bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of Tumor Necrosis Factor-Alpha in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease
Authors: Vachliotis Ilias D. , Polyzos Stergios A.
Published: July 2023

Purpose of Review

To summarize experimental and clinical evidence on the association between tumor necrosis factor-α (TNF-α) and nonalcoholic fatty liver disease (NAFLD) and discuss potential treatment considerations.

Recent Findings

Experimental evidence suggests that TNF-α is a cytokine with a critical role in the pathogenesis of NAFLD. Although, the production of TNF-α may be an early event during the course of nonalcoholic fatty liver (NAFL), TNF-α may play a more substantial role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and NAFLD-associated fibrosis. Moreover, TNF-α may potentiate hepatic insulin resistance, thus interconnecting inflammatory with metabolic signals and possibly contributing to the development of NAFLD-related comorbidities, including cardiovascular disease, hepatocellular carcinoma, and extra-hepatic malignancies. In clinical terms, TNF-α is probably associated with the severity of NAFLD; circulating TNF-α gradually increases from controls to patients with NAFL, and then, to patients with NASH. Given this potential association, various therapeutic interventions (obeticholic acid, peroxisome proliferator-activated receptors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, probiotics, synbiotics, rifaximin, vitamin E, pentoxifylline, ursodeoxycholic acid, fibroblast growth factor-21, n-3 polyunsaturated fatty acids, statins, angiotensin receptor blockers) have been evaluated for their effect on TNF-α and NAFLD. Interestingly, anti-TNF biologics have shown favorable metabolic and hepatic effects, which may open a possible therapeutic window for the management of advanced NAFLD.

The potential key pathogenic role of TNF-α in NAFLD warrants further investigation and may have important diagnostic and therapeutic implications.
Examining Motivation of First-Year Undergraduate Anatomy Students Through the Lens of Universal Design for Learning (UDL): A Single Institution Study
Authors: Dempsey Audrey M. K. , Nolan Yvonne M. , Lone Mutahira , Hunt E.
Published: July 2023

Motivation is critical for meaningful learning among healthcare students studying anatomy. Learners are highly variable, and it is important to ensure learners are equally supported in the diverse aspects of an anatomy curriculum. The implementation of the educational framework, Universal Design for Learning (UDL), in anatomy curricula could potentially enhance student motivation. The multiple means of engagement principle of UDL refers to the enhancement of motivation among students. This study aimed to identify healthcare students’ motivation levels at the start and end of their anatomy module and whether there was any change in motivation. The Motivated Strategies for Learning Questionnaire (MSLQ) was distributed to gather the self-reported motivation levels of first-year undergraduate medical, dental and occupational therapy (OT) and speech and language therapy (SLT) students studying anatomy at the start of their respective anatomy modules and again at the end of the module. The overall response rate was 74% and 69%, at the start and end of the study, respectively. Responses were analysed by the respective programme of study. Motivation to study anatomy among medical, dental, OT and SLT students ranged from medium to high on the MSLQ at the start of their respective anatomy modules. By the end of the anatomy modules, dental students reported high levels of motivation to study anatomy, whereas motivation among medical, OT and SLT students ranged from medium to high. A change in students’ self-reported motivation levels while studying anatomy was identified. The study emphasises the benefits of UDL and its flexible nature to enhance motivation.
Fixing the Problem of Unlawfully Appointed Judges in Poland in the Light of the ECHR
Authors: Szwed Marcin
Published: July 2023

This article seeks to answer the question of how to deal with the problem of unlawful judicial appointments in Poland in a way consistent with the European Convention on Human Rights (ECHR). According to the Polish Constitution, appointments of judges are made upon the request of the National Council of the Judiciary (NCJ). After controversial reforms in 2017, this body lost its independence from politicians. In the four judgments issued so far, the European Court of Human Rights (ECtHR) ruled that appointments of Supreme Court judges made upon the request of politicised NCJ were burdened with manifest violation of domestic law and, as a result, panels of courts composed of persons appointed in this way were not ‘tribunal established by law’. Arguably, this conclusion may be extended to other judges appointed in the same way. The question remains, however, what to do with persons appointed with violation of law; in particular, whether such persons can simply be removed from the judiciary. This article argues that even though the domestic authorities have some discretion with regards to choosing the proper measures to fix the problem of unlawfully appointed judges, this is limited by the need to comply with the standards stemming from the ECHR. In particular, it is important to respect unlawfully appointed persons’ right to court. This means that instead of removing all of them without any judicial review, a more individualised approach would be preferable.
Requiring Mobile Devices in the Classroom: the Use of Web-Based Polling Does Not Lead to Increased Levels of Distraction
Authors: Ives Joss , Rieger Georg , Renani Fatemeh Rostamzadeh
Published: July 2023

We conducted an observational exploratory study of distraction by digital devices in multiple different sections across three large undergraduate physics courses. We collected data from two different settings based on the type of devices used for classroom polling: lecture sections that required mobile devices for polling and those that used standalone clickers. Our analysis shows no difference in the average distraction level between the two settings. However, we did observe an overall lower level of distraction during active learning modes, as compared to passive learning modes. Based on there being no observable difference in distraction levels in the mobile polling and standalone clicker classrooms, we recommend that instructors should choose the polling technology that best suits their needs without worrying about the impact on student distraction. The observed difference in distraction between the active and passive learning modes is consistent with previous results from the literature, which reinforces support for the use of active learning modes as much as possible.
3D printed reactors and Kessil lamp holders for flow photochemistry: design and system standardization
Authors: Penny Matthew R. , Hilton Stephen T.
Published: July 2023

A low-cost 3D printed standardized flow-photochemistry setup has been designed and developed for use with a pressure-driven flow system using photochemistry lamps available in most laboratories. In this research, photochemical reactors were 3D printed from polypropylene which facilitated rapid optimization of both reactor geometry and experimental setup of the lamp housing system. To exemplify the rapidity of this approach to optimization, a Kessil LED lamp was used in the bromination of a range of toluenes in the 3D printed reactors in good yields with residence times as low as 27 s. The reaction compared favorably with the batch photochemical procedure and was able to be scaled up to a productivity of 75 mmol h−1.
Relational autonomy and paternalism – why the physician-patient relationship matters
Authors: Hirsch Anna
Published: July 2023

Both paternalism and relational autonomy are two concepts that are much discussed in medical ethics. Strangely enough, they have hardly been considered together. How does the understanding and justification of medical paternalism change if we take a (constitutively) relational understanding of autonomy as a basis? From an individualistic understanding of autonomy, medical paternalism interferes in the individual sphere of a patient. It can be justified if the benefit to the patient clearly outweighs the extent of the violation of their autonomy. I argue that according to a relational understanding of autonomy other justification criteria come to the fore than those we know from the ‘classic paternalism debate’. Building on the concept of maternalism introduced by Laura Specker-Sullivan and Fay Niker, I propose that the nature and quality of the physician-patient relationship, the epistemic access to the patient’s pro-attitudes, the physician’s motivation to intervene, and intersubjective recognition constitute relevant justification criteria. In addition, I argue that these criteria provide helpful indications of how physician-patient relationships should be structured in order to enable relational autonomy in patient care and avoid medical paternalism in general.
Preparation, characterization and densification studies of W-Ag nanocomposites produced by chemical route
Authors: Reddy M. Venkat , Krishnaiah A. , Venkateshwar Reddy P.
Published: July 2023

W-Ag has applications in a wide range of cutting-edge fields, counting heat sinks and microwave absorbers for micro—electronic components, electric arc ends, and filaments for welding processes, electrical contacts, and durable electronic connections. Chemical methods provide a number of benefits, including improved purity, and controlled particle size. The present study focused on the fabrication of W-Ag nano composites using chemical synthesis. W-Ag nanocomposites with average size less than 50 nm were synthesized using Tungsten hexacarbonyl (W(CO)6, and silver acetate (CH3-COOAg) as metal precursors in the present study. The W-Ag composites were sintered using conventional sintering. X-ray diffraction studies of as-prepared powders showed amorphous W-phase and FCC Ag, while sintered W-Ag composites exhibited crystalline BCC W and FCC Ag phase. The effect of sintering temperature on relative density and mechanical properties of W-Ag sintered compacts was investigated. Relative density in excess of 97.6%, 98.2% and 98.8% was achieved for W-20.3 wt.% Ag, W-30.1 wt.% Ag and W-39.8 wt.% Ag composites on conventional sintering at 1000°C for 1 h. Vickers hardness of 364 ± 10 and 320 ± 8 Hv and 279 ± 6 were achieved for W-20.3 wt.% Ag, W-30.1 wt.% Ag and W-39.8 wt.% Ag composite compacts respectively. The hardness value of W-Ag composites decreased with an increase in Ag content. The combination of properties realized in this study renders the composites suitable for automotive and heat sink applications.
Post-intensive care syndrome in pediatrics—enhancing understanding through a novel bioecological theory of human development lens
Authors: Rahmaty Zahra , Manning Joseph C. , Macdonald Ibo , Perez Maria-Helene , Ramelet Anne-Sylvie
Published: July 2023

Background

The post-intensive care syndrome in pediatrics (PICS-p) framework offers a new understanding of the long-term impact of critical illness on child’s and family’s health. However, a comprehensive theoretical guide to investigate potential factors influencing these outcomes and recoveries is needed.

Objective

The aim of the study is to conceptualize post-intensive care outcomes in children and their families after PICU discharge in the context of the child’s surrounding environment and systems.

Method

We used Theory Adaptation, a shift in the use and perspective of the Bioecological Theory of Human Development (BTHD), and Theory Synthesis, the integration of BTHD and the PICS-p, to provide a novel PICSS-PF perspective for understanding PICS-p within the broader context of the child and family. This integration helps to see higher-order perspectives to link post-PICU outcomes and child development within the context of child’s surroundings.

Results

While PICS-p is a model for understanding and studying post-PICU outcomes and recovery in four domains of physical, cognitive, emotional, and social health, the BTHD offers a new lens for a holistic view of the contextual systems and factors affecting the outcomes and recovery. The BTHD contextual systems include intrapersonal (demographics, clinical), interpersonal (adjacent people’s characteristics and interactions), institutional (family situations, PICU environment), community, social resources, and networks.

Conclusions

Knowing the complex nature of post-PICU outcomes in children and their families, the PICSS-PF helps in the better understanding of the complex interplay of factors that contribute to PICS in children and their families, leading to the development of more effective interventions to address this condition.
How Casinoization Affects the Police in Macao
Authors: Lao Tang In , Xu Jianhua
Published: July 2023

The past two decades have witnessed Macao’s development into the casino capital of the world. Casinos have significantly transformed all respects of Macao society—a phenomenon termed as the casinoization of Macao. While much research has explored how casinoization has affected Macao’s socioeconomic developments, empirical research on the relationship between casinoization and law enforcement agencies is extremely limited. Using official statistics and interviews with serving and retired police officers as well as police applicants in Macao, this article examines the quick-money mentality, laissez-faire regulation, and the paradox of plenty, three features of casinoization, and their profound impact on the Macao police. First, the early phase of casino liberalization created a draining effect on human capital from the police force. Second, the lucrative casino tax revenues empowered the government to resolve the labour shortage issue and significantly improve the police image. Third, casinoization inadvertently reinforced the colonial legacy of laissez-faire regulation, hampering the progress of institutional reforms. Fourth, the decline of casino has contributed to the unprecedented “police fever” among the youth in Macao.
How do we engineer trustworthy digital twins?
Authors: Larsen Peter Gorm , Fitzgerald John , Woodcock Jim
Published: July 2023

There has been a rapid rise of interest in the potential of digital twins to transform a vast range of Cyber-Physical System (CPS) applications, from national infrastructure to surgical robots. But what frameworks, methods and tools are needed to create and maintain digital twins on which we can depend?
Early post-Keynesian journeys from Cambridge into development: Bridges and boundaries
Authors: Saith Ashwani
Published: July 2023

This synthetic commentary offers a handful of observations. First, it highlights structural differences between the advanced market/capitalist economy that forms the theoretical scaffolding of Keynesian theory, as against the diverse range of structural and institutional configurations that characterise contemporary developing economies. Second, bearing these distinctions in mind, how far does the notion of “full employment” hold relevance in the context of developing economies? Third, the focus shifts to the central Keynesian policy prescription: reflating economic activity through injecting additional demand into the system, in extremis through pump-priming, digging and filling trenches – would this perform in a poor agrarian economy? Would the multiplier work and deliver in the realities of developing economies? Fourth, the central policy agenda in the South was that of launching industrialisation, leading to a sustained structural transformation of the economy – a la the Kaldorian industrialisation paradigm, which is scarcely visible in the (post-)Keynesianism template. Fifth, it queries the investment function and the role of state investment, and/or of “animal spirits” of capitalist entrepreneurs and agents, whether of domestic or foreign origins. Sixth, there is need to widen the focus, as well argued by Hans Singer, Amiya Bagchi and others, from Keynes-I of The General Theory, to Keynes-II of Bretton Woods, thereby substantially widening the interface with the agenda of development. Finally, there is the inevitable question concerning the nature and role of the state in the contrasting developed-vs-developing-economy, then-and-now scenarios. This discursive commentary is largely a Cambridge dialogue, not inappropriate in a tribute to Geoff Harcourt.
Perceptions, attitudes and beliefs towards soya among healthy Asian women participating in a soya randomised controlled trial
Authors: Yap Beverley , Rajaram Nadia , Ho Weang Kee , Khor Geok Lin , Teo Soo Hwang
Published: July 2023

The soya–breast cancer risk relationship remains controversial in Asia due to limited and inconsistent research findings and is exacerbated by difficulties in recruiting and retaining participants in intervention trials. Understanding public perceptions towards soya is important for designing effective intervention trials. Here, we administered a close-ended, quantitative survey to healthy, peri- and post-menopausal Asian women in the Malaysian Soy and Mammographic Density (MiSo) Study to assess perception towards soya and explore motivators and barriers that affect study adherence using the Capability, Opportunity, Motivation and Belief (COM-B) Model and Theoretical Domains Framework (TDF). Of 118 participants, the majority reported the belief that soya promotes good health (Supplement = 85⋅7 %, Diet = 90⋅0 %, Control = 87⋅9 %). Most participants reported obtaining information about soya from the internet (Supplement = 61⋅0 %, Diet = 55⋅3 %, Control = 35⋅9 %), while health professionals were least reported (Supplement = 9⋅8 %, Diet = 7⋅9 %, Control = 5⋅1 %). Stratified analyses by study completion and adherence status yielded comparable findings. By the end of the study, dietary arm participants reported a strong belief that soya has no impact on their health (Supplement = 7⋅1 % v. Diet = 20⋅0 % v. Control = 0⋅0 %, P = 0⋅012). Motivation and opportunity strongly facilitated soya consumption, while psychological capability was the most common barrier to consumption though less evident among dietary arm participants. While most Asian women have a positive perception towards soya, theory-based intervention trials are warranted to understand the perception–study adherence relationship and to accurately inform the public of the health effects of soya.
Deliberative processes in health technology assessment of medicines: the case of Spain
Authors: Pinilla-Dominguez Pilar , Pinilla-Dominguez Jaime
Published: July 2023

Objectives

Spain incorporated in 2020 changes in its health technology assessment (HTA), pricing, and reimbursement system for medicines including publishing reports, development of networks of experts, or consultation with stakeholders. Despite these changes, it is unclear how deliberative frameworks are applied and the process has been criticized for not being sufficiently transparent. This study analyses the level of implementation of deliberative processes in HTA for medicines in Spain.

Methods

We review the grey literature and summarize the Spanish HTA, pricing, and reimbursement process of medicines. We apply the deliberative processes for HTA checklist, developed to assess the overall context of the deliberative process, and identify the stakeholders involved and type of involvement following the framework for evidence-informed deliberative processes, a framework for benefit package design that aims to optimize the legitimacy of decision making.

Results

In the Spanish HTA, pricing, and reimbursement process deliberation takes place in order to exchange viewpoints and reach common ground, mainly during the prioritization, assessment, and appraisal steps. It is closed to the public, not clearly summarized in published documents and limited to the Ministry of Health, the regulatory agency, other Ministries, and experts with mostly clinical and/or pharmaceutical background. The views of stakeholders are only represented through consultation. Communication is the most commonly used form of stakeholder engagement.

Conclusions

Despite improvements in transparency of the Spanish HTA process for evaluating medicines, aspects related to stakeholder involvement and implementation of deliberative frameworks need further attention in order to achieve further legitimacy of the process.
Intravenous prostaglandin E1 (alprostadil) bolus in ductus arteriosus-dependent CHD: valid or absolutely contraindicated?
Authors: Colín Ortiz Jose L. , Cruz Hernández Angel , Silva Estrada Jorge A. , Maldonado Alonso Roberto , Corona Villalobos Carlos A. , González Rebeles Guerrero Carlos , Pérez Pérez Linda F.
Published: July 2023

The use of prostaglandin E1 is well documented in ductus arteriosus-dependent CHD or in neonatal pulmonary pathologies that cause severe pulmonary hypertension. The intravenous infusion is well established in loading infusion and maintenance with an onset of action of 30 minutes until 2 hours or even more. Our aim is to report three patients with pulmonary atresia that presented hypercyanotic spell due to a ductal spasm during cardiac catheterisation in whom the administration of a bolus of alprostadil reversed the spasm and increased pulmonary flow, immediately stabilising the condition of the patients allowing subsequent successful stent placement with no serious complications or sequelae after the administration of the bolus. More studies are needed to make a recommendation regarding the use of alprostadil in bolus in cases where the ductal spasm might jeopardise the life of the patient.
An Efficient Solver for ASP(Q)
Authors: FABER WOLFGANG , MAZZOTTA GIUSEPPE , RICCA FRANCESCO
Published: July 2023

Answer Set Programming with Quantifiers ASP(Q) extends Answer Set Programming (ASP) to allow for declarative and modular modeling of problems from the entire polynomial hierarchy. The first implementation of ASP(Q), called QASP, was based on a translation to Quantified Boolean Formulae (QBF) with the aim of exploiting the well-developed and mature QBF-solving technology. However, the implementation of the QBF encoding employed in qasp is very general and might produce formulas that are hard to evaluate for existing QBF solvers because of the large number of symbols and subclauses. In this paper, we present a new implementation that builds on the ideas of QASP and features both a more efficient encoding procedure and new optimized encodings of ASP(Q) programs in QBF. The new encodings produce smaller formulas (in terms of the number of quantifiers, variables, and clauses) and result in a more efficient evaluation process. An algorithm selection strategy automatically combines several QBF-solving back-ends to further increase performance. An experimental analysis, conducted on known benchmarks, shows that the new system outperforms QASP.
MLK4 promotes glucose metabolism in lung adenocarcinoma through CREB-mediated activation of phosphoenolpyruvate carboxykinase and is regulated by KLF5
Authors: Cheung Alvin Ho-Kwan , Wong Kit-Yee , Liu Xiaoli , Ji Fenfen , Hui Chris Ho-Lam , Zhang Yihan , Kwan Johnny Sheung-Him , Chen Bonan , Dong Yujuan , Lung Raymond Wai-Ming , Yu Jun , Lo Kwok Wai , Wong Chi Chun , Kang Wei , To Ka-Fai
Published: July 2023

MLK4, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, has been implicated in cancer progression. However, its role in lung adenocarcinoma has not been characterized. Here, we showed that MLK4 was overexpressed in a significant subset of lung adenocarcinoma, associated with a worse prognosis, and exerted an oncogenic function in vitro and in vivo. Bioinformatics analyses of clinical datasets identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a novel target of MLK4. We validated that MLK4 regulated PCK1 expression at transcriptional level, by phosphorylating the transcription factor CREB, which in turn mediated PCK1 expression. We further demonstrated that PCK1 is an oncogenic factor in lung adenocarcinoma. Given the importance of PCK1 in the regulation of cellular metabolism, we next deciphered the metabolic effects of MLK4. Metabolic and mass spectrometry analyses showed that MLK4 knockdown led to significant reduction of glycolysis and decreased levels of glycolytic pathway metabolites including phosphoenolpyruvate and lactate. Finally, the promoter analysis of MLK4 unravelled a binding site of transcription factor KLF5, which in turn, positively regulated MLK4 expression in lung adenocarcinoma. In summary, we have revealed a KLF5-MLK4-PCK1 signalling pathway involved in lung tumorigenesis and established an unusual link between MAP3K signalling and cancer metabolism.
Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity
Authors: Ferlazzo Giorgia Maria , Gambetta Anna Maria , Amato Sonia , Cannizzaro Noemi , Angiolillo Silvia , Arboit Mattia , Diamante Linda , Carbognin Elena , Romani Patrizia , La Torre Federico , Galimberti Elena , Pflug Florian , Luoni Mirko , Giannelli Serena , Pepe Giuseppe , Capocci Luca , Di Pardo Alba , Vanzani Paola , Zennaro Lucio , Broccoli Vania , Leeb Martin , Moro Enrico , Maglione Vittorio , Martello Graziano
Published: July 2023

Huntington’s disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity. Among the identified suppressors, linked to HD-associated processes, we focus on Metal response element binding transcription factor 1 (Mtf1). Forced expression of Mtf1 counteracts cell death and oxidative stress caused by mHTT in mouse ESCs and in human neuronal precursor cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mHTT. In R6/2 mice, Mtf1 ablates motor defects and reduces mHTT aggregates and oxidative stress. Our screening strategy enables a quick in vitro identification of promising suppressor genes and their validation in vivo, and it can be applied to other monogenic diseases.
Cavity-enhanced single-shot readout of a quantum dot spin within 3 nanoseconds
Authors: Antoniadis Nadia O. , Hogg Mark R. , Stehl Willy F. , Javadi Alisa , Tomm Natasha , Schott Rüdiger , Valentin Sascha R. , Wieck Andreas D. , Ludwig Arne , Warburton Richard J.
Published: July 2023

Rapid, high-fidelity single-shot readout of quantum states is a ubiquitous requirement in quantum information technologies. For emitters with a spin-preserving optical transition, spin readout can be achieved by driving the transition with a laser and detecting the emitted photons. The speed and fidelity of this approach is typically limited by low photon collection rates and measurement back-action. Here we use an open microcavity to enhance the optical readout signal from a semiconductor quantum dot spin state, largely overcoming these limitations. We achieve single-shot readout of an electron spin in only 3 nanoseconds with a fidelity of (95.2 ± 0.7)%, and observe quantum jumps using repeated single-shot measurements. Owing to the speed of our readout, errors resulting from measurement-induced back-action have minimal impact. Our work reduces the spin readout-time well below both the achievable spin relaxation and dephasing times in semiconductor quantum dots, opening up new possibilities for their use in quantum technologies.
UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
Authors: Kostyrko Kaja , Román Marta , Lee Alex G. , Simpson David R. , Dinh Phuong T. , Leung Stanley G. , Marini Kieren D. , Kelly Marcus R. , Broyde Joshua , Califano Andrea , Jackson Peter K. , Sweet-Cordero E. Alejandro
Published: July 2023

KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.
Modular synthesis of clickable peptides via late-stage maleimidation on C(7)-H tryptophan
Authors: Wang Peng , Liu Jiang , Zhu Xiaomei , Kenry  , Yan Zhengqing , Yan Jiahui , Jiang Jitong , Fu Manlin , Ge Jingyan , Zhu Qing , Zheng Yuguo
Published: July 2023

Cyclic peptides have attracted tremendous attention in the pharmaceutical industry owing to their excellent cell penetrability, stability, thermostability, and drug-like properties. However, the currently available facile methodologies for creating such peptides are rather limited. Herein, we report an efficient and direct peptide cyclization via rhodium(III)-catalyzed C(7)-H maleimidation. Notably, this catalytical system has excellent regioselectivity and high tolerance of functional groups which enable late-stage cyclization of peptides. This architecture of cyclic peptides exhibits higher bioactivity than its parent linear peptides. Moreover, the Trp-substituted maleimide displays excellent reactivity toward Michael addition, indicating its potential as a click functional group for applications in chemical biology and medicinal chemistry. As a proof of principle, RGD-GFLG-DOX, which is a peptide-drug-conjugate, is constructed and it displays a strong binding affinity and high antiproliferative activity toward integrin-αvβ3overexpressed cancer cell lines. The proposed strategy for rapid preparation of stapled peptides would be a robust tool for creating peptide-drug conjugates.
Improved oxidation resistance of Cr-Si coated Zircaloy with an in-situ formed Zr2Si diffusion barrier
Authors: Zeng Song , Li Jun-Feng , Chen Chen , Meng Yan , Zhu Chao-Wen , Han Xiao-Chun , Bao Yi-Wang , Zhang Hai-Bin
Published: July 2023

In the present study, the dense Cr and Cr0.92Si0.08 coatings have been deposited on Zircaloy-4 substrates by the magnetron sputtering technique. The high-temperature oxidation resistance of coatings is evaluated in 1200 °C steam for 1–4 h. The Cr0.92Si0.08 coating shows better oxidation resistance than the Cr coating. The in-situ formed Zr2Si diffusion barrier inhibits the mutual diffusion of Cr and Zr. And the formation of a Cr2O3/SiO2 double-layer scale effectively improves the oxidation resistance of a single Cr2O3 layer. The formation of the in-situ diffusion barrier, Cr2O3/SiO2 scales and oxidation protection mechanisms of the Cr0.92Si0.08 coating have been discussed in detail.
Diversity under a magnifier lens: the case of Typhlotanaidae (Crustacea: Tanaidacea) in the N Atlantic
Authors: Gellert Marta , Błażewicz Magdalena , Mamos Tomasz , Bird Graham J.
Published: July 2023

Research focusing on ‘stout-bodied’ typhlotanaids collected from several sites around Iceland and adjacent N Atlantic region has resulted in the description of 15 species new to science, as well as the creation of eight new genera.Typhlotanais eximiusHansen, 1913 is redescribed and transferred to a new genus, whileTyphlotanais crassusandPeraeospinosus adipatusare transferred to the genusLarsenotanais. The morphological and the molecular data were combined to consolidate and confirm the validity of the results obtained from both approaches. The polyphyletic nature of the Typhlotanaidae and its serious of its taxonomic diversity are emphasized, although molecular analysis reveals that the ‘stout-bodied’ Typhlotanaidae form monophyletic clade. Depth and temperature are identified as the main environmental parameters determining the distribution of this group of Typhlotanaidae. Several species are clearly associated with the shelf and upper bathyal of Iceland. The Greenland-Iceland-Faroe Ridge is shown to be a distinct zoogeographical barrier for typhlotanaids inhabiting the deeper slope and abyssal regions around Iceland.
Methods for assessing change in brain plasticity at night and psychological resilience during daytime between repeated long-duration space missions
Authors: Otsuka Kuniaki , Cornelissen Germaine , Kubo Yutaka , Shibata Koichi , Mizuno Koh , Aiba Tatsuya , Furukawa Satoshi , Ohshima Hiroshi , Mukai Chiaki
Published: July 2023

This study was designed to examine the feasibility of analyzing heart rate variability (HRV) data from repeat-flier astronauts at matching days on two separate missions to assess any effect of repeated missions on brain plasticity and psychological resilience, as conjectured by Demertzi. As an example, on the second mission of a healthy astronaut studied about 20 days after launch, sleep duration lengthened, sleep quality improved, and spectral power (ms2) co-varying with activity of the salience network (SN) increased at night. HF-component (0.15–0.50 Hz) increased by 61.55%, and HF-band (0.30–0.40 Hz) by 92.60%. Spectral power of HRV indices during daytime, which correlate negatively with psychological resilience, decreased, HF-component by 22.18% and HF-band by 37.26%. LF-component and LF-band, reflecting activity of the default mode network, did not change significantly. During the second mission, 24-h acrophases of HRV endpoints did not change but the 12-h acrophase of TF-HRV did (P < 0.0001), perhaps consolidating the circadian system to help adapt to space by taking advantage of brain plasticity at night and psychological resilience during daytime. While this N-of-1 study prevents drawing definitive conclusions, the methodology used herein to monitor markers of brain plasticity could pave the way for further studies that could add to the present results.
A novel method of determining the active drag profile in swimming via data manipulation of multiple tension force collection methods
Authors: Haskins A. , McCabe C. , Kennedy R. , McWade R. , Lennon A. B. , Chandar D.
Published: July 2023

A novel method aimed at evaluating the active drag profile during front-crawl swimming is proposed. Fourteen full trials were conducted with each trial using a stationary load cell set-up and a commercial resistance trainer to record the tension force in a rope, caused by an athlete swimming. Seven different stroke cycles in each experiment were identified for resampling time dependent data into position dependent data. Active drag was then calculated by subtracting resistance trainer force data away from the stationary load cell force data. Mean active drag values across the stroke cycle were calculated for comparison with existing methods, with mean active drag values calculated between 76 and 140 N depending on the trial. Comparing results with established active drag methods, such as the Velocity Perturbation Method (VPM), shows agreement in the magnitude of the mean active drag forces. Repeatability was investigated using one athlete, repeating the load cell set-up experiment, indicating results collected could range by 88 N depending on stroke cycle position. Variation in results is likely due to inconsistencies in swimmer technique and power output, although further investigation is required. The method outlined is proposed as a representation of the active drag profile over a full stroke cycle.
Soliton solutions of fractional extended nonlinear Schrödinger equation arising in plasma physics and nonlinear optical fiber
Authors: Ahmad Jamshad , Akram Sonia , Noor Kanza , Nadeem Muhammad , Bucur Amelia , Alsayaad Yahya
Published: July 2023

In this research, we study traveling wave solutions to the fractional extended nonlinear SchrÖdinger equation (NLSE), and the effects of the third-order dispersion parameter. This equation is used to simulate the propagation of femtosecond, plasma physic and in nonlinear optical fiber. To accomplish this goal, we use the extended simple equation approach and the improved F-expansion method to secure a variety of distinct solutions in the form of dark, singular, periodic, rational, and exponential waves. Also, the stability of the outcomes is effectively examined. Several graphs have been sketched under appropriate parametric values to reinforce some reported findings. Computational work along with a graphical demonstration confirms the exactness of the proposed methods. The issue has not previously been investigated by taking into account the impact of the third order dispersion parameter. The main objective of this study is to obtain the different kinds of traveling wave solutions of fractional extended NLSE which are absent in the literature which justify the novelty of this study. We believe that these novel solutions hold a prominent place in the fields of nonlinear sciences and optical engineering because these solutions will enables a through understanding of the development and dynamic nature of such models. The obtained results indicate the reliability, efficiency, and capability of the implemented technique to determine wide-spectral stable traveling wave solutions to nonlinear equations emerging in various branches of scientific, technological, and engineering domains.
Novel aminopyridazine derivative of minaprine modified by radiolysis presents potent anti-inflammatory effects in LPS-stimulated RAW 264.7 and DH82 macrophage cells
Authors: Jeong Gyeong Han , Lee Hanui , Woo So-Yeun , Lee Hong-Ki , Chung Byung Yeoup , Bai Hyoung-Woo
Published: July 2023

Radiation molecularly transforms naturally occurring products by inducing the methoxylation, hydroxylation, and alkylation of parent compounds, thereby affecting the anti-inflammatory capacities of those compounds. Minaprine (1) modified by ionizing radiation generated the novel hydroxymethylation hydropyridazine (2), and its chemical structure was determined based on NMR and HRESIMS spectra. Compared to the original minaprine, the novel generated product showed a highly enhanced anti-inflammatory capacity inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 and DH82 macrophage cells. In addition, minaprinol (2) effectively inhibited cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) at the protein level and pro-inflammatory cytokine (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-10) production in macrophages.
A new point cloud processing method unveiled hidden coastal boulders from deep vegetation
Authors: Nakata Koki , Yanagisawa Hideaki , Goto Kazuhisa
Published: July 2023

Huge coastal boulders are useful to reconstruct the size of past extreme waves such as those associated with tsunamis and storms using inverse-type or forward-type boulder transport models. These models fundamentally require the precise shape of boulders. Traditionally, they have often been assumed to be rectangular or ellipsoidal with three axes measured in the field. However, if the boulder’s shape is complex, this method is unable to represent the actual shape accurately. Therefore, it prevents estimation of the tsunami or storm size reasonably using models. For this reason, boulders have recently been surveyed using 3D scanning techniques such as LiDAR. However, coastal boulders now on land in tropical and subtropical areas such as Japan and Tonga are often covered by deep vegetation, which makes 3D surveys difficult. This report presents new methods to ascertain boulder shapes when they are obscured by vegetation. First, using UAV-type and mobile-type LiDAR, we scanned well-known tsunami boulders in southwestern Japan that had been covered with deep vegetation. Then, we developed a new method to extract only boulders and filter out vegetation from a point cloud. Thereby, we created 3D models of the boulders. We improved the boulder transport model further to assume the 3D boulder model accurately. In addition to coastal boulders, this filtering method is expected to be useful for unveiling any object, such as an archaeological structure, that is hidden in deep vegetation.
Optimal lipid-lowering therapy in patients who were functionally deferred percutaneous coronary intervention
Authors: Abe Takuro , Shimazaki Kensuke , Moriyama Tetsu , Murohashi Akira , Iwanami Yuji , Sasaki Akihito , Saito Katsumi , Jujo Kentaro
Published: July 2023

Deferral of percutaneous coronary intervention (PCI) for functionally insignificant stenosis, defined as fractional flow reserve (FFR) > 0.80, is associated with favorable long-term prognoses. The lower-the-better strategy for low-density lipoprotein cholesterol (LDL-C) management is an established non-angioplasty therapy to improve the clinical outcomes of patients undergoing PCI. We examined the optimal LDL-C management in cases of intermediate coronary stenosis with deferred PCI on the basis of FFR values. This observational study included 273 consecutive patients with a single target vessel and deferred PCI with an FFR > 0.80. Patients with an FFR of 0.81–0.85 (n = 93) and those with FFR > 0.85 (n = 180) were classified into the lower (< 100 mg/dL) and higher (≥ 100 mg/dL) LDL-C groups. The endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including death, non-fatal myocardial infarction, ischemic stroke, heart failure hospitalization, and unplanned revascularization. Patients with an FFR of 0.81–0.85 had a significantly higher MACCE rate than those with an FFR > 0.85 (log-rank, p = 0.003). In patients with an FFR of 0.81–0.85, the lower LDL-C group showed a significantly lower MACCE rate than the higher LDL-C group (log-rank, p = 0.006). However, the event rate did not differ significantly between the two groups in patients with FFR > 0.85 (log-rank, p = 0.84). Uncontrolled LDL-C levels were associated with higher MACCE rates in cases with deferred PCI due to an FFR of 0.81–0.85. This high-risk population for adverse cardiovascular events should receive strict LDL-C-lowering therapy.
Regulatory mechanisms of glucose absorption in the mouse proximal small intestine during fasting and feeding
Authors: Nakamura Chisato , Ishizuka Noriko , Yokoyama Kanako , Yazaki Yuyu , Tatsumi Fumiya , Ikumi Naotaka , Hempstock Wendy , Ikari Akira , Yoshino Yuta , Hayashi Hisayoshi
Published: July 2023

Fasting is known to alter the function of various organs and the mechanisms of glucose metabolism, which affect health outcomes and slow aging. However, it remains unclear how fasting and feeding affects glucose absorption function in the small intestine. We studied the effects of the fasting and feeding on glucose-induced short-circuit current (Isc) in vitro using an Ussing chamber technique. Glucose-induced Isc by SGLT1 was observed in the ileum, but little or no Isc was observed in the jejunum in ad libitum-fed mice. However, in mice fasted for 24–48 h, in addition to the ileum, robust glucose-induced Isc was observed over time in the jejunum. The expression of SGLT1 in the brush border membranes was significantly decreased in the jejunum under fed conditions compared to 48 h fasting, as analyzed by western blotting. Additionally, when mice were fed a 60% high glucose diet for 3 days, the increase in glucose-induced Isc was observed only in the ileum, and totally suppressed in the jejunum. An increase in Na+ permeability between epithelial cells was concomitantly observed in the jejunum of fasted mice. Transepithelial glucose flux was assessed using a non-metabolizable glucose analog, 14C-methyl α-d-glucopyranoside glucose (MGP). Regardless of whether fed or fasted, no glucose diffusion mechanism was observed. Fasting increased the SGLT1-mediated MGP flux in the jejunum. In conclusion, segment-dependent up- and down-regulation mechanisms during fasting and feeding are important for efficient glucose absorption once the fast is broken. Additionally, these mechanisms may play a crucial role in the small intestine's ability to autoregulate glucose absorption, preventing acute hyperglycemia when large amounts of glucose are ingested.
Improving adsorption performance of l-ascorbic acid from aqueous solution using magnetic rice husk as an adsorbent: experimental and RSM modeling
Authors: Aslani Azam , Masoumi Hadiseh , Ghanadzadeh Gilani Hossein , Ghaemi Ahad
Published: July 2023

In this research, rice husk (RH) was utilized to prepare a magnetic adsorbent for adsorption of ascorbic acid (AA). The magnetic agent is iron(III) chloride (FeCl3). The impact of acid concentration in the range of 400–800 ppm, adsorbent dosage in the range of 0.5–1 g, and contact time in the range of 10–130 min were studied. The Langmuir model had the highest R2 of 0.9982, 0.9996, and 0.9985 at the temperature of 15, 25, and 35 °C, respectively, and the qmax values in these temperatures have been calculated at 19.157, 31.34, and 38.75 mg/g, respectively. The pseudo-second-order kinetic model had the best agreement with the experimental results. In this kinetic model, the values of q have been measured at 36.496, 45.248, and 49.019 mg/g at the acid concentration of 418, 600, and 718 ppm, respectively. The values of ΔHo and ΔSo were measured 31.972 kJ/mol and 120.253 kJ/mol K, respectively, which proves the endothermic and irregularity nature of the adsorption of AA. Besides, the optimum conditions of the design-expert software have been obtained 486.929 ppm of acid concentration, 0.875 g of the adsorbent dosage, and 105.397 min of the contact time, and the adsorption efficiency in these conditions was determined at 92.94%. The surface area of the RH and modified RH was determined of 98.17 and 120.23 m2/g, respectively, which confirms the high surface area of these two adsorbents.
Unsupervised feature extraction of aerial images for clustering and understanding hazardous road segments
Authors: Francis John , Bright Jonathan , Esnaashari Saba , Hashem Youmna , Morgan Deborah , Straub Vincent J.
Published: July 2023

Aerial image data are becoming more widely available, and analysis techniques based on supervised learning are advancing their use in a wide variety of remote sensing contexts. However, supervised learning requires training datasets which are not always available or easy to construct with aerial imagery. In this respect, unsupervised machine learning techniques present important advantages. This work presents a novel pipeline to demonstrate how available aerial imagery can be used to better the provision of services related to the built environment, using the case study of road traffic collisions (RTCs) across three cities in the UK. In this paper, we show how aerial imagery can be leveraged to extract latent features of the built environment from the purely visual representation of top-down images. With these latent image features in hand to represent the urban structure, this work then demonstrates how hazardous road segments can be clustered to provide a data-augmented aid for road safety experts to enhance their nuanced understanding of how and where different types of RTCs occur.