal of the influence of LDWR, identified that the proposed method can produce a satisfactory result.Originality/valueThis article helps realize detection of track irregularity on operating vehicle, reduce equipment production, installation and maintenance costs and improve detection density.
Biorthogonal flatlet multiwavelet collocation method for solving the singular nonlinear system with initial and boundary conditions
Authors: Mohseni Maryam , Rostamy Davood 
Published: November 2023

PurposeThe numerical methods are of great importance for approximating the solutions of a system of nonlinear singular ordinary differential equations. In this paper, the authors present the biorthogonal flatlet multiwavelet collocation method (BFMCM) as a numerical scheme for a class of system of Lane–Emden equations with initial or boundary or four-point boundary conditions.Design/methodology/approachThe approach is involved in combining the biorthogonal flatlet multiwavelet (BFM) with the collocation method. The authors investigate the properties and procedure of the BFMCM for first time on this class of equations. By using the BFM and the collocation points, the method is constructed and it transforms the nonlinear differential equations problem into a system of nonlinear algebraic equations. The unknown coefficients of the assuming solution are determined by solving the obtained system. Additionally, convergence analysis and numerical stability of the suggested method are provided.FindingsAccording to the attained results, the proposed BFMCM has more accurate results in comparison with results of other methods. The maximum absolute errors are calculated by using the BFMCM for comparison purposes provided.Originality/valueThe key desirable properties of BFMCM are its efficiency, simple applicability and minimizes errors. Therefore, the proposed method can be used to solve nonlinear problems or problems with singular points.
The impact of multidisciplinary program requirements on student attitudes toward sustainability and education for sustainability
Authors: Pennell Natasha , Sabau Gabriela 
Published: November 2023

Purpose
This paper aims to investigate the role of multidisciplinary course requirements in shaping student attitudes toward sustainability and education for sustainable development. Previous research indicates that students conceptualize sustainability based on their academic discipline; thus, this research investigates whether there is a difference in student attitudes toward sustainability at Grenfell Campus, Memorial University of Newfoundland, where students are encouraged to cross the borders of their academic disciplines.

Design/methodology/approach
This research reports on the findings from a mixed-methods study to assess the impact of program requirements on student attitudes toward sustainability and education for sustainable development at Grenfell Campus, Memorial University of Newfoundland. In phase one, an anonymous survey was administered to students regarding their perceptions and attitudes toward sustainability and education for sustainable development. The survey yielded 100 usable responses. Phase 2 consisted of a series of 10 semi-structured expert interviews with key faculty and staff at Grenfell Campus and a representative from the City of Corner Brook, which gave further insights regarding sustainability programming and campus culture.

Findings
Contrary to previous research, the results of this research indicate that the School of Study does not have a statistically significant impact on student attitudes toward sustainability. This may be attributed to Grenfell Campus’s Breadth of Knowledge requirement within the School of Arts and Social Science and the School of Science and the Environment, which requires that students take elective courses from a broad range of subject matter to develop their holistic awareness of social, cultural, scientific and political issues.

Practical implications
The results of this research indicate that students who are exposed to broad multidisciplinary requirements may be more likely to have positive attitudes toward sustainability than students who focus on a single discipline.

Originality/value
A limited number of studies investigate the impact of core program requirements on student attitudes toward sustainability. This paper promotes an effective way of raising sustainability-literate young people/citizens in a Canadian higher education context.
Exploring new product development team problem-solving creativity in the base of the pyramid B2B firms
Authors: Getnet Hailu , O’Cass Aron , Siahtiri Vida , Ahmadi Hormoz 
Published: November 2023

Purpose
This study aims to investigate the role of team problem-solving creativity in new product development (NPD) in the bottom-of-the-pyramid (BoP) in business-to-business firms. This study synthesizes perspectives from NPD, creativity and leadership to examine how work-related factors such as NPD managers’ role ambiguity and individual-related factors such as CEO’s ambidextrous leadership style interact to determine team problem-solving creativity and its effect on new product performance (NPP).

Design/methodology/approach
The hypotheses are tested using data from a multi-informant survey of 274 middle-level managers within 137 local BoP manufacturing firms in a sub-Saharan African country.

Findings
The results show that an NPD team’s ability to solve problems creatively determines NPP in BoP markets. The findings also show that NPD managers’ role ambiguity has a negative effect on team problem-solving creativity. However, a CEO’s ambidextrous leadership neutralizes the negative impact of role ambiguity on problem-solving creativity.

Originality/value
This study combines three distinct streams of literature, including NPD, creativity and leadership, to explore the antecedents and outcomes of problem-solving creativity. Drawing on creativity and leadership theories, this study reports that the success of creative idea exchanges depends heavily on a supportive environment for NPD team members and minimizing the NPD manager’s role ambiguity.
Customer value creation and Moroccan hotels' performance: a multi-party and multi-phase vision
Authors: Nejjari Ridouan , Slaoui Samira 
Published: November 2023

PurposeThis study examines the impact of customer value creation on hotel performance. Customer value is seen as a multi-phase and multi-party process that combines hotel and tourist perspectives while also integrating the participation of frontline employees. The study also investigates financial performance (FP) and customer-based performance (CBP).Design/methodology/approachData were collected from Morocco through multiple-informant design surveys to explore three perspectives related to three actors involved in the process, that is, the managers, the employees and the tourists. The hypotheses were tested with SmartPLS4.FindingsThe findings reveal that customer value positively and significantly impacts not only the FP of hotels but also the CBP. The results highlight a sequential relationship in which each actor drives the subsequent phase to definitively enhance the hotel's performance. The results further show significant mediation effects in the customer value sequence. Moreover, the results show a significant and positive effect of CBP on FP.Research limitations/implicationsTheoretical and managerial implications of the research are discussed and future important researches are drawn from the study limitations.Practical implicationsManagers must be aware that frontline employees and guests are crucial for creating customer value, which enables to improve their performance. The results highlight that hotels should motivate and involve frontline employees in value propositions (VP) development. Furthermore, the guests are the final arbiters of value who drive hotels' performance. Moreover, for additional FP, managers are required both to deliver superior value and create loyal customers.Originality/valueThis study mostly confirms previous findings and highlights a sequential relationship among three phases involving three actors of customer value. However, it reveals more reasonable and robust results in the mediation effect of the value offering (VO) between the VP and the perceived value-in-use (PVI). This study is also the first to provide evidence on the mediation effect of the PVI between the VO and the CBP.