bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural correlates of blood flow measured by ultrasound
Authors: Nunez-Elizalde Anwar O. , Krumin Michael , Bai Reddy Charu , Montaldo Gabriel , Urban Alan , Harris Kenneth D. , Carandini Matteo
Published: April 2021

Functional ultrasound imaging (fUSI) is a popular method for measuring blood flow and thus infer brain activity, but it relies on the physiology of neurovascular coupling and requires extensive signal processing. To establish to what degree its trial-by-trial signals reflect neural activity, we performed simultaneous fUSI and neural recordings with Neuropixels probes in awake mice. fUSI signals strongly correlated with the slow (<0.3 Hz) fluctuations in local firing rate, and were closely predicted by the smoothed firing rate of local neurons, particularly putative inhibitory neurons. The optimal smoothing filter had width ~3 s, matched the hemodynamic response function of awake mouse, was invariant across mice and stimulus conditions, and similar in cortex and hippocampus. fUSI signals also matched neural firing spatially: firing rates were as highly correlated across hemispheres as fUSI signals. Thus, hemodynamic signals measured by ultrasound bear a simple and accurate relationship to neuronal firing.
Structural dynamics of the β-coronavirus Mpro protease ligand binding sites
Authors: Cho Eunice , Rosa Margarida , Anjum Ruhi , Mehmood Saman , Soban Mariya , Mujtaba Moniza , Bux Khair , Dantu Sarath , Pandini Alessandro , Yin Junqi , Ma Heng , Ramanathan Arvind , Islam Barira , Mey Antonia S J S , Bhowmik Debsindhu , Haider Shozeb
Published: April 2021

β-coronaviruses alone have been responsible for three major global outbreaks in the 21st century. The current crisis has led to an urgent requirement to develop therapeutics. Even though a number of vaccines are available, alternative strategies targeting essential viral components are required as a back-up against the emergence of lethal viral variants. One such target is the main protease (Mpro) that plays an indispensible role in viral replication. The availability of over 270 Mpro X-ray structures in complex with inhibitors provides unique insights into ligand-protein interactions. Herein, we provide a comprehensive comparison of all non-redundant ligand-binding sites available for SARS-CoV2, SARS-CoV and MERS-CoV Mpro. Extensive adaptive sampling has been used to explore conformational dynamics employing convolutional variational auto encoder-based deep learning, and investigates structural conservation of the ligand binding sites using Markov state models across β-coronavirus homologs. Our results indicate that not all ligand-binding sites are dynamically conserved despite high sequence and structural conservation across β-coronavirus homologs. This highlights the complexity in targeting all three Mpro enzymes with a single pan inhibitor.
Age differences in the functional architecture of the human brain
Authors: Setton Roni , Mwilambwe-Tshilobo Laetitia , Girn Manesh , Lockrow Amber W. , Baracchini Giulia , Hughes Colleen , Lowe Alexander J. , Cassidy Benjamin N. , Li Jian , Luh Wen-Ming , Bzdok Danilo , Leahy Richard M. , Ge Tian , Margulies Daniel S. , Misic Bratislav , Bernhardt Boris C. , Stevens W. Dale , De Brigard Felipe , Kundu Prantik , Turner Gary R. , Spreng R. Nathan
Published: April 2021

The intrinsic functional organization of the brain changes into older adulthood. Age differences are observed at multiple spatial scales, from global reductions in modularity and segregation of distributed brain systems, to network-specific patterns of dedifferentiation. Whether dedifferentiation reflects an inevitable, global shift in brain function with age, circumscribed, experience dependent changes, or both, is uncertain. We employed a multi-method strategy to interrogate dedifferentiation at multiple spatial scales. Multi-echo (ME) resting-state fMRI was collected in younger (n=181) and older (n=120) healthy adults. Cortical parcellation sensitive to individual variation was implemented for precision functional mapping of each participant, while preserving group-level parcel and network labels. ME-fMRI processing and gradient mapping identified global and macroscale network differences. Multivariate functional connectivity methods tested for microscale, edge-level differences. Older adults had lower BOLD signal dimensionality, consistent with global network dedifferentiation. Gradients were largely age-invariant. Edge-level analyses revealed discrete, network-specific dedifferentiation patterns in older adults. Visual and somatosensory regions were more integrated within the functional connectome; default and frontoparietal control network regions showed greater connectivity; and the dorsal attention network was more integrated with heteromodal regions. These findings highlight the importance of multi-scale, multi-method approaches to characterize the architecture of functional brain aging.
Influence of substrate stiffness on barrier function in an iPSC-derived in vitro blood-brain barrier model
Authors: Bosworth Allison M. , Kim Hyosung , O’Grady Kristin P. , Richter Isabella , Lee Lynn , O’Grady Brian J. , Lippmann Ethan S.
Published: April 2021

Introduction

Vascular endothelial cells respond to a variety of biophysical cues such as shear stress and substrate stiffness. In peripheral vasculature, extracellular matrix (ECM) stiffening alters barrier function, leading to increased vascular permeability in atherosclerosis and pulmonary edema. The effect of ECM stiffness on blood-brain barrier (BBB) endothelial cells, however, has not been explored. To investigate this topic, we incorporated hydrogel substrates into an in vitro model of the human BBB.

Methods

Induced pluripotent stem cells were differentiated to brain microvascular endothelial-like (BMEC-like) cells and cultured on hydrogel substrates of varying stiffness. Cellular changes were measured by imaging, functional assays such as transendothelial electrical resistance (TEER) and p-glycoprotein efflux activity, and bulk transcriptome readouts.

Results

The magnitude and longevity of TEER in iPSC-derived BMEC-like cells is enhanced on compliant substrates. Quantitative imaging shows that BMEC-like cells form fewer intracellular actin stress fibers on substrates of intermediate stiffness (20 kPa relative to 1 kPa and 150 kPa). Chemical induction of actin polymerization leads to a rapid decline in TEER, agreeing with imaging readouts. P-glycoprotein activity is unaffected by substrate stiffness. Modest differences in RNA expression corresponding to specific signaling pathways were observed as a function of substrate stiffness.

Conclusions

iPSC-derived BMEC-like cells exhibit differences in passive but not active barrier function in response to substrate stiffness. These findings may provide insight into BBB dysfunction during neurodegeneration, as well as aid in the optimization of more complex threedimensional neurovascular models utilizing compliant hydrogels.
OME-NGFF: scalable format strategies for interoperable bioimaging data
Authors: Moore Josh , Allan Chris , Besson Sebastien , Burel Jean-Marie , Diel Erin , Gault David , Kozlowski Kevin , Lindner Dominik , Linkert Melissa , Manz Trevor , Moore Will , Pape Constantin , Tischer Christian , Swedlow Jason R.
Published: April 2021

Biological imaging is one of the most innovative fields in the modern biological sciences. New imaging modalities, probes, and analysis tools appear every few months and often prove decisive for enabling new directions in scientific discovery. One feature of this dynamic field is the need to capture new types of data and data structures. While there is a strong drive to make scientific data Findable, Accessible, Interoperable and Reproducible (FAIR1), the rapid rate of innovation in imaging impedes the unification and adoption of standardized data formats. Despite this, the opportunities for sharing and integrating bioimaging data and, in particular, linking these data to other “omics” datasets have never been greater. Therefore, to every extent possible, increasing “FAIRness” of bioimaging data is critical for maximizing scientific value, as well as for promoting openness and integrity.

In the absence of a common, FAIR format, two approaches have emerged to provide access to bioimaging data: translation and conversion. On-the-fly translation produces a transient representation of bioimage metadata and binary data but must be repeated on each use. In contrast, conversion produces a permanent copy of the data, ideally in an open format that makes the data more accessible and improves performance and parallelization in reads and writes. Both approaches have been implemented successfully in the bioimaging community but both have limitations. At cloud-scale, those shortcomings limit scientific analysis and the sharing of results. We introduce here next-generation file formats (NGFF) as a solution to these challenges.
Attention improves information flow between neuronal populations without changing the communication subspace
Authors: Srinath Ramanujan , Ruff Douglas A. , Cohen Marlene R.
Published: April 2021

Visual attention allows observers to flexibly use or ignore visual information, suggesting that information can be flexibly routed between visual cortex and neurons involved in decision-making. We investigated the neural substrate of flexible information routing by analyzing the activity of populations of visual neurons in the medial temporal area (MT) and oculomotor neurons in the superior colliculus (SC) while rhesus monkeys switched spatial attention. We demonstrated that attention increases the efficacy of visuomotor communication: trial-to-trial variability of the population of SC neurons was better predicted by the activity of MT neurons (and vice versa) when attention was directed toward their joint receptive fields. Surprisingly, this improvement in prediction was not explained or accompanied by changes in the dimensionality of the shared subspace or in local or shared pairwise noise correlations. These results suggest a mechanism by which visual attention can affect perceptual decision-making without altering local neuronal representations.
The Time Complexity of Self-Assembly
Authors: Gartner Florian M. , Graf Isabella R. , Frey Erwin
Published: April 2021

Time efficiency of self-assembly is crucial for many biological processes. Moreover, with the advances of nanotechnology, time efficiency in artificial self-assembly becomes ever more important. While structural determinants and the final assembly yield are increasingly well understood, kinetic aspects concerning the time efficiency, however, remain much more elusive. In computer science, the concept oftime complexityis used to characterize the efficiency of an algorithm and describes how the algorithm’s runtime depends on the size of the input data. Here we characterize the time complexity of non-equilibrium self-assembly processes by exploring how the time required to realize a certain, substantial yield of a given target structure scales with its size. We identify distinct classes of assembly scenarios, i.e. ‘algorithms’ to accomplish this task, and show that they exhibit drastically different degrees of complexity. Our analysis enables us to identify optimal control strategies for non-equilibrium self-assembly processes. Furthermore, we suggest an efficient irreversible scheme for the artificial self-assembly of nanostructures, which complements the state-of-the-art approach using reversible binding reactions and requires no fine-tuning of binding energies.
Tissue specific requirements for ECSIT in mitochondrial complex I assembly
Authors: Nicol Thomas L , Falcone Sara , Blease Andrew , Vikhe Pratik , Civiletto Gabriele , Omairi Saleh Salman , Viscomi Carlo , Patel Ketan , Potter Paul K
Published: April 2021

Here we describe a mutation in the mitochondrial complex I assembly factor (Evolutionarily conserved signalling intermediate in Toll pathway) ECSIT which reveals tissue specific requirements for this factor in complex I assembly. Mitochondrial complex I assembly is a multi-step process dependant on assembly factors that organise and arrange the individual subunits, allowing for their incorporation into the complete enzyme complex. We have identified an ENU induced mutation in ECSIT (N209I) that exhibits a profound effect on complex I assembly only in heart tissue resulting in hypertrophic cardiomyopathy in the absence of other phenotypes. Mitochondrial function was reduced by 98% in mitochondria isolated from cardiac tissue but mitochondria from other tissues such as skeletal muscle, brain, liver, and kidney were unaffected. This data suggests the mechanisms underlying complex I assembly are tissue specific and has implications in understanding the pathogenesis of cardiomyopathy.
Acylation of the incretin peptide exendin-4 directly impacts GLP-1 receptor signalling and trafficking
Authors: Lucey Maria , Ashik Tanyel , Marzook Amaara , Wang Yifan , Goulding Joëlle , Oishi Atsuro , Broichhagen Johannes , Hodson David J , Minnion James , Elani Yuval , Jockers Ralf , Briddon Stephen J , Bloom Stephen R , Tomas Alejandra , Jones Ben
Published: April 2021

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitisation and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to promote albumin binding in order to prolong their pharmacokinetics, but the potential for these ligand changes to influence GLP-1R signalling has rarely been investigated beyond potency assessments for cyclic adenosine monophosphate (cAMP). In this work we directly compare the prototypical GLP-1RA exendin-4 with its C-terminally acylated analogue, exendin-4-C16, for their relative propensities to recruit and activate G proteins and β-arrestins, endocytic and post-endocytic trafficking profiles, and interactions with model and cellular membranes. Both ligands had similar cAMP potency but the exendin-4-C16 showed ∼2.5-fold bias towards G protein recruitment and a ∼60% reduction in β-arrestin-2 recruitment efficacy compared to exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting towards recycling pathways. These effects were associated with a reduced ability to promote the movement of the GLP-1R extracellular domain, as determined using a conformational biosensor approach, and a ∼70% increase in insulin secretion. Interactions with plasma membrane lipids were enhanced by the acyl chain. Exendin-4-C16 showed extensive albumin binding and was highly effective for lowering of blood glucose in mice over at least 72 hours. Overall, our study highlights the importance of a broad approach to the evaluation of GLP-1RA pharmacology.

Significance statement

Acylation is a common strategy to enhance the pharmacokinetics of peptide-based drugs. Our work shows how acylation can also affect various other pharmacological parameters, including biased agonism, receptor trafficking and interactions with the plasma membrane, which may be therapeutically important.
Genetic basis of chemical communication in eusocial insects
Authors: Yan Hua , Liebig Jürgen
Published: April 2021

Social behavior is one of the most fascinating and complex behaviors in humans and animals. A fundamental process of social behavior is communication among individuals. It relies on the capability of the nervous system to sense, process, and interpret various signals (e.g., pheromones) and respond with appropriate decisions and actions. Eusocial insects, including ants, some bees, some wasps, and termites, display intriguing cooperative social behavior. Recent advances in genetic and genomic studies have revealed key genes that are involved in pheromone synthesis, chemosensory perception, and physiological and behavioral responses to varied pheromones. In this review, we highlight the genes and pathways that regulate queen pheromone-mediated social communication, discuss the evolutionary changes in genetic systems, and outline prospects of functional studies in sociobiology.
Sustainability rating and moral fictionalism: opening the black box of nonfinancial agencies
Authors: Boiral Olivier , Talbot David , Brotherton Marie-Christine , Heras-Saizarbitoria Iñaki
Published: April 2021

Purpose

The purpose of this paper is to explore the practices, challenges and ethical issues underlying the fabric and dissemination of corporate sustainability ratings.

Design/methodology/approach

Based on 36 semi-structured interviews with sustainability rating practitioners, the study shows the trade-offs, ethical judgments and customizable aspects involved in rating practices, which cannot rely only on formal and predefined methods.

Findings

In contrast with the official optimistic rhetoric about the rationality and rigor of sustainability rating methods, agencies face serious challenges in the measurement and comparison of performance in this area, particularly in terms of the aggregation of scattered and fuzzy indicators, commercial pressures and the availability, materiality and reliability of the information collected. Despite these concerns, sustainability ratings do appear to be useful in improving corporate responsiveness and increasing investor awareness of the complex and difficult-to-measure aspects of nonfinancial reports.

Practical implications

Rating agencies should collaborate to set up common indicators that would be easier for firms to produce and should better separate their sustainability rating production activities from other services they offer to companies (e.g. consultancy).

Originality/value

This study contributes to the literature on the measurement and promotion of corporate sustainability by analyzing rating practices through the lens of moral fictionalism, which here refers to the human tendency to build ethical judgments on fictional but convenient and useful representations.
Artificial intelligence video interviewing for employment: perspectives from applicants, companies, developer and academicians
Authors: Kim Jin-Young , Heo WanGyu
Published: April 2021

Purpose

In 2018, an artificial intelligence (AI) interview platform was introduced and adopted by companies in Korea. This study aims to explore the perspectives of applicants who have experienced an AI-based interview through this platform and examines the opinions of companies, a platform developer and academia.

Design/methodology/approach

This study uses a phenomenological approach. The participants, who had recent experience of AI video interviews, were recruited offline and online. Eighteen job applicants in their 20s, two companies that have adopted this interview platform, a software developer who created the platform and three professors participated in the study. To collect data, focus group interviews and in-depth interviews were conducted.

Findings

As a result, all of them believed that an AI-based interview was more efficient than a traditional one in terms of cost and time savings and is likely to be adopted by more companies in the future. They pointed to the possibility of data bias requiring an improvement in AI accountability. Applicants perceived an AI-based interview to be better than traditional evaluation procedures in procedural fairness, objectivity and consistency of algorithms. However, some applicants were dissatisfied about being assessed by AI. Digital divide and automated inequality were recurring themes in this study.

Originality/value

The study is important, as it addresses the real application of AI in detail, and a case study of smart hiring tools would be valuable in finding the practical and theoretical implications of such hiring in the fields of employment and AI.
E-participation decision across different channels
Authors: Yao Yurong , Xu Peng
Published: April 2021

Purpose

This study focuses on understanding how channel features can affect people's intention to continue to use an electronic channel in public affairs and their recommendation behaviors. Specifically, three different channels are focused on: email, microblogs and online meetings.

Design/methodology/approach

A research model on an e-participation channel based on the channel-disposition framework was developed and an online survey was conducted to collect data from 397 individuals who used three e-participation channels to validate seven hypotheses.

Findings

The study found that information quality, channel interaction quality and the social appearance of other citizens all had a significant impact on users' intention to continue to use an electronic channel, which, in turn, affected their recommendation behaviors. However, the impact differed across the three e-participation channels. Information quality had a stronger impact on microblog and online meeting users' intention to continue to use these channels than on email users' intention to continue using email to participate in public affairs. Channel interaction quality had a stronger impact on email users' intention to continue to use email than on microblog and online meeting users' intention to continue to use these channels in public affairs.

Originality/value

This study helps better explain how various channels and their features can affect participants' use intentions and behaviors in e-participation. It also provides practical guidance for government to better manage e-participation channels and effectively engage citizens in public affairs.
Children of the palms: growing plants and growing people in a Papuan Plantationocene
Authors: Chao Sophie
Published: April 2021

This article explores how ecological change transforms children and child‐rearing among Indigenous Marind in West Papua. Marind children become ‘anim' (persons) by immersing themselves within the ecology of sago palms and their suckers, or ‘sago children’. Conversely, deforestation and oil palm expansion – the defining traits of the place, period, and production mode I term ‘Papuan Plantationocene’ – subvert the mutual maturation of humans and sago by confining children to the oppressive environment of the village and preventing them from supporting sago's growth through sago transplanting and felling. Meanwhile, oil palm itself is alternately characterized by Marind as a vulnerable child subjected to totalizing human control and as a figure of hope for future Marind generations. The article provides a deeper and broader consideration of ‘childhood’ beyond the human in understanding how monocrop capitalist production reconfigures the form and possibility of multispecies social reproduction for people and plants.
The effect of various herbs and packaging material on antioxidant activity and colour parameters of whey (Lor) cheese
Authors: Akan Ecem , Yerlikaya Oktay , Akpinar Asli , Karagozlu Cem , Kinik Ozer , Uysal Harun Rasit
Published: April 2021

This study aimed to research the effects of some herbs and the packaging material on total phenolic compound content and the antioxidant activity of Lor cheeses. The total phenolic content and antioxidant activity of Lor cheeses containing only black cumin were found to be significantly lower than cheeses containing black cumin and rosemary or black cumin and thyme (P < 0.05). 2,2‐azino‐di‐(3‐ethylbenzothialozine‐ sulfonic acid) (ABTS) and Cupric Ion Reducing Antioxidant Capacity (CUPRAC) methods were found to be more reliable than the 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) method in evaluating the antioxidant activity of herbs added to Lor cheeses. It has been observed that the packaging material effects the antioxidant activity of the samples differently during the storage.
Testing for association in multiview network data
Authors: Gao Lucy L. , Witten Daniela , Bien Jacob
Published: April 2021

In this paper, we consider data consisting of multiple networks, each composed of a different edge set on a common set of nodes. Many models have been proposed for the analysis of such multiview network data under the assumption that the data views are closely related. In this paper, we provide tools for evaluating this assumption. In particular, we ask: given two networks that each follow a stochastic block model, is there an association between the latent community memberships of the nodes in the two networks? To answer this question, we extend the stochastic block model for a single network view to the two‐view setting, and develop a new hypothesis test for the null hypothesis that the latent community memberships in the two data views are independent. We apply our test to protein–protein interaction data from the HINT database. We find evidence of a weak association between the latent community memberships of proteins defined with respect to binary interaction data and the latent community memberships of proteins defined with respect to cocomplex association data. We also extend this proposal to the setting of a network with node covariates. The proposed methods extend readily to three or more network/multivariate data views.
Debugging by design: A constructionist approach to high school students' crafting and coding of electronic textiles as failure artefacts
Authors: Fields Deborah A. , Kafai Yasmin B. , Morales‐Navarro Luis , Walker Justice T.
Published: April 2021

Much attention in constructionism has focused on designing tools and activities that support learners in designing fully finished and functional applications and artefacts to be shared with others. But helping students learn to debug their applications often takes on a surprisingly more instructionist stance by giving them checklists, teaching them strategies or providing them with test programmes. The idea of designing bugs for learning—or debugging by design—makes learners agents of their own learning and, more importantly, of making and solving mistakes. In this paper, we report on our implementation of ‘Debugging by Design’ activities in a high school classroom over a period of 8 hours as part of an electronic textiles unit. Students were tasked to craft the electronic textile artefacts with problems or bugs for their peers to solve. Drawing on observations and interviews, we answer the following research questions: (1) How did students participate in making bugs for others? (2) What did students gain from designing and solving bugs for others? In the discussion, we address the opportunities and challenges that designing personally and socially meaningful failure artefacts provides for becoming objects‐to‐think‐with and objects‐to‐share‐with in student learning and promoting new directions in constructionism.

Practitioner notes

What is already known about this topic

There is substantial evidence for the benefits of learning programming and debugging in the context of constructing personally relevant and complex artefacts, including electronic textiles.

Related, work on productive failure has demonstrated that providing learners with strategically difficult problems (in which they ‘fail’) equips them to better handle subsequent challenges.

What this paper adds

In this paper, we argue that designing bugs or ‘failure artefacts’ is as much a constructionist approach to learning as is designing fully functional artefacts.

We consider how ‘failure artefacts’ can be both objects‐to‐learn‐with and objects‐to‐share‐with.

We introduce the concept of ‘Debugging by Design’ (DbD) as a means to expand application of constructionism to the context of developing ‘failure artifacts’.

Implications for practice and/or policy

We conceptualise a new way to enable and empower students in debugging—by designing creative, multimodal buggy projects for others to solve.

The DbD approach may support students in near‐transfer of debugging and the beginning of a more systematic approach to debugging in later projects and should be explored in other domains beyond e‐textiles.

New studies should explore learning, design and teaching that empower students to design bugs in projects in mischievous and creative ways.
The biodesign studio: Constructions and reflections of high school youth on making with living media
Authors: Walker Justice T. , Kafai Yasmin B.
Published: April 2021

Most constructionist efforts have focused on supporting learners with tools for designing with digital and/or physical media. Recent developments in life sciences now allow K‐12 learners to design with living materials, or to biodesign. In this paper, we report on the development of a biodesign studio activity called biocakes wherein teams of high school youth genetically modified a yeast strain to bake a nutrient fortified food product. Using a qualitative deductive analysis of classroom observations, interviews and projects, we examined high school youth experiences and reflections of these activities to answer three research questions: (1) What kind of artefacts did youth make with living media? (2) How did youth engage in biodesign? and (3) What did youth have to say about their biodesign experiences? We discuss how our analyses of biodesign applications highlight the importance of assembly practices, social engagement and imaginative design for constructionist learning. These insights provide compelling examples for designing with living media in K‐12 education.

Practitioner notes

What is already known about this topic?

Constructionist perspectives shape important ideas about what we know about science learning, and notably in computer science fields.

One widely taken up example includes making, where learners use crafts to make interactive computational objects.

In life science, constructionism also provides insights about learning using digital media to model biological systems or interact with living materials.

What this paper adds?

This paper extends these perspectives by examining production and engagement when learners construct with living materials—an approach that has only recently been possible with the development of accessible wet lab tools.

We frame learning activities as a studio model—that emphasised application design, iteration and critique—to better assess the roles assembly, construction and speculative design play in production that uses living materials.

Our findings suggest that assembly is important for creating accessible points of entry to complex biological fabrication processes.

We also find that speculative design provides an opportunity for learners to extend their existing abilities beyond what is otherwise available given their expertise or access to resources, and thus expansively explore related ideas.

Implications for practice and/or policy

Assembly and speculative design have important places in constructionist‐driven production with living materials and could, therefore, be leveraged in practice.
The detection of circulating plasma cells may improve the Revised International Staging System (R‐ISS) risk stratification of patients with newly diagnosed multiple myeloma
Authors: Galieni Piero , Travaglini Fosco , Vagnoni Davide , Ruggieri Miriana , Caraffa Patrizia , Bigazzi Catia , Falcioni Sadia , Picardi Paola , Mazzotta Serena , Troiani Emanuela , Dalsass Alessia , Mestichelli Francesca , Angelini Mario , Camaioni Elisa , Maravalle Denise , Angelini Stefano , Pezzoni Valerio
Published: April 2021

The Revised International Staging System (R‐ISS) stratifies patients affected by Multiple Myeloma (MM) into three distinct risk groups: R‐ISS I [ISS Stage I, Standard‐Risk cytogenetics and normal Lactase DeHydrogenase (LDH)], R‐ISS III (ISS stage III and either high‐risk cytogenetics or high LDH) and R‐ISS II (any other characteristics). With the aim to verify whether the three R‐ISS groups could be divided into subgroups with different prognostic factors based on the detection of Circulating Plasma Cells (CPCs) at diagnosis, in this retrospective analysis, we evaluated 161 patients with MM treated at our centre between 2005 and 2017. In all, 57 patients (33·9%) were staged as R‐ISS III, 98 (58·3%) as R‐ISS II and six (3·6%) as R‐ISS I. CPCs were detected in 125 patients (74·4%), while in 43 patients (25·6%) no CPCs were seen. Our analysis revealed that Overall Survival (OS) and progression‐free survival (PFS) rates in R‐ISS II patients were higher in the subgroup without CPCs compared to the subgroup with ≥1 CPCs (OS: 44·7% vs. 16·3%, P = 0·0089; PFS: 27·8% vs. 8·1%, P = 0·0118). Our present findings suggest that the detection of CPCs at diagnosis may be used as a further prognostic biomarker to improve the risk stratification of patients with MM staged as R‐ISS II.
An item response tree model with not‐all‐distinct end nodes for non‐response modelling
Authors: Chang Yu‐Wei , Hsu Nan‐Jung , Tsai Rung‐Ching
Published: April 2021

The non‐response model in Knott et al. (1991, Statistician, 40, 217) can be represented as a tree model with one branch for response/non‐response and another branch for correct/incorrect response, and each branch probability is characterized by an item response theory model. In the model, it is assumed that there is only one source of non‐responses. However, in questionnaires or educational tests, non‐responses might come from different sources, such as test speededness, inability to answer, lack of motivation, and sensitive questions. To better accommodate such more realistic underlying mechanisms, we propose a a tree model with four end nodes, not all distinct, for non‐response modelling. The Laplace‐approximated maximum likelihood estimation for the proposed model is suggested. The validation of the proposed estimation procedure and the advantage of the proposed model over traditional methods are demonstrated in simulations. For illustration, the methodologies are applied to data from the 2012 Programme for International Student Assessment (PISA). The analysis shows that the proposed tree model has a better fit to PISA data than other existing models, providing a useful tool to distinguish the sources of non‐responses.
Risk of cancer in long‐term levothyroxine users: Retrospective population‐based study
Authors: Wu Chieh‐Chen , Islam Md. Mohaimenul , Nguyen Phung‐Anh , Poly Tahmina Nasrin , Wang Ching‐Huan , Iqbal Usman , Li Yu‐Chuan (Jack) , Yang Hsuan‐Chia
Published: April 2021

Levothyroxine is a widely prescribed medication for the treatment of an underactive thyroid. The relationship between levothyroxine use and cancer risk is largely underdetermined. To investigate the magnitude of the possible association between levothyroxine use and cancer risk, this retrospective case‐control study was conducted using Taiwan’s Health and Welfare Data Science Center database. Cases were defined as all patients who were aged ≥20 years and had a first‐time diagnosis for cancer at any site for the period between 2001 and 2011. Multivariable conditional logistic regression models were used to calculate an adjusted odds ratio (AOR) to reduce potential confounding factors. A total of 601 733 cases and 2 406 932 controls were included in the current study. Levothyroxine users showed a 50% higher risk of cancer at any site (AOR: 1.50, 95% CI: 1.46‐1.54; P < .0001) compared with non–users. Significant increased risks were also observed for brain cancer (AOR: 1.90, 95% CI: 1.48‐2.44; P < .0001), skin cancer (AOR: 1.42, 95% CI: 1.17‐1.72; P < .0001), pancreatic cancer (AOR: 1.27, 95% CI: 1.01‐1.60; P = .03), and female breast cancer (AOR: 1.24, 95% CI: 1.15‐1.33; P < .0001). Our study results showed that levothyroxine use was significantly associated with an increased risk of cancer, particularly brain, skin, pancreatic, and female breast cancers. Levothyroxine remains a highly effective therapy for hypothyroidism; therefore, physicians should carefully consider levothyroxine therapy and monitor patients’ condition to avoid negative outcomes. Additional studies are needed to confirm these findings and to evaluate the potential biological mechanisms.
Synthesis, in vitro and in silico anti‐bacterial analysis of piperine and piperic ester analogues
Authors: Sivashanmugam Arthi , Velmathi Sivan
Published: April 2021

A set of 12 analogues of piperine was designed, replacing the amide functional group of the molecule with different aliphatic and aromatic ester functional groups. Molecular docking studies of these molecules with FDA‐approved target proteins for anti‐bacterial drugs were done. The binding energy of the proteins and the ligands were low and the analogues were found to be drug‐like based on the ADME results; hence, the molecules were synthesized. The synthesized compounds were tested for their anti‐bacterial property against six bacterial species via Agar well‐diffusion method. Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus epidermidis were the strains tested. The overall susceptibility is higher in gram‐positive. The analogues showed better activity than piperine. The analogues, propyl piperic ester (P3) and 2‐fluorophenyl piperic ester (P9) and 4‐fluorophenyl piperic ester (P10) showed comparatively bigger inhibition zones for all the strains.
Intraductal papillary mucinous neoplasm of the pancreas: Cytomorphology, imaging, molecular profile, and prognosis
Authors: Geramizadeh Bita , Marzban Mahsa , Shojazadeh Alireza , Kadivar Ana , Maleki Zahra
Published: April 2021

Background

Intraductal papillary mucinous neoplasm (IPMN) constitutes up to 20% of all pancreatic resections, and has been increasing in recent years. Histomorphological findings of IPMN are well established; however, there are not many published papers regarding the cytological findings of IPMN on fine needle aspiration (FNA) specimens. We review the cytomorphological features, molecular profile, imaging findings, and prognosis of IPMN.

Methods

The English literature was thoroughly searched with key phrases containing IPMN.

Observations

IPMN is a rare entity, affecting men and women equally and is usually diagnosed at the age of 60‐70 years. The characteristic imaging features include a cystic lesion with associated dilatation of the main or branch pancreatic duct, and atrophy of surrounding pancreatic parenchyma. Cytomorphological features of IPMN include papillary fragments of mucinous epithelium in a background of abundant thick extracellular mucin, a hallmark feature. IPMNs should be evaluated for high‐grade dysplasia, which manifests with nuclear atypia, nuclear moulding, prominent nucleoli, nuclear irregularity, and cellular crowding. Molecular profiling of IPMN along with carcinoembryonic antigen and amylase levels is useful in predicting malignancy or high‐grade dysplasia arising in IPMN. Overall, the prognosis of IPMN is excellent except in those cases with high‐grade dysplasia and malignant transformation. Postoperative surveillance is required for resected IPMNs.

Conclusion

IPMN requires a multidisciplinary approach for management. Cytomorphological findings of IPMN on FNA, in conjunction with tumour markers in pancreatic fluid cytology and imaging findings, are of paramount importance in clinical decision‐making for IPMN.
Emerging concepts on bradykinesia in non‐parkinsonian conditions
Authors: Paparella Giulia , Fasano Alfonso , Hallett Mark , Berardelli Alfredo , Bologna Matteo
Published: April 2021

Background and purpose

Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease. However, clinical and experimental studies indicate that bradykinesia may also be observed in various neurological diseases not primarily characterized by parkinsonism. These conditions include hyperkinetic movement disorders, such as dystonia, chorea, and essential tremor. Bradykinesia may also be observed in patients with neurological conditions that are not seen as "movement disorders," including those characterized by the involvement of the cerebellum and corticospinal system, dementia, multiple sclerosis, and psychiatric disorders.

Methods

We reviewed clinical reports and experimental studies on bradykinesia in non‐parkinsonian conditions and discussed the major findings.

Results

Bradykinesia is a common motor abnormality in non‐parkinsonian conditions. From a pathophysiological standpoint, bradykinesia in neurological conditions not primarily characterized by parkinsonism may be explained by brain network dysfunction.

Conclusion

In addition to the pathophysiological implications, the present paper highlights important terminological issues and the need for a new, more accurate, and more widely used definition of bradykinesia in the context of movement disorders and other neurological conditions.
Metabolic rewiring: a new master of Th17 cell plasticity and heterogeneity
Authors: Papadopoulou Gina , Xanthou Georgina
Published: April 2021

T helper type 17 (Th17) cells are characterized by inherent plasticity and heterogeneity displaying both pathogenic and tissue‐protective functions. Emerging evidence has illuminated a pivotal role for metabolic reprogramming in shaping Th17 cell fate determination. Metabolic responses are regulated by a constellation of factors and environmental triggers, including cytokines, nutrients, oxygen levels, and metabolites. Dysregulation of metabolic pathways not only influences Th17 cell plasticity and effector function but also affects the outcome of Th17‐linked autoimmune, inflammatory, and antitumor responses. Understanding the molecular mechanisms underpinning metabolic reprogramming can allow the enhancement of protective Th17 cell‐mediated responses during infections and cancer, concomitant with the suppression of detrimental Th17 processes during autoimmune and inflammatory diseases. In the present review, we describe major metabolic pathways underlying the differentiation of Th17 cells and their crosstalk with intracellular signaling mediators, we discuss how metabolic reprogramming affects Th17 cell plasticity and functions, and, finally, we outline current advances in the exploitation of metabolic checkpoints for the development of novel therapeutic interventions for the management of tissue inflammation, autoimmune disorders, and cancer.
“Very little but a lot.” Solidarity within the sex workers' community in Poland during the COVID‐19 pandemic
Authors: Dziuban Agata , Możdrzeń Martyna , Ratecka Anna
Published: April 2021

This article is an account of the struggle of the sex workers' community in Poland during the COVID‐19 pandemic. It unfolds as a dialog between three members of Sex Work Polska, a sex worker‐led activist and advocacy collective in Poland. While positioned as researchers, activists, and/or sex workers, we transgress the boundaries between academia and activism, permitting a grassroots insight into the crisis situation of the sex workers' community. This method enables us to present the embodied experience of community solidarity in crisis. We recall our thoughts and emotions from the moment of lockdown and our response to the pandemic by organizing an Emergency Fund to support sex workers. We reflect on how the pandemic evoked solidarity, the conditionality of institutionalized support, and our resistance to it. In capturing our experiences, we also show how the pandemic exposed the pre‐existing vulnerabilities of sex workers, their invisibility as a community in crisis, and their overvisibility as subjects of punitive measures. Our collective work and discussion allowed for engagement in feminist knowledge production, but also constituted a community care process.
Alarming rates of virological failure and HIV‐1 drug resistance amongst adolescents living with perinatal HIV in both urban and rural settings: evidence from the EDCTP READY‐study in Cameroon
Authors: Fokam J , Takou D , Njume D , Pabo W , Santoro MM , Njom Nlend A‐E , Beloumou G , Sosso S , Moudourou S , Teto G , Dambaya B , Djupsa S , Tetang Ndiang S , Ateba FN , Billong SC , Kamta C , Bala L , Lambo V , Tala V , Chenwi Ambe C , Mpouel ML , Cappelli G , Cham F , Ndip R , Mbuagbaw L , Koki Ndombo P , Ceccherini‐Silberstein F , Colizzi V , Perno C‐F , Ndjolo A
Published: April 2021

Objectives

Adolescents living with perinatal HIV infection (ALPHI) experience persistently high mortality rates, particularly in resource‐limited settings. It is therefore clinically important for us to understand the therapeutic response, acquired HIV drug resistance (HIVDR) and associated factors among ALPHI, according to geographical location.

Methods

A study was conducted among consenting ALPHI in two urban and two rural health facilities in the Centre Region of Cameroon. World Health Organization (WHO) clinical staging, self‐reported adherence, HIVDR early warning indicators (EWIs), immunological status (CD4 count) and plasma viral load (VL) were assessed. For those experiencing virological failure (VF, VL ≥ 1000 copies/mL), HIVDR testing was performed and interpreted using the Stanford HIV Drug Resistance Database v.8.9–1.

Results

Of the 270 participants, most were on nonnucleoside reverse transcriptase inhibitor (NNRTI)‐based regimens (61.7% urban vs. 82.2% rural), and about one‐third were poorly adherent (30.1% vs. 35.1%). Clinical failure rates (WHO‐stage III/IV) in both settings were < 15%. In urban settings, the immunological failure (IF) rate (CD4 < 250 cells/μL) was 15.8%, statistically associated with late adolescence, female gender and poor adherence. The VF rate was 34.2%, statistically associated with poor adherence and NNRTI‐based antiretroviral therapy. In the rural context, the IF rate was 26.9% and the VF rate was 52.7%, both statistically associated with advanced clinical stages. HIVDR rate was over 90% in both settings. EWIs were delayed drug pick‐up, drug stock‐outs and suboptimal viral suppression.

Conclusions

Poor adherence, late adolescent age, female gender and advanced clinical staging worsen IF. The VF rate is high and consistent with the presence of HIVDR in both settings, driven by poor adherence, NNRTI‐based regimen and advanced clinical staging.
Public debt, sovereign spreads and the unpleasant arithmetic of fiscal consolidations
Authors: Di Pietro Marco , Marattin Luigi , Minetti Raoul
Published: April 2021

In response to severe fiscal consolidation policies implemented after the Great Recession and the euro area sovereign debt crisis, many have questioned the effectiveness of fiscal consolidations in reducing the burden of public debt. This paper revisits this fundamental policy debate qualitatively and quantitatively, studying conditions under which primary budget balance changes can successfully reduce government debt‐to‐GDP ratios. We first illustrate these conditions through a partial equilibrium setting. We then investigate the conditions quantitatively using a medium‐scale New Keynesian DSGE model calibrated on periphery countries of the euro area. The analysis highlights the critical role of sovereign spreads in driving the debt‐to‐GDP dynamics following a restrictive primary balance shock. Fiscal consolidations turn out to successfully reduce the debt‐to‐GDP even for fairly low elasticities of spreads to fiscal variables. However, their effectiveness is quantitatively moderate and varies crucially with the initial spread level, with the degree of monetary policy accommodation, and with the responsiveness of market investors to economic fundamentals.