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Background: Children who have been exposed in utero to maternal filarial infection are immunologically less responsive to filarial antigens, have less pathology, and are more susceptible to acquire infection than offspring of uninfected mothers. Moreover children from filaria infected mothers have been shown to be less responsive to vaccination as a consequence of an impairment of their immune response. However, it is not well known how in utero exposure to parasite antigens affects cellular immune responses., Methodology: Here, 30 pregnant women were examined for the presence of microfilaria of Loa loa and Mansonella perstans in peripheral blood. At delivery, cord blood mononuclear cells (CBMC) were obtained and the CD4+T cells were phenotyped by expression of the transcription factors Tbet, RORγt, and FOXP3., Results: No significant difference was observed between newborns from infected versus uninfected mothers in the frequencies of total CD4+T cells and CD4+T cells subsets including CD4+Tbet+, CD4+RORγt+ T and CD4+CD25hiFOXP3+ T cells. However, there was a negative association between CD4+CD25hiFOXP3+T cells and CD4+Tbet+ as well as CD4+RORγt+ T cells in the infected group only (B = -0.242, P = 0.002; B = -0.178, P = 0.013 respectively)., Conclusion: Our results suggest that filarial infection during pregnancy leads to an expansion of functionally active regulatory T cells that keep TH1 and TH17 in check.

Accurate detection of tumor margins is essential for successful cancer surgery. While indocyanine green (ICG)-based near-infrared (NIR) fluorescence (FL) surgical navigation enhances the visual identification of tumor margins, its accuracy remains subjective, underscoring the need for quantitative approaches. In this study, a high spatiotemporal fluorescence lifetime (FLT) imaging technology is developed in the second near-infrared window (NIR-II, 1000-1700 nm) for quantitative tumor margin detection, utilizing folate receptor-targeted ICG nanoprobes (FPH-ICG). FPH-ICG exhibits a significantly prolonged NIR-II FLT (750 ± 7 ps vs 260 ± 3 ps) and increased NIR-II FL brightness (FPH-ICG/ICG = 3.8). In vitro and in vivo studies confirm that FPH-ICG specifically targets folate receptor-α (FRα) on SK-OV-3 ovarian cancer cells, achieving high-contrast NIR-II FL imaging with a signal-to-background ratio of 10.8. Notably, NIR-II FLT imaging demonstrates superior accuracy (90%) and consistency in defining tumor margins compared to NIR-II FL imaging (58%) in both SK-OV-3 tumor-bearing mice and clinical tumor samples. These findings underscore the potential of NIR-II FLT imaging as a quantitative tool for guiding surgical tumor margin detection., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Habitat loss can lead to biotic homogenization (decrease in β diversity) or differentiation (increase in β diversity) of biological communities. However, it is unclear which of these ecological processes predominates in human-modified landscapes. We used data on vertebrates, invertebrates, and plants to quantify β diversity based on species occurrence and abundance among communities in 1367 landscapes with varying amounts of habitat (<30%, 30-60%, or >60% of forest cover) throughout the Brazilian Atlantic Forest. Decreases in habitat amount below 30% led to increased compositional similarity of vertebrate and invertebrate communities, which may indicate a process of biotic homogenization throughout the Brazilian Atlantic Forest. No pattern was detected in plant communities. We found that habitat loss was associated with a deterministic increase in faunal community similarity, which is consistent with a selected subset of species being capable of thriving in human-modified landscapes. The lack of pattern found in plants was consistent with known variation between taxa in community responses to habitat amount. Brazilian legislation requiring the preservation of 20% of Atlantic Forest native vegetation may be insufficient to prevent the biotic homogenization of faunal communities. Our results highlight the importance of preserving large amounts of habitat, providing source areas for the recolonization of deforested landscapes, and avoiding large-scale impacts of homogenization of the Brazilian Atlantic Forest., (© 2024 Society for Conservation Biology.)

Age-related macular degeneration (AMD) is an emerging cause of blindness in aged people worldwide. One of the key signs of AMD is the degeneration of the retinal pigment epithelium (RPE), which is indispensable for the maintenance of the adjacent photoreceptors. Because of impaired energy metabolism resulting from constant light exposure, hypoxia, and oxidative stress, accumulation of drusen in AMD-affected eyes is observed. Drusen contain damaged cellular proteins, lipoprotein particles, lipids and carbohydrates and they are related to impaired protein clearance, inflammation, and extracellular matrix modification. When autophagy, a major cellular proteostasis pathway, is impaired, the accumulations of intracellular lipofuscin and extracellular drusen are detected. As these aggregates grow over time, they finally cause the disorganisation and destruction of the RPE and photoreceptors leading to visual loss. In this review, the role of autophagy in drusen biogenesis is discussed since impairment in removing cellular waste in RPE cells plays a key role in AMD progression. In the future, means which improve intracellular clearance might be of use in AMD therapy to slow the progression of drusen formation., (© 2024 The Author(s). Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Atherosclerosis is an age-related pathological process associated with elevated levels of legumain in plaques and plasma. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the role of legumain in the progression of atherosclerotic plaques, with a particular focus on functional and phenotypic changes in CD4 + T cells. Apolipoprotein E-deficient (Apoe -/- ) mice were crossed with legumain-deficient (Lgmn -/- ) mice to generate Lgmn -/- Apoe -/- mice. CD4 + T cells accumulated in the atherosclerotic plaques of Apoe -/- mice fed a high-fat diet. Deletion of legumain attenuated the deposition of CD4 + T cells in plaques and reduced the number of atherosclerotic lesions. The levels of CD4 + T cells in the blood, lymph nodes, and spleen were decreased in Lgmn -/- mice. Transcriptomic analysis revealed that the deletion of legumain decreased the differentiation, survival, and function of CD4 + memory T cells by suppressing the T cell receptor (TCR) signaling pathway. These changes are accompanied by the downregulation of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and the reduced release of interleukin (IL)-2 and interferon (IFN)-γ. These results suggest that legumain deficiency may play a role in the development of atherosclerosis by impairing the survival, proliferation, and function of CD4 + T cells. Inhibition of legumain activity may be an innovative therapy for the treatment of atherosclerosis., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The genetic analysis of potato is hampered by the complexity of tetrasomic inheritance. An ongoing effort aims to transform the clonally propagated tetraploid potato into a seed-propagated diploid crop, which would make genetic analyses much easier owing to disomic inheritance. Here, we construct and report the large-scale genetic and heterotic characteristics of a diploid F 2 potato population derived from the cross of two highly homozygous inbred lines. We investigate 20,382 traits generated from multi-omics dataset and identify 25,770 quantitative trait loci (QTLs). Coupled with gene expression data, we construct a systems-genetics network for gene discovery in potatoes. Importantly, we explore the genetic basis of heterosis in this population, especially for yield and male fertility heterosis. We find that positive heterotic effects of yield-related QTLs and negative heterotic effects of metabolite QTLs (mQTLs) contribute to yield heterosis. Additionally, we identify a PME gene with a dominance heterotic effect that plays an important role in male fertility heterosis. This study provides genetic resources for the potato community and will facilitate the application of heterosis in diploid potato breeding., (© 2024. The Author(s).)

Background: Glycoprotein (GP)VI is a platelet-specific collagen receptor required for platelet activation during hemostasis. Platelet reactivity toward collagen is routinely assessed during diagnostic workup of platelet disorders. GPVI can be activated by inducing receptor clustering with suspensions of fibrillar collagen or synthetic cross-linked collagen-related peptide (CRP-XL). However, these suspensions are poorly standardized or difficult to produce. Nanobodies are small recombinant camelid-derived heavy-chain antibody variable regions. They are highly stable, specific, and ideal candidates for developing a stable GPVI agonist for diagnostic assays., Objectives: Develop a stable nanobody-based GPVI agonist., Methods: Nanobody D2 (NbD2) was produced as dimers and purified. Tetramers were generated via C-terminal fusion of dimers with click chemistry. Nanobody constructs were functionally characterized with light transmission aggregometry (LTA) in platelet-rich plasma and whole blood flow cytometry. Diagnostic performance was assessed in patients with inherited platelet function disorders with LTA and flow cytometry., Results: NbD2 was specific for human platelet GPVI. Dimers did not result in platelet activation in LTA or flow cytometry settings and fully inhibited CRP-XL-induced P-selectin expression and fibrinogen binding in whole blood and attenuated collagen-induced platelet aggregation in platelet-rich plasma. However, NbD2 tetramers caused full platelet aggregation, as well as P-selectin expression and fibrinogen binding. NbD2 tetramers were able to discriminate between inherited platelet function disorder patients and healthy controls based on fibrinogen binding, similar to CRP-XL., Conclusion: Nanobody tetramers to GPVI induce platelet activation and can be used to assess the GPVI pathway in diagnostic assays., (© 2024 The Author(s).)

This review highlights the development of plant proteins from a wide variety of sources, as most of the research and development efforts to date have been limited to a few sources including soy, chickpea, wheat, and pea. The native structure of plant proteins during production and their impact on food colloids including emulsions, foams, and gels are considered in relation to their fundamental properties, while highlighting the recent developments in the production and processing technologies with regard to their impacts on the molecular properties and aggregation of the proteins. The ability to quantify structural, morphological, and rheological properties can provide a better understanding of the roles of plant proteins in food systems. The applications of plant proteins as dairy and meat alternatives are discussed from the perspective of food structure formation. Future directions on the processing of plant proteins and potential applications are outlined to encourage the generation of more diverse plant-based products., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The existence of LUCA in the distant past is the logical consequence of the binary mechanism of cell division. The biosphere in which LUCA and contemporaries were living was the product of a long cellular evolution from the origin of life to the second age of the RNA world. A parsimonious scenario suggests that the molecular fabric of LUCA was much simpler than those of modern organisms, explaining why the evolutionary tempo was faster at the time of LUCA than it was during the diversification of the three domains. Although LUCA was possibly equipped with a RNA genome and most likely lacked an ATP synthase, it was already able to perform basic metabolic functions and to produce efficient proteins. However, the proteome of LUCA and its inferred metabolism remains to be correctly explored by in-depth phylogenomic analyses and updated datasets. LUCA was probably a mesophile or a moderate thermophile since phylogenetic analyses indicate that it lacked reverse gyrase, an enzyme systematically present in all hyperthermophiles. The debate about the position of Eukarya in the tree of life, either sister group to Archaea or descendants of Archaea, has important implications to draw the portrait of LUCA. In the second alternative, one can a priori exclude the presence of specific eukaryotic features in LUCA. In contrast, if Archaea and Eukarya are sister group, some eukaryotic features, such as the spliceosome, might have been present in LUCA and later lost in Archaea and Bacteria. The nature of the LUCA virome is another matter of debate. I suggest here that DNA viruses only originated during the diversification of the three domains from an RNA-based LUCA to explain the odd distribution pattern of DNA viruses in the tree of life., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mid-density targeted genotyping-by-sequencing (GBS) combines trait-specific markers with thousands of genomic markers at an attractive price for linkage mapping and genomic selection. A 2.5K targeted GBS assay for potato (Solanum tuberosum L.) was developed using the DArTag technology and later expanded to 4K targets. Genomic markers were selected from the potato Infinium single nucleotide polymorphism (SNP) array to maximize genome coverage and polymorphism rates. The DArTag and SNP array platforms produced equivalent dendrograms in a test set of 298 tetraploid samples, and 83% of the common markers showed good quantitative agreement, with RMSE (root mean squared error) <0.5. DArTag is suited for genomic selection candidates in the clonal evaluation trial, coupled with imputation to a higher density platform for the training population. Using the software polyBreedR, an R package for the manipulation and analysis of polyploid marker data, the RMSE for imputation by linkage analysis was 0.15 in a small half-diallel population (N = 85), which was significantly lower than the RMSE of 0.42 with the random forest method. Regarding high-value traits, the DArTag markers for resistance to potato virus Y, golden cyst nematode, and potato wart appeared to track their targets successfully, as did multi-allelic markers for maturity and tuber shape. In summary, the potato DArTag assay is a transformative and publicly available technology for potato breeding and genetics., (© 2024 The Author(s). The Plant Genome published by Wiley Periodicals LLC on behalf of Crop Science Society of America.)

Background and Aims: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related cirrhosis has been increasing these last decades. There are no data regarding the prevalence of MASLD-related cirrhosis in intensive care unit (ICU)., Methods: Prospective single-centre study in a cohort of patients hospitalized in the ICU of Hepatology La Pitié-Salpêtrière Hospital between January 2019 and September 2021. We analysed three groups of patients: MASLD-cirrhosis (alcohol ≤210 g for men and 140 g weekly for women), ALD (alcohol-related liver disease, alcohol>140 g weekly for women or >210 g for men)-cirrhosis alone and MetALD (metabolic and alcohol-related liver disease)-cirrhosis. Endpoints were 1-year transplant-free survival (TFS), further acute decompensation (AD) and re-admission., Results: A total of 410 patients were hospitalized, and 315 analysed: 39 in MASLD, 160 in ALD and 116 in MetALD groups. The global prevalence was 10% for MASLD, 41% ALD and 29.7% for MetALD. Patients in the MASLD group were significantly older (65 vs. 57 and 59 years, p < 0.001), and had lower Child-Pugh (8 vs. 11 vs. 10, p < 0.001) and MELD score (17 vs. 22 vs. 21, p < 0.001). The 1-year TFS was not different between groups (53% vs. 54% vs. 54%, p = 0.96). Cardiovascular mortality was <5% in all groups. The 1-year probability of developing hepatic encephalopathy was significantly higher in the MASLD group (73% vs. 27% and 21%, p < 0.001). There was no difference regarding the development of other complications between groups., Conclusion: MASLD or MetALD was responsible for 1/3 of the causes of cirrhosis in the ICU. MASLD-related cirrhosis is as severe as ALD-related cirrhosis. Liver transplantation should be rapidly discussed., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Acyl-CoA-Binding Proteins (ACBPs) bind acyl-CoA esters and function in lipid metabolism. Although acbp3-1, the ACBP3 mutant in Arabidopsis thaliana ecotype Col-0, displays normal floral development, the acbp3-2 mutant from ecotype Ler-0 characterized herein exhibits defective adaxial anther lobes and improper sporocyte formation. To understand these differences and identify the role of ERECTA in ACBP3 function, the acbp3 mutants and acbp3-erecta (er) lines were analyzed by microscopy for anther morphology and high-performance liquid chromatography for lipid composition. Defects in Landsberg anther development were related to the ERECTA-mediated pathway because the progenies of acbp3-2 × La-0 and acbp3-1 × er-1 in Col-0 showed normal anthers, contrasting to that of acbp3-2 in Ler-0. Polymorphism in the regulatory region of ACBP3 enabled its function in anther development in Ler-0 but not Col-0 which harbored an AT-repeat insertion. ACBP3 expression and anther development in acbp3-2 were restored using ACBP3pro (Ler)::ACBP3 not ACBP3pro (Col)::ACBP3. SPOROCYTELESS (SPL), a sporocyte formation regulator activated ACBP3 transcription in Ler-0 but not Col-0. For anther development, the ERECTA-related role of ACBP3 is required in Ler-0, but not Col-0. The disrupted promoter regulatory region for SPL binding in Col-0 eliminates the role of ACBP3 in anther development., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

Introduction: Systemic inflammation and endothelial dysfunction are potentially modifiable factors implicated in Alzheimer's disease (AD), which offer potential therapeutic targets to slow disease progression., Methods: We investigated the relationship between baseline circulating levels of inflammatory (TNF-α, IL-1ß) and endothelial cell markers (VCAM-1, ICAM-1, E-selectin) and 18-month cognitive decline (ADAS-cog12) in 266 mild-to-moderate AD patients from the NILVAD study. We employed individual growth models to examine associations, potential mediation, and interaction effects while adjusting for confounders., Results: The average increase in ADAS-cog12 scores over all patients was 8.1 points in 18 months. No significant association was found between the markers and the rate of cognitive decline. Mediation analysis revealed no mediating role for endothelial cell markers, and interaction effects were not observed., Discussion: Our results do not support the role of systemic inflammation or endothelial dysfunction in progression in persons with AD., (© 2024. The Author(s).)

Microtubule-based kinesin motor proteins are crucial for intracellular transport, but their hyperactivation can be detrimental for cellular functions. This study investigated the impact of a constitutively active ciliary kinesin mutant, OSM-3CA, on sensory cilia in C. elegans. Surprisingly, we found that OSM-3CA was absent from cilia but underwent disposal through membrane abscission at the tips of aberrant neurites. Neighboring glial cells engulf and eliminate the released OSM-3CA, a process that depends on the engulfment receptor CED-1. Through genetic suppressor screens, we identified intragenic mutations in the OSM-3CA motor domain and mutations inhibiting the ciliary kinase DYF-5, both of which restored normal cilia in OSM-3CA-expressing animals. We showed that conformational changes in OSM-3CA prevent its entry into cilia, and OSM-3CA disposal requires its hyperactivity. Finally, we provide evidence that neurons also dispose of hyperactive kinesin-1 resulting from a clinic variant associated with amyotrophic lateral sclerosis, suggesting a widespread mechanism for regulating hyperactive kinesins., (© 2024. The Author(s).)

Positive-sense single-stranded RNA viruses significantly reshape intracellular membranes to generate viral replication organelles that form a controlled niche in which nucleic acids, enzymes, and cofactors accumulate to assure an efficient replication of the viral genome. In recent years, advancements in electron microscopy (EM) techniques have enabled imaging of these viral factories in a near-native state providing significantly higher molecular details that have led to progress in our general understanding of virus biology. In this review, we describe the contribution of the cutting-edge EM approaches to the current knowledge of replication organelles biogenesis, structure, and functions., (© 2023 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)

Introduction: Patients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks., Methods and Analysis: The L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients., Ethics and Dissemination: The protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences., Trial Registration Number: NCT06087952., Competing Interests: Competing interests: MC has received financial support for research from Bayer, CSL Behring, Roche, Novo Nordisk and UniQure and lees for lecturing or consultancy from Alexion, Bayer, CSL Behring, Daiichi Sankyo, Sobi and Viatris, all unrelated to the present work and paid to his institution. NvE has received a lecture fee from Bristol Myers Squibb, which was unrelated to this work and paid to his institution. JL reports grants or contracts from BMS-Pfizer, Viatris, AstraZeneca and Synapse, all unrelated to this work and paid to her institution. KM reports speaker fees from Alexion, Bayer and CSL Behring, participation in trial steering committees for Bayer and AstraZeneca, consulting fees from Uniqure, participation in data monitoring and endpoint adjudication committee for Octapharma. All payments are made to her institution. SM reports grants and personal fees from Daiichi-Sankyo, Bayer, Pfizer and Boehringer-Ingelheim, personal fees from Portola/Alexion, AbbVie, Pfizer/Bristol-Meyers Squibb, Norgine, Viatris and Sanofi, all paid to her institution and outside the submitted work. MVH reports grants from Dutch Heart Foundation, Netherlands Organisation for Health Research and Development, Bayer Health Care, Pfizer-BMS Leo Pharma Boehringer-Ingelheim, all outside this work. FAK reports grants or contracts from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program, all unrelated to this work and paid to his institution. All others report no conflicts of interest related to this project., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Several studies showed that during the pandemic patients have refrained from visiting their general practitioner (GP). This resulted in medical care being delayed, postponed or completely forgone. The provision of low-value care, i.e. care which offers no net benefit for the patient, also could have been affected. We therefore assessed the impact of the COVID-19 restrictions on three types of low-value GP care: 1) imaging for back or knee problems, 2) antibiotics for otitis media acuta (OMA), and 3) repeated opioid prescriptions, without a prior GP visit., Methods: We performed a retrospective cohort study using registration data from GPs part of an academic GP network over the period 2017-2022. The COVID-19 period was defined as the period between April 2020 to December 2021. The periods before (January 2017 to April 2020) and after the COVID-19 period (January 2022 to December 2022) are the pre- and post-restrictions periods. The three clinical practices examined were selected by two practicing GPs from a top 30 of recommendations originating from the Dutch GP guidelines, based on their perceived prevalence and relevance in practice (van Dulmen et al., BMC Primary Care 23:141, 2022). Multilevel Poisson regression models were built to examine changes in the incidence rates (IR) of both registered episodes and episodes receiving low-value treatment., Results: During the COVID-19 restrictions period, the IRs of episodes of all three types of GP care decreased significantly. The IR of episodes of back or knee pain decreased by 12%, OMA episodes by 54% and opioid prescription rate by 13%. Only the IR of OMA episodes remained significantly lower (22%) during the post-restrictions period. The provision of low-value care also changed. The IR of imaging for back or knee pain and low-value prescription of antibiotics for OMA both decreased significantly during the COVID-restrictions period (by 21% and 78%), but only the low-value prescription rate of antibiotics for OMA remained significantly lower (by 63%) during the post-restrictions period. The IR of inappropriately repeated opioid prescriptions remained unchanged over all three periods., Conclusions: This study shows that both the rate of episodes as well as the rate at which low-value care was provided have generally been affected by the COVID-19 restrictions. Furthermore, it shows that the magnitude of the impact of the restrictions varies depending on the type of low-value care. This indicates that deimplementation of low-value care requires tailored (multiple) interventions and may not be achieved through a single disruption or intervention alone., (© 2024. The Author(s).)

Here we present a sample of 12 massive quiescent galaxy candidates at [Formula: see text] observed with the James Webb Space Telescope (JWST) Near Infrared Spectrograph (NIRSpec). These galaxies were pre-selected from the Hubble Space Telescope imaging and 10 of our sources were unable to be spectroscopically confirmed by ground based spectroscopy. By combining spectroscopic data from NIRSpec with multi-wavelength imaging data from the JWST Near Infrared Camera (NIRCam), we analyse their stellar populations and their formation histories. We find that all of our galaxies classify as quiescent based on the reconstruction of their star formation histories but show a variety of quenching timescales and ages. All our galaxies are massive ([Formula: see text] M[Formula: see text]), with masses comparable to massive galaxies in the local Universe. We find that the oldest galaxy in our sample formed [Formula: see text] M[Formula: see text] of mass within the first few hundred million years of the Universe and has been quenched for more than a billion years by the time of observation at [Formula: see text] ([Formula: see text] billion years after the Big Bang). Our results point to very early formation of massive galaxies requiring a high conversion rate of baryons to stars in the early Universe., (© 2024. Crown.)

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome., (© 2024. The Author(s).)

Rheumatoid arthritis (RA) is a prevalent autoimmune disorder with a significant global economic burden. Epigenetic modifications, particularly DNA methylation, play a crucial role in RA. This study conducted a bibliometric analysis to explore the evolving trends and predominant themes in RA and DNA methylation research over the past two decades. A total of 1800 articles met the inclusion criteria, and the analysis revealed consistent growth in the literature, with a notable increase in output after 2019. The research involved 70 countries, 2139 academic institutions, 23,365 unique authors, and 58,636 co-cited authors. The United States emerged as a dominant contributor in this research domain. The significance of DNA methylation in shaping research directions for RA management is increasingly evident. Recent investigations have shed light on the pivotal role of DNA methylation in RA, particularly in characterizing synovial tissue and exploring the underlying mechanisms of disease pathogenesis. This study provides valuable insights into the landscape of DNA methylation research in RA and highlights the importance of epigenetics in autoimmune diseases., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Spontaneous chromosomal rearrangements (CRs) play an essential role in speciation, genome evolution and crop domestication. To be able to use the potential of CRs for breeding, plant chromosome engineering was initiated by fragmenting chromosomes by X-ray irradiation. With the rise of the CRISPR/Cas system, it became possible to induce double-strand breaks (DSBs) in a highly efficient manner at will at any chromosomal position. This has enabled a completely new level of predesigned chromosome engineering. The genetic linkage between specific genes can be broken by inducing chromosomal translocations. Natural inversions, which suppress genetic exchange, can be reverted for breeding. In addition, various approaches for constructing minichromosomes by downsizing regular standard A or supernumerary B chromosomes, which could serve as future vectors in plant biotechnology, have been developed. Recently, a functional synthetic centromere could be constructed. Also, different ways of genome haploidization have been set up, some based on centromere manipulations. In the future, we expect to see even more complex rearrangements, which can be combined with previously developed engineering technologies such as recombinases. Chromosome engineering might help to redefine genetic linkage groups, change the number of chromosomes, stack beneficial genes on mini cargo chromosomes, or set up genetic isolation to avoid outcrossing., (© 2023 The Authors New Phytologist © 2023 New Phytologist Foundation.)

Understanding the evolutionary mechanisms underlying the maintenance of individual differences in behavior and physiology is a fundamental goal in ecology and evolution. The pace-of-life syndrome hypothesis is often invoked to explain the maintenance of such within-population variation. This hypothesis predicts that behavioral traits are part of a suite of correlated traits that collectively determine an individual's propensity to prioritize reproduction or survival. A key assumption of this hypothesis is that these traits are underpinned by genetic trade-offs among life-history traits: genetic variants that increase fertility, reproduction and growth might also reduce lifespan. We performed a systematic literature review and meta-analysis to summarize the evidence for the existence of genetic trade-offs between five key life-history traits: survival, growth rate, body size, maturation rate, and fertility. Counter to our predictions, we found an overall positive genetic correlation between survival and other life-history traits and no evidence for any genetic correlations between the non-survival life-history traits. This finding was generally consistent across pairs of life-history traits, sexes, life stages, lab vs. field studies, and narrow- vs. broad-sense correlation estimates. Our study highlights that genetic trade-offs may not be as common, or at least not as easily quantifiable, in animals as often assumed., (© 2023 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)

Background: We aimed to quantify ductular reaction (DR) in biliary atresia using a neural network in relation to underlying pathophysiology and prognosis., Methods: Image-processing neural network model was applied to 259 cytokeratin-7-stained native liver biopsies of patients with biliary atresia and 43 controls. The model quantified total proportional DR (DR%) composed of portal biliary epithelium (BE%) and parenchymal intermediate hepatocytes (PIH%). The results were related to clinical data, Sirius Red-quantified liver fibrosis, serum biomarkers, and bile acids., Results: In total, 2 biliary atresia biopsies were obtained preoperatively, 116 at Kasai portoenterostomy (KPE) and 141 during post-KPE follow-up. DR% (8.3% vs. 5.9%, p=0.045) and PIH% (1.3% vs. 0.6%, p=0.004) were increased at KPE in patients remaining cholestatic postoperatively. After KPE, patients with subsequent liver transplantation or death showed an increase in DR% (7.9%-9.9%, p = 0.04) and PIH% (1.6%-2.4%, p = 0.009), whereas patients with native liver survival (NLS) showed decreasing BE% (5.5%-3.0%, p = 0.03) and persistently low PIH% (0.9% vs. 1.3%, p = 0.11). In Cox regression, high DR predicted inferior NLS both at KPE [DR% (HR = 1.05, p = 0.01), BE% (HR = 1.05, p = 0.03), and PIH% (HR = 1.13, p = 0.005)] and during follow-up [DR% (HR = 1.08, p<0.0001), BE% (HR = 1.58, p = 0.001), and PIH% (HR = 1.04, p = 0.008)]. DR% correlated with Sirius red-quantified liver fibrosis at KPE (R = 0.47, p<0.0001) and follow-up (R = 0.27, p = 0.004). A close association between DR% and serum bile acids was observed at follow-up (R = 0.61, p<0.001). Liver fibrosis was not prognostic for NLS at KPE (HR = 1.00, p = 0.96) or follow-up (HR = 1.01, p = 0.29)., Conclusions: DR predicted NLS in different disease stages before transplantation while associating with serum bile acids after KPE., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Populus species play a foundational role in diverse ecosystems and are important renewable feedstocks for bioenergy and bioproducts. Hybrid aspen Populus tremula × P. alba INRA 717-1B4 is a widely used transformation model in tree functional genomics and biotechnology research. As an outcrossing interspecific hybrid, its genome is riddled with sequence polymorphisms which present a challenge for sequence-sensitive analyses. Here we report a telomere-to-telomere genome for this hybrid aspen with two chromosome-scale, haplotype-resolved assemblies. We performed a comprehensive analysis of the repetitive landscape and identified both tandem repeat array-based and array-less centromeres. Unexpectedly, the most abundant satellite repeats in both haplotypes lie outside of the centromeres, consist of a 147 bp monomer PtaM147, frequently span >1 megabases, and form heterochromatic knobs. PtaM147 repeats are detected exclusively in aspens (section Populus) but PtaM147-like sequences occur in LTR-retrotransposons of closely related species, suggesting their origin from the retrotransposons. The genomic resource generated for this transformation model genotype has greatly improved the design and analysis of genome editing experiments that are highly sensitive to sequence polymorphisms. The work should motivate future hypothesis-driven research to probe into the function of the abundant and aspen-specific PtaM147 satellite DNA., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Objective: Our objective was to correlate staging PSMA PET imaging parameters to final histopathology. Second objective was to assess the performance of standard versus delayed PSMA PET to detect primary prostate tumor., Methods: Thirty-one patients (mean age, 61.4 ± 8.2) who underwent radical prostatectomy and preoperative staging PSMA PET scans were included in the study. After defining dominant lesion in pathology, correlations with PET images were performed. Additionally, two physicians blind to clinical and pathological information retrospectively reviewed staging Ga-68 PSMA PET scans with standard and delayed imaging., Results: Dominant lesion SUV's increased with time 8.2(± 4.5), 10(± 7.1), and 10.2(± 7.8) at 1, 2, and 3 h (P = .03 T1-T3). WHO Grade group 3 had highest SUV (group 3 11.9 ± 5.6 vs. group 2 7.9 ± 1.5, p = .02). Addition of cribriform pattern on intraductal component was associated with higher SUV's (11 ± 2.9 vs. 6.5 ± 2.1, p = .01) and higher Gleason four ratios (64 ± 9% vs. 37 ± 17%, p = .01). Intraductal carcinoma was associated with larger tumors (6.3 ± 2.3 cm 3 vs. 2.6 ± 1.7 cm 3 , p < .001). Physician sensitivities ranged from 61 to 81%. Excluding Gleason 3 + 3 lesions and small lesions (< 1 cm 3 ), sensitivities increased to 80-100%. Differences of sensitivity between different time points were not significant. Combined evaluation of all time points did not increase sensitivity., Conclusions: Cribriform pattern correlates with higher Gleason 4 ratios and SUVs in PSMA PET. Intraductal carcinoma is associated with larger tumors but not higher Gleason 4 ratios and SUVs. Multiple late imaging times did not enhance tumor detection and may pose tolerability issues for some patients., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Background: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have different effects on bones, cartilage and joints, sometimes destroying the spine and joints, and other times causing new bone formation. This study aimed to evaluate the effects of RA and AS on the types (radiolucent, radiopaque and mixed) of periapical lesions in jaw bones., Methods: This study included 708 individuals (97 with AS, 327 with RA and 284 healthy controls (C)) and a total of 17,118 teeth (AS: 2,442; RA: 7,638; C: 7,038). The number of teeth, extracted teeth and teeth with root canal treatment and the presence of radiopaque, radiolucent and mixed periapical lesions were recorded from dental panoramic radiographs. Kruskal-Wallis and chi-square tests were used for statistical analysis., Results: The frequency of radiopaque lesions in the AS and RA groups was similar (p > 0.05) and significantly higher than in the C group (p < 0.05) (AS: 13.4%; RA: 6.1%; C: 2%). Mixed lesions (AS: 3.1%; RA: 4.0%; C: 0.4%) were statistically significantly higher for the RA group compared to the C group (p < 0.05), while the AS-C and AS-RA groups were similar (p > 0.05). There was no significant difference in terms of radiolucent lesions among groups (p > 0.05)., Conclusion: Radiopaque apical lesions were frequent in RA and AS patients, while mixed lesions were significantly higher in RA patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: In this study, we aimed to decipher the gut microbiome (GM) and serum metabolic characteristic of individuals at high risk for rheumatoid arthritis (RA) and to investigate the causative effect of GM on the mucosal immune system and its involvement in the pathogenesis of arthritis., Methods: Fecal samples were collected from 38 healthy individuals and 53 high-risk RA individuals with anti-citrullinated protein antibody (ACPA) positivity (Pre-RA), 12 of 53 Pre-RA individuals developed RA within 5 years of follow-up. The differences in intestinal microbial composition between the healthy controls and Pre-RA individuals or among Pre-RA subgroups were identified by 16S ribosomal RNA sequencing. The serum metabolite profile and its correlation with GM were also explored. Moreover, antibiotic-pretreated mice that received GM from the healthy control or Pre-RA groups were then evaluated for intestinal permeability, inflammatory cytokines, and immune cell populations. Collagen-induced arthritis (CIA) was also applied to test the effect of fecal microbiota transplantation (FMT) from Pre-RA individuals on arthritis severity in mice., Results: Stool microbial diversity was lower in Pre-RA individuals than in healthy controls. The bacterial community structure and function significantly differed between healthy controls and Pre-RA individuals. Although there were differences to some extent in the bacterial abundance among the Pre-RA subgroups, no robust functional differences were observed. The metabolites in the serum of the Pre-RA group were dramatically different from those in the healthy controls group, with KEGG pathway enrichment of amino acid and lipid metabolism. Moreover, intestinal bacteria from the Pre-RA group increased intestinal permeability in FMT mice and zonula occludens-1 expression in the small intestine and Caco-2 cells. Moreover, Th17 cells in the mesenteric lymph nodes and Peyer's patches were also increased in mice receiving Pre-RA feces compared to healthy controls. The changes in intestinal permeability and Th17-cell activation prior to arthritis induction enhanced CIA severity in PreRA-FMT mice compared with HC-FMT mice., Conclusion: Gut microbial dysbiosis and metabolome alterations already occur in individuals at high risk for RA. FMT from preclinical individuals triggers intestinal barrier dysfunction and changes mucosal immunity, further contributing to the development of arthritis., (© 2023 American College of Rheumatology.)

The biomass higher heating value (HHV) is an important thermal property that determines the amount of recoverable energy from agriculture byproducts. Precise laboratory measurement or accurate prediction of the HHV is essential for designing biomass conversion equipment. The current study combines feature selection scenarios and machine learning tools to establish a general model for estimating biomass HHV. Multiple linear regression and Pearson's correlation coefficients justified that volatile matter, nitrogen, and oxygen content of biomass samples have a slight effect on the HHV and it is better to ignore them during the HHV modeling. Then, the prediction performance of random forest, multilayer and cascade feedforward neural networks, group method of data handling, and least-squares support vector regressor are compared to determine the intelligent estimator with the highest accuracy toward biomass HHV prediction. The ranking test shows that the multilayer perceptron neural network better predicts the HHV of 532 biomass samples than the other intelligent models. This model presents the outstanding absolute average relative error of 2.75% and 3.12% and regression coefficients of 0.9500 and 0.9418 in the learning and testing stages. The model performance is also superior to a recurrent neural network which was recently developed in the literature using the same databank., (© 2023. Springer Nature Limited.)

Irrigation is limited by water scarcity. Here, we show how a drip irrigation system inspired by the leaf of the fig tree Ficus religiosa (also known as the bodhi tree) can improve irrigation efficiency. The reverse curvature of the leaf regulates the convergence process of multiple water streams, while its long-tail apex allows for fast water drainage with the droplet separation centroid beyond the leaf apex. We explain why drip frequency increases after the break-up of contact line pinning at the apex tip by using scaling laws for drip volume and analyzing drainage dynamics. We build a drip irrigation emitter inspired by the bodhi leaf apex and compare the germination efficiency of wheat, cotton, and maize under different irrigation modes. These results show that the proposed bodhi-leaf-apex-mimetic (BLAM) drip irrigation can improve water saving while ensuring germination and seedling growth., (© 2023. Springer Nature Limited.)

Background: Persistent high-risk Human papillomavirus (HR-HPV) infections are the main cause of cervical cancer. Cumulative evidence implicates regulatory T cells (Tregs) as a critical factor in the failure to eliminate HPV-induced cancers leading to their persistence and progression to cancer. Also, the WHO recognised cervical cancer as 100% attributable to persistent HR-HPV infection. The province of KwaZulu-Natal (KZN) in South Africa has a high prevalence of cervical cancer and HIV infection., Materials and Methods: We evaluated Treg frequency in dual infection of HR HPV and HIV coinfection using phenotypic markers, CD4, CD25 and intracellular Foxp3, in the peripheral blood of 51 cervical cancer and 46 non-cervical cancer participants and evaluated the effect of HIV on regulatory T cell proportion. Peripheral blood mononuclear cells were surface stained with a cocktail fluorescent labelled CD4 and CD25 and subsequently with APC anti-human FoxP3 (eBioscience). Flow cytometry was performed with FACS analysis. Statistical analysis of results was done using Instat 3 program (GraphpadR). Tregs results were expressed as median ± interquartile range (IQR). Associations of cervical cancer with demographic, clinical and laboratory variables were evaluated by univariate and multivariate logistic regression analysis using SPSS version 27 (IBM)., Results: Tregs frequency was significantly higher in individuals with cervical cancer (11.00 ± 19.79%) compared to controls (1.71 ± 8.91%) (p < 0.0001). HIV infection was associated with an increase in Tregs frequency. In controls a significant difference in Tregs frequency was noted between women living with HIV (6.00 ± 10.57%, n = 9) and those without HIV (1.30 ± 6.10%, n = 37), p = 0.0023. In multivariate logistic regression, Tregs frequency was significantly associated with cervical cancer after controlling for age, smoking, weight loss, presence of STI, HIV and HPV genotype., Discussion/conclusion: Higher Tregs frequency was significantly associated with cervical cancer highlighting the immunosuppressive role of Tregs in cervical cancer. Treg frequency was more strongly associated with cervical cancer than HIV infection. We provide baseline data for monitoring Treg frequencies in response to new preventive and therapeutic strategies in the management of cervical cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

T cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is an aggressive malignancy of progenitor T cells. Despite significant improvements in survival of T-ALL/LBL over the past decades, treatment of relapsed and refractory T-ALL (R/R T-ALL/LBL) remains extremely challenging. The prognosis of R/R T-ALL/LBL patients who are intolerant to intensive chemotherapy remains poor. Therefore, innovative approaches are needed to further improve the survival of R/R T-ALL/LBL patients. With the widespread use of next-generation sequencing in T-ALL/LBL, a range of new therapeutic targets such as NOTCH1 inhibitors, JAK-STAT inhibitors, and tyrosine kinase inhibitors have been identified. These findings led to pre-clinical studies and clinical trials of molecular targeted therapy in T-ALL/LBL. Furthermore, immunotherapies such as CD7 CAR T cell therapy and CD5 CAR T cell therapy have shown profound response rate in R/R T-ALL/LBL. Here, we review the progress of targeted therapies and immunotherapies for T-ALL/LBL, and look at the future directions and challenges for the further use of these therapies in T-ALL/LBL., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality., Methods: In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41., Findings: Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations., Interpretation: A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution., Funding: The Netherlands Organisation for Health Research and Development and Amsterdam UMC., Competing Interests: T.M. received research grants from Celgene/BMS, Genentech, and Siemens, and received consulting fees from Kite/Gilead, Janssen, Lilly (all payments made to institution). All other authors declare no competing financial interests., (© 2023 The Author(s).)

Aim: Patients with Turner syndrome have a high rate of developmental dyscalculia, but the underlying neurocognitive mechanisms are not well-understood. Some studies have implicated visuospatial impairments in patients with Turner syndrome, but others have focused on poor procedural skills in patients with Turner syndrome. This study used brain imaging data to test these two alternative views., Methods: This study recruited 44 girls with Turner syndrome (mean age,  12.91 years; SD,  2.02), with 13 (29.5%) of them meeting the criterion for developmental dyscalculia, and 14 normally developing girls (mean age,  14.26 years; SD,  2.18) as a comparison group. All participants were given basic mathematical ability tests and an intelligence test and were scanned using magnetic resonance imaging. We compared patients with Turner syndrome who had dyscalculia, patients with Turner syndrome who did not have dyscalculia, and the normal controls in terms of brain structures and resting-state functional activity., Results: Compared with normal controls, both groups of patients with Turner syndrome (with or without dyscalculia) showed similarly altered functional connectivity in the occipitoparietal dorsal stream. Importantly, compared with patients with Turner syndrome without dyscalculia and normal controls, patients with Turner syndrome with dyscalculia showed decreased functional connectivity between the prefrontal and the lateral occipital cortex., Conclusion: We concluded that both groups of patients with Turner syndrome shared visual deficits, and patients with Turner syndrome with dyscalculia had a deficit in frontal cortex-based higher cognitive processing. It is not their visuospatial deficits but rather their deficits in higher cognitive processing that are responsible for the development of dyscalculia in patients with Turner syndrome., (© 2023 The Authors. Psychiatry and Clinical Neurosciences © 2023 Japanese Society of Psychiatry and Neurology.)

Objective: This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints., Methods: We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE)., Results: Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE., Conclusion: A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Renal fibrosis is the final common pathophysiological pathway in chronic kidney disease (CKD) regardless of the underlying cause of kidney injury. Tubulointerstitial fibrosis (TIF) is considered to be the key pathological predictor of CKD progression. Currently, the gold-standard tool to identify TIF is kidney biopsy, an invasive method that carries risks. Non-invasive diagnostics rely on an estimation of glomerular filtration rate and albuminuria to assess kidney function, but these fail to diagnose early CKD accurately or to predict progressive decline in kidney function. In this review, we summarize the current and emerging molecular biomarkers that have been studied in various clinical settings and in animal models of kidney disease and that are correlated with the degree of TIF. We examine the potential of these biomarkers to diagnose TIF non-invasively and to predict disease progression. We also examine the potential of new technologies and non-invasive diagnostic approaches in assessing TIF. Limitations of current and potential biomarkers are discussed and knowledge gaps identified., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Purpose: Although liver transplantation (LT) outcomes have improved significantly over the last decades, early vascular complications are still associated with elevated risks of graft failure. Doppler ultrasound (DUS) enables detection of vascular complications, provides hepatic artery Resistive Index (RI). The aim of our study was to evaluate the association of the RI parameters of DUS performed in the first post-transplant week with post-transplant outcomes., Methods: All consecutive patients undergoing a first LT between 2001 and 2019 at a single center were included. Patients were divided into two groups: RI < 0.55 and RI ≥ 0.55. Patients were also divided according to the presence or absence of hepatic artery thrombosis (HAT). Graft survival was compared between groups., Results: Overall, 338 patients were included. HAT occurred in 23 patients (6.8%), of which 7 were partial and 16, complete. Biliary complications were more common in patients with HAT (10 [43.5%]) vs. 38 [12.1%] [p < 0.001]). Graft survival was lower for patients with HAT (p = 0.047). Also, RI < 0.55 was associated with increased incidence of HAT (p < 0.001). Additionally, patients with RI < 0.55 on post-operative day 1 had decreased graft survival as compared to patients with RI > 0.55 (p = 0.041). RI on post-operative day 3 and 5 was not predictive of inferior graft outcomes., Conclusions: Intensive use of DUS in the early post-LT period offers the possibility of early diagnosis of vascular complications, guiding medical and surgical management of HAT. Additionally, according to our data, low RI (< 0.55) on the first postoperative day also is a predictor of HAT and decreased graft-survival., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The Ask-Advise-Connect (AAC) approach can help primary care providers to increase the number of people who attempt to quit smoking and enrol into cessation counselling. We implemented AAC in Dutch general practice during the COVID-19 pandemic. In this study we describe how AAC was received in Dutch general practice and assess which factors played a role in the implementation., Methods: A mixed-methods approach was used to evaluate the implementation of AAC. Implementation took place between late 2020 and early 2022 among 106 Dutch primary care providers (general practitioners (GPs), practice nurses and doctor's assistants). Quantitative and qualitative data were collected through four online questionnaires. A descriptive analysis was conducted on the quantitative data. The qualitative data (consisting of answers to open-ended questions) were inductively analysed using axial codes. The Consolidated Framework for Implementation Research was used to structure and interpret findings., Results: During the study, most participants felt motivated (84-92%) and able (80-94%) to apply AAC. At the end of the study, most participants reported that the AAC approach is easy to apply (89%) and provides advantages (74%). Routine implementation of the approach was, however, experienced to be difficult. More GPs (30-48%) experienced barriers in the implementation compared to practice nurses and doctor's assistants (7-9%). The qualitative analysis showed that especially external factors, such as a lack of time or priority to discuss smoking due to the COVID-19 pandemic, negatively influenced implementation of AAC., Conclusions: Although AAC was mostly positively received in Dutch general practice, implementation turned out to be challenging, especially for GPs. Lack of time to discuss smoking was a major barrier in the implementation. Future efforts should focus on providing additional implementation support to GPs, for example with the use of e-health., (© 2023. The Author(s).)

Introduction: Coronavirus disease-2019 (COVID-19) is still a global health problem nowadays. A particular COVID-19 patients develop severe symptoms. Some biomarkers can be used to determine disease severity and improve outcome. Homocysteine is one of the novel biomarkers. The objective of this study is to determine the role of serum homocysteine level in stratifying severity of COVID-19., Methods: A cross-sectional study was conducted in Medan, Indonesia from May to December 2021. Subjects were obtained using consecutive sampling method. Inclusion criteria was COVID-19 patients aged 18 years or older and willing to participate in the study. Patients with malignancy, chronic kidney disease, thyroid disease, coronary heart disease, and who consume several medications including cholestyramine, metformin, methotrexate, fibrate, and contraceptive pill, were excluded. Data regarding demographic, laboratory, and biomarker were gathered from each subject. Statistical analyses were conducted at 95% confidence interval., Results: A total of 100 patients were enrolled. Most subjects were males (59%) and from Batak ethnicity (64%). Twenty percent subjects had severe COVID-19. The levels of serum high-sensitivity C-reactive protein (hs-CRP), D dimer, homocysteine, and procalcitonin were significantly higher in severe COVID-19 subjects. D dimer had the highest sensitivity (91.7%) and specificity (94.7%) in stratifying severe COVID-19, followed by hs-CRP (91.7% and 85.5%, respectively), homocysteine (87.5% and 78.9%, respectively), and procalcitonin (58.3% and 74.0%, respectively)., Conclusion: Homocysteine can be used as a biomarker to determine COVID-19 severity., (© 2023 Jelita Siregar et al., published by Sciendo.)

Background: Clinically relevant postoperative pancreatic fistula (CR-POPF) is a common complication after pancreaticoduodenectomy (PD). However, whether irrigation-suction (IS) decreases the incidence and severity of CR-POPF has not yet been well elucidated., Methods: One hundred and twenty patients with planned PD were enrolled in the study at a high-volume pancreatic center in China from August 2018 to January 2020. A randomized controlled trial (RCT) was conducted to evaluate whether irrigation-suction (IS) decreases the incidence and severity of CR-POPF and other postoperative complications after PD. The primary endpoint was the incidence of CR-POPF, and the secondary endpoints were other postoperative complications., Results: Sixty patients were assigned to the control group and 60 patients to the IS group. The IS group had a comparable POPF rate (15.0% vs. 18.3%, p = 0.806) but a lower incidence of intra-abdominal infection (8.3% vs. 25.0%, p = 0.033) than the control group. The incidences of other postoperative complications were comparable in the two groups. The subgroup analysis for patients with intermediate/high risks for POPF also showed an equivalent POPF rate (17.0% vs. 20.4%, p = 0.800) and a significantly decreased incidence of intra-abdominal infection (8.5% vs. 27.8%, p = 0.020) in the IS group than that in the control group. The logistic regression models indicated that POPF was an independent risk factor for intra-abdominal infection (OR 0.049, 95% CI 0.013-0.182, p = 0.000)., Conclusions: Irrigation-suction near pancreaticojejunostomy does not reduce the incidence or severity of postoperative pancreatic fistula but decreases the incidence of intra-abdominal infection after pancreaticoduodenectomy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine (BrainGENIE) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood-brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan, a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947-11,816 genes (false-discovery rate-adjusted p < 0.05), including many transcripts that cannot be predicted significantly by a transcriptome-imputation method such as PrediXcan. BrainGENIE recapitulated measured diagnosis-related gene-expression changes in the brain for autism, bipolar disorder, and schizophrenia better than direct correlations from blood and predictions from PrediXcan. We developed a convenient software toolset for deploying BrainGENIE, and provide recommendations for how best to implement models. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues., (© 2023. The Author(s).)

Autophagy, an intracellular degradation system conserved in eukaryotes, has been increasingly recognized as a key battlefield in plant-pathogen interactions. However, the role of plant autophagy in nematode parasitism is mostly unknown. We report here the identification of a novel and conserved effector, Nematode Manipulator of Autophagy System 1 (NMAS1), from plant-parasitic cyst nematodes (Heterodera and Globodera spp.). We used molecular and genetic analyses to demonstrate that NMAS1 is required for nematode parasitism. The NMAS1 effectors are potent suppressors of reactive oxygen species (ROS) induced by flg22 and cell death mediated by immune receptors in Nicotiana benthamiana, suggesting a key role of NMAS1 effectors in nematode virulence. Arabidopsis atg mutants defective in autophagy showed reduced susceptibility to nematode infection. The NMAS1 effectors contain predicted AuTophaGy-related protein 8 (ATG8)-interacting motif (AIM) sequences. In planta protein-protein interaction assays further demonstrated that NMAS1 effectors specifically interact with host plant ATG8 proteins. Interestingly, mutation in AIM2 of GrNMAS1 from the potato cyst nematode Globodera rostochiensis abolishes its interaction with potato StATG8 proteins and its activity in ROS suppression. Collectively, our results reveal for the first time that cyst nematodes employ a conserved AIM-containing virulence effector capable of targeting a key component of host autophagy to promote disease., (© 2022 Cornell University. New Phytologist © 2022 New Phytologist Foundation. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: Hepatic artery-related complications (HARC) after live donor liver transplantation (LDLT) is associated with high morbidity and mortality rate., Methods: Prospectively maintained data from July 2011 to September 2020 was analyzed for etiology, detection, management, and outcome of HARC., Results: Six hundred fifty-seven LDLT (adult 572/pediatrics 85) were performed during the study period. Twenty-one (3.2%) patient developed HARC; 16 (2.4%) hepatic artery thrombosis (HAT) and 5 (0.76%) non-thrombotic hepatic artery complication (NTHAC). Ninety percent (19/21) HARC were asymptomatic and detected on protocol Doppler. Median time to detection was day 4 (range - 1 to 35), which included 18 early (within 7 days) vs 3 late incidents. Only one pediatric patient had HAT. Seven patients underwent surgical revascularization, 11 had endovascular intervention and 3 with attenuated flow required only systemic anticoagulation. All NTHAC survived without any sequelae. Revascularization was successful in 81% (13/16) with HAT. Biliary complications were seen in 5 (23.8%); four were managed successfully. Overall mortality was 14.8% (3/21). The 1-year and 5-year survival were similar to those who did not develop HARC (80.9% vs 84.2%, p = 0.27 and 71.4% vs 75.19%, p = 0.36 respectively) but biliary complications were significantly higher (23.8% vs 14.2%, p = 0.03). On multivariate analysis, clockwise technique of arterial reconstruction was associated with decreased risk of HAT (1.7% vs 4.1% (p value - 0.003))., Conclusion: Technical refinement, early detection, and revascularization can achieve good outcome in patients with HARC after LDLT., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In order to establish malignant lesions, tumors must first evade their detection by immune cells. Tumors achieve this by embellishing and tailoring their glycocalyx, a network of polysaccharides and glycosylated proteins that refracts the phagocytic efforts of myeloid cells, shrouds neoantigens and other ligands from cells of the acquired immune system, and skews immune responses. The barriers imposed by the glycocalyx are biophysical and also linked to the inhibitory receptor signaling pathways of immune cells that engage tumor sialic acids as markers of healthy "self". This would explain the pressure for cancers to upregulate the synthases, transmembrane mucins, and other heavily sialylated glycoproteins involved in establishing a repulsive glycocalyx. Accordingly, individual tumor cells that are best capable of constructing a shielding glycocalyx on their surface show higher metastatic potential in immunocompetent mice. Reciprocally, therapeutics have recently been devised to edit and dismantle the glycocalyx barrier in an effort to invigorate an immune response aimed at tumor destruction. We discuss the features of the tumor-associated glycocalyx that afford immune evasion of cancers and how strategies that target this barrier may potentiate antitumor immunity., (© 2021 Federation of European Biochemical Societies.)

The early detection of graft failure in pediatric liver transplantation is crucial for appropriate intervention. Graft failure is associated with numerous perioperative risk factors. This study aimed to develop an individualized predictive model for 90-days graft failure in pediatric liver transplantation using machine learning methods. We conducted a single-center retrospective cohort study. A total of 87 liver transplantation cases performed in patients aged < 12 years at the Severance Hospital between January 2010 and September 2020 were included as data samples. Preoperative conditions of recipients and donors, intraoperative care, postoperative serial laboratory parameters, and events observed within seven days of surgery were collected as features. A least absolute shrinkage and selection operator (LASSO) -based method was used for feature selection to overcome the high dimensionality and collinearity of variables. Among 146 features, four variables were selected as the resultant features, namely, preoperative hepatic encephalopathy, sodium level at the end of surgery, hepatic artery thrombosis, and total bilirubin level on postoperative day 7. These features were selected from different times and represent distinct clinical aspects. The model with logistic regression demonstrated the best prediction performance among various machine learning methods tested (area under the receiver operating characteristic curve (AUROC) = 0.898 and area under the precision-recall curve (AUPR) = 0.882). The risk scoring system developed based on the logistic regression model showed an AUROC of 0.910 and an AUPR of 0.830. Together, the prediction of graft failure in pediatric liver transplantation using the proposed machine learning model exhibited superior discrimination power and, therefore, can provide valuable information to clinicians for their decision making during the postoperative management of the patients., (© 2022. The Author(s).)

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and persistently threatens to humanity. With tireless efforts from scientists around the world, understanding of the biology of coronavirus has been greatly enhanced over the past 2 years. Structural biology has demonstrated its powerful impact on uncovering structures and functions for the vast majority of SARS-CoV-2 proteins and guided the development of drugs and vaccines against COVID-19. In this review, we summarize current progress in the structural biology of SARS-CoV-2 and discuss important biological issues that remain to be addressed. We present the examples of structure-based design of Pfizer's novel anti-SARS-CoV-2 drug PF-07321332 (Paxlovid), Merck's nucleotide inhibitor molnupiravir (Lagevrio), and VV116, an oral drug candidate for COVID-19. These examples highlight the importance of structure in drug discovery to combat COVID-19. We also discussed the recent variants of Omicron and its implication in immunity escape from existing vaccines and antibody therapies., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

The emergence of SARS-CoV-2 variants of concern and repeated outbreaks of coronavirus epidemics in the past two decades emphasize the need for next-generation pan-coronaviral therapeutics. Drugging the multi-functional papain-like protease (PLpro) domain of the viral nsp3 holds promise. However, none of the known coronavirus PLpro inhibitors has been shown to be in vivo active. Herein, we screened a structurally diverse library of 50,080 compounds for potential coronavirus PLpro inhibitors and identified a noncovalent lead inhibitor F0213 that has broad-spectrum anti-coronaviral activity, including against the Sarbecoviruses (SARS-CoV-1 and SARS-CoV-2), Merbecovirus (MERS-CoV), as well as the Alphacoronavirus (hCoV-229E and hCoV-OC43). Importantly, F0213 confers protection in both SARS-CoV-2-infected hamsters and MERS-CoV-infected human DPP4-knockin mice. F0213 possesses a dual therapeutic functionality that suppresses coronavirus replication via blocking viral polyprotein cleavage, as well as promoting antiviral immunity by antagonizing the PLpro deubiquitinase activity. Despite the significant difference of substrate recognition, mode of inhibition studies suggest that F0213 is a competitive inhibitor against SARS2-PLpro via binding with the 157K amino acid residue, whereas an allosteric inhibitor of MERS-PLpro interacting with its 271E position. Our proof-of-concept findings demonstrated that PLpro is a valid target for the development of broad-spectrum anti-coronavirus agents. The orally administered F0213 may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and future coronavirus outbreaks., (© 2022. The Author(s).)

Selective logging disrupts forests, changing their structure and species composition. Long-term monitoring helps in identifying the factors influencing it and aids in designing management plans. We conducted a quantitative re-assessment of trees ≥ 30 cm girth at breast height in four 1 ha plots in logged and two 1 ha plots in adjacent unlogged compartments of Uppangala forest continuum in the Western Ghats, India to compare the structural and compositional changes after a decade (2010-2021). Altogether, four species disappeared and three species were newly recruited. Mean species richness and stem density of both the forest sites decreased. Logged plots showed a slight increase in basal area (2.5%) and biomass (5.1%), whereas unlogged plots showed a decline in basal area (3.92%) and biomass (2.9%). As compared to unlogged plots, all the demographic rates were higher for logged forest sites. Across the six individual plots, the growth rates varied significantly owing to wood density and forest strata categories. Non-metric multidimensional scaling (NMDS) identified three groups with significant difference in species composition, where logged and unlogged plots have a distinct composition except for one plot. Although species richness and stem diversity remained stable, the species composition is different 37 years after logging, and the impacts of logging are still evident in the forest., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To identify a panel of serum biomarkers that could specifically identify imminent cases of rheumatoid arthritis (RA) before diagnosis., Methods: Serum samples were collected at 4 time points from active component US military personnel, including 157 anti-citrullinated protein antibody (ACPA)-seropositive and 50 ACPA-seronegative RA subjects, 100 reactive arthritis (ReA) subjects, and 76 healthy controls. The cohorts were split into 2 phases, with samples tested on independent proteomic platforms for each phase. Classification models of RA diagnosis based on samples obtained within 6 months prior to diagnosis were developed both in univariate analyses and by multivariate random forest modeling of training sample sets and testing sample sets from each phase., Results: Increases in serum analytes, including C-reactive protein levels, serum amyloid A, and soluble programmed cell death 1 (PD-1), were observed in seropositive RA subjects at the time point closest to diagnosis, up to several years before diagnosis. Only a small fraction of RA subjects had levels above the 95th percentile of healthy control levels until the time period within 6 months of diagnosis. For classification of RA diagnosis using samples obtained within 6 months prior to diagnosis, soluble PD-1 provided superior specificity compared to ReA cases (>89%), with a sensitivity of 48% for RA classification. An 8-analyte model provided superior sensitivity (69%), with comparable specificity relative to ReA (>82%)., Conclusion: Our findings demonstrate that imminent RA diagnosis could be classified with high specificity, relative to healthy controls and ReA cases, using a panel of cytokines measured in serum samples collected within 6 months before actual diagnosis., (© 2022 American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background and Objectives: Gender-affirming hormone therapy modifies body composition and lean muscle mass in transgender persons. We sought to characterize the change in serum creatinine, other kidney function biomarkers, and GFR in transgender persons initiating masculinizing and feminizing gender-affirming hormone therapy., Design, Setting, Participants, & Measurements: We searched PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov from inception to September 16, 2020 for randomized controlled trials, observational studies, and case series that evaluated the change in serum creatinine, other kidney function biomarkers, and GFR before and after the initiation of gender-affirming hormone therapy in adult transgender persons. Two reviewers independently screened and abstracted data, and disagreements were resolved by a third reviewer. A random effects meta-analysis was performed to determine the change in outcomes over follow-up of 3, 6, and 12 months., Results: Of the 4758 eligible studies, 26 met the inclusion criteria, including nine studies that recruited 488 transgender men and 593 women in which data were meta-analyzed. There was heterogeneity in study design, populations, gender-affirming hormone therapy routes, and dosing. At 12 months after initiating gender-affirming hormone therapy, serum creatinine increased by 0.15 mg/dl (95% confidence interval, 0.00 to 0.29) in 370 transgender men and decreased by -0.05 mg/dl (95% confidence interval, -0.16 to 0.05) in 361 transgender women. No study reported the effect of gender-affirming hormone therapy on albuminuria, proteinuria, cystatin C, or measured GFR., Conclusions: Gender-affirming hormone therapy increases serum creatinine in transgender men and does not affect serum creatinine in transgender women. The effect on gender-affirming hormone therapy on other kidney function biomarkers and measured GFR is unknown., Clinical Trial Registry Name and Registration Number: Change in Kidney Function Biomarkers in Transgender Persons on Gender Affirmation Hormone Therapy-A Systematic Review and Meta-Analysis, CRD42020214248., (Copyright © 2022 by the American Society of Nephrology.)