bluuebunny/crossref_metadata_2025 huggingface dataset:
A customized ConvNeXt‐XL network with fusion of deep and handcrafted features for colposcopy image classification
Authors: Natarajan Thendral , Devan Lakshmi , Palayanoor Seethapathy Ramaprabha , Balakrishnan Senthil Kumar
Published: February 2024

Cervical cancer is the second most frequent cancer among women of all age groups worldwide. It occurs due to human papillomavirus. In the premature stages, the symptoms will not be predominant until they reach the final stage of cancer. Detection and classification of cervical cancer always demand gynecologists with the necessary skills and experience. The goal of the proposed work is to develop a deep learning framework to facilitate the automated classification of cervical cancer using colposcopy images. The following Deep Convolutional Neural Network (DCNN) models are proposed to detect cervical cancer and classify cervix‐type images. (i) the pre‐trained DCNNs, namely VGG16, ResNet50, InceptionV3, InceptionResNetV2, and ConvNeXtXLarge (ConvNeXt‐XL) using Softmax classifier based on deep features; (ii) the ConvNeXt‐XL model with classification using Support Vector Machine (SVM), K Nearest Neighbor (KNN) and Decision Tree (DT) based on deep features; (iii) a customized ConvNeXt‐XL network to enhance the classification accuracy using serially concatenated handcrafted and deep features. The research experiment was carried out separately using two datasets: the Cervix‐Type dataset (Type 1, Type 2, and Type 3) and the Real Time Cervical dataset (Normal and Abnormal). The simulation outcome confirms that the customized ConvNeXt‐XL helped to improve the classification accuracy with the Cervix‐Type dataset (>97%) and Real Time Cervical dataset (>98%).
Risk and protective factors for suicidality among lesbian, gay, bisexual, transgender, and queer (LGBTQ+) young people, from countries with a high global acceptance index (GAI), within the context of the socio‐ecological model: A scoping review
Authors: Wallace Emma Rebecca , O'Neill Siobhan , Lagdon Susan
Published: February 2024

Introduction

Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) young people experience higher prevalence rates of suicidality than their heterosexual and/or cisgender peers. However, there is limited research that can inform suicide prevention efforts. Our aim was to synthesize quantitative, qualitative, and mixed methods research on risk and protective factors among LGBTQ+ young people, from countries with a high Global Acceptance Index.

Methods

A scoping review guided by Arksey and O'Malley's five‐stage framework, using the Preferred Reporting Items for Systematic Reviews and Meta‐analysis Extension for Scoping Reviews protocol. Five databases and grey literature were searched for relevant studies. Identified factors were clustered by thematic type, according to the socio‐ecological model to identify empirical trends and knowledge gaps. The mixed methods appraisal tool was used for quality assessment of studies.

Results

Sixty‐six studies met our inclusion criteria. Overall, 59 unique risk factors and 37 unique protective factors were identified. Key risk factors include past suicidality, adverse childhood experiences, internalized queerphobia, minority stress, interpersonal violence, bullying, familial conflict, and anti‐LGBTQ+ policies/legislation. Key protective factors include self‐affirming strategies, adult/peer support, at‐school safety, access to inclusive healthcare, family connectedness, positive coming out experiences, gender‐affirming services and LGBTQ+ inclusive policies and legislation.

Conclusions

Overall, our findings affirm that multiple risk and protective factors, at all levels of the socio‐ecological model, interact in complex, unique and diverse ways upon suicidality among LGBTQ+ young people. Implications for suicide prevention are discussed. Further empirical studies are required, particularly at the communities, policies, and societal levels of the socio‐ecological model, and these studies should include a focus on protective factors and significant within‐group differences.
Cis‐regulatory control of mammalian Trps1 gene expression
Authors: Abrar Muhammad , Ali Shahid , Hussain Irfan , Khatoon Hizran , Batool Fatima , Ghazanfar Shakira , Corcoran Dylan , Kawakami Yasuhiko , Abbasi Amir Ali
Published: February 2024

TRPS1 serves as the causative gene for tricho‐rhino phalangeal syndrome, known for its craniofacial and skeletal abnormalities. The Trps1 gene encodes a protein that represses Wnt signaling through strong interactions with Wnt signaling inhibitors. The identification of genomic cis‐acting regulatory sequences governing Trps1 expression is crucial for understanding its role in embryogenesis. Nevertheless, to date, no investigations have been conducted concerning these aspects of Trps1. To identify deeply conserved noncoding elements (CNEs) within the Trps1 locus, we employed a comparative genomics approach, utilizing slowly evolving fish such as coelacanth and spotted gar. These analyses resulted in the identification of eight CNEs in the intronic region of the Trps1 gene. Functional characterization of these CNEs in zebrafish revealed their regulatory potential in various tissues, including pectoral fins, heart, and pharyngeal arches. RNA in‐situ hybridization experiments revealed concordance between the reporter expression pattern induced by the identified set of CNEs and the spatial expression pattern of the trps1 gene in zebrafish. Comparative in vivo data from zebrafish and mice for CNE7/hs919 revealed conserved functions of these enhancers. Each of these eight CNEs was further investigated in cell line‐based reporter assays, revealing their repressive potential. Taken together, in vivo and in vitro assays suggest a context‐dependent dual functionality for the identified set of Trps1‐associated CNE enhancers. This functionally characterized set of CNE‐enhancers will contribute to a more comprehensive understanding of the developmental roles of Trps1 and can aid in the identification of noncoding DNA variants associated with human diseases.
RNA‐seq analysis of parasitism by Intoshia linei (Orthonectida) reveals protein effectors of defence, communication, feeding and growth
Authors: Skalon Elizaveta K. , Starunov Viktor V. , Slyusarev George S.
Published: February 2024

Orthonectida is a group of multicellular endoparasites of a wide range of marine invertebrates. Their parasitic stage is a multinuclear shapeless plasmodium infiltrating host tissues. The development of the following worm‐like sexual generation takes place within the cytoplasm of the plasmodium. The existence of the plasmodial stage and the development of a sexual stage within the plasmodium are unique features to Bilateria. However, the molecular mechanisms that maintain this peculiar organism, and hence enable parasitism in orthonectids, are unknown. Here, we present the first‐ever RNA‐seq analysis of the plasmodium, aimed at the identification and characterization of the plasmodium‐specific protein‐coding genes and corresponding hypothetical proteins that distinguish the parasitic plasmodium stage from the sexual stage of the orthonectid Intoshia linei Giard, 1877, parasite of nemertean Lineus ruber Müller, 1774. We discovered 119 plasmodium‐specific proteins, 82 of which have inferred functions based on known domains. Thirty‐five of the detected proteins are orphans, at least part of which may reflect the unique evolutionary adaptations of orthonectids to parasitism. Some of the identified proteins are known effector molecules of other endoparasites suggesting convergence. Our data indicate that the plasmodium‐specific proteins might be involved in the plasmodium defense against the host, host–parasite communication, feeding and nutrient uptake, growth within the host, and support of the sexual stage development. These molecular processes in orthonectids have not been described before, and the particular protein effectors remained unknown until now.
Polyhedra without cubic vertices are prism‐hamiltonian
Authors: Špacapan Simon
Published: February 2024

The prism over a graph is the Cartesian product of with the complete graph on two vertices. A graph is prism‐hamiltonian if the prism over is hamiltonian. We prove that every polyhedral graph (i.e., 3‐connected planar graph) of minimum degree at least four is prism‐hamiltonian.
Dominant epitopes of cross‐reactive anti‐domain III human antibody response change from early to late convalescence of infection with dengue virus
Authors: González‐Lodeiro Luis Gabriel , Martín Dunn Alejandro , Martín Prieto Dayron , Medina‐Carrasco Danya , García de Castro Lisandra E. , Maldonado Bauzá Daniela , Chinea Santiago Glay , Huerta Galindo Vivian
Published: February 2024

Cross‐neutralizing activity of human antibody response against Dengue virus complex (DENV) changes importantly over time. Domain III (DIII) of the envelope protein of DENV elicits a potently neutralizing and mostly type‐specific IgG response. We used sera from 24 individuals from early‐ or late convalescence of DENV1 infection to investigate the evolution of anti‐DIII human IgG with the time lapse since the infection. We evaluated the correlation between the serotype‐specific reactivity against recombinant DIII proteins and the neutralization capacity against the four serotypes, and examined its behavior with the time of convalescence. Also, we use a library of 71 alanine mutants of surface‐exposed amino acid residues to investigate the dominant epitopes. In early convalescence anti‐DIII titers and potency of virus neutralization were positively associated with correlation coefficients from 0.82 to 1.0 for the four serotypes. For late convalescence, a positive correlation (r = 0.69) was found only for DENV1. The dominant epitope of the type‐specific response is centered in the FG‐loop (G383, E384, and K385) and includes most of the lateral ridge. The dominant epitope of the anti‐DIII cross‐reactive IgG in secondary infections shifts from the A‐strand during early convalescence to a site centered in residues E314‐H317 of the AB‐loop and I352‐E368 of the DI/DIII interface, in late convalescence. An immunoassay based on the detection of IgG anti‐DIII response can be implemented for detection of infecting serotype in diagnosis of DENV infection, either primary or secondary. Human dominant epitopes of the cross‐reactive circulating antibodies change with time of convalescence.
Type‐II IFN inhibits SARS‐CoV‐2 replication in human lung epithelial cells and ex vivo human lung tissues through indoleamine 2,3‐dioxygenase‐mediated pathways
Authors: Yang Dong , Chan Jasper Fuk‐Woo , Yoon Chaemin , Luk Tsz‐Yat , Shuai Huiping , Hou Yuxin , Huang Xiner , Hu Bingjie , Chai Yue , Yuen Terrence Tsz‐Tai , Liu Yuanchen , Zhu Tianrenzheng , Liu Huan , Shi Jialu , Wang Yang , He Yixin , Sit Ko‐Yung , Au Wing‐Kuk , Zhang Anna Jinxia , Yuan Shuofeng , Zhang Bao‐Zhong , Huang Yao‐Wei , Chu Hin
Published: February 2024

Interferons (IFNs) are critical for immune defense against pathogens. While type‐I and ‐III IFNs have been reported to inhibit SARS‐CoV‐2 replication, the antiviral effect and mechanism of type‐II IFN against SARS‐CoV‐2 remain largely unknown. Here, we evaluate the antiviral activity of type‐II IFN (IFNγ) using human lung epithelial cells (Calu3) and ex vivo human lung tissues. In this study, we found that IFNγ suppresses SARS‐CoV‐2 replication in both Calu3 cells and ex vivo human lung tissues. Moreover, IFNγ treatment does not significantly modulate the expression of SARS‐CoV‐2 entry‐related factors and induces a similar level of pro‐inflammatory response in human lung tissues when compared with IFNβ treatment. Mechanistically, we show that overexpression of indoleamine 2,3‐dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts the replication of ancestral SARS‐CoV‐2 and the Alpha and Delta variants. Meanwhile, loss‐of‐function study reveals that IDO1 knockdown restores SARS‐CoV‐2 replication restricted by IFNγ in Calu3 cells. We further found that the treatment of l‐tryptophan, a substrate of IDO1, partially rescues the IFNγ‐mediated inhibitory effect on SARS‐CoV‐2 replication in both Calu3 cells and ex vivo human lung tissues. Collectively, these results suggest that type‐II IFN potently inhibits SARS‐CoV‐2 replication through IDO1‐mediated antiviral response.
ESPGHAN recommendations on treatment of chronic hepatitis C virus infection in adolescents and children including those living in resource‐limited settings
Authors: Indolfi Giuseppe , Gonzalez‐Peralta Regino P. , Jonas Maureen M. , Sayed Manal Hamdy‐El , Fischler Björn , Sokal Etienne , Wirth Stefan , Nicastro Emanuele ,   Hepatology Committee of the ESPGHAN
Published: February 2024

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide, with more than three million viraemic adolescents and children. Treatment of adults with HCV infection and HCV‐related liver disease has advanced considerably thanks to development and improvements in therapy. Direct‐acting antiviral regimens are safe and effective. Three regimens with pangenotypic activity (glecaprevir/pibrentasvir, sofosbuvir/velpatasvir and sofosbuvir/velpatasvir/voxilaprevir) and three regimens with genotype‐specific activity (sofosbuvir/ribavirin, sofosbuvir/ledipasvir and elbasvir/grazoprevir) have been approved with age‐specific limitation for treatment of children with chronic hepatitis C by the European Medicines Agency and the United States Food and Drug Administration. The World Health Organization has set the ambitious target to eliminate hepatitis C as a major public health threat by 2030 and based its actions against HCV on the large use of direct acting antivirals. These updated European Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations on treatment of hepatitis C describe the optimal therapeutic management of adolescents and children with HCV infection including specific indications for those living in resource‐limited settings.
Controlled Polymerization of N‐Vinyl Imidazole, N‐Vinyl Pyrrolidone, and N‐Vinyl Carbazole with Dithiocarbamates toward High Molar Mass Polymers
Authors: Haribabu P. M. , Vijayakrishna Kari
Published: February 2024

Achieving control over the polymerization of less activated monomers like N‐vinyl carbazole (NVC), N‐vinyl pyrrolidone (NVP), and N‐vinyl imidazole (NVIm) to produce high molar mass polymers poses a significant challenge. To accomplish this, eight different dithiocarbamate‐based reversible addition–fragmentation chain transfer (RAFT) agents are synthesized and employed to polymerize NVIm, NVC, and NVP in order to understand and establish a suitable agent for their controlled polymerization to achieve high molar mass polymers. Chain end presence of these RAFT‐derived polymers is established through 1H NMR studies. Further, these active chain ends are used for chain extension reactions to prepare block copolymers. Synthesized RAFT agents 04, 05, 06, and 08 that are bearing primary leaving groups (methyl 2‐acetate, ethyl 2‐acetate, tert‐butyl 2‐acetate, and cyanomethane) display moderate to good control over the polymerization of NVIm and NVC. Among these, RAFT agent‐08 with cyanomethane leaving group produces poly(NVIm) and poly(NVC) with the highest molar masses of 44 670 Da (1.52) and 53 620 Da (1.4), respectively. Interestingly, RAFT agents bearing both secondary and primary leaving groups show good control over the NVP polymerization. Notably, RAFT agent‐02 with ethyl‐2‐propionate leaving group yields poly(NVP) with the highest molar mass of 89 450 Da and dispersity of 1.43.
Analysis of complex mixtures with benchtop nuclear magnetic resonance: Solvent suppression with T2 and diffusion filters
Authors: Le‐McClain Anh , Zanelotti Curt , Robert Hector , Casanova Federico
Published: February 2024

Benchtop nuclear magnetic resonance (NMR) spectrometers are being employed in a wide variety of applications from undergraduate teaching and research in academia to quality control and process monitoring in industrial settings. Incorporating benchtop NMR in some of these applications presents opportunities for new practical uses of the technology and challenges that truly test the capabilities of compact NMR spectrometers. For instance, the use of protonated solvents in manufacturing or process monitoring requires separating and quantitating the analyte signals of interest from the strong (overwhelming) response from the solvents. Furthermore, due to the lower field strength available with permanent magnet spectrometers, the NMR spectra of complex mixtures can be more difficult to analyze due to partial or complete signal overlap. To address some of these challenges and to extend the range of applications of benchtop NMR, we investigate NMR techniques that enable quantitative analysis of different components in mixtures. These pulse sequences can be used to suppress one or multiple solvent peaks, to filter out signals by spin–spin relaxation time (T2), or to separate signal components by a molecule's diffusion coefficient (NMR diffusometry). In this paper, we discuss quantitative analysis of excipients in buffers for therapeutic proteins to highlight the usefulness of these NMR pulse sequences in the analysis of complex samples with benchtop NMR spectrometers.
From professor to trucker: How Wendy Farkas learned, at age 54, to drive a semi
Authors: May Rachel
Published: February 2024

When she enrolled in trucking school, Wendy Farkas had been both a professor and adult learner for more than fifteen years. She first went back to school when she was in her thirties, after a career as a K‐12 educator. Even after she earned her PhD and was hired as a professor, she continued to take courses in administration every semester, slowly adding to her credentials. Her latest transition, however, into her life as a trucker, proved to be one of her most challenging experiences.
An innovative mobile app for the provision of medical information and collection of safety data on exposure to medicines during pregnancy or breastfeeding: An IHI ConcePTION contribution
Authors: Alexe Amalia , Lewis David , Harrison Kendal
Published: February 2024

Objective

To increase the volume, quality, and comprehensiveness of pregnancy and breastfeeding reports related to medication exposure.

Methods

Innovative Health Initiative (IHI) ConcePTION, in collaboration with the Medicines and Healthcare products Regulatory Agency (MHRA), has developed a mobile application designed for exchange of safety information for pregnancy and breastfeeding. The users will also be able to report medication exposure during pregnancy and breastfeeding, regardless of the outcome, by answering simple questions, tailored for their level of medical knowledge.

Results

Through the first version of the app, the users will receive trusted safety information on their medication of interest, from the Health Authority (RSS feeds, tagged for ‘pregnancy’ and ‘breastfeeding’). By using the app, women and healthcare providers will also be able to help future mothers, by reporting the events they experienced following the utilization of medications during pregnancy and breastfeeding. These will be analyzed by MHRA to further characterize the safety profiles of the medications required to be used in these situations.

Conclusion

Collection of pregnancy outcomes after exposure to medications during pregnancy is limited by under‐reporting and focused on reporting of harms. By developing the app, ConcePTION brings reliable safety information closer to healthcare professionals and pregnant and breastfeeding women and proposes an easy‐to‐use, general data protection regulation‐compliant, secure tool tailored for safety in pregnancy and breastfeeding.
Prescribed‐time sensor fault estimation for linear systems with unknown inputs by periodic delayed observers
Authors: Li Haifang , Zhou Bin , Michiels Wim
Published: February 2024

This paper studies the problem of sensor fault estimation for linear systems in the presence of unknown inputs in both input and output channels. Relying on matrix equation theory, the unknown inputs are first removed from the output channel. Second, an augmented descriptor system is constructed by treating both system state and sensor fault as (pseudo)‐state variables. Third, the augmented descriptor system is transformed into a regular one, followed by the elimination of the unknown input from the state equation. Finally, a reduced‐order prescribed‐time sensor fault estimator is obtained by using periodic delayed observers. This matrix equation based approach is then complemented by an alternative one, which relies on successive transformations of state, input and outputs. This approach sheds light on the adopted solvability conditions throughout the paper and on the role of different directions in the output space in handling unknown inputs, sensor faults and the core state estimation problem. Finally, two numerical examples are presented to illustrate the effectiveness of the proposed methodologies.
Weakly saturated random graphs
Authors: Bartha Zsolt , Kolesnik Brett
Published: February 2024

As introduced by Bollobás, a graph is weakly ‐saturated if the complete graph is obtained by iteratively completing copies of minus an edge. For all graphs , we obtain an asymptotic lower bound for the critical threshold , at which point the Erdős–Rényi graph is likely to be weakly ‐saturated. We also prove an upper bound for , for all which are, in a sense, strictly balanced. In particular, we improve the upper bound by Balogh, Bollobás, and Morris for , and we conjecture that this is sharp up to constants.
Economic fluctuations and mortality in Canada revisited
Authors: Janko Zuzana , Popli Gurleen
Published: February 2024

This paper uses panel data for Canada from 1976 to 2018, across 10 provinces, to reassess the relationship between mortality rates and economic fluctuations. The key contribution of our paper lies in examining the extent to which this relationship is driven by the employment rate (extensive margin) versus average hours worked (intensive margin). We find evidence of procyclical mortality for females at the aggregate level; aggregate male mortality remains largely unaffected by economic fluctuations. Our findings also reveal temporal heterogeneity, as the extensive margin becomes the driving force for female mortality rates during the more recent period (1990 onwards). These findings remain robust when accounting for personal income and pollution. Finally, we find some support for a procyclical relationship for individuals in the working age groups, while mortality exhibits a countercyclical pattern for children (age 0 to 14) and the elderly (age 65 and above).
Early detection of prostate cancer: a screening charity's perspective
Authors: Booth Chris
Published: February 2024

CHAPS Men's Health Charity is playing a key role in raising awareness of prostate cancer in the UK. In particular, it seeks to educate both the public and health care professionals on the importance of early diagnosis and campaigns for a national prostate cancer screening programme.
Self‐awareness, empathy, and inclusion: a powerful trio
Authors: Engbrecht Jason , Hoefferle Caroline , Jasper Daniel , Williams Hilary
Published: February 2024

Leading with empathy is a hallmark of many leadership strategies. As members of the 2021–2022 cohort of the Senior Leadership Academy (SLA) run by the Council of Independent Colleges (CIC) and the American Academic Leadership Institute (AALI), we set out to understand what leading with empathy should look like. Simultaneously, as part of our introversion and leadership group project, we conducted both secondary research and primary research interviews with introverted leaders on our group members’ campuses. Our examination happened during a time in which colleges and universities were just beginning to sort out what postpandemic higher education would look like. Events such as the murder of George Floyd were also shining a spotlight in higher education on diversity, equity, and inclusion. This context only served to highlight for us the need to center empathy in leadership conversations and reinforced lessons we were learning from our personal experiences, from our institutions, from our SLA colleagues, and from each other. Here we present some of the lessons we have learned about understanding ourselves as leaders and how that understanding can inform the way we respond to those we lead with empathy.
Locoregional therapies for hepatocellular carcinoma: The current status and future perspectives
Authors: Chen Jian‐Jian , Jin Zhi‐Cheng , Zhong Bin‐Yan , Fan Wenzhe , Zhang Wei‐Hua , Luo Biao , Wang Yu‐Qing , Teng Gao‐Jun , Zhu Hai‐Dong
Published: February 2024

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer‐related mortality. Locoregional therapies (LRTs) play a crucial role in HCC management and are selectively adopted in real‐world practice across various stages. Choosing the best form of LRTs depends on technical aspects, patient clinical status and tumour characteristics. Previous studies have consistently highlighted the efficacy of combining LRTs with molecular targeted agents in HCC treatment. Recent studies propose that integrating LRTs with immune checkpoint inhibitors and molecular targeted agents could provide substantial therapeutic benefits, a notion underpinned by both basic and clinical evidence. This review summarised the current landscape of LRTs in HCC and discussed the anticipated outcomes of combinations with immunotherapy regimens.
Nepal
Authors: Devkota Khim Lal , Khanal Gopi Krishna
Published: February 2024

The Constitution of 2015 provides local governments ample space within which to safeguard their political, fiscal, and administrative autonomy. It fully recognises them as an integral part of federalism in Nepal. Their powers and functions are broadly outlined in the Constitution, which embraces the principles of federalism, inclusiveness, and republicanism and envisages non-hierarchical relationships among the three levels of government. The main responsibility of the local level is to deliver essential basic services to the people. The Local Government Operation Act, 2017 provides detailed descriptions of the power and functions of local governments in this regard. Local governments meet their expenditure needs mainly through tax revenues, fiscal transfers, borrowings, and royalties on natural resources. Citizens have great faith and trust in the local level. Nepali citizens have more confidence in the local government than the federal and provincial governments.
Nigeria
Authors: Suberu Rotimi T.
Published: February 2024

Major constitutional reforms in Nigeria positioned local government as the third tier of the country’s federal system after the central government and the states. The reforms entrenched the boundaries of Local Government Areas (LGAs); codified a schedule of exclusive, advisory, and concurrent functions for the localities; mandated the transfer of federal and state revenue to local authorities; and guarantee the existence of democratically elected local councils. Despite the grand constitutional rhetoric of three-tier federalism, however, local government in Nigeria remains chronically weak and thereby contributes to the violent instability plaguing the north-east and other areas of the country. Local government has hardly been reflective of the agency of local grassroots’ communities. Instead, the centralising agendas of a paternalistic federal government, and the political machinations of predatory subnational state governments, have undermined the development of truly local institutions of government. This chapter examines the historical, constitutional, and intergovernmental contexts of Nigeria’s delocalised local government system.
South Africa
Authors: de Visser Jaap
Published: February 2024

Since the year 2000, local government has entered South Africa’s system of intergovernmental relations with a new institutional appearance and has been granted constitutional protection. Intergovernmental relations among municipalities, provinces, and the national government have thus become more dynamic yet also more complex and demanding. This chapter analyses the constitutional and policy frameworks for those relations, and provides insight into current debates and the dynamics related to them. The legal and constitutional recognition of local government is impressive and propels it to a status that at times equals or surpasses that of provincial government. Yet this constitutional status provides no guarantee of strong local government. In reality, many municipalities are incapable of asserting their financial and political autonomy for reasons both within and beyond their control.
Argentina
Authors: Avila Penélope Vaca
Published: February 2024

In terms of its Constitution of 1853, Argentina is a federal, republican, and democratic state. It has 24 subnational districts (23 provinces and the Autonomous City of Buenos Aires (CABA), which has special status) and about 2400 local governments (municipalities and others). Local governments are democratically elected by the citizens, and their autonomy is constitutionally recognised. The legal status of local governments is regulated largely in provincial laws and constitutions, as a result of which they enjoy wide heterogeneity in size, powers, tax capacity, and electoral rules. Despite their limited ability to collect taxes, their chronic impecunity, and their moderate organisational capacity, Argentine local governments play a growing role in political and social life—a fact which was spotlighted during the Covid-19 crisis.
Canada
Authors: Slack Enid , Taylor Zack
Published: February 2024

The vast majority of Canadians live within the jurisdiction of a general-purpose municipality to which they elect representatives and pay taxes and fees, and from which they receive a wide range of services. Municipalities function in a variety of contexts, from ones of rapid growth, as in metropolitan areas, to ones of relative or absolute decline, as occurs on the periphery. More widely, they function in a context of intergovernmental entanglement: in Canada, local governance is multilevel governance.  As local governments are creations of provincial legislation, their legal authority and fiscal resources are defined by the provinces. The Covid-19 pandemic has intensified debates regarding the constraints imposed by municipalities’ constitutional position.
Problem Solving in East Africa: A Contextualised Approach to Defining the Construct
Authors: Care Esther , Giacomazzi Mauro
Published: February 2024

Problem solving is a term that describes a vast number of processes and applications. Countries in East Africa, as well as globally, are looking to equip their young people with problem-solving competencies, which are then hoped to resolve the major issues that all societies confront. Accordingly, it is one of the competencies included in curricula developed by East African education systems. The development of conceptual and assessment frameworks by the ALiVE team was contextualised through reference to recent research undertaken in the ALiVE participating countries. Aspects of this conceptualisation differ from those used in most large-scale assessments; and the ALiVE approach to design and development of the assessment was construct-driven. This means that the form of the assessment tasks, coding criteria, and intended reporting style, are determined by the substance of the construct and how visible signs of this substance might best be captured. The framework was developed through a realistic appraisal of what would be possible to assess at household level. In development of the assessment tool, three factors were considered: the nature of the construct itself; the medium through which the assessment would be conducted; and the use to which the assessment results would be put. The chapter describes the formal process followed in defining problem solving and developing its assessment tools. A set of six workshops attended by 47 representatives of the collaborating organisations structured the process of creation; initially engaging at a level of simplicity to ground differing understandings of the skill, and then moving to the complexity of test and scale development processes. The data from the large-scale assessment indicate that ALiVE’s measurement of problem solving is robust, with the results reflecting maturation with more education. This means that instructional time in the context of a general curriculum is providing a learning environment in which problem-solving processes can be nurtured.
The Strong Force meets the Dark Sector: a robust estimate of QCD uncertainties for anti-matter dark matter searches
Authors: Jueid Adil , Kip Jochem , Ruiz de Austri Roberto , Skands Peter
Published: February 2024

Abstract

In dark-matter annihilation channels to hadronic final states, stable particles — such as positrons, photons, antiprotons, and antineutrinos — are produced via complex sequences of phenomena including QED/QCD radiation, hadronisation, and hadron decays. These processes are normally modelled by Monte Carlo (MC) event generators whose limited accuracy imply intrinsic QCD uncertainties on the predictions for indirect-detection experiments like Fermi-LAT, Pamela, IceCube or Ams–02. In this article, we perform a comprehensive analysis of QCD uncertainties, meaning both perturbative and nonperturbative sources of uncertainty are included — estimated via variations of MC renormalization-scale and fragmentation-function parameters, respectively — in antimatter spectra from dark-matter annihilation, based on parametric variations of the Pythia 8 event generator. After performing several retunings of light-quark fragmentation functions, we define a set of variations that span a conservative estimate of the QCD uncertainties. We estimate the effects on antimatter spectra for various annihilation channels and final-state particle species, and discuss their impact on fitted values for the dark-matter mass and thermally-averaged annihilation cross section. We find dramatic impacts which can go up to $$ \mathcal{O} $$
O
(40) GeV for uncertainties on the dark-matter mass and up to $$ \mathcal{O} $$
O
(10%) for the annihilation cross section. We provide the spectra in tabulated form including QCD uncertainties and code snippets to perform fast dark-matter fits, in this github repository.
Probing axion-like particles at the Electron-Ion Collider
Authors: Balkin Reuven , Hen Or , Li Wenliang , Liu Hongkai , Ma Teng , Soreq Yotam , Williams Mike
Published: February 2024

Abstract

The Electron-Ion Collider (EIC), a forthcoming powerful high-luminosity facility, represents an exciting opportunity to explore new physics. In this article, we study the potential of the EIC to probe the coupling between axion-like particles (ALPs) and photons in coherent scattering. The ALPs can be produced via photon fusion and decay back to two photons inside the EIC detector. In a prompt-decay search, we find that the EIC can set the most stringent bound for ma ≲ 20 GeV and probe the effective scales Λ ≲ 105 GeV. In a displaced-vertex search, which requires adopting an EM calorimeter technology that provides directionality, the EIC could probe ALPs with ma ≲ 1 GeV at effective scales Λ ≲ 107 GeV. Combining the two search strategies, the EIC can probe a significant portion of unexplored parameter space in the 0.2 < ma < 20 GeV mass range.
A Necessary Condition on a Singular Kernel for the Continuity of an Integral Operator in Hölder Spaces
Authors: Lanza de Cristoforis Massimo
Published: February 2024

We prove that a condition of boundedness of the maximal function of a singular integral operator, that is known to be sufficient for the continuity of a corresponding integral operator in Hölder spaces, is actually also necessary in case the action of the integral operator does not decrease the regularity of a function. We do so in the frame of metric measured spaces with a measure satisfying certain growth conditions that include nondoubling measures. Then we present an application to the case of an integral operator defined on a compact differentiable manifold.
Targeted CRISPR activation is functional in engineered human pluripotent stem cells but undergoes silencing after differentiation into cardiomyocytes and endothelium
Authors: Karbassi Elaheh , Padgett Ruby , Bertero Alessandro , Reinecke Hans , Klaiman Jordan M. , Yang Xiulan , Hauschka Stephen D. , Murry Charles E.
Published: February 2024

Human induced pluripotent stem cells (hiPSCs) offer opportunities to study human biology where primary cell types are limited. CRISPR technology allows forward genetic screens using engineered Cas9-expressing cells. Here, we sought to generate a CRISPR activation (CRISPRa) hiPSC line to activate endogenous genes during pluripotency and differentiation. We first targeted catalytically inactive Cas9 fused to VP64, p65 and Rta activators (dCas9-VPR) regulated by the constitutive CAG promoter to the AAVS1 safe harbor site. These CRISPRa hiPSC lines effectively activate target genes in pluripotency, however the dCas9-VPR transgene expression is silenced after differentiation into cardiomyocytes and endothelial cells. To understand this silencing, we systematically tested different safe harbor sites and different promoters. Targeting to safe harbor sites hROSA26 and CLYBL loci also yielded hiPSCs that expressed dCas9-VPR in pluripotency but silenced during differentiation. Muscle-specific regulatory cassettes, derived from cardiac troponin T or muscle creatine kinase promoters, were also silent after differentiation when dCas9-VPR was introduced. In contrast, in cell lines where the dCas9-VPR sequence was replaced with cDNAs encoding fluorescent proteins, expression persisted during differentiation in all loci and with all promoters. Promoter DNA was hypermethylated in CRISPRa-engineered lines, and demethylation with 5-azacytidine enhanced dCas9-VPR gene expression. In summary, the dCas9-VPR cDNA is readily expressed from multiple loci during pluripotency but induces silencing in a locus- and promoter-independent manner during differentiation to mesoderm derivatives. Researchers intending to use this CRISPRa strategy during stem cell differentiation should pilot their system to ensure it remains active in their population of interest.
Cellular forgetting, desensitisation, stress and ageing in signalling networks. When do cells refuse to learn more?
Authors: Veres Tamás , Kerestély Márk , Kovács Borbála M. , Keresztes Dávid , Schulc Klára , Seitz Erik , Vassy Zsolt , Veres Dániel V. , Csermely Peter
Published: February 2024

Recent findings show that single, non-neuronal cells are also able to learn signalling responses developing cellular memory. In cellular learning nodes of signalling networks strengthen their interactions e.g. by the conformational memory of intrinsically disordered proteins, protein translocation, miRNAs, lncRNAs, chromatin memory and signalling cascades. This can be described by a generalized, unicellular Hebbian learning process, where those signalling connections, which participate in learning, become stronger. Here we review those scenarios, where cellular signalling is not only repeated in a few times (when learning occurs), but becomes too frequent, too large, or too complex and overloads the cell. This leads to desensitisation of signalling networks by decoupling signalling components, receptor internalization, and consequent downregulation. These molecular processes are examples of anti-Hebbian learning and ‘forgetting’ of signalling networks. Stress can be perceived as signalling overload inducing the desensitisation of signalling pathways. Ageing occurs by the summative effects of cumulative stress downregulating signalling. We propose that cellular learning desensitisation, stress and ageing may be placed along the same axis of more and more intensive (prolonged or repeated) signalling. We discuss how cells might discriminate between repeated and unexpected signals, and highlight the Hebbian and anti-Hebbian mechanisms behind the fold-change detection in the NF-κB signalling pathway. We list drug design methods using Hebbian learning (such as chemically-induced proximity) and clinical treatment modalities inducing (cancer, drug allergies) desensitisation or avoiding drug-induced desensitisation. A better discrimination between cellular learning, desensitisation and stress may open novel directions in drug design, e.g. helping to overcome drug resistance.
Challenges of responsible AI in practice: scoping review and recommended actions
Authors: Sadek Malak , Kallina Emma , Bohné Thomas , Mougenot Céline , Calvo Rafael A. , Cave Stephen
Published: February 2024

Responsible AI (RAI) guidelines aim to ensure that AI systems respect democratic values. While a step in the right direction, they currently fail to impact practice. Our work discusses reasons for this lack of impact and clusters them into five areas: (1) the abstract nature of RAI guidelines, (2) the problem of selecting and reconciling values, (3) the difficulty of operationalising RAI success metrics, (4) the fragmentation of the AI pipeline, and (5) the lack of internal advocacy and accountability. Afterwards, we introduce a number of approaches to RAI from a range of disciplines, exploring their potential as solutions to the identified challenges. We anchor these solutions in practice through concrete examples, bridging the gap between the theoretical considerations of RAI and on-the-ground processes that currently shape how AI systems are built. Our work considers the socio-technical nature of RAI limitations and the resulting necessity of producing socio-technical solutions.
Comparative investigation and optimization of cutting tools performance during milling machining of titanium alloy (Ti6Al4V) using response surface methodology
Authors: Phokobye Solomon Ntshiniki , Desai Dawood Ahmed , Tlhabadira Isaac , Sadiku Emmanuel Rotimi , Mutombo Kalenda
Published: February 2024

The purpose of this paper is to study the optimization of the cutting performance of three different cutting inserts, during the machining operation of titanium alloy (Ti6Al4V) by making use of the response surface methodology (RSM) on a computer numerical control (CNC) milling. The cutting tools employed for the optimisation of the cutting performance during machining operation are silicon, aluminium, oxygen, nitrogen (SiAlON), cubic-boron nitride and carbide cutting inserts. Scanning electron microscope (SEM) was used for the determination of the tool wear for the cutting inserts being compared during machining of Ti6Al4V, and the cutting parameters, which are cutting speed (Vc), feed per tooth (fz) and depth-of-cut that were evaluated from the cutting tools as per the manufacturer’s design specifications. The determination of the tool wear on the cutting inserts was achieved by using the SEM, while the machining operation for the experimental trails was performed from the CNC milling machine, where face milling operation was executed. The optimization process showed that carbide cutting inserts yielded the best performing results and were considered the most significant choice of cutting insert in machining Ti6Al4V when compared to SiAlON and CBN cutting inserts. This choice was from the cutting tool life obtained where a cutting tool life of 29 min was obtained from a use of carbide cutting inserts; 28 min resulted from a use SiAlON cutting inserts and 26 min from a use of CBN cutting inserts. This work finds appropriate value in assisting the machinists in the selection of the best most performing and cost-effective cutting tool.
Overlapping coefficient in network-based semi-supervised clustering
Authors: Conversano Claudio , Frigau Luca , Contu Giulia
Published: February 2024

Network-based Semi-Supervised Clustering (NeSSC) is a semi-supervised approach for clustering in the presence of an outcome variable. It uses a classification or regression model on resampled versions of the original data to produce a proximity matrix that indicates the magnitude of the similarity between pairs of observations measured with respect to the outcome. This matrix is transformed into a complex network on which a community detection algorithm is applied to search for underlying community structures which is a partition of the instances into highly homogeneous clusters to be evaluated in terms of the outcome. In this paper, we focus on the case the outcome variable to be used in NeSSC is numeric and propose an alternative selection criterion of the optimal partition based on a measure of overlapping between density curves as well as a penalization criterion which takes accounts for the number of clusters in a candidate partition. Next, we consider the performance of the proposed method for some artificial datasets and for 20 different real datasets and compare NeSSC with the other three popular methods of semi-supervised clustering with a numeric outcome. Results show that NeSSC with the overlapping criterion works particularly well when a reduced number of clusters are scattered localized.
Immune-related serious adverse events with immune checkpoint inhibitors: Systematic review and network meta-analysis
Authors: Oliveira Clara , Mainoli Beatrice , Duarte Gonçalo S. , Machado Tiago , Tinoco Rita G. , Esperança-Martins Miguel , Ferreira Joaquim J. , Costa João
Published: February 2024

Purpose

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs.

Methods

We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA).

Results

We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients).

Conclusion

Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients.