bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cri du chat syndrome patients have DNA methylation changes in genes linked to symptoms of the disease
Authors: Holland Petter , Wildhagen Mari , Istre Mette , Reiakvam Olaug Marie , Dahl John Arne , Søraas Arne 
Published: October 2022

Abstract
Background
Cri du chat (also called 5p deletion, or monosomy 5p) syndrome is a genetic disease caused by deletions of various lengths in the short (p) arm of chromosome 5. Genetic analysis and phenotyping have been used to suggest dose-sensitive genes in this region that may cause symptoms when a gene copy is lost, but the heterogeneity of symptoms for patients with similar deletions complicates the picture. The epigenetics of the syndrome has only recently been looked at with DNA methylation measurements of blood from a single patient, suggesting epigenetic changes in these patients. Here, we conduct the deepest epigenetic analysis of the syndrome to date with DNA methylation analysis of eight Cri du chat patients with sibling- and age-matched controls.

Results
The genome-wide patterns of DNA methylation in the blood of Cri du chat patients reveal distinct changes compared to controls. In the p-arm of chromosome 5 where patients are hemizygous, we find stronger changes in methylation of CpG sites than what is seen in the rest of the genome, but this effect is less pronounced in gene regulatory sequences. Gene set enrichment analysis using patient DNA methylation changes in gene promoters revealed enrichment of genes controlling embryonic development and genes linked to symptoms which are among the most common symptoms of Cri du chat syndrome: developmental delay and microcephaly. Importantly, this relative enrichment is not driven by changes in the methylation of genes on chromosome 5. CpG sites linked to these symptoms where Cri du chat patients have strong DNA methylation changes are enriched for binding of the polycomb EZH2 complex, H3K27me3, and H3K4me2, indicating changes to bivalent promoters, known to be central to embryonic developmental processes.

Conclusions
Finding DNA methylation changes in the blood of Cri du chat patients linked to the most common symptoms of the syndrome is suggestive of epigenetic changes early in embryonic development that may be contributing to the development of symptoms. However, with the present data we cannot conclude about the sequence of events between DNA methylation changes and other cellular functions—the observed differences could be directly driving epigenetic changes, a result of other epigenetic changes, or they could be a reflection of other gene regulatory changes such as changed gene expression levels. We do not know which gene(s) on the p-arm of chromosome 5 that causes epigenetic changes when hemizygous, but an important contribution from this work is making the pool of possible causative genes smaller.
An investigation of Plk1 PBD inhibitor KBJK557 as a tumor growth suppressor in non-small cell lung cancer
Authors: Gunasekaran Pethaiah , Lee Gong-Hyeon , Hwang Yeon Sil , Koo Bon-Chul , Han Eun Hee , Bang Guel , La Yeo Kyung , Park Sunghyun , Kim Hak Nam , Kim Mi-Hyun , Bang Jeong Kyu , Ryu Eun Kyoung 
Published: October 2022

AbstractLung cancer is the second most commonly reported type of cancer worldwide. Approximately 80–85% of lung cancer occurrences are accounted by non-small cell lung cancer (NSCLC). Polo-like kinase-1 (Plk1) plays multiple roles in cell cycle progression and its overexpression is observed in majority of malignancies, including NSCLC. A combination of frontline drugs and inhibitors targeting the Plk kinase domain (KD) has been used to overcome drug resistance in NSCLC. Plk1 KD inhibitors are highly prone to cross-reactivity with similar kinases, eventually leading to undesirable side effects. Moreover, there have been no reports of Plk1 PBD inhibitors showing antitumorigenic effects on NSCLC cells or animal models so far. To address this issue herein, for the first time, our recently reported Plk1 PBD inhibitor KBJK557 was evaluated for the anticancer potential against NSCLC cells. KBJK557 displayed notable cytotoxic effects in A549, PC9, and H1975 cells. Mechanistic investigations revealed that KBJK557-treated cells underwent G2/M cell cycle arrest, triggering subsequent apoptosis. In vivo antitumorigenic activity in xenograft mice model demonstrates that KBJK557-treated mice showed a considerable decrease in tumor size, proving the significances of Plk1 in lung cancer. Collectively, this study demonstrates that KBJK557 can serve as a promising drug candidate for treating the lung cancer through Plk1 PBD inhibition.
A state-of-the-art review of prestressed concrete tub girders for bridge structures
Authors: Wang Jun , Kim Yail J. 
Published: October 2022

AbstractThis paper presents a state-of-the-art review of prestressed concrete tub girders for bridge structures, which are a resilient solution to reduce the occurrence probability of disruptive events and to extend the longevity of built-environments. Technical parameters are categorized in accordance with physical characteristics and corresponding contents are examined. Unlike the case of box girders, the open-section tub girders demand secondary structural elements to improve stability. As far as application is concerned, pre- and post-tensioning methods are taken into account with a focus on the implications of geometric variables, on-site splice, and applied forces. The applicability of existing design provisions is also evaluated in the context of live load distributions and end zone cracking. While the strand size of 12.7 mm and 15.2 mm is dominant in the United States, research has commenced on the use of 17.8 mm strands to accommodate a high level of prestressing force. The effectiveness of precast decking panels is elaborated against conventional cast-in-place decks, and the extension of overhangs is delineated.
Inhibition of Glycogen Metabolism Induces Reactive Oxygen Species-Dependent Cytotoxicity in Anaplastic Thyroid Cancer in Female Mice
Authors: Davidson Cole D , Tomczak Jennifer A , Amiel Eyal , Carr Frances E 
Published: October 2022

AbstractAnaplastic thyroid cancer (ATC) is one of the most lethal solid tumors, yet there are no effective, long-lasting treatments for ATC patients. Most tumors, including tumors of the endocrine system, exhibit an increased consumption of glucose to fuel cancer progression, and some cancers meet this high glucose requirement by metabolizing glycogen. Our goal was to determine whether ATC cells metabolize glycogen and if this could be exploited for treatment. We detected glycogen synthase and glycogen phosphorylase (PYG) isoforms in normal thyroid and thyroid cancer cell lines and patient-derived biopsy samples. Inhibition of PYG using CP-91,149 induced apoptosis in ATC cells but not normal thyroid cells. CP-91,149 decreased NADPH levels and induced reactive oxygen species accumulation. CP-91,149 severely blunted ATC tumor growth in vivo. Our work establishes glycogen metabolism as a novel metabolic process in thyroid cells, which presents a unique, oncogenic target that could offer an improved clinical outcome.
Animal Models of Cushing's Syndrome
Authors: Nishiyama Mitsuru , Iwasaki Yasumasa , Makino Shinya 
Published: October 2022

AbstractEndogenous Cushing's syndrome is characterized by unique clinical features and comorbidities, and progress in the analysis of its genetic pathogenesis has been achieved. Moreover, prescribed glucocorticoids are also associated with exogenous Cushing's syndrome. Several animal models have been established to explore the pathophysiology and develop treatments for Cushing's syndrome. Here, we review recent studies reporting animal models of Cushing's syndrome with different features and complications induced by glucocorticoid excess. Exogenous corticosterone (CORT) administration in drinking water is widely utilized, and we found that CORT pellet implantation in mice successfully leads to a Cushing's phenotype. Corticotropin-releasing hormone overexpression mice and adrenal-specific Prkar1a-deficient mice have been developed, and AtT20 transplantation methods have been designed to examine the medical treatments for adrenocorticotropic hormone–producing pituitary neuroendocrine tumors. We also review recent advances in the molecular pathogenesis of glucocorticoid-induced complications using animal models.
New insights into FAK structure and function in focal adhesions
Authors: Le Coq Johanne , Acebrón Iván , Rodrigo Martin Bárbara , López Navajas Pilar , Lietha Daniel 
Published: October 2022

ABSTRACT
Focal adhesion kinase (FAK; also known as PTK2) was discovered three decades ago and is now recognised as a key player in the regulation of cell–matrix adhesion and mesenchymal cell migration. Although it is essential during development, FAK also drives invasive cancer progression and metastasis. On a structural level, the basic building blocks of FAK have been described for some time. However, a picture of how FAK integrates into larger assemblies in various cellular environments, including one of its main cellular locations, the focal adhesion (FA) complex, is only beginning to emerge. Nano-resolution data from cellular studies, as well as atomic structures from reconstituted systems, have provided first insights, but also point to challenges that remain for obtaining a full structural understanding of how FAK is integrated in the FA complex and the structural changes occurring at different stages of FA maturation. In this Review, we discuss the known structural features of FAK, the interactions with its partners within the FA environment on the cell membrane and propose how its initial assembly in nascent FAs might change during FA maturation under force.
Information Design for Congested Social Services: Optimal Need-Based Persuasion
Authors: Anunrojwong Jerry , Iyer Krishnamurthy , Manshadi Vahideh 
Published: October 2022

We study the effectiveness of information design in reducing congestion in social services catering to users with varied levels of need. In the absence of price discrimination and centralized admission, the provider relies on sharing information about wait times to improve welfare. We consider a stylized model with heterogeneous users who differ in their private outside options: low-need users have an acceptable outside option to the social service, whereas high-need users have no viable outside option. Upon arrival, a user decides to wait for the service by joining an unobservable first-come-first-serve queue, or leave and seek her outside option. To reduce congestion and improve social outcomes, the service provider seeks to persuade more low-need users to avail their outside option, and thus better serve high-need users. We characterize the Pareto-efficient signaling mechanisms and compare their welfare outcomes against several benchmarks. We show that if either type is the overwhelming majority of the population, then information design does not provide improvement over sharing full information or no information. On the other hand, when the population is sufficiently heterogeneous, information design not only Pareto-dominates full-information and no-information mechanisms, in some regimes it also achieves the same welfare as the “first-best,” that is, the Pareto-efficient centralized admission policy with knowledge of users’ types. This paper was accepted by Gabriel Weintraub, revenue management and market analytics. Funding: This work was supported by the National Science Foundation, Division of Civil, Mechanical and Manufacturing Innovation [Grants CMMI-2002155 and CMMI-2002156]. Supplemental Material: The data and e-companion are available at https://doi.org/10.1287/mnsc.2022.4548 .
Multi-Depot Routing with Split Deliveries: Models and a Branch-and-Cut Algorithm
Authors: Gouveia Luis , Leitner Markus , Ruthmair Mario 
Published: October 2022

We study the multi-depot split-delivery vehicle routing problem (MDSDVRP) that combines the advantages and potential cost savings of multiple depots and split deliveries and develop the first exact algorithm for this problem. We propose an integer programming formulation using a small number of decision variables and several sets of valid inequalities. These inequalities focus on ensuring the vehicles’ capacity limits and that vehicles return to their initial depot. As we show that the new constraints do not guarantee these aspects, our branch-and-cut framework also includes an efficient feasibility check for candidate solutions and explicit feasibility cuts. The algorithm that also uses a comparably simple, yet effective heuristic to compute high-quality initial solutions is tested on the MDSDVRP and two well-known special cases, the split-delivery vehicle routing problem (SDVRP) and the multi-depot traveling salesman problem (MDTSP). The results show that the new inequalities tighten the linear programming relaxation, increase the performance of the branch-and-cut algorithm, and reduce the number of required feasibility cuts. We report the first proven optimal results for the MDSDVRP and show that our algorithm significantly outperforms the state-of-the-art for the MDTSP while being competitive on the SDVRP. For the latter, 20 instances are solved for the first time, and new best primal and dual bounds are found for others. Funding: This work was supported by the Fundação para a Ciência e a Tecnologia [Project UIDB/04561/2020]. Supplemental Material: The online appendix is available at https://doi.org/10.1287/trsc.2022.1179 .
The effect of photomodulation on fibroblast growth factor and the Ras/MAPK signalling pathway: a review
Authors: Kasowanjete Patricia , Houreld Nicolette N , Abrahamse Heidi 
Published: October 2022

Objective: Current therapies and technologies used to treat hard-to-heal diabetic wounds are limited to a 50% healing rate. The rise in the percentage of lower limb non-traumatic amputations in patients with diabetes has caused an increased demand for alternative, effective and safe treatment modalities. Photobiomodulation therapy (PBMT) utilises light to induce physiological changes and provide therapeutic benefits and has been shown to increase the healing of hard-to-heal wounds through the release of growth factors. The aim of this narrative review is to investigate the effect of photobiomodulation (PBM) on fibroblast growth factor (FGF) and the role of the Ras/MAPK signalling pathway in diabetic wound healing. Method: Relevant journal articles were obtained through PubMed and Google Scholar. Results: Experimental and clinical findings from the review show that PBM can stimulate the release of growth factors, including FGF, an essential cytokine in wound healing, and one which is present at lower concentrations in diabetic wounds. There is also activation of the Ras/MAPK signalling pathway. Conclusion: One mechanism through which healing may be stimulated by PBM is via the FGF-Ras/MAPK signalling pathway, although strong evidence under hyperglycaemic conditions is lacking.
Determination of the effectiveness of Dorema ammoniacum gum on wound healing: an experimental study
Authors: Siahpoosh Amir , Malayeri Alireza , Salimi Anayatollah , Khorsandi Layasadat , Abdevand Zeinab Zaheri 
Published: October 2022

Objective: For a long time, natural compounds have been used to accelerate wound healing. In this study, the topical effects of ammoniacum gum extract on wound healing were investigated in white male rats. Method: Following skin wound induction in aseptic conditions, 48 Wistar rats were divided into six equal groups; phenytoin cream 1% (standard), untreated (control), Eucerin (control), and 5%, 10% and 20% ointments of Dorema ammoniacum gum extract (treatment groups). All experimental groups received topical drugs daily for 14 days. The percentage of wound healing, hydroxyproline content, histological parameters, and growth factors (endothelial growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-α) were measured in experimental groups. Results: The areas of the wounds in the treatment groups were significantly decreased compared with the wound areas of control groups at 5, 7 and 10 days after wounding. On the 12th day, the wounds in the treatment groups were completely healed. Hydroxyproline contents were significantly increased in the treatment groups compared with the control groups (p<0.001). In histological evaluation, the re-epithelialisation, increasing thickness of the epithelial layer, granulation tissue and neovascularisation parameters in the treatment groups showed significant increases compared with the control groups. Also, serum levels of TGF-β, PDGF, EGF and VEGF in the treatment groups were significantly increased compared to the control groups. Conclusion: The topical application of ammoniacum gum extract significantly increases the percentage of wound healing in rats and reduces the time of wound closure.
Women in trauma and orthopaedics: are we losing them at the first hurdle?
Authors: Malik-Tabassum K , Lamb JN , Seewoonarain S , Ahmed M , Normahani P , Pandit H , Aderinto J , Rogers B 
Published: October 2022

Introduction Diversity in the healthcare workforce is associated with improved performance and patient-reported outcomes. Gender disparity in Trauma and Orthopaedics (T&O) is well recognised. The aim of this study was to compare factors that influence career choice in T&O between male and female final-year students. Furthermore, the trend of representation of women in T&O over the last decade was also compared with other surgical specialities. Methods An online survey of final-year students who attended nationally advertised T&O courses over a 2-year period was conducted. Data from NHS digital was obtained to assess gender diversity in T&O compared with other surgical specialities. Results A total of 414 students from 13 UK medical schools completed the questionnaire. Compared with male students (34.2%), a significantly higher proportion of women (65.8%) decided against a career in T&O, p<0.001. Factors that dissuaded a significantly higher percentage of women included gender bias, technical aspects of surgery, unsociable hours, on-call commitments, inadequate undergraduate training and interest in another specialty (p<0.05). Motivating factors for choosing a career in T&O were similar between both sexes. T&O was the surgical specialty with the lowest proportion of women at both consultant and trainee level over the last decade. Conclusion T&O remains an unpopular career choice among women. To enhance recruitment of women in T&O, future strategies should be directed toward medical students. Universities, orthopaedic departments and societies must work collaboratively to embed culture change, improve the delivery of the undergraduate curriculum, and facilitate students’ exposure to operating theatres and female role models.
Use of radiological information system data in Clinical Portal database to screen for missed abdominal aortic aneurysms
Authors: Lu C , Gordon AC , Murphy P , Sicely L , Aiono S 
Published: October 2022

Introduction New Zealand lacks a formal abdominal aortic aneurysm screening programme and owing to its rural nature, many patients have limited access to vascular surgery. Patients with vascular emergencies often have limited treatment options locally, especially if they present perimortem. In our small hospital in Whanganui, with the nearest vascular centre more than 150km away, there are cases of aneurysms diagnosed incidentally on radiology reporting but lost to follow-up. Methods Clinical Portal (CP) is a widely used patient-centred dashboard for viewing health information that is managed by Orion Health. A search strategy utilising the CP common database was devised that aimed to find aneurysms which were not followed up. This search was performed retrospectively for all imaging within a 5-month period. Results Some 294 scans were flagged and 53 patients with aneurysms were found. Of these patients, 36 had follow-up by the ordering provider and 17 (32%) were found to have been lost to follow-up. Conclusions Our pilot study demonstrated high rates of loss to follow-up and a lack of communication of important health information across multiple health disciplines in the region, and represents a potential method for identifying ‘lost’ aneurysms. For patients in rural communities, this may be critical to preventing future complications from aneurysmal disease.
Entrepreneurial thinking: the politics and practice of policy impact
Authors: Flinders Matthew 
Published: October 2022

Background:This comment piece responds to points raised by Steve Johnson in ‘The policy impact of entrepreneurship research: challenging received wisdom’ (Johnson, 2022).
Aims and objectives:To build upon the intellectual foundations that Johnson has provided so expertly and to continue the debate through a focus on two issues – problem definition, and the need for continuing criticality.
Methods:Commentary.
Findings: Johnson stimulates a debate not just about the past, present and future of entrepreneurship research but about the science-society nexus more generally.
Discussion and conclusion:Taken together, the issues of problem definition, and the need for continuing criticality, highlight ‘the politics of policy impact’ and have direct implications for how academics, in general, and entrepreneurship researchers, in particular, face the emerging research, innovation and development ecosystem.
The feasibility of SARS-CoV-2 surveillance using wastewater and environmental sampling in Indonesia
Authors: Murni Indah K. , Oktaria Vicka , Handley Amanda , McCarthy David T. , Donato Celeste M. , Nuryastuti Titik , Supriyati Endah , Putri Dwi Astuti Dharma , Sari Hendri Marinda , Laksono Ida Safitri , Thobari Jarir At , Bines Julie E. 
Published: October 2022

Background
Wastewater-based epidemiology (WBE) surveillance as an early warning system (EWS) for monitoring community transmission of SARS-CoV-2 in low- and middle-income country (LMIC) settings, where diagnostic testing capacity is limited, needs further exploration. We explored the feasibility to conduct a WBE surveillance in Indonesia, one of the global epicenters of the COVID-19 pandemic in the middle of 2021, with the fourth largest population in the world where sewer and non-sewered sewage systems are implemented. The feasibility and resource capacity to collect samples on a weekly or fortnightly basis with grab and/or passive sampling methods, as well as to conduct qualitative and quantitative identification of SARS-CoV-2 ribonucleic acid (RNA) using real-time RT-PCR (RT-qPCR) testing of environmental samples were explored.

Materials and methods
We initiated a routine surveillance of wastewater and environmental sampling at three predetermined districts in Special Region of Yogyakarta Province. Water samples were collected from central and community wastewater treatment plants (WWTPs), including manholes flowing to the central WWTP, and additional soil samples were collected for the near source tracking (NST) locations (i.e., public spaces where people congregate).

Results
We began collecting samples in the Delta wave of the COVID-19 pandemic in Indonesia in July 2021. From a 10-week period, 54% (296/544) of wastewater and environmental samples were positive for SARS-CoV-2 RNA. The sample positivity rate decreased in proportion with the reported incidence of COVID-19 clinical cases in the community. The highest positivity rate of 77% in week 1, was obtained for samples collected in July 2021 and decreased to 25% in week 10 by the end of September 2021.

Conclusion
A WBE surveillance system for SARS-CoV-2 in Indonesia is feasible to monitor the community burden of infections. Future studies testing the potential of WBE and EWS for signaling early outbreaks of SARS-CoV-2 transmissions in this setting are required.