bluuebunny/crossref_metadata_2025_split huggingface dataset:
The associations of long-term physical activity in adulthood with later biological ageing and all-cause mortality – a prospective twin study
Authors: Kankaanpää Anna , Tolvanen Asko , Joensuu Laura , Waller Katja , Heikkinen Aino , Kaprio Jaakko , Ollikainen Miina , Sillanpää Elina 
Published: June 2023

AbstractObjectivesThe association between leisure-time physical activity (LTPA) and a lower risk of mortality is susceptible to bias from multiple sources. We investigated the potential of biological ageing to mediate the association between long-term LTPA and mortality and whether the methods used to account for reverse causality affect the interpretation of this association.MethodsStudy participants were twins from the older Finnish Twin Cohort (n=22,750; 18–50 years at baseline). LTPA was assessed using questionnaires in 1975, 1981 and 1990. The mortality follow-up lasted until 2020 and biological ageing was assessed using epigenetic clocks in a subsample (n=1,153) with blood samples taken during the follow-up. Using latent profile analysis, we identified classes with distinct longitudinal LTPA patterns and studied differences in biological ageing between these classes. We employed survival models to examine differences in total, short-term and long-term all-cause mortality, and multilevel models for twin data to control for familial factors.ResultsWe identified four classes of long-term LTPA: sedentary, moderately active, active and highly active. Although biological ageing was accelerated in sedentary and highly active classes, after adjusting for other lifestyle-related factors, the associations mainly attenuated. Physically active classes had a maximum 7% lower risk of total mortality over the sedentary class, but this association was consistent only in the short term and could largely be accounted for by familial factors. LTPA exhibited less favourable associations when prevalent diseases were exclusion criteria rather than covariate.ConclusionBeing active may reflect a healthy phenotype instead of causally reducing mortality.
Development of MAPT S305 mutation models exhibiting elevated 4R tau expression, resulting in altered neuronal and astrocytic function
Authors: Bowles KR , Pugh DA , Pedicone C , Oja L , Weitzman SA , Liu Y , Chen JL , Disney MD , Goate AM 
Published: June 2023

ABSTRACTDue to the importance of 4R tau in the pathogenicity of primary tauopathies, it has been challenging to model these diseases in iPSC-derived neurons, which express very low levels of 4R tau. To address this problem we have developed a panel of isogenic iPSC lines carrying theMAPTsplice-site mutations S305S, S305I or S305N, derived from four different donors. All three mutations significantly increased the proportion of 4R tau expression in iPSC-neurons and astrocytes, with up to 80% 4R transcripts in S305N neurons from as early as 4 weeks of differentiation. Transcriptomic and functional analyses of S305 mutant neurons revealed shared disruption in glutamate signaling and synaptic maturity, but divergent effects on mitochondrial bioenergetics. In iPSC-astrocytes, S305 mutations induced lysosomal disruption and inflammation and exacerbated internalization of exogenous tau that may be a precursor to the glial pathologies observed in many tauopathies. In conclusion, we present a novel panel of human iPSC lines that express unprecedented levels of 4R tau in neurons and astrocytes. These lines recapitulate previously characterized tauopathy-relevant phenotypes, but also highlight functional differences between the wild type 4R and mutant 4R proteins. We also highlight the functional importance ofMAPTexpression in astrocytes. These lines will be highly beneficial to tauopathy researchers enabling a more complete understanding of the pathogenic mechanisms underlying 4R tauopathies across different cell types.
Mechanical Force Works as a Biological Cue in Postnatal Murine Tendon Development
Authors: Usami Yuna , Jiang Xi , Dyment Nathaniel A , Kokubun Takanori 
Published: June 2023

AbstractThe musculoskeletal system provides structural stability and coordination to enable movement. Tendons have the essential role of efficiently transmitting force generated from muscle contraction to bone to enable ambulation. In doing so, they resist high external forces. In fact, muscle contraction during embryonic development is required to maintain tendon growth and differentiation. Nonetheless, defining the types and magnitudes of loads that act on tendons during embryonic and early postnatal periods is quite difficult. In this study, we aimed to define the physiologic limb movement and forces experienced during these stages in the murine model. We found that late-stage embryos had limited amniotic space, which attenuated limb movement. In the neonatal phase, physical ability, as measured by rollover function and locomotion, increased. These changes, which likely corresponded to increased forces applied to the tendons, corresponded with the expression of tenogenic markers during the embryo to postnatal phase. In particular, we found that the upregulation ofScxandTnmdcorrelated with increased movement during the two weeks after birth. Our results help define the spatiotemporal role of mechanical force, including internal and external factors, in tendon growth and development.HighlightsAssessed limb movement in amnion.Space limitation attenuated limb movement in the late-stage embryos.Defined the mechanical force from the limb’s physiological environment.Scx and Tnmd were upregulated synchronically with rollover function and locomotion.Mechanical forces may work as the cue of tendon development
Jaw size variation is associated with a novel craniofacial function for galanin receptor 2 in an adaptive radiation of pupfishes
Authors: Palominos M. Fernanda , Muhl Vanessa , Richards Emilie J. , Miller Craig T. , Martin Christopher H. 
Published: June 2023

AbstractUnderstanding the genetic basis of novel adaptations in new species is a fundamental question in biology that also provides an opportunity to uncover new genes and regulatory networks with potential clinical relevance. Here we demonstrate a new role forgalr2in vertebrate craniofacial development using an adaptive radiation of trophic specialist pupfishes endemic to San Salvador Island in the Bahamas. We confirmed the loss of a putativeSrytranscription factor binding site in the upstream region ofgalr2in scale-eating pupfish and found significant spatial differences ingalr2expression among pupfish species in Meckel’s cartilage and premaxilla using in situ hybridization chain reaction (HCR). We then experimentally demonstrated a novel function for Galr2 in craniofacial development and jaw elongation by exposing embryos to drugs that inhibit Galr2 activity. Galr2-inhibition reduced Meckel’s cartilage length and increased chondrocyte density in both trophic specialists but not in the generalist genetic background. We propose a mechanism for jaw elongation in scale-eaters based on the reduced expression ofgalr2due to the loss of a putativeSrybinding site. Fewer Galr2 receptors in the scale-eater Meckel’s cartilage may result in their enlarged jaw lengths as adults by limiting opportunities for a postulated Galr2 agonist to bind to these receptors during development. Our findings illustrate the growing utility of linking candidate adaptive SNPs in non-model systems with highly divergent phenotypes to novel vertebrate gene functions.
The Time Required for Primary Care Consultations: Estimates of the Expected Duration of Initial Sick Child Visits in Low- and Middle-income Countries Using the Integrated Management of Childhood Illness (IMCI) Clinical Algorithm
Authors: Carter Anthony 
Published: June 2023

AbstractBackgroundLittle is known about the time required for primary care consultations, particularly those involving sick children in low- and middle-income countries (LMICs). This paper begins to fill that gap by providing evidence-based estimates of the time needed for initial visits with under-five infants and children at public or not-for-profit facilities in LMICs that use the Integrated Management of Childhood Illness (IMCI) clinical algorithm. The estimates are evidence-based and case-mix adjusted.MethodsThe expected duration of IMCI consultations in any given setting is a function of the health issues presented by patients less than 5 years old, the kind and number of tasks health workers must perform to care for such patients, and the time required to complete those tasks. Determining the time needed to complete tasks with no minimum duration requires, in addition to tabulations of health issues and lists of tasks to be performed, information on rates of task performance and the mean observed duration of consultations. All this information was located, first, by searching MEDLINE, the database of the International Network for Rational Use of Medicines, the websites of the WHO and its regional offices, GOOGLE, and GOOGLE SCHOLAR using search terms such as ‘Integrated Management of Childhood Illness’, ‘observational’, ‘prospective’, ‘classification’, ‘clinical signs’, ‘health facility survey’, ‘validity’, ‘algorithm’, and ‘chart booklet’. Additional information was found by reviewing work that cited a qualified study and, conversely, material included in the bibliographies of qualified studies.ResultsEstimates of the expected mean duration of initial consultations were constructed for 39 patient populations in 22 countries. The mean ranges from 17.1 to 20.5 minutes in the infant populations and from 15.5 to 26.4 minutes in the child populations. The shortest consultations range from 16.1 to 16.7 minutes in the infant populations and from 11.0 to 17.4 minutes in the child populations. The 98thpercentile of expected durations ranges from 21.5 to 25.7 minutes in the infant populations and from 22.5 to 35.2 minutes in the child populations.ConclusionsIMCI consultations with infants and children presenting for the first time with a new concern require considerably more time than previously recognized. This suggests that the personnel costs of providing appropriate IMCI services may be substantial. It also confirms that the quality of most IMCI consultations is low.
HIV-1 5’-Leader Mutations in Plasma Viruses Before and After the Development of Reverse Transcriptase Inhibitor-Resistance Mutations
Authors: Nouhin Janin , Tzou Philip L. , Rhee Soo-Yon , Sahoo Malaya K. , Pinsky Benjamin A. , Krupkin Miri , Puglisi Joseph D. , Puglisi Elisabetta V. , Shafer Robert W. 
Published: June 2023

ABSTRACTBackgroundHIV-1 RT initiation depends on interaction between viral 5’-leader RNA, RT, and host tRNA3Lys. We therefore sought to identify co-evolutionary changes between the 5’-leader and RT in viruses developing RT-inhibitor resistance mutations.MethodsWe sequenced 5’-leader positions 37-356 of paired plasma virus samples from 29 individuals developing the NRTI-resistance mutation M184V, 19 developing an NNRTI-resistance mutation, and 32 untreated controls. 5’-leader variants were defined as positions where ≥20% of NGS reads differed from the HXB2 sequence. Emergent mutations were defined as nucleotides undergoing ≥4-fold change in proportion between baseline and follow-up. Mixtures were defined as positions containing ≥2 nucleotides each present in ≥20% of NGS reads.ResultsAmong 80 baseline sequences, 87 positions (27.2%) contained a variant; 52 contained a mixture. Position 201 was the only position more likely to develop a mutation in the M184V (9/29 vs. 0/32; p=0.0006) or NNRTI-resistance (4/19 vs. 0/32; p=0.02; Fisher’s Exact Test) groups than the control group. Mixtures at positions 200 and 201 occurred in 45.0% and 28.8%, respectively, of baseline samples. Because of the high proportion of mixtures at these positions, we analyzed 5’-leader mixture frequencies in two additional datasets: five publications reporting 294 dideoxyterminator clonal GenBank sequences from 42 individuals and six NCBI BioProjects reporting NGS datasets from 295 individuals. These analyses demonstrated position 200 and 201 mixtures at proportions similar to those in our samples and at frequencies several times higher than at all other 5’-leader positions.ConclusionsAlthough we did not convincingly document co-evolutionary changes between RT and 5’-leader sequences, we identified a novel phenomenon, wherein positions 200 and 201, immediately downstream of the HIV-1 primer binding site exhibited an extraordinarily high likelihood of containing a nucleotide mixture. Possible explanations for the high mixture rates are that these positions are particularly error-prone or provide a viral fitness advantage.
Investigating Alternative Models of Acute HIV Infection
Authors: Mainou Ellie , Ribeiro Ruy , Conway Jessica M 
Published: June 2023

AbstractUnderstanding the dynamics to acute HIV infection may provide insights into the mechanisms of early viral control with potential implications for vaccine design. The standard viral dynamics model explains HIV viral dynamics during acute infection reasonably well. However, the model makes simplifying assumptions, neglecting some aspects of HIV. For example, in the standard model, target cells are infected by a single HIV virion. Yet, cellular multiplicity of infection (MOI) may have considerable effects in pathogenesis and viral evolution. Further, when using the standard model, we take constant infected cell death rates, simplifying the dynamic immune responses. Here, we use four models—1) the standard viral dynamics model, 2) an alternate model incorporating cellular MOI, 3) a model assuming density-dependent death rate of infected cells and 4) a model combining (2) and (3)—to investigate acute infection dynamics in 43 people tested very early after HIV exposure. We find that all models explain the data, but different models describe differing features of the dynamics more accurately. For example, while the standard viral dynamics model may be the most parsimonious model, viral peaks are better explained by a model allowing for cellular MOI. These results suggest that heterogeneity in within-host viral dynamics cannot be captured by a single model. Thus depending on the aspect of interest, a corresponding model should be employed.
Compartmentalization and synergy of osteoblasts drive bone formation in the regenerating fin
Authors: Cudak N , López-Delgado AC , Rost F , Kurth T , Lesche M , Reinhardt S , Dahl A , Rulands S , Knopf F 
Published: June 2023

SummaryZebrafish faithfully regenerate their fins after amputation which includes restoration of bone tissue and a component of cell plasticity. It is currently unclear how different cell populations of the regenerate divide labor to allow for efficient regenerate growth and proper patterning. Here, we studied lineage relationships of FACS-enriched epidermal, blastemal and bone forming fin regenerate cells by single cell (sc) RNA sequencing, lineage tracing, targeted osteoblast ablation and electron microscopy to show that the majority of osteoblasts in the outgrowing regenerate derive fromosterix+ osteoblasts, whilemmp9+ cells give rise to a limited cell number at the fin segment joints. A third population of distal blastema cells contributes to distal osteoblast progenitors, suggesting compartmentalization during appendage regeneration. Fin elongation and bone formation are carried out by distinct regenerate cell populations, and these variably depend on Fgf signaling. Ablation ofosterix+ osteoblasts irreversibly impairs patterning of segment joints, and prevents bone matrix formation in the proximal regenerate. The resulting reduced regenerate length is partially compensated for by the distal regenerate which shows increased Wnt signaling activity. Surprisingly, ablation of joint cells does not abolish the formation of segment joints. Our study characterizes rare fin regenerate cell populations, indicates intricate osteoblast-blastema lineage relationships, inherent detection and compensation of impaired regeneration, and demonstrates zonation of the elongating regenerate. Furthermore, it sheds light on the variable dependence of bone formation on growth factor signaling.
Effects of plasmapheresis frequency on health status and exercise performance in men: a randomized controlled trial
Authors: Mortier Alexandre , Khoudary Jina , van Doorslaer de Ten Ryen Sophie , Lannoy Camille , Benoit Nicolas , Antoine Nancy , Copine Sylvie , Van Remoortel Hans , Vandekerckhove Philippe , Compernolle Veerle , Deldicque Louise 
Published: June 2023

ABSTRACTObjectivesTo collect data on 1) haematological and biochemical markers, 2) physiological and exercise-related parameters and 3) adverse events to get a comprehensive picture of the safety of intensive or less intensive plasma donation protocols.MethodsSixty-three male subjects participated in this randomized controlled trial and were divided into a low-frequency (LF, 1x/month, n=16), high-frequency (HF, 3x/month, n=16), very high-frequency (VHF, 2x/week, n=16) and a placebo (P, 1x/month, n=15) group. Biochemical, haematological, clinical, physiological and sport performance-related data were collected before (D0), after 1½ month (D42) and after 3 months (D84).ResultsIn VHF, red blood cells, haemoglobin and haematocrit levels decreased while reticulocyte levels increased from D0 to D84. In both HF and VHF, plasma ferritin levels were lower at D42 and D84 compared to D0. In VHF, the plasma levels of albumin, IgG, IgA and IgM dropped from D0 to D42 and remained lower at D84 than at D0. In HF, plasma IgG, IgA and IgM were lower at D42 and IgG and IgM were lower at D84 compared to D0. Few adverse events (haematoma, anaemia, vasovagal reactions without syncope) were reported in HF and VHF. Repeated plasma donation had no effect on blood pressure, body composition or exercise performance.ConclusionHaematological and biochemical parameters were severely impacted when plasmapheresis was repeated twice a week, mildly impacted with a frequency of three times per month and not impacted with a frequency of once a month. Despite those changes, markers for exercise performance were not altered when plasmapheresis, whatever the frequency, was repeated over 3 months.Summary Box:What is already known on this topic?Plasmapheresis may induce a series of health consequences, such as adverse events of diverse severities. However, those events have mainly been studied separately and retrospectively with no appropriate placebo group.What this study adds?This is the first randomized controlled trial prospectively investigating the effects of repeated plasma donation on a whole range of health consequences, namely biochemical and haematological, blood pressure, body composition, adverse events and, exercise performance.How this study might affect research, practice or policy?Worldwide efforts need to be made to increase the amount of plasma collected for manufacturing plasma-derived product. To avoid negative effects to donors, a sustainable plasma supply should be based on a large donorbase of low-frequency donors.
Scalable noninvasive amplicon-based precision sequencing (SNAPseq) for genetic diagnosis and screening of β-thalassemia and sickle cell disease using a next-generation sequencing platform
Authors: Gupta Pragya , Arvinden VR , Thakur Priya , Bhoyer Rahul C , Saravanakumar Vinodh , Gottumukkala Narendra Varma , Goswami Sangam Giri , Nafiz Mehwish , Iyer Aditya Ramdas , Vignesh Harie , Soni Rajat , Bhargava Nupur , Gunda Padma , Jain Suman , Gupta Vivek , Sivasubbu Sridhar , Scaria Vinod , Ramalingam Sivaprakash 
Published: June 2023

Abstractβ-hemoglobinopathies such as β-thalassemia (BT) and Sickle cell disease (SCD) are inherited monogenic blood disorders with significant global burden. Hence, early and affordable diagnosis can alleviate morbidity and reduce mortality given the lack of effective cure. Currently, Sanger sequencing is considered to be the gold standard genetic test for BT and SCD, but it has a very low throughput requiring multiple amplicons and more sequencing reactions to cover the entire HBB gene. To address this, we have demonstrated an extraction-free single amplicon-based approach for screening the entire β-globin gene with clinical samples usingScalablenoninvasiveamplicon-basedprecisionsequencing (SNAPSeq) assay catalyzing with next-generation sequencing (NGS). We optimized the assay using noninvasive buccal swab samples and simple finger prick blood for direct amplification with crude lysates. SNAPseq demonstrates 100% sensitivity and 100% specificity, having a 100% agreement with Sanger sequencing. Furthermore, to facilitate seamless reporting, we have created a much simpler automated pipeline with comprehensive resources for pathogenic mutations in BT and SCD through data integration after systematic classification of variants according to ACMG & AMP guidelines. To the best of our knowledge, this is the first report of the NGS-based high throughput SNAPseq approach for the detection of both BT and SCD in a single assay with high sensitivity.
The use of blockchain technology to build smart cities: creating public value in Kuwait
Authors: Alkhaldi Afnan , Alrashidi Huda , Alhasan Khawla , Alsadeeqi Ahmad , Alshami Abdullah 
Published: June 2023

Purpose
The purpose of this study is to understand the public value of the government of Kuwait using blockchain technology to develop the capabilities of smart cities.

Design/methodology/approach
Research was conducted in Kuwait, where the increased use of blockchain technology has been evidenced in both the private and public sectors. A total of seven IT managers were interviewed to gauge their responses to blockchain and its use in Kuwait ministries.

Findings
Blockchain technology offers many benefits for the development of smart cities in Kuwait. This is a statement that received almost mutual agreement amongst all the IT managers interviewed. However, as regards wider acceptance, the majority mentioned that a framework is necessary to better articulate the public value of using blockchain in smart cities in Kuwait.

Originality/value
This paper develops research hypotheses and a framework for articulating the public value of blockchain technology for smart cities in Kuwait.
Integrability of linear structure of components of modified Korteweg–De Vries hierarchy: multiple soliton solutions and breathers solutions
Authors: Wazwaz Abdul-Majid , Alhejaili Weaam , El-Tantawy Samir 
Published: June 2023

Purpose
The purpose of this study is to form a linear structure of components of the modified Korteweg–De Vries (mKdV) hierarchy. The new model includes 3rd order standard mKdV equation, 5th order and 7th order mKdV equations.

Design/methodology/approach
The authors investigate Painlevé integrability of the constructed linear structure.

Findings
The Painlevé analysis demonstrates that established sum of integrable models retains the integrability of each component.

Research limitations/implications
The research also presents a set of rational schemes of trigonometric and hyperbolic functions to derive breather solutions.

Practical implications
The authors also furnish a variety of solitonic solutions and complex solutions as well.

Social implications
The work formally furnishes algorithms for extending integrable equations that consist of components of a hierarchy.

Originality/value
The paper presents an original work for developing Painlevé integrable model via using components of a hierarchy.