Search

Background: Pure frailty and obese frailty are common types of frailty syndrome. However, the overlapping and distinct characteristics between pure frailty and obese frailty remain unclear. This study aims to reveal the overlapping/distinct physical and biological phenotypes of pure frailty and obese frailty, providing theoretical support for their prevention, diagnosis, and treatment., Method: Mice were fed either a normal or high-fat diet and assessed at 20 months of age. They were assigned to one of the four groups: control, obesity, pure frailty, and obese frailty. Grip strength, walking speed, physical activity, endurance, and body weight were measured to determine pure frailty and obese frailty. Physical and biological phenotypes were assessed., Results: Distinct physical phenotypes were observed between pure frailty and obese frailty in terms of body weight, lean mass, fat mass, fat mass in tissue, grip strength, endurance, and physical activity, while walking speed overlapped. In biological phenotypes, levels of Smad2/3, FoxO3a, P62, LAMP-2, and cathepsin L expression were distinct, while AKT, p-AKT, mTOR, p-mTOR, p-Smad2/3, p-FoxO3a, Beclin-1, ATG7, and LC3 overlapped., Conclusion: Distinct physical phenotypes observed in obese frailty are primarily attributable to the effect of obesity, with further impairment of muscle function resulting from the combined effects of frailty syndromes and obesity. Pure frailty and obese frailty share overlapping biological phenotypes, particularly in the regulation of muscle protein synthesis. Moreover, the interaction between obesity and frailty syndromes gives rise to both overlapping and distinct biological phenotypes, especially in the regulation of specific degradation signaling proteins., (© 2024 The Author(s).)

Background: Many studies have shown that seed traits, which are among the most important plant traits, can be inherited stably, a finding which is of great value for the improvement of seed germination, seed propagation, seedling establishment, plant breeding, and ecological restoration. The differences in phenotype and nutritional traits and their interactions in Zanthoxylum planispinum var. dingtanensis were ascertained, and the nutrient input rule and the strategy of resource balancing were analyzed in order to provide a scientific basis for the screening of improved variants of the test plant., Results: The nutrient distribution with in the tissues of Z. planispinum var. dingtanensis fruit was that the pericarp had adequate concentrations of N and P concentrations and the seed was also sufficient in P, but low in N concentration. Inorganic nutrients were particularly invested in the pericarp, while organic nutrients are more likely to be stored in the seed. In the economic spectrum of seed traits, the large leaf Zanthoxylum variant represented the low-investment economic type, the tufted leaf Zanthoxylum variant represented the high-investment luxury type, and the safflower Zanthoxylum and acutifoliate leaf Zanthoxylum variants represented transitional types., Conclusions: Inorganic nutrients were more invested in the pericarp to produce secondary metabolites, while organic nutrients are more likely to be stored in the seed to ensure seed germination and seedling establishment in order to achieve inheritance. The variants of Z. planispinum var. dingtanensis differ in terms of resource allocation and balance, which could be further exploited through combining characters in breeding programs., Competing Interests: Declarations Ethics approval and consent to participate This study was conducted in accordance with the relevant guidelines and legislation of the People’s Republic of China and international authorities. Permission for collection of the four variants of Z. planispinum var. dingtanensis in the experiments was obtained from Zhenfeng County, Qianxinan Prefecture, Guizhou Province, China. The Z. planispinum var. dingtanensis used in this study was identified by Changsheng Wei, Senior Engineer of Zhengfeng County Forestry, and voucher specimens are preserved in the Zhenfeng County Ding Tan Jiao Ye Co., Ltd (voucher ID: 991005, 992003, 221007, and 222005). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Main Conclusion: Association analysis identified 77 marker-trait associations (MTAs) for PUE traits, of which 10 were high-confidence MTAs. Candidate-gene mining and in-silico expression analysis identified 13 putative candidate genes for PUE traits. Bread wheat (Triticum aestivum L.) is a major cereal crop affected by phosphorus (P) deficiency, which affects root characteristics, plant biomass, and other attributes related to P-use efficiency (PUE). Understanding the genetic mechanisms of PUE traits helps in developing bread wheat cultivars that perform well in low-P environments. With this objective, we evaluated a bread wheat panel comprising 304 accessions for 14 PUE traits with high-throughput phenotyping under low-P and optimum-P treatments and observed a significant genetic variation among germplasm lines for studied traits. Genome-wide association study (GWAS) using 14,025 high-quality single-nucleotide polymorphisms identified 77 marker-trait associations (MTAs), of which 10 were chosen as high-confidence MTAs as they had > 10% phenotypic variation with logarithm of odds (LOD) scores of more than five. Candidate-gene (CG) mining from high-confidence MTAs identified 180 unique gene models, of which 78 were differentially expressed (DEGs) with at least twofold change in expression under low-P over optimum-P. Of the 78-DEGs, 13 were thought to be putative CGs as they exhibited functional relevance to PUE traits. These CGs mainly encode for important proteins and their products involved in regulating root system architecture, P uptake, transport, and utilization. Promoter analysis from 1500 bp upstream of gene start site for 13 putative CGs revealed the presence of light responsive, salicylic-acid responsive, gibberellic-acid (GA)-responsive, auxin-responsive, and cold responsive cis-regulatory elements. High-confidence MTAs and putative CGs identified in this study can be employed in breeding programs to improve PUE traits in bread wheat., Competing Interests: Declarations Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical approval and consent to participate Not applicable. Consent to participate Not applicable. Consent for publication Not applicable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Key Message: The gene regulating fruit pedicel length in wax gourd was finely mapped to a 211 kb region on chromosome 8. The major gene, Bch08G017310 (BhGA2ox3), was identified through forward genetics. Fruit pedicel length (FPL) is a crucial trait in wax gourd (Benincasa hispida) that affects fruit development and cultivation management. However, the key regulatory genes and mechanisms of FPL in wax gourds remain poorly understood. In this study, we constructed an F 2 population using wax gourd plants with long fruit pedicels (GF-7-1-1) and short fruit pedicels (YSB-1-1-2) as parents. Through BSA-seq, we initially localised the FPL candidate gene to an 8.4 Mb region on chromosome 8, which was further narrowed down to a 1.1 Mb region via linkage analysis. A large F 2 population of 2163 individuals was used to screen for recombinants, and the locus was ultimately narrowed to within a 211 kb (62,299,856-62,511,174 bp) region. Sequence and expression analyses showed that Bch08G017310 (named BhGA2ox3) is a strong candidate gene for FPL in wax gourds. It encodes gibberellin (GA) 2-beta-dioxygenase, a member of the GA 2-oxidase (GA2ox) family. Cytology showed that GA treatment significantly elongated the fruit pedicels and enlarged the cells in the plants with short fruit pedicels. Ectopic expression of BhGA2ox3 showed that BhGA2ox3 overexpression in Arabidopsis thaliana resulted in significantly shorter fruit pedicels. This study lays a theoretical foundation for the regulatory mechanism of FPL in wax gourds and molecular breeding., Competing Interests: Declarations Conflict of interests The authors declare that they have no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Key Message: Two closely linked novel loci, qKRN2-1 and qKRN2-2, associated with kernel row number were fine-mapped on chromosome 2, and a key candidate gene for qKRN2-1 was identified through expression analysis. Kernel row number (KRN) is a crucial factor influencing maize yield and serves as a significant target for maize breeding. The use of wild progenitor species can aid in identifying the essential traits for domestication and breeding. In this study, teosinte (MT1) served as the donor parent, the inbred maize line of Mo17 was used as the recurrent parent, we identified a major quantitative trait locus (QTL) for KRN, designated qKRN2, into two closely linked loci, qKRN2-1 and qKRN2-2. Here, fine mapping was performed to investigate two QTLs, qKRN2-1 and qKRN2-2, within a genomic range of 272 kb and 775 kb, respectively. This was achieved using a progeny test strategy in an advanced backcross population, with the two QTLs explaining 33.49% and 35.30% of the phenotypic variance. Molecular marker-assisted selection resulted in the development of two nearly isogenic lines (NILs), qKRN2-1 and qKRN2-2, which differed only in the segment containing the QTL. Notably, the maize (Mo17) alleles increased the KRN relative to teosinte by approximately 1.4 and 1.2 rows for qKRN2-1 and qKRN2-2, respectively. Zm00001d002989 encodes a cytokinin oxidase/dehydrogenase and its expression in the immature ears exhibited significant differences among the qKRN2-1 NILs. In situ hybridization localized Zm00001d002989 to the primordia of the inflorescence meristem and spikelet pair meristems, is predicted to be the causal gene of qKRN2-1. The findings of this study deepen our understanding of the genetic basis of KRN and hold significant potential for improving maize grain yields., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflict of interest. Human and animal rights This study does not include human or animal subjects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The mutation-selection mechanism of Darwinian evolution gives rise not only to adaptation to environmental conditions but also to the enhancement of robustness against mutations. When two or more phenotypes have the same fitness value, the robustness distribution for different phenotypes can vary. Thus, we expect that some phenotypes are favored in evolution and that some are hardly selected because of a selection bias for mutational robustness. In this study, we investigated this selection bias for phenotypes in a model of gene regulatory networks (GRNs) using numerical simulations. The model had one input gene accepting a signal from the outside and one output gene producing a target protein, and the fitness was high if the output for the full signal was much higher than that for no signal. The model exhibited three types of responses to changes in the input signal: monostable, toggle switch, and one-way switch. We regarded these three response types as three distinguishable phenotypes. We constructed a randomly generated set of GRNs using the multicanonical Monte Carlo method originally developed in statistical physics and compared it to the outcomes of evolutionary simulations. One-way switches were strongly suppressed during evolution because of their lack of mutational robustness. By examining one-way switch GRNs in detail, we found that mutationally robust GRNs obtained by evolutionary simulations and non-robust GRNs obtained by McMC have different network structures. While robust GRNs have a common core motif, non-robust GRNs lack this motif. The bistability of non-robust GRNs is considered to be realized cooperatively by many genes, and these cooperative genotypes have been suppressed by evolution., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Macoto Kikuchi. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pericytes play a crucial role in controlling inflammation and vascular functions in the central nervous system, which are disrupted in Parkinson's disease (PD). Still, there is a lack of studies on the impact of pericytes on neurodegenerative diseases, and their involvement in the pathology of PD is unclear. Our objective was to investigate the molecular and functional differences between healthy pericytes and pericytes with the LRRK2 G2019S mutation, which is one of the most common mutations associated with PD., Methods: Our study employed pericyte-like cells obtained from induced pluripotent stem cells produced from PD patients with the LRRK2 G2019S mutation as well as from healthy individuals. We examined the gene expression profiles of the cells and analyzed how the alterations reflect on their functionality., Results: We have shown differences in the expression of genes related to inflammation and angiogenesis. Furthermore, we observe modified migration speed in PD pericyte-like cells as well as enhanced secretion of inflammatory mediators, such as soluble VCAM-1 and MCP-1, in these pericyte-like cells following exposure to proinflammatory stimuli., Conclusions: In summary, our findings support the notion that pericytes play a role in the inflammatory and vascular changes observed in PD. Further investigation of pericytes could provide valuable insight into understanding the pathogenesis of PD., Competing Interests: Declarations Consent for publication Not applicable. Competing interests The authors declare no competing interests. Ethical approval The use of the patient-derived material has been approved by the Hospital District of Northern Savo, research Ethics committee (#42//2010 and #123//2016)., (© 2024. The Author(s).)

Maple Syrup Urine Disease (MSUD, OMIM# 248600) is an autosomal recessive inborn error of metabolism characterized by elevated branched chain amino acids (BCAA) leucine/isoleucine and valine in blood of affected children. The phenotypic and genotypic spectrum of MSUD is largely unreported in Egypt. We recruited ten patients (4 males/6 females, 2weeks-12years) from nine unrelated families with clinical and biochemical evidence of MSUD. We performed Sanger sequencing for the three most-commonly responsible genes: BCKDHA, BCKDHB and DBT and conducted exome sequencing for unresolved cases. Through Sanger sequencing, we detected eight homozygous pathogenic/likely pathogenic variants (four in BCKDHB, three in BCKDHA and one in DBT gene) in eight different families. The proband of family VI, who had no significant genetic findings by Sanger, had a peculiar phenotype and atypical radiological findings. His exome sequencing revealed a previously reported homozygous likely pathogenic variant in the RARS2 gene (NM_020320.5:c.1026G > A;p.(Met342Ile)) causing the mitochondrial-encephalopathy disorder pontocerebellar hypoplasia, type 6 (OMIM# 611523). Furthermore, the copy-number-variant analysis of the exome data revealed a biallelic duplication affecting exons 2-6 of the BCKDHB gene (GRCh38: Chr.6-g.80127496:80171441dup) evaluated as variant of uncertain significance but expected to cause a breakpoint and may disrupt gene function, which can explain the markedly elevated BCAA levels in the patient's blood. In conclusion, we expanded the genotypic and phenotypic spectrum of the disease and showed that aggressive intervention with specific treatment in the first few days of life resulted in normal development even in a developing country setting. Inclusion of MSUD in the national newborn screening program in Egypt is highly recommended., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics declaration The study was conducted in accordance with the Declaration of Helsinki for studies involving human participants and was approved by the institutional research ethics committees at the Faculty of Medicine, Cairo University (#Approval code: #N-138-2021). Written informed consent was obtained from the parents/legal guardians of all study participants., (© 2024. The Author(s).)

Repressor elements significantly influence economically relevant phenotypes in pigs; however, their precise roles and characteristics are inadequately understood. In the present study, we employed H3K27me3 profiling, assay for transposase-accessible chromatin with highthroughput sequencing (ATAC-seq), and RNA sequencing (RNA-seq) data across six tissues derived from three embryonic layers to identify and map 2 034 super repressor elements (SREs) and 22 223 typical repressor elements (TREs) in the pig genome. Notably, many repressor elements were conserved across mesodermal and ectodermal tissues. SREs exhibited tight regulation of their target genes, affecting a limited number of genes within a specific genomic region with pronounced effects, while TREs exerted broader but weaker regulation over a wider range of target genes. Furthermore, in neuronal tissues, genes regulated by repressor elements started to be repressed during the differentiation of stem cells into progenitor cells. Notably, analysis showed that many repressor elements exhibited cooperative and additive effects on the modulation of KLF4 expression. This research provides the first comprehensive map of pig repressor elements, serving as an essential reference for future studies on repressor elements.

Context: Hierarchical clustering (HC) identifies subtypes of polycystic ovary syndrome (PCOS)., Objective: This work aimed to identify clinically significant subtypes in a PCOS cohort diagnosed with the Rotterdam criteria and to further characterize the distinct subtypes., Methods: Clustering was performed using the variables body mass index (BMI), luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulfate, sex hormone-binding globulin (SHBG), testosterone, insulin, and glucose. Subtype characterization was performed by analyzing the variables estradiol, androstenedione, dehydroepiandrosterone, cortisol, anti-Müllerian hormone (AMH), total follicle count (TFC), lipid profile, and blood pressure. Study participants were girls and women who attended our university hospital for reproductive endocrinology screening between February 1993 and February 2021. In total, 2502 female participants of European ancestry, aged 13 to 45 years with PCOS (according to the Rotterdam criteria), were included. A subset of these (n = 1067) fulfilled the National Institutes of Health criteria (ovulatory dysfunction and hyperandrogenism). Main outcome measures included the identification of distinct PCOS subtypes using cluster analysis. Additional clinical variables associated with these subtypes were assessed., Results: Metabolic, reproductive, and background PCOS subtypes were identified. In addition to high LH and SHBG levels, the reproductive subtype had the highest TFC and levels of AMH (all P < .001). In addition to high BMI and insulin levels, the metabolic subtype had higher low-density lipoprotein levels and higher systolic and diastolic blood pressure (all P < .001). The background subtype had lower androstenedione levels and features of the other 2 subtypes., Conclusion: Reproductive and metabolic traits not used for subtyping differed significantly in the subtypes. These findings suggest that the subtypes capture distinct PCOS causal pathways., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Cutaneous melanoma incidence varies consistently across body sites between men and women, but the underlying causes of these differences remain unclear. To date, no prospective studies have examined risk factors for melanoma separately for men and women according to body site., Objectives: We aimed to examine the association between identified constitutional, genetic and environmental risk factors for invasive melanoma of different body sites among men and women., Methods: We compared the association between constitutional, genetic and environmental risk factors for invasive melanoma on different body sites separately for men and women in a population-based prospective cohort study of 17 774 men and 21 070 women aged between 40 and 69 years who were residents of Queensland, Australia at baseline in 2011. Participants were followed until December 2021. We examined risk factors including hair colour, tanning ability, naevus density and proxies for high cumulative sun exposure, all self-reported at baseline. We also examined polygenic risk score (PRS) derived from summary statistics from a melanoma genome-wide association study meta-analysis., Results: During a median 10.4 years of follow-up, 455 men and 331 women developed an incident invasive melanoma; the mean age at diagnosis was lower in women than in men (62.6 vs. 65.0 years). The most common body site was the trunk in men (45.1%), and the upper (36.8%) and lower limbs (27.4%) in women. High naevus density and proxy measures of high cumulative sun exposure were similarly associated with melanoma at all sites in men and women. In both sexes, high genetic risk was associated with melanoma on all body sites except the head and neck. We observed differences between men and women in the association between PRS and melanoma of the trunk [highest vs. lowest tertile of PRS: hazard ratio (HR) 2.78, 95% confidence interval (CI) 1.64-4.69 for men; HR 1.55, 95% CI 0.63-3.80 for women] and nonsignificant but large differences for the lower limbs (HR 5.25, 95% CI 1.80-15.27 for men; HR 1.75, 95% CI 0.88-3.47 for women)., Conclusions: While there are a number of potential explanations for these findings, this raises the possibility that genetic factors other than those related to pigmentation and naevus phenotypes may play a role in the predilection for melanoma to arise on different sites in men and women., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Behavioral larval zebrafish screens leverage a high-throughput small molecule discovery format to find neuroactive molecules relevant to mammalian physiology. We screen a library of 650 central nervous system active compounds in high replicate to train deep metric learning models on zebrafish behavioral profiles. The machine learning initially exploited subtle artifacts in the phenotypic screen, necessitating a complete experimental re-run with rigorous physical well-wise randomization. These large matched phenotypic screening datasets (initial and well-randomized) provide a unique opportunity to quantify and understand shortcut learning in a full-scale, real-world drug discovery dataset. The final deep metric learning model substantially outperforms correlation distance-the canonical way of computing distances between profiles-and generalizes to an orthogonal dataset of diverse drug-like compounds. We validate predictions by prospective in vitro radio-ligand binding assays against human protein targets, achieving a hit rate of 58% despite crossing species and chemical scaffold boundaries. These neuroactive compounds exhibit diverse chemical scaffolds, demonstrating that zebrafish phenotypic screens combined with metric learning achieve robust scaffold hopping capabilities., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Key Message: A major locus for spike compactness and length was mapped on chromosome 7H and its pleiotropic effects, candidate genes and transcriptional regulatory network were analyzed. Spike compactness (SC) and length (SL) are important traits of barley (Hordeum vulgare L.) due to their close association with grain yield. In this study, a major SC and SL locus QSc/Sl.cib-7H was primarily identified on chromosome 7H by bulked segregant analysis, and further fine mapped to a recombination cold spot expanding 244.36-388.09 Mb by developing a secondary population using residual heterozygous lines. This region is much more accurate than previously reported spike compactness loci on chromosome 7H. The strong effects of QSc/Sl.cib-7H on SL and SC were validated in two pair of near isogenic lines (NILs) and diverse genetic backgrounds. QSc/Sl.cib-7H exhibited pleiotropic effects on plant height (PH), thousand grain weight and grain length, and did not significantly influence the spikelet number of main spike (SMS) and grain width. Transcriptome analysis based on NILs showed that regulation of SC and SL might be related to the plant circadian rhythm pathway. The candidate genes were mined by analyzing variants and expression patterns of genes in the target region employing multiple genome and transcriptome data. This study takes a further step towards cloning of QSc/Sl.cib-7H, and the data obtained and the developed molecular markers will facilitate its utilization in barley breeding., Competing Interests: Declarations Conflict of interest All authors declare that they have no conflict of interest. Ethics approval The authors declare that this research has no human and animal participants and that the experiments comply with the current laws of China. Consent to participate Not applicable. Consent for publication Not applicable., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Prolonged labor, defined as labor extending beyond 20 hours for nulliparas and 14 hours for multiparas, poses significant risks to both maternal and neonatal health. The inflammatory response plays a crucial role in the pathophysiology of prolonged labor, with neutrophils being key players in this process. Neutrophils, the most abundant leukocytes, exhibit diverse phenotypes and functions in response to prolonged labor, influencing both the onset and progression of labor through their inflammatory actions. Classical neutrophils (N1) are involved in acute inflammatory responses, aiding in tissue remodeling and labor onset, but their prolonged activation can lead to tissue damage. Regulatory neutrophils (N2), which produce anti-inflammatory cytokines, help resolve inflammation and facilitate labor progression. Low-density granulocytes and aged neutrophils, associated with chronic inflammation and impaired function respectively, contribute to labor complications. The balance among these neutrophil phenotypes is crucial for maintaining a controlled inflammatory response during labor. Therapeutic strategies targeting neutrophil recruitment, NETosis, and cytokine production hold promise for managing prolonged labor. Modulating chemokine pathways, regulating NET formation, and balancing cytokine profiles may reduce inflammation and improve labor outcomes. Further research into the mechanisms of neutrophil regulation and the development of targeted therapies is essential for mitigating the adverse effects of prolonged labor and enhancing maternal and neonatal health., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Bioarchaeology uses human skeletal remains to reconstruct varied experiences of individuals and populations in the past, including patterns of health across time periods and cultural contexts. In the past three decades, bioarchaeological studies have highlighted the concept of "frailty," operationalizing it as increased risk of mortality or cumulative phenotypes. Using data from medieval London cemeteries, we integrate these two approaches to frailty in past populations. First, we estimate the risks of mortality and survivorship (hazard and survival analyses) associated with 10 biomarkers and use these results to construct population-specific frailty and resilience indices. Then, we apply the indices to adult individuals to explore frailty and resilience differentials between males and females in medieval London. Findings suggest that the male-female morbidity-mortality paradox observed in modern populations may not have existed in this context, which may be explained by preferential cultural buffering of men in this patriarchal, urban setting.

Artificial intelligence and machine learning (AI/ML) can be used to automatically analyze large image datasets. One valuable application of this approach is estimation of plant trait data contained within images. Here we review 39 papers that describe the development and/or application of such models for estimation of stomatal traits from epidermal micrographs. In doing so, we hope to provide plant biologists with a foundational understanding of AI/ML and summarize the current capabilities and limitations of published tools. While most models show human-level performance for stomatal density (SD) quantification at superhuman speed, they are often likely to be limited in how broadly they can be applied across phenotypic diversity associated with genetic, environmental, or developmental variation. Other models can make predictions across greater phenotypic diversity and/or additional stomatal/epidermal traits, but require significantly greater time investment to generate ground-truth data. We discuss the challenges and opportunities presented by AI/ML-enabled computer vision analysis, and make recommendations for future work to advance accelerated stomatal phenotyping., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Aims: Microglia activation after spinal cord injury (SCI) is a double-edged sword, modulation of the activated microglia populations toward pro-regenerative phenotypes highlights the potential therapeutic implications. P2Y12, a microglia-specific marker, remains underexplored in its capacity to polarize microglial activation populations in SCI repair. We aimed to explore the effects of modulating P2Y12 on microglia function after spinal cord injury, and further on axonal regeneration and motor recovery after spinal cord injury., Materials and Methods: The study employed both in vitro and in vivo models, using BV2 cells and a mouse model of SCI, respectively. Ticagrelor, a P2Y12 antagonist, was administered via a collagen scaffold to ensure stable and sustained release. Transcriptome sequencing analysis, immunofluorescence staining, and Basso Mouse Scale (BMS) scores were used to assess microglial activation, axonal regeneration, and functional recovery., Key Findings: Herein, we observed P2Y12 + microglia localized predominantly at the lesion periphery within 3 days post injury (dpi), manifesting a pro-inflammatory phenotype, but not anti-inflammatory phenotype. In vitro investigations revealed that P2Y12 inhibition of the activated microglia curtailed pro-inflammatory differentiation while augmenting anti-inflammatory differentiation., Significance: Leveraging this insight, we engineered a collagen scaffold-based delivery system for sustained release of the P2Y12 antagonist, ticagrelor, at the injury site in a mouse complete SCI model. Notably, P2Y12 suppression markedly enhanced axonal regeneration within the injured site and ameliorated lower limb motor functions in SCI mice. Collectively, our findings illuminate P2Y12-targeted microglial modulation as a promising therapeutic approach for SCI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Atherosclerosis is a chronic vascular disease. Its prevalence increases with aging. However, atherosclerosis may also affect young subjects without significant exposure to the classical risk factors. Recent evidence indicates clonal hematopoiesis of indeterminate potential (CHIP) as a novel cardiovascular risk factor that should be suspected in young patients. CHIP represents a link between impaired bone marrow and atherosclerosis. Atherosclerosis may present with an acute symptomatic manifestation or subclinical events that favor plaque growth. The outcome of a plaque relies on a balance of innate and environmental factors. These factors can influence the processes that initiate and propagate acute plaque destabilization leading to intraluminal thrombus formation or subclinical vessel healing. Thirty years ago, the first autopsy study revealed that coronary plaques can undergo rupture even in subjects without a known cardiovascular history. Nowadays, cardiac magnetic resonance studies demonstrate that this phenomenon is not rare. Myocardial infarction is mainly due to plaque rupture and plaque erosion that have different pathophysiological mechanisms. Plaque erosion carries a better prognosis as compared to plaque rupture. Thus, a tailored conservative treatment has been proposed and some studies demonstrated it to be safe. On the contrary, plaque rupture is typically associated with inflammation and anti-inflammatory treatments have been proposed in response to persistently elevate biomarkers of systemic inflammation. In conclusion, atherosclerosis may present in different forms or phenotypes. Vulnerable patient phenotypes, identified by using intravascular imaging techniques, biomarkers, or even genetic analyses, are characterized by distinctive pathophysiological mechanisms. These different phenotypes merit tailored management., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Prostate cancer rarely responds to immune-checkpoint blockade (ICB) therapies. Cancer-associated fibroblasts (CAF) are critical components of the immunologically "cold" tumor microenvironment and are considered a promising target to enhance the immunotherapy response. In this study, we aimed to reveal the mechanisms regulating CAF plasticity to identify potential strategies to switch CAFs from protumorigenic to antitumor phenotypes and to enhance ICB efficacy in prostate cancer. Integration of four prostate cancer single-cell RNA sequencing datasets defined protumorigenic and antitumor CAFs, and RNA-seq, flow cytometry, and a prostate cancer organoid model demonstrated the functions of two CAF subtypes. Extracellular matrix-associated CAFs (ECM-CAF) promoted collagen deposition and cancer cell progression, and lymphocyte-associated CAFs (Lym-CAF) exhibited an antitumor phenotype and induced the infiltration and activation of CD8+ T cells. YAP1 activity regulated the ECM-CAF phenotype, and YAP1 silencing promoted switching to Lym-CAFs. NF-κB p65 was the core transcription factor in the Lym-CAF subset, and YAP1 inhibited nuclear translocation of p65. Selective depletion of YAP1 in ECM-CAFs in vivo promoted CD8+ T-cell infiltration and activation and enhanced the therapeutic effects of anti-PD-1 treatment on prostate cancer. Overall, this study revealed a mechanism regulating CAF identity in prostate cancer and highlighted a therapeutic strategy for altering the CAF subtype to suppress tumor growth and increase sensitivity to ICB. Significance: YAP1 regulates cancer-associated fibroblast phenotypes and can be targeted to switch cancer-associated fibroblasts from a protumorigenic subtype that promotes extracellular matrix deposition to a tumor-suppressive subtype that stimulates antitumor immunity and immunotherapy efficacy., (©2024 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Evidence on the association of arterial stiffness and left ventricular (LV) concentric remodelling/LVH assessed by echocardiography, with abnormal blood pressure (BP) phenotypes, defined by office and ambulatory BP monitoring (ABPM) in the community is scanty. Thus, we investigated this issue in the participants to the Pressioni Monitorate E Loro Associazioni (PAMELA) study., Methods: The present study included 491 participants who attended the second and third survey of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, blood examinations, office, ABPM, echocardiographic and Cardio-Ankle Vascular Index (CAVI) measurements., Results: In the whole study sample (age 66+10 years, 50% males), the prevalence rates of sustained normotension (NT), white coat hypertension (WCH), masked hypertension (MH), sustained hypertension (SH) and non-dipping (ND) were 31.2, 10.0, 24.2, 34.6, and 35.8% and respectively. The likelihood of having SH, the BP phenotype carrying the greatest CV risk, was four times higher (OR= 4.31, CI:2.39-7.76, p<0.0001) in participants with increased CAVI and LV remodelling/LVH compared to their counterparts without organ damage. This association showed an incremental value in discriminating SH compared to both isolated markers of organ damage (OR=1.92,p=0.03 for increased CAVI and OR= 2.02, p=0.02 for LV remodelling/LVH). The presence of isolated but also combined organ damage was unrelated to ND., Conclusions: Our study provides new evidence of the incremental value of looking for both vascular and cardiac target organ damage to optimize the identification and clinical management of SH in the general population., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

Mutated skeletal muscle ryanodine receptor-1 (RYR1) gene is associated with a spectrum of autosomal dominant and recessive RyR1-related disorders with a wide phenotype. This report describes a variable phenotype associated with a previously unreported RYR1 frameshift pathogenic variant, (NM&#95;000540.2) c.12815&#95;12825del; p.Ala4272Glyfs*307, common in Libyan Jews. Clinical and genetic features of 14 carriers from 8 unrelated families were collected. There were 12 heterozygotes and 2 compound heterozygotes. Six heterozygotes (median age 49.8) were asymptomatic, and six (median age 24.5) presented with myopathy (n = 3) or severe arthrogryposis-like features, severe scoliosis, pes planus, post-anesthesia malignant hyperthermia, or cystic hygroma (in a fetus) (n = 1 each). None had an abnormal echocardiogram study or elevated creatine phosphokinase (CPK) levels. One bi-allelic carrier had a severe skeletal phenotype and myopathy; the other was a fetus with a cystic hygroma. Assessment of variant frequency in 447 Libyan Jews who underwent exome testing for unrelated reason yielded a prevalence of 1:55. The RYR1 p.Ala4272Glyfs*307 variant is common in Libyan Jews. It is associated with a broad phenotypic spectrum, with possible presentation among heterozygotes. Further genotype-phenotype studies are essential to delineate the clinical significance of the variant in mono- and bi-allelic carriers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to determine the correlation between gingival stippling (GS) and other phenotypic characteristics. Adult subjects in need of CBCT scans and comprehensive dental treatment in the anterior maxilla were recruited. Facial gingival thickness (GT) and buccal bone thickness (BT) were assessed utilizing CBCT. Standardized intraoral photographs were obtained to determine keratinized tissue width (KTW), presence of GS in all facial and interproximal areas between the maxillary canines, and other variables of interest, such as gingival architecture (GA), tooth shape, and location. Statistical analyses were conducted to assess different correlations among recorded variables. A total of 100 participants and 600 maxillary anterior teeth constituted the study population and sample, respectively. Facial GS was observed in 56% of men and 44% of women, and it was more frequently associated with flat GA, triangular and square/tapered teeth, central incisors, and men. Greater mean GT, BT, and KTW values were observed in facial areas that exhibited GS. Interdental GS was present in 73% of the sites, and it was more frequently observed in men, in the central incisor region, and when facial GS was present. Multilevel logistic regression revealed a statistically significant association between the presence of GS and KTW, BT measured at 3 mm apical to the bone crest, and tooth type. This information can be used to recognize common periodontal phenotypical patterns associated with specific features of great clinical significance.

Background: Mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A syndrome, is a rare lysosomal storage disease characterized by autosomal recessive inheritance of mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. This leads to a deficiency of the GALNS enzyme, causing the accumulation of glycosaminoglycans in tissues. Morquio A syndrome primarily affects the skeletal system and joints but can also impact various organs, resulting in symptoms such as hearing and vision loss, respiratory issues, spinal cord compression, heart diseases, and hepatomegaly. The genotype-phenotype relationship is diverse, with studies highlighting variants associated with classic, nonclassic, or intermediate phenotypes. Understanding these genetic factors is crucial for predicting disease prognosis and tailoring effective treatment strategies for individuals with Morquio A syndrome., Objective: The aim of this meta-analysis is to comprehend the relationship between the severity of the phenotype and the genotype of patients with MPS IVA, considering factors such as the type of variant and its location in the different domains of the protein., Methods: This meta-analysis will include articles featuring participants of all genders and age groups who have a molecular diagnosis of MPS IVA and a description of the phenotype. Literature published in English, Spanish, and Portuguese will be considered. Exclusion criteria will encompass studies lacking full-text availability and those involving patients with an MPS IVA diagnosis but without phenotype information. The databases to be searched include PubMed, MEDLINE, ScienceDirect, and Scopus. The screening of literature, paper selection, and data extraction will involve 2 independent reviewers, who will conduct the process blindly. In the event of disagreements between the 2 reviewers at any stage, resolution will be sought through discussion or with the involvement of an additional reviewer. The final selection of manuscripts will be based on consensus. The results of the review will be presented using descriptive statistics, and the information will be organized in either diagrammatic or tabular formats, following the guidelines provided by the Joanna Briggs Institute. Genotype-phenotype relationships will be analyzed using IBM SPSS Statistics, using chi-square tests, Fisher exact tests, and regression analysis to interpret the data., Results: A literature search conducted in January 2024 produced 760 results. The review is expected to be completed by the end of 2024., Conclusions: This meta-analysis will gather and analyze information on the phenotype-genotype relationship in patients diagnosed with MPS IVA. The data collection and resulting analyses will make a substantial contribution to understanding the underlying mechanism of the disease, enabling the prediction of the syndrome's progression and severity., International Registered Report Identifier (irrid): DERR1-10.2196/56649., (©Lorena Diaz-Ordoñez, Paola Andrea Duque-Cordoba, Daniel Andrés Nieva-Posso, Wilmar Saldarriaga, Juan David Gutierrez-Medina, Harry Pachajoa. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 14.11.2024.)

Translocator protein (TSPO) is a mitochondrial protein expressed by microglia, ligands for which are used as a marker of neuroinflammation in PET studies of Alzheimer's disease (AD). We previously showed increasing TSPO load in the cerebral cortex with AD progression, consistent with TSPO PET scan findings. Here, we aim to characterise the microglial phenotype associated with TSPO expression to aid interpretation of the signal generated by TSPO ligands in patients. Human post-mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak group (0-II, III-IV, V-VI; each n = 10) were fluorescently double labelled for TSPO and microglial markers: Iba1, HLA-DR, CD68, MSR-A and CD64. Quantification was performed on scanned images using QuPath software to assess the microglial phenotype of TSPO. Qualitative analysis was also performed for TSPO with GFAP (astrocytes), CD31 (endothelial cells) and CD163 (perivascular macrophages) to characterise the cellular profile of TSPO. The percentage of CD68 + TSPO + double-labelled cells was significantly higher than for other microglial markers in both brain regions and in all Braak stages, followed by MSR-A + TSPO + microglia. Iba1 + TSPO + cells were more numerous in the cerebellum than the temporal lobe, while CD64 + TSPO + cells were more numerous in the temporal lobe. No differences were observed for the other microglial markers. TSPO expression was also detected in endothelial cells, but not detected in astrocytes nor in perivascular macrophages. Our data suggest that TSPO is mainly related to a phagocytic profile of microglia (CD68 + ) in human AD, potentially highlighting the ongoing neurodegeneration., Competing Interests: Declarations Conflict of interests The authors report no competing interests. Ethical approval The study was carried out in accordance with relevant guidelines and regulations under the South–West Dementia Brain Bank ethical approval (NRES Committee South–West Central Bristol, REC reference: 08/H0106/28 + 5)., (© 2024. The Author(s).)

Genomic prediction (GP) has been evaluated in durum wheat breeding programs for several years, but prediction accuracy (PA) remains insufficient for some traits. Recently, multivariate (MV) analysis has gained much attention due to its potential to significantly improve PA. In this study, PA was evaluated for several agronomic traits using a univariate (UV) model in durum wheat, subsequently, different multivariate genomic prediction models were performed to attempt to increase PA. The panel was phenotyped for 10 agronomic traits over two consecutive crop seasons and under two different field conditions: high nitrogen and well-watered (HNW), and low nitrogen and rainfed (LNR). Multivariate GP was implemented using two cross-validation (CV) schemes: MV-CV1, testing the model for each target trait using only the markers, and MV-CV2, testing the model for each target trait using additional phenotypic information. These two MV-CVs were applied in two different analyses: modelling the same trait under both HNW and LNR conditions, and modelling grain yield together with the five most genetically correlated traits. PA for all traits in HNW was higher than LNR for the same trait, except for the trait yellow index. Among all traits, PA ranged from 0.34 (NDVI in LNR) to 0.74 (test weight in HNW). In modelling the same traits in both HNW and LNR, MV-CV1 produced improvements in PA up to 12.45% (NDVI in LNR) compared to the univariate model. By contrast, MV-CV2 increased PA up to 56.72% (thousand kernel weight in LNR). The MV-CV1 scheme did not improve PA for grain yield when it was modelled with the five most genetically correlated traits, whereas MV-CV2 significantly improved PA by up to ~18%. This study demonstrated that increases in prediction accuracy for agronomic traits can be achieved by modelling the same traits in two different field conditions using MV-CV2. In addition, the effectiveness of MV-CV2 was established when grain yield was modelled with additional correlated traits., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Key Message: Key message A major quantitative trait locus (qGW12) for grain shape and weight has been isolated in rice, corresponding to LOC&#95;Os12g17900/OsPUB23, and its encoded protein interacts with OsMADS1. Grain shape in rice is an important trait that influences both yield and quality. The primary determinants of grain shape are quantitative trait loci (QTLs) inherited from natural variation in crops. In recent years, much attention has been paid to the molecular role of QTLs in regulating grain shape and weight. In this study, we report the cloning and characterization of qGW12, a major QTL regulating grain shape and weight in rice, using a series of chromosome fragment substitution lines (CSSLs) derived from Oryza sativa indica cultivar 9311 (acceptor) and Oryza rufipogon Griff (donor). One CSSL line, Q187, harboring the introgression of qGW12, exhibited a significant decrease in grain-shape-related traits (including grain length and width) and thousand-grain weight compared to the cultivar 9311. Subsequent backcrossing of Q187 with 9311 resulted in the generation of secondary segregating populations, which were used to fine-map qGW12 to a 24-kb region between markers Seq-44 and Seq-48. Our data indicated that qGW12 encodes a previously unreported U-box type E3 ubiquitin ligase, designated OsPUB23, which exhibited E3 ubiquitin ligase activity. Overexpression of OsPUB23 in rice resulted in higher plant yield than the wild type due to an increase in grain size and weight. Conversely, loss of OsPUB23 function resulted in the opposite tendency. Yeast two-hybrid screening and split luciferase complementation assays revealed that OsPUB23 interacts with OsMADS1. The functional characterization of OsPUB23 provides new genetic resources for improving of grain yield and quality in crops., Competing Interests: Declarations Conflicts of interest The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Key Message: QKl/Tgw/Gns.yaas-2D associates with KL, TGW, and GNS, and QKl/Tgw.yaas-5A associates with KL and TGW. Significantly pleiotropic and additive effects of these two QTL were validated. The YM5 allele both at QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A was proved to be the best allelic combination for improving yield potential. Kernel length (KL), kernel width (KW), thousand grain weight (TGW), and grain number per spike (GNS) play important roles in the yield improvement of wheat. In this study, one recombinant inbred line (RIL) derived from a cross between Yangmai 5 (YM5) and Yanzhan 1 (YZ1) was used to identify quantitative trait loci (QTL) associated with KL, KW, TGW, and GNS across three years. Two pleiotropic QTL namely QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A were located in two genomic regions on chromosomes 2D and 5A, respectively. Breeder-friendly Kompetitive Allele-Specific PCR (KASP) markers for QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A were developed and validated in a set of 246 wheat cultivars/lines. Analysis of allelic combinations indicated that the YM5 allele both at QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A is probably the best one to promote TGW, GNS, and grain weight per spike. Based on the analysis of gene annotation, sequence variations, expression patterns, and GO enrichment, twenty-five and twenty-four candidate genes of QKl/Tgw/Gns.yaas-2D and QKl/Tgw.yaas-5A, respectively, were identified. These results provide the basis of fine-mapping the target QTL and marker-assisted selection in wheat yield-breeding programs., Competing Interests: Declarations Conflict of interest The authors have declared that no competing interests exist. Ethical approval All experiments and data analyses were conducted in Jiangsu. All authors contributed to the study and approved the final version for submission. The manuscript has not been submitted to any other journal., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Biallelic PDX1 variants are a rare cause of isolated pancreatic agenesis and neonatal diabetes (NDM) without exocrine pancreatic insufficiency, with 17 cases reported in the literature., Research Design and Methods: To determine the phenotypic variability caused by this rare genetic aetiology, we investigated 19 individuals with NDM resulting from biallelic disease-causing PDX1 variants., Results: Of the 19 individuals, 8 (42%) were confirmed to have exocrine insufficiency requiring replacement therapy. Twelve individuals (63.2%) had extrapancreatic features, including 8 (42%) with conditions affecting the duodenum and/or hepatobiliary tract. Defects in duodenum development are consistent with previous Pdx1 ablation studies in mice which showed abnormal rostral duodenum development., Conclusions: Our findings show that recessive PDX1 variants can cause a syndromic form of NDM, highlighting the need for clinical assessment of extrapancreatic features in individuals with NDM caused by PDX1 variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Key Message: Robust QTLs conferring resistance to bacterial leaf streak in wheat were mapped on chromosomes 3B and 5A from the variety Boost and on chromosome 7D from the synthetic wheat line W-7984. Bacterial leaf streak (BLS), caused by Xanthomonas translucens pv. undulosa poses a significant threat to global wheat production. High levels of BLS resistance are rare in hexaploid wheat. Here, we screened 101 diverse wheat genotypes under greenhouse conditions to identify new sources of BLS resistance. Five lines showed good levels of resistance including the wheat variety Boost and the synthetic hexaploid wheat line W-7984. Recombinant inbred populations derived from the cross of Boost × ND830 (BoostND population) and W-7984 × Opata 85 (ITMI population) were subsequently evaluated in greenhouse and field experiments to investigate the genetic basis of resistance. QTLs on chromosomes 3B, 5A, and 5B were identified in the BoostND population. The 3B and 5A QTLs were significant in all environments, but the 3B QTL was the strongest under greenhouse conditions explaining 38% of the phenotypic variation, and the 5A QTL was the most significant in the field explaining up to 29% of the variation. In the ITMI population, a QTL on chromosome 7D explained as much as 46% of the phenotypic variation in the greenhouse and 18% in the field. BLS severity in both populations was negatively correlated with days to heading, and some QTLs for these traits overlapped, which explained the tendency of later maturing lines to have relatively higher levels of BLS resistance. Markers associated with the QTLs were converted to KASP markers, which will aid in the deployment of the QTLs into elite lines for the development of BLS-resistant wheat varieties., Competing Interests: Declarations Conflict of interest The authors have no relevant financial or non-financial interests to disclose. Ethics approval NA. Consent to participate NA. Consent to publish NA., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The main monogenic causes of pulmonary fibrosis in adults are mutations in telomere-related genes. These mutations may be associated with extrapulmonary signs (hepatic, haematological and dermatological) and typically present radiologically as usual interstitial pneumonia or unclassifiable fibrosis. In children, the monogenic causes of pulmonary fibrosis are dominated by mutations in surfactant-related genes. These mutations are not associated with extrapulmonary signs and often manifest radiologically as unclassifiable fibrosis with cysts that can lead to chest wall deformities in adults. This review discusses these mutations, along with most of the monogenic causes of interstitial lung disease, including interferon-related genes, mutations in genes causing cystic lung disease, Hermansky-Pudlak syndrome, pulmonary alveolar proteinosis, lysinuric protein intolerance and lysosomal storage disorders, and their pulmonary and extrapulmonary manifestations., Competing Interests: Conflict of interest: R. Borie reports consultancy fees from Boerhinger Ingelheim, Ferrer and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, and support for attending meetings from Boehringer Ingelheim. L. Berteloot and C. Kannengiesser have nothing to disclose. M. Griese reports grants from Deutsche Forschungsgemeinschaft, and participation on a data safety monitoring board or advisory board with Boehringer Ingelheim. A. Cazes reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim. B. Crestani reports grants from Boehringer Ingelheim, consultancy fees from BMS, Boehringer Ingelheim, Chiesi, CSL Behring, GSK and Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca, BMS, Boehringer Ingelheim, GSK, Novartis, Roche and Sanofi, support for attending meetings from AstraZeneca, BMS, Boehringer Ingelheim, Roche and Sanofi, participation on a data safety monitoring board or advisory board with BMS, Boehringer Ingelheim, Horizon and Sanofi, and a leadership role with Fondation du Souffle (President of the board of trustees). A. Hadchouel has nothing to disclose. M.P. Debray reports consultancy fees from Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, Sanofi and Bracco, and support for attending meetings from Boehringer Ingelheim., (Copyright ©The authors 2024.)

Background and Aims: Diversity in pappus shapes and size in Asteraceae suggests an adaptive response to dispersion challenges adjusting diaspores to optimal phenotypic configurations. Here, by analysing the relationship among pappus-cypsela size relationships, flight performance and pappus types in an evolutionary context, we evaluate the role of natural selection acting on the evolution of diaspore configuration at a macro-ecological scale in the daisy family., Methods: To link pappus-cypsela size relationships with flight performance we collected published data on these traits from 82 species. This allowed us to translate morphometric traits in flight performance for 150 species represented in a fully resolved backbone phylogeny of the daisy family. Through ancestral reconstructions and evolutionary model selection, we assessed whether flight performance was associated with and constrained by different pappus types. Additionally, we evaluated, through phylogenetic regressions, whether species with different pappus types exhibited evolutionary allometric pappus-cypsela size relationships., Results: The setose pappus type had the highest flight performances and represented the most probable ancestral state in the family. Stepwise changes in pappus types independently led from setose to multiple instances of pappus loss with associated reduction in flight performance. Flight performance evolution was best modelled as constrained by five adaptive regimes represented by specific pappus types which correspond to specific optimal diaspore configurations that are distinct in pappus-cypsela allometric relationships., Conclusions: Evolutionary modelling suggests natural selection as the main factor of diaspore configuration changes which proceeded towards five optima, often overcoming constraints imposed by allometric relationships and favouring evolution in certain directions. With the perspective that natural selection is the main process driving the observed patterns, various biotic and abiotic are suggested as principal drivers of transitions in diaspore configurations along space and time in the daisy family history. The results also allow discussion of evolutionary changes in a historical context., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Annals of Botany Company. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Persistent airflow limitation (PAL) in childhood asthma is associated with a poor prognosis. The aim of this study was to categorize asthmatic children with PAL into distinct phenotypes and investigate the risk factors associated with each phenotype., Methods: We conducted a case-control study with a total of 119 PAL patients and 120 non-PAL (NPAL) individuals. To classify the patients into appropriate clusters, unsupervised cluster analysis using K-means clustering was employed. The clusters were then compared to explore different PAL phenotypes. Univariate and multivariate logistic regression analyses were performed to identify risk factors for PAL and calculate odds ratios (ORs) with 95% confidence intervals (95%CIs)., Results: K-means clustering divided patients into three clusters: Cluster 0 included 120 NPAL patients, Cluster 1 characterized by elevated blood neutrophils included 66 PAL patients, and Cluster 2 exhibited elevated blood eosinophils and FeNO levels, containing 53 PAL patients. Independent risk factors for PAL included older age in both Cluster 1 (9 ∼ 11y: OR 12.67, 95%CI 3.30-55.74; ≥ 11y: OR 5.42, 95%CI 1.26-25.69) and Cluster 2 (9 ∼ 11y: OR 7.25, 95%CI 1.70-33.35; ≥ 11y: OR 11.28, 95%CI 2.79-51.89), as well as pneumonia history, with an OR of 6.41(95%CI 1.34-33.41) in Cluster 1 and an OR of 7.92(95%CI 1.83-37.44) in Cluster 2. Furthermore, specific factors associated with Cluster 1 included BMI above 22 kg/ m 2 (OR 12.28, 95%CI 2.68-70.45), asthma duration exceeding three years (OR 4.77, 95%CI 1.60-15.94), and a blood neutrophil percentage between 0.4 and 0.5 (OR 4.13, 95%CI 1.17-16.6). In Cluster 2, independent risk factors included a blood eosinophil percentage greater than 0.07 (OR 4.36, 95%CI 1.16-19.73) and a high FeNO level (OR 3.94, 95%CI 1.35-11.97)., Conclusion: Our study identified two phenotypes of PAL in asthmatic children: non-eosinophilic and eosinophilic inflammation. Older age and a history of pneumonia were independent risk factors for both phenotypes. For non-eosinophilic inflammation PAL, specific contributing factors included higher BMI, long duration of asthma, and a blood neutrophil percentage between 0.4 and 0.5. Elevated FeNO levels and blood eosinophilic percentage were independently associated with eosinophilic inflammation PAL., Competing Interests: Declarations Ethics approval and consent to participate This case-control study has been approved by the Ethics Committee of the Children’s Hospital, Capital Institute of Pediatrics, Beijing, China (Approval No: SHERLL 2014040). All patient identities and private information have been rigorously protected in compliance with ethical guidelines. Consequently, a waiver of informed consent has been granted by the Ethics Committee of the Children’s Hospital, Capital Institute of Pediatrics. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: As the inflorescence of wheat, spike architecture largely determines grain productivity. Dissecting the genetic basis for the spike morphology of wheat can contribute to the designation of ideal spike morphology to improve grain production., Results: The present study characterizes a dense spike1 (ds1) mutant, derived from Nongda3753, induced by EMS treatment, which exhibits a dense spike and reduced plant height. Through bulked segregant analysis sequencing (BSA-Seq) of two segregating populations, ds1 was mapped to the short arm of chromosome 7B. Further genotypic and phenotypic analyses of the residual heterozygous lines from F 3 to F 6 of Yong3002×ds1 revealed that there was a 0-135 Mb deletion in chromosome 7B associated with the dense spike phenotype. The reads count analysis of the two bulks in BSA-Seq, along with the cytological analysis of ds1, ND3753, NIL-ds1 and NIL-Y3002, confirmed that the partial unidirectional translocation of 5AL (543-713 Mb) to 7BS (0-135 Mb) exists in ds1. This translocation led to an increase in both copy number and expression of the Q gene, which is one of the reasons for the dense spike phenotype observed in ds1., Conclusion: Partial unidirectional translocation from 5AL to 7BS was identified in the EMS-induced mutant ds1, which exhibits dense spike phenotype. This research illustrates the effect of one chromosome structure variation on wheat spike morphology, and provides new materials with several chromosome structure variations for future wheat breeding., Competing Interests: Declarations Ethics approval and consent to participate No specific permit is required for the samples in this study. We comply with relevant institutional, national, and international guidelines and legislation for plant studies. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Hypertrophic cardiomyopathy (HCM) is an inherited disease of the heart muscle that is dominated by variations in eight genes encoding sarcomere proteins. Although there are clinical or basic research reports that carrying double mutations can lead to more severe HCM phenotypes, there are also research reports that after reanalyzing the reported mutations, the severity of clinical symptoms in patients with double mutations did not significantly increase compared to patients with only one mutation. To determine whether double pathogenic mutations can aggravate the phenotype of hypertrophic cardiomyopathy in mice, we constructed mice carrying single pathogenic heterozygous mutation Myh6-R453C or Tnnt2-R92W and mice carrying both pathogenic heterozygous mutations. Our results showed that mice with double heterozygous mutations exhibited significant hypertrophic cardiomyopathy phenotypes at 4 weeks of age, and the degree of hypertrophy was significantly higher than that of single heterozygous mutant mice of the same age. Our study suggests that carrying the two pathogenic heterozygous mutations simultaneously can aggravate the phenotype of HCM in mice, which provides experimental evidence for the genotype-phenotype relationship of double pathogenic mutations and provides reference significance for clinical risk stratification of HCM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Compatibility between plant parasites and their hosts is genetically determined {Citation}both interacting organisms. For example, plants may carry resistance (R) genes or deploy chemical defences. Aphid saliva contains many proteins that are secreted into host tissues. Subsets of these proteins are predicted to act as effectors, either subverting or triggering host immunity. However, associating particular effectors with virulence or avirulence outcomes presents challenges due to the combinatorial complexity. Here we use defined aphid and host genetics to test for co-segregation of expressed aphid transcripts and proteins with virulent or avirulent phenotypes., Results: We compared virulent and avirulent pea aphid parental genotypes, and their bulk segregant F1 progeny on Medicago truncatula genotypes carrying or lacking the RAP1 (Resistance to Acyrthosiphon pisum 1) resistance quantitative trait locus. Differential gene expression analysis of whole body and head samples, in combination with proteomics of saliva and salivary glands, enabled us to pinpoint proteins associated with virulence or avirulence phenotypes. There was relatively little impact of host genotype, whereas large numbers of transcripts and proteins were differentially expressed between parental aphids, likely a reflection of their classification as divergent biotypes within the pea aphid species complex. Many fewer transcripts intersected with the equivalent differential expression patterns in the bulked F1 progeny, providing an effective filter for removing genomic background effects. Overall, there were more upregulated genes detected in the F1 avirulent dataset compared with the virulent one. Some genes were differentially expressed both in the transcriptome and in the proteome datasets, with aminopeptidase N proteins being the most frequent differentially expressed family. In addition, a substantial proportion (27%) of salivary proteins lack annotations, suggesting that many novel functions remain to be discovered., Conclusions: Especially when combined with tightly controlled genetics of both insect and host plant, multi-omics approaches are powerful tools for revealing and filtering candidate lists down to plausible genes for further functional analysis as putative aphid effectors., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Variant transthyretin amyloidosis (ATTRv) is a hereditary multisystem disorder with clinical spectrum ranging from predominant cardiomyopathy to polyneuropathy. In the Irish population, the T60A mutation has been previously recognised as the most common genotype., Objectives: The aim of this study is to describe the diagnostic and phenotypic spectrum of patients with T60A ATTRv attending an Irish Expert Amyloidosis Network., Methods: In this observational study design, the medical, laboratory and radiological records of patients enrolled in our amyloidosis registry with a confirmed genotype diagnosis of T60A ATTRv were reviewed., Results: A cohort of 24 patients (12 female) met criteria for inclusion. The median age at diagnosis was 65 years (IQR 59.5-66.5) and median follow-up 44 months (IQR 31-58). Carpal tunnel syndrome was the initial manifestation in almost half (46%) of patients. Overall, a mixed cardioneuro phenotype was demonstrated including autonomic (75%), small (58%) and large fibre (46%) neuropathy largely predating a cardiac phenotype consisting of heart failure (63%), atrial arrhythmia (42%) and bradycardia (13%)., Conclusion: The contemporary clinical spectrum of T60A ATTRv in Ireland is one of patients typically presenting in the seventh decade with an already manifest neuropathy phenotype, largely predating a cardiac phenotype dominated by heart failure., Competing Interests: Competing interests: Professor Emer Joyce is a Principal Investigator in the multi-centre RCT “ATTRibute-CM: Efficacy and Safety of AG-10 in Subjects with Transthyretin Amyloid Cardiomyopathy”. Professor Emer Joyce and Dr Gerard Giblin have received speaker fees from Pfizer Pharmaceutical company. Professor Sinead Murphy has received support for attending meetings and/or travel from Sobi Pharmaceutical company and support for attending meetings/travel and advisory board fees from Alnylam Pharmaceuticals. Dr Gerard Giblin has received educational support from Alnylam Pharmaceuticals., (© 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.)

Objective: To explore the clinical phenotype and pathogenesis of a child with partial duplication in the long arm of chromosome 10 (10q), and conduct a review of relevant literature., Methods: A child presented at Lianyungang Maternal and Child Health Care Hospital in April 2018 for growth retardation, intellectual disability, and autism spectrum disorder (ASD) was selected as the study subject. Peripheral blood samples were collected from the child and his parents for G-banded chromosomal karyotyping analysis. Genomic DNA was also extracted for chromosomal microarray analysis (CMA). The clinical phenotype and relevant genes were searched in the Online Mendelian Inheritance in Man (OMIM) and the UK Database of Genomic Variation and Phenotype in Humans using Ensembl Resources (DECIPHER). The pathogenicity of chromosomal variation was analyzed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Relevant literature was searched from the CNKI, Wanfang Data, and PubMed databases by using keywords such as "10q" "duplication" and "trisomy", with the time set as from the establishment of database to December 1, 2023. This study has been approved by the Medical Ethics Committee of the Lianyungang Maternal and Child Health Care Hospital (No. XM2023030)., Results: The clinical phenotype of child had included growth retardation, intellectual disability, and ASD. G-banded chromosomal analysis suggested that the child has a karyotype of 46,XY,dup(10)(q23.31q24.33), whilst both of his parents were normal. CMA analysis of the child revealed that the child was arr[19]10q23.31q24.33(87603382&#95;104948862)×3, with a 17.34 Mb duplication in the 10q23.31q24.33 region. Search of the OMIM database suggested that the duplicated segment has contained 171 genes associated with various diseases, and search of the DECIPHER database has identified cases with overlapping with the duplication. A search of the PubMed database has identified 2 publications involving 2 patients with chromosomal duplications overlapping the 10q23.31q24.33 region with a segment length of > 10 Mb. The 2 patients had mainly manifested growth retardation, intellectual disability, ASD, and facial and limb malformations. The main pathogenic genes had included PTEN, WNT8B, LZTS2, NFKB2, PAX2, KIF11, FRA10AC1, and CNNM2. No similar case was retrieved from the CNKI and Wanfang Data databases., Conclusion: The partial 10q duplication as a novel CNV involving genes such as PTEN and WNT8B probably underlay the growth retardation, intellectual disability and ASD in child 1 . This study has enriched the genotype-phenotype spectrum of patients with partial 10q23.31q24.33 duplications.

Slow progress towards implementation of conventional clinical bacteriology in low resource settings and strong interest in greater speed for antimicrobial susceptibility testing (AST) more generally has focused attention on next-generation rapid AST technologies. In this Review, we systematically synthesize publications and submissions to regulatory agencies describing technologies that provide phenotypic AST faster than conventional methods. We characterize over ninety technologies in terms of underlying technical innovations, technology readiness level, extent of clinical validation, and time-to-results. This work provides a guide for technology developers and clinical microbiologists to understand the rapid phenotypic AST technology landscape, current development pipeline, and AST-specific validation milestones., (© 2024. The Author(s).)

Cancer transcriptional patterns reflect both unique features and shared hallmarks across diverse cancer types, but whether differences in these patterns are sufficient to characterize the full breadth of tumor phenotype heterogeneity remains an open question. We hypothesized that these shared transcriptomic signatures reflect repurposed versions of functional tasks performed by normal tissues. Starting with normal tissue transcriptomic profiles, we use non-negative matrix factorization to derive six distinct transcriptomic phenotypes, called archetypes, which combine to describe both normal tissue patterns and variations across a broad spectrum of malignancies. We show that differential enrichment of these signatures correlates with key tumor characteristics, including overall patient survival and drug sensitivity, independent of clinically actionable DNA alterations. Additionally, we show that in HR+/HER2- breast cancers, metastatic tumors adopt transcriptomic signatures consistent with the invaded tissue. Broadly, our findings suggest that cancer often arrogates normal tissue transcriptomic characteristics as a component of both malignant progression and drug response. This quantitative framework provides a strategy for connecting the diversity of cancer phenotypes and could potentially help manage individual patients., (© 2024. The Author(s).)

Key Message: Two novel and one known genomic regions associated with R-gene resistance to Phytophthora sojae were identified by genome-wide association analysis and linkage analysis in soybean. Phytophthora root and stem rot (PRR) caused by Phytophthora sojae is a severe disease that causes substantial economic losses in soybean [Glycine max (L.) Merr.]. The primary approach for successful disease management of PRR is using R-gene-mediated resistance. Based on the phenotypic evaluation of 376 cultivated soybean accessions for the R-gene type resistance to P. sojae (isolate 2457), a genome-wide association analysis identified two regions on chromosomes 3 and 8. The most significant genomic region (20.7-21.3 Mbp) on chromosome 8 was a novel resistance locus where no Rps gene was previously reported. Instead, multiple copies of the UDP-glycosyltransferase superfamily protein-coding gene, associated with disease resistance, were annotated in this new locus. Another genomic region on chromosome 3 was a well-known Rps cluster. Using the Daepung × Ilpumgeomjeong RIL population, a linkage analysis confirmed these two resistance loci and identified a resistance locus on chromosome 2. A unique feature of the resistance in Ilpumgeomjeong was discovered when phenotypic distribution was projected upon eight groups of RILs carrying different combinations of resistance alleles for the three loci. Interestingly, the seven groups carrying at least one resistance allele statistically differed from the other with none, regardless of the number of resistance alleles. This suggests that the respective three different resistance genes can confer resistance to P. sojae isolate 2457. Deployment of the three regions via marker-assisted selection will facilitate effectively improving resistance to particular P. sojae isolates in soybean breeding programs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Researchers have developed a variety of indices to assess frailty. Recent research indicates that the human voice reflects frailty status. Frailty phenotypes are seldom discussed in the literature on the aging voice., Objective: This study aims to examine potential phenotypes of frail older adults and determine their correlation with vocal biomarkers., Methods: Participants aged ≥60 years who visited the geriatric outpatient clinic of a teaching hospital in central Taiwan between 2020 and 2021 were recruited. We identified 4 frailty phenotypes: energy-based frailty, sarcopenia-based frailty, hybrid-based frailty-energy, and hybrid-based frailty-sarcopenia. Participants were asked to pronounce a sustained vowel "/a/" for approximately 1 second. The speech signals were digitized and analyzed. Four voice parameters-the average number of zero crossings (A1), variations in local peaks and valleys (A2), variations in first and second formant frequencies (A3), and spectral energy ratio (A4)-were used for analyzing changes in voice. Logistic regression was used to elucidate the prediction model., Results: Among 277 older adults, an increase in A1 values was associated with a lower likelihood of energy-based frailty (odds ratio [OR] 0.81, 95% CI 0.68-0.96), whereas an increase in A2 values resulted in a higher likelihood of sarcopenia-based frailty (OR 1.34, 95% CI 1.18-1.52). Respondents with larger A3 and A4 values had a higher likelihood of hybrid-based frailty-sarcopenia (OR 1.03, 95% CI 1.002-1.06) and hybrid-based frailty-energy (OR 1.43, 95% CI 1.02-2.01), respectively., Conclusions: Vocal biomarkers might be potentially useful in estimating frailty phenotypes. Clinicians can use 2 crucial acoustic parameters, namely A1 and A2, to diagnose a frailty phenotype that is associated with insufficient energy or reduced muscle function. The assessment of A3 and A4 involves a complex frailty phenotype., (©Yu-Chun Lin, Huang-Ting Yan, Chih-Hsueh Lin, Hen-Hong Chang. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.11.2024.)

Key Message: The QTLs and candidate genes governing the multifoliolate phenotype were identified by combining linkage mapping with BSR-seq, revealing a possible interplay between genetics and the environment in soybean leaf development. Soybean, as a legume, is typified by trifoliolate leaves. Although multifoliolate leaves (compound leaves with more than three leaflets each) have been reported in soybean, including sporadic appearances in the first compound leaves in a recombinant inbred line (RIL) population from a cross between cultivated soybean C08 and wild soybean W05 from this study, the genetic basis of this phenomenon is still unclear. Here, we integrated quantitative trait locus (QTL) mapping with bulked segregant RNA sequencing (BSR-seq) to identify the genetic loci associated with the multifoliolate phenotype in soybean. Using linkage mapping, ten QTLs related to the multifoliolate trait were identified. Among these, a significant and major QTL, qMF-2-1 on chromosome 2 and consistently detected across biological replicates, explained more than 10% of the phenotypic variation. Together with BSR-seq analyses, which analyzed the RILs with the highest multifoliolate frequencies and those with the lowest frequencies as two distinct bulks, two candidate genes were identified: Glyma.06G204300 encoding the transcription factor TCP5, and Glyma.06G204400 encoding LONGIFOLIA 2 (LNG2). Transcriptome analyses revealed that stress-responsive genes were significantly differentially expressed between high-multifoliolate occurrence lines and low occurrence ones, indicating environmental factors probably influence the appearance of multifoliolate leaves in soybean through stress-responsive genes. Hence, this study offers new insights into the genetic mechanism behind the multifoliolate phenotype in soybean., (© 2024. The Author(s).)

Cell growth and gene expression are heterogeneous processes at the single-cell level, leading to the emergence of multiple physiological states within bacterial populations. Aging is a known deterministic driver of growth asymmetry; however, its role in gene expression heterogeneity remains elusive. Here, we show that aging mother cells undergo a progressive decline in old pole activity, generating asymmetry in protein partitioning, gene expression, and cell morphology. We demonstrate that mother cells, when compared to their daughters, exhibit lower product inheritance and gene expression rates independently of promoter dynamics. The declining activity of maternal old poles generates gene expression gradients that manifest as mother-daughter asymmetry upon division, showing that asymmetry is progressively built over time within the maternal intracellular environment. Moreover, old pole aging correlates with a gradual increase in cell length, leading to morphological asymmetry. These findings provide further evidence for aging as a mechanism to enhance phenotypic heterogeneity in bacterial populations, with possible consequences for stress response and survival.

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE). The 32 CC strains studied captured a wide spectrum of EAE severity, trajectory, and presentation, including severe-progressive, monophasic, relapsing remitting, and axial rotary-EAE (AR-EAE), accompanied by distinct immunopathology. Sex differences in EAE severity were observed in 6 strains. Quantitative trait locus analysis revealed distinct genetic linkage patterns for different EAE phenotypes, including EAE severity and incidence of AR-EAE. Machine learning-based approaches prioritized candidate genes for loci underlying EAE severity (Abcc4 and Gpc6) and AR-EAE (Yap1 and Dync2h1). This work expands the EAE phenotypic repertoire and identifies potentially novel loci controlling unique EAE phenotypes, supporting the hypothesis that heterogeneity in MS disease course is driven by genetic variation.

Introduction: COVID-19 provides an opportunity to examine biological phenotypes (observable morphological, functional and biological characteristics) in individuals who experience the same acute condition, potentially revealing differences in response to acute external stressors. The aim our study was to investigate biological phenotypes in older patients hospitalized for COVID-19, exploiting a panel of aging biomarkers., Methods: Data were gathered from the FRACOVID Project, an observational multicenter study, aimed to evaluate the impact of frailty on health-related outcomes in patients 60 + with COVID-19 in Northern Italy. A hierarchical cluster analysis was run using log-transformed and scaled values of TNF-a, IL-1 beta, IL-6, PAI-1, GDF-15, NT-proBNP, and Cystatin C evaluated at admission., Results: Eighty-one participants (mean age 75.3 years; 60.5% male) were evaluated. Frailty was identified in 42% of the sample and 27.2% were unable to ambulate outdoors. The mean hospital stay was 24.7 days, with an in-hospital mortality rate of 18.5%. Three biological phenotypes were found: (1) 'inflammatory', with high inflammatory biomarkers; (2) 'organ dysfunction', characterized by elevated cystatin C and NT-proBNP, and lower inflammatory markers; and (3) 'unspecific', with lower NT-proBNP and GDF-15 levels, and intermediate concentrations of other biomarkers. The 'organ dysfunction' phenotype showed the highest mean age and prevalence of frailty, disability, and chronic diseases. The 'inflammatory' phenotype showed the highest burden of respiratory and systemic signs and symptoms of infection., Conclusion: Biological phenotypes might be used to identify different clinical and functional phenotypes in individuals affected by COVID-19., (© 2024. The Author(s).)

Domestication can be understood as a symbiotic relationship that benefits both domesticator and domesticated species, involving multiple genetic changes that configure the phenotype of the domesticated species. One of the most important domesticated species is the yeast Saccharomyces cerevisiae, with both domesticated strains used for different fermentations processes for thousands of years and wild strains existing only in environments without human intervention; however, little is known about the phenotypic effects associated with its domestication. In the present work, we studied the effect of domestication on yeast TORC1 activation, a pleiotropic signalling pathway conserved across the eukaryotic domain. To achieve this goal, we improved a previously generated methodology to assess TORC1 activation, which turned out to be as effective as the original one but also presents several practical advantages for its application (such as facilitating confirmation of transformants and putting the Luc reporter gene under the control of the same P RPL26A promoter for each transformed strain). We then generated a mapping population, the so-called TOMAN-G population, derived from the "1002 Yeast Genomes Project" population, the most comprehensive catalogue of the genetic variation in yeasts. Finally, strains belonging to the TOMAN-G population were phenotyped for TORC1 activation, and then we compared the results obtained between yeast strains with different ecological origins, finding differences in TORC1 activation between wild and domesticated strains, particularly wine strains. These results are indicative of the effect of domestication on TORC1 activation, specifically that the different evolutionary trajectories of wild and domesticated strains have in fact caused differences in the activation of this pathway; furthermore, the phenotypic data obtained in this work could be used to continue underlying the genetic bases of TORC1 activation, a process that is still not fully understood, using techniques such as GWAS to search for specific genetic variants underlying the observed phenotypic variability and phylogenetic tree inferences to gain insight into the evolutionary relationships between these genetic variants., (© 2024. The Author(s).)

A plausible, but largely unexplored reason for many weed biocontrol agents failing to establish or being ineffective, could involve abiotically induced changes to an invasive plants' biochemical phenotype and consequent enhanced herbivore resistance. Considerable literature demonstrates that chemically altered plant phenotypes can impair insect life history performance. Heather beetle, (Lochmaea suturalis), introduced to control invasive heather (Calluna vulgaris) in New Zealand (NZ) was difficult to establish and displays variable effectiveness. Using UHPLC-MS non-targeted metabolomics, we analysed primary and secondary metabolites of C. vulgaris from its native range (Scotland) and it's introduced range (NZ), between which, differences in soil nutrients and ultraviolet light exist. We also explored secondary metabolite variation between sites within each range. New Zealand samples had the highest number of amplified metabolites, most notably defensive phenylpropanoids, supporting the concept of abiotically induced upregulation of key biosynthetic pathways. Analysis of secondary metabolite variation within each range revealed differences between sites but found little correlation of phenylpropanoid levels being influenced by variable soil nutrients. These results validate questions about the possibility of abiotically altered biochemical phenotypes in invasive plants, influencing weed biocontrol agent establishment and effectiveness, and show the potential for metabolomics in assisting future, or retrospectively analysing biological control programmes., (© 2024. The Author(s).)

20p chromosome inverted duplication deletion syndrome is a rare chromosomal disorder in which the short arm segment 20p11.2-p13 and the deleted subtopic region 20p13-20 replicate simultaneously. Patients with this syndrome are mainly presented with intellectual disability and motor development delay. We report here a middle childhood case of this syndrome characterised by intellectual disability, backward movement, unique facial features, congenital heart disease: ventricular septal defect, patent foramen ovale, pulmonary hypertension and congenital anorectal malformation. The patient's chromosome karyotyping analysis showed a short arm duplication on chromosome 20, described as 46, XY, 20p+?; his parents' karyotyping analysis is normal. Later genotype analysis by array-single nucleotide polymorphisms identified a total of 107 genome-wide copy number variations and we detected a new 1.3 Mb deletion (chr20:63 244-1 349 002) and 20.2 Mb duplication (chr20:1 608 108-24 174 965) from 20p13 to 20p11.2 using infinium asian screening array-24 V1.0 BeadChip (Illumina Inc., San Diego, USA)., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Obesity is associated with an increased risk of reflux esophagitis (RE). Metabolic abnormalities have been implicated in the pathogenesis of RE. However, the role of metabolic status in the risk of RE among individuals with varying degrees of obesity remains unclear. Therefore, our study aimed to assess the association between metabolic obesity phenotypes and the risk of RE., Methods: This study included a cohort of 24,368 participants aged 18 years and older who underwent upper gastrointestinal endoscopy at the First Affiliated Hospital of Dalian Medical University during health checkups between January 1, 2008, and December 31, 2021. Among these participants, a total of 9,947 individuals were classified into four groups based on their obesity phenotype: metabolically healthy normal weight (MHNW), metabolically healthy obesity (MHO), metabolically unhealthy normal weight (MUNW), and metabolically unhealthy obesity (MUO). To account for potential confounding factors, multivariate logistic regression analysis was applied to examine the association between metabolic obesity phenotypes and the risk of RE, with stratification by sex and age., Results: Among all participants, the MUNW, MHO, and MUO groups demonstrated a higher risk of RE when compared to the MHNW group. After controlling for all confounding factors, the MUO group exhibited the highest risk, with an odds ratio (OR) of 3.723 (95% CI: 2.751-5.040) in males and 5.482 (95% CI: 4.080-7.367) in females. The prevalence of RE increased in proportion to the number of metabolic risk factors. Subgroup analyses, which accounted for all confounders, revealed that the MHO, MUNW, and MUO phenotypes were associated with an elevated risk of RE in individuals under 60 years old as well as those over 60 years old. Interestingly, a more comprehensive analysis indicated that obesity may have a greater effect on the risk of RE than metabolic disorders., Conclusions: Both metabolic disorders and obesity were associated with an increased risk of RE. The effect of obesity on RE prevalence may be stronger than that of metabolic disorders, emphasizing the significance of obesity regardless of metabolic health status. Clinical interventions should address not only obesity but also metabolic disorders in order to reduce the risk of RE., (© 2024. The Author(s).)