SynGenes: a Python class for standardizing nomenclatures of mitochondrial and chloroplast genes and a web form for enhancing searches for evolutionary analyses.

BACKGROUND: The reconstruction of the evolutionary history of organisms has been greatly influenced by the advent of molecular techniques, leading to a significant increase in studies utilizing genomic data from different species. However, the lack of standardization in gene nomenclature poses a challenge in database searches and evolutionary analyses, impacting the accuracy of results obtained. RESULTS: To address this issue, a Python class for standardizing gene nomenclatures, SynGenes, has been developed. It automatically recognizes and converts different nomenclature variations into a standardized form, facilitating comprehensive and accurate searches. Additionally, SynGenes offers a web form for individual searches using different names associated with the same gene. The SynGenes database contains a total of 545 gene name variations for mitochondrial and 2485 for chloroplasts genes, providing a valuable resource for researchers. CONCLUSIONS: The SynGenes platform offers a solution for standardizing gene nomenclatures of mitochondrial and chloroplast genes and providing a standardized search solution for specific markers in GenBank. Evaluation of SynGenes effectiveness through research conducted on GenBank and PubMedCentral demonstrated its ability to yield a greater number of outcomes compared to conventional searches, ensuring more comprehensive and accurate results. This tool is crucial for accurate database searches, and consequently, evolutionary analyses, addressing the challenges posed by non-standardized gene nomenclature.

Low-pass whole genome sequencing is a reliable and cost-effective approach for copy number variant analysis in the clinical setting.

INTRODUCTION: Next generation sequencing technology has greatly reduced the cost and time required for sequencing a genome. An approach that is rapidly being adopted as an alternative method for CNV analysis is the low-pass whole genome sequencing (LP-WGS). Here, we evaluated the performance of LP-WGS to detect copy number variants (CNVs) in clinical cytogenetics. MATERIALS AND METHODS: DNA samples with known CNVs detected by chromosomal microarray analyses (CMA) were selected for comparison and used as positive controls; our panel included 44 DNA samples (12 prenatal and 32 postnatal), comprising a total of 55 chromosome imbalances. The selected cases were chosen to provide a wide range of clinically relevant CNVs, the vast majority being associated with intellectual disability or recognizable syndromes. The chromosome imbalances ranged in size from 75 kb to 90.3 Mb, including aneuploidies and two cases of mosaicism. RESULTS: All CNVs were successfully detected by LP-WGS, showing a high level of consistency and robust performance of the sequencing method. Notably, the size of chromosome imbalances detected by CMA and LP-WGS were compatible between the two different platforms, which indicates that the resolution and sensitivity of the LP-WGS approach are at least similar to those provided by CMA. DISCUSSION: Our data show the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection. The diagnostic effectiveness and feasibility of LP-WGS, in this technical validation study, were evidenced by a clinically representative dataset of CNVs that allowed a systematic assessment of the detection power and the accuracy of the sequencing approach. Further, since the software used in this study is commercially available, the method can easily be tested and implemented in a routine diagnostic setting.

Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil.

In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X-linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting.

New parameters for in vitro development of cell lines of the species Astyanax bimaculatus (Linnaeus, 1758) and Geophagus proximus (Castelnau, 1855).

Intending to compare in vitro cell growth in different conditions, we established cell cultures using fin biopsies of two freshwater fishes, Astyanax bimaculatus and Geophagus proximus. Three different culture media (Leibovitz-L-15, Dulbecco's Modified Eagle Medium [DMEM], and 199) were employed, with or without the addition of AmnioMax, maintaining a standard temperature of 29°C. Based on the results obtained, we standardized a cell growth protocol in which medium 199 was less efficient for both species. Notably, G. proximus cells exhibited superior proliferation in DMEM and L-15 media, whereas A. bimaculatus cells demonstrated better parameters exclusively in the DMEM medium. Successful subculturing of cells with good proliferation index was observed, accompanied by preserved morphological characteristics. Therefore, the methodology outlined in this study represents an advancement in establishing fish cell cultures.

Evaluation of gamma-aminobutyric acid content in Portuguese cheeses with protected designation of origin status.

Health-conscious consumers are increasingly paying attention to healthy diets and focusing on natural bioactive compounds in foods and their effects on mental health. This opens new opportunities for the study of artisanal cheeses as biofunctional foods. In the work described in this Research Communication, the gamma-aminobutyric acid (GABA) content of seven different Portuguese cheeses produced from unpasteurized cow, sheep, and goat milk and granted with protected designation of origin (PDO) status was analysed. The PDO cheeses made from cow milk analysed in this study were São Jorge (3, 4, 7, 12 and 24 months of maturation) and Pico cheeses. PDO cheeses made from sheep milk were Serra da Estrela, Serpa, Nisa and Azeitão. Cheeses made from sheep and goat milk included Beira Baixa yellow cheese. The GABA content in the Azorean PDO cheeses (made from cow milk) ranged from 1.23 to 2.64 g/kg of cheese. Higher variations in GABA content were observed in cheeses made from sheep and goat milk (0.73-2.31 g/kg). This study provides information on the GABA content in different Portuguese PDO cheeses and shows that hard or semi-hard ripened cheeses are a suitable matrix for GABA production by lactic acid bacteria.

Characterization of a new cytotype and ocurrence of a B microchromosome in two spot astyanax, Astyanax bimaculatus Linnaeus, 1758 (Characiformes: Characidae).

Although Astyanax bimaculatus is the most representative species of the genus in the Amazon region, there are no cytogenetic studies of A. bimaculatus species in Amazon region. Thus, we aimed to analyse the chromosome complements of specimens from this area using classic and molecular cytogenetic approaches. The results revealed the existence of a distinct cytotype and this is the first report of the occurrence of a B microchromosome in the species. Overall, these data indicate that the karyotypic evolution of this species is complex, involving the occurrence of chromosomal rearrangements.

Degradation of Pesticides Using Semiconducting and Tetrapyrrolic Macrocyclic Photocatalysts-A Concise Review.

Exposure to pesticides is inevitable in modern times, and their environmental presence is strongly associated to the development of various malignancies. This challenge has prompted an increased interest in finding more sustainable ways of degrading pesticides. Advanced oxidation processes in particular appear as highly advantageous, due to their ability of selectively removing chemical entities form wastewaters. This review provides a concise introduction to the mechanisms of photochemical advanced oxidation processes with an objective perspective, followed by a succinct literature review on the photodegradation of pesticides utilizing metal oxide-based semiconductors as photosensitizing catalysts. The selection of reports discussed here is based on relevance and impact, which are recognized globally, ensuring rigorous scrutiny. Finally, this literature review explores the use of tetrapyrrolic macrocyclic photosensitizers in pesticide photodegradation, analyzing their benefits and limitations and providing insights into future directions.

The impact of fast-growing eucalypt plantations on C emissions in tropical soil: effect of belowground and aboveground C inputs.

Planted forest soils can have great potential for CO2-C sequestration, mainly due to belowground C inputs, which impact deep soil C (DSC) accumulation. However, there are still gaps in understanding the CO2 emission dynamics in eucalypt plantations. Therefore, we used isotopic techniques to investigate the dynamics of the soil surface CO2-C flux and CO2-C concentration with depth for a eucalypt plantation influenced by different C inputs (above- and belowground). The gas evaluations were carried in depth the root to valuation of root priming effect (RPE) was calculated. In addition, measurements of the plant (C-fine root and C-litterfall) and soil (total organic carbon - TOC, total nitrogen - TN, soil moisture - SM, and soil temperature - ST) were performed. After planting the eucalypt trees, there was an increase in the soil surface CO2-C flux with plant growth. Root growth contributed greatly to the soil surface CO2-C flux, promoting greater surface RPE over time. In comparison to the other factors, SM had a greater influence on litterfall decomposition and root respiration. It was not possible to detect losses in TOC and TN in the different soil layers for the 31-month-old eucalypt. However, the 40-month-old eucalypt showed a positive RPE with depth, indicating possible replacement of DSC ("old C") by rhizodeposition-C ("new C") in the soil. Thus, in eucalyptus plantations, aboveground plant growth influences CO2 emissions on the soil surface, while root growth and activity influence C in deeper soil layers. This information indicates the need for future changes in forest management, with a view to reducing CO2 emissions.

A transcriptome-based signature of pathological angiogenesis predicts breast cancer patient survival.

The specific genes and molecules that drive physiological angiogenesis differ from those involved in pathological angiogenesis, suggesting distinct mechanisms for these seemingly related processes. Unveiling genes and pathways preferentially associated with pathologic angiogenesis is key to understanding its mechanisms, thereby facilitating development of novel approaches to managing angiogenesis-dependent diseases. To better understand these different processes, we elucidated the transcriptome of the mouse retina in the well-accepted oxygen-induced retinopathy (OIR) model of pathological angiogenesis. We identified 153 genes changed between normal and OIR retinas, which represent a molecular signature relevant to other angiogenesis-dependent processes such as cancer. These genes robustly predict the survival of breast cancer patients, which was validated in an independent 1,000-patient test cohort (40% difference in 15-year survival; p = 2.56 x 10-21). These results suggest that the OIR model reveals key genes involved in pathological angiogenesis, and these may find important applications in stratifying tumors for treatment intensification or for angiogenesis-targeted therapies.

Phytoremediation of quinclorac and tebuthiuron-polluted soil by green manure plants.

Quinclorac and tebuthiuron are residual herbicides that may remain in the soil longer than for the cropping season. The objective of this research was to evaluate the use of green manure plants to remediate soils treated with quinclorac and tebuthiuron. Soils were separately treated with 14C-quinclorac and 14C-tebuthiuron at 266.4 and 132 g ha-1, respectively. After 21 days, four green manure plants, namely Crotalaria spectabilis, Canavalia ensiformis, Stizolobium aterrimum, and Lupinus albus, were separately sown in the treated soils. Overall, all four species absorbed more 14C-tebuthiuron [C. ensiformes (22.49%), S. aterrimum (16.71%), L. albus (15%), and C. spectabilis (4.48%)] than 14C-quinclorac [C. ensiformis (13.44%), L. albus (10.02%), S. aterrimum (6.2%), and C. spectabilis (1.75%)]. Quinclorac translocation in all four plants was greater in young leaves compared to old leaves, cotyledons, or roots, and 14C-tebuthiuron translocation in all four plant species was greater in old leaves and cotyledons compared to young leaves or roots. Regardless of the differences in translocation between the two herbicides, the four green manure plants are capable to remediate soils that have been treated with quinclorac and tebuthiuron. However, C. ensiformis is more efficient for the remediation of tebuthiuron-treated soil compared to the other plants.

Indaziflam sorption-desorption and its three metabolites from biochars- and their raw feedstock-amended agricultural soils using radiometric technique.

This study aimed to characterize the effect of amending soils with biochars derived from soybean residues, sugarcane bagasse, and wood chips on the sorption-desorption of indaziflam and indaziflam-triazinediamine (FDAT), indaziflam-triazine-indanone (ITI), and indaziflam-carboxylic acid (ICA) metabolites applied to soils from three Midwestern U.S. states, a silt loam and a silty clay loam. Biochars produced from different feedstock were used as soil amendments and compared with raw feedstock. Sorption-desorption experiments of indaziflam and its three metabolites were performed using the batch equilibration method and analyzed for 14C activity by liquid scintillation counting (radiometric technique). In all soils, the use of organic amendments promoted greater sorption and less desorption of indaziflam and ITI. The addition of biochar to soils promoted greater sorption of the four tested chemical products compared with the corresponding raw materials. Among the biochars, grape wood chips showed greater potential in sorb indaziflam and ITI. In general, none of the biochars affected the sorption and desorption of FDAT and ICA. Characterization of biochar to be used as a soil amendment (immobilizer) is highly recommended prior to field addition to optimize the sorption process and to prevent increased soil and water contamination of indaziflam and its metabolites following biochar addition.

Cow bonechar decreases indaziflam pre-emergence herbicidal activity in tropical soil.

The addition of carbonaceous material such as cow bonechar to the soil can affect the availability of applied pre-emergent herbicides such as indaziflam. However, how cow bonechar affects the bioavailability of indaziflam is not yet known. The aim of this study was to evaluate the effect of cow bonechar on herbicidal activity of indaziflam on weeds in a tropical soil. Cow bonechar was added homogeneously to top soil, at 1, 2, 5, 10, and 20 t ha-1, in addition to treatment with unamended soil. At 21 days after indaziflam (75 g ha-1) application, injury weed levels, weed species that emerged spontaneously were identified and the weeds present in each sampling unit were collected. Only 1.4 t ha-1 cow bonechar added to soil was enough to reduce the weed injury level by 50%. From the addition of 2 t ha-1 cow bonechar the application of indaziflam was not efficient to weed control, being equivalent to treatments without herbicide application. Eight weed species (3 monocots and 5 dicots) were identified in all treatments. Eleusine indica and Digitaria horizontalis accounted for about 99.7% of the entire infestation of the weed community. Cow bonechar decreases indaziflam pre-emergence herbicidal activity in tropical soil for weed control, most likely due to the high sorption and unavailability of the product in the soil solution.

T-Cell Immunophenotyping and Cytokine Production Analysis in Patients with Chagas Disease 4 Years after Benznidazole Treatment.

The major problem with Chagas disease is evolution of the chronic indeterminate form to a progressive cardiac disease. Treatment diminishes parasitemia but not clinical progression, and the immunological features involved are unclear. Here, we studied the clinical course and the immune response in patients with chronic-phase Chagas disease at 48 months after benznidazole treatment. Progression to the cardiac form of Chagas disease or its aggravation was associated with higher in vitro antigen-specific production of interferon gamma (IFN-γ) in patients with cardiac Chagas disease than in patients with the indeterminate form. Predominance of IFN-γ production over interleukin-10 (IL-10) production in antigen-specific cultures was associated with cardiac involvement. Significantly higher numbers of antigen-specific T helper 1 cells (T-Bet+ IFN-γ+) and a significantly higher IFN-γ+/IL-10+ ratio were observed in patients with cardiac Chagas disease than in patients with the indeterminate form. Cardiac damage was associated with higher numbers of T helper cells than cytotoxic T lymphocytes producing IFN-γ. Patients with cardiac Chagas disease had predominant CD25- and CD25low T regulatory (Treg) subpopulations, whereas patients with the indeterminate form manifested a higher relative mean percentage of CD25high Treg subpopulations. These findings suggest that at 48 months after benznidazole treatment, the disease can worsen or progress to the cardiac form. The progression may be related to increased IFN-γ production (mostly from CD4+ T cells) relative to IL-10 production and increased Treg percentages. Patients with the indeterminate form of Chagas disease show a more balanced ratio of proinflammatory and anti-inflammatory cytokines.

Range distribution and contributions to taxonomy of Elops smithi (ELOPIFORMES: ELOPIDAE).

This study presents the first record of Elops smithi for northern Brazil. The evidence suggests this species is being misidentified incorrectly as Elops saurus in estuaries of the Western Atlantic Ocean. Here, morphological, molecular, and cytogenetic evidence identified all ladyfish specimens from one estuary in the region as E. smithi. Thus, at least Elops smithi occurs in the northern coast of Brazil and it is recommended that specimens from this region identified as E. saurus be further investigated with genetic and cytogenetic tools in order to assure a correct species identification.

Effect of Irrigation on Sugarcane Morphophysiology in the Brazilian Cerrado.

Since sugarcane is semi-perennial, it has no escape from water stresses in the Brazilian Cerrado, and consequently, drought impacts plant growth and industrial quality. The objective of this study was to evaluate the morphophysiology and quality of the first ratoon of two sugarcane varieties submitted to irrigated and stressed treatments under field conditions. For the biometric characteristics, in general, significant decreases were observed under the stressed treatment for all periods, and only minor differences were detected between the studied cultivars. Physiological parameters decreased under stressed conditions, but to a different extent between the varieties. RB855536 was able to maintain a greater rate of transpiration. Productivity was reduced by 103 t ha-1 for variety RB855536 and 121 t ha-1 for RB867515, compared to plants with full irrigation during the dry period, but cane quality was similar in both genotypes. Measurements of physiological and morphological parameters may prove useful in the rapid identification of genotypes with greater tolerance to abiotic stress.

Comparative cytogenetics of microsatellite distribution in two tetra fishes Astyanax bimaculatus (Linnaeus, 1758) and Psalidodon scabripinnis (Jenyns, 1842).

Background: The main cytogenetic studies of the Characidae family comprise the genera Astyanax and Psalidodon involving the use of repetitive DNA probes. However, for the microsatellite classes, studies are still scarce and the function of these sequences in the genome of these individuals is still not understood. Thus, we aimed to analyze and compare the distribution of microsatellite sequences in the species Astyanax bimaculatus and Psalidodon scabripinnis. Methods: We collected biopsies from the fins of A. bimaculatus and P. scabripinnis to perform cell culture, followed by chromosome extraction, and mapped the distribution of 14 microsatellites by FISH in both species. Results and Discussion: The diploid number observed for both species was 2n = 50, with an acrocentric B microchromosome in A. bimaculatus and a metacentric B chromosome in P. scabripinnis. Regarding FISH, 11 probes hybridized in the karyotype of A. bimaculatus mainly in centromeric regions, and 13 probes hybridized in P. scabripinnis, mainly in telomeric regions, in addition to a large accumulation of microsatellite hybridization on its B chromosome. Conclusion: Comparative FISH mapping of 14 microsatellite motifs revealed different patterns of distribution both in autosomes and supernumerary chromosomes of A. bimaculatus and P. scabripinnis, suggesting independent evolutionary processes in each of these species, representing excellent data on chromosome rearrangements and cytotaxonomy.

Comparative molecular and conventional cytogenetic analyses of three species of Rhinella (Anura; Bufonidae).

The genus Rhinella corresponds to a group of anurans characterized by numerous taxonomic and systemic challenges, leading to their organization into species complexes. Cytogenetic data for this genus thus far are limited to the diploid number and chromosome morphology, which remain highly conserved among the species. In this study, we analyse the karyotypes of three species of the genus Rhinella (Rhinella granulosa, Rhinella margaritifera, and Rhinella marina) using both classical (conventional staining and C-banding) and molecular (FISH-fluorescence in situ hybridization with 18S rDNA, telomeric sequences, and microsatellite probes) cytogenetic approaches. The aim of this study is to provide data that can reveal variations in the distribution of repetitive sequences that can contribute to understanding karyotypic diversification in these species. The results revealed a conserved karyotype across the species, with 2n = 22 and FN = 44, with metacentric and submetacentric chromosomes. C-banding revealed heterochromatic blocks in the pericentromeric region for all species, with a proximal block on the long arms of pairs 3 and 6 in R. marina and on the short arms of pairs 4 and 6 in R. margaritifera. Additionally, 18S rDNA probes hybridized to pair 5 in R. granulosa, to pair 7 in R. marina, and to pair 10 in R. margaritifera. Telomeric sequence probes displayed signals exclusively in the distal region of the chromosomes, while microsatellite DNA probes showed species-specific patterns. These findings indicate that despite a conserved karyotypical macrostructure, chromosomal differences exist among the species due to the accumulation of repetitive sequences. This variation may be attributed to chromosome rearrangements or differential accumulation of these sequences, highlighting the dynamic role of repetitive sequences in the chromosomal evolution of Rhinella species. Ultimately, this study emphasizes the importance of the role of repetitive DNAs in chromosomal rearrangements to elucidate the evolutionary mechanisms leading to independent diversification in the distinct phylogenetic groups of Rhinella.

Increased BMI associated with decreased breastfeeding initiation in Million Veteran Program participants.

Background: Breastfeeding has been associated with maternal and infant health benefits but has been inversely associated with body mass index (BMI) prepartum. Breastfeeding and BMI are both linked to socioeconomic factors. Methods: Data from parous female participants with available breastfeeding information from the Million Veteran Program cohort was included. BMI at enrollment and earliest BMI available were extracted, and polygenic scores (PGS) for BMI were calculated. We modeled breastfeeding for one month or more as a function of BMI at enrollment; earliest BMI where available pre-pregnancy; and PGS for BMI. We conducted Mendelian randomization for breastfeeding initiation using PGS as an instrumental variable. Results: A higher BMI predicted a lower likelihood of breastfeeding for one month or more in all analyses. A +5 kg/m 2 BMI pre-pregnancy was associated with a 24% reduced odds of breastfeeding, and a +5 kg/m 2 genetically predicted BMI was associated with a 17% reduced odds of breastfeeding. Conclusions: BMI predicts a lower likelihood of breastfeeding for one month or longer. Given the high success of breastfeeding initiation regardless of BMI in supportive environments as well as potential health benefits, patients with elevated BMI may benefit from additional postpartum breastfeeding support.

Plasma proteomic signatures for type 2 diabetes mellitus and related traits in the UK Biobank cohort.

Aims/hypothesis: The plasma proteome holds promise as a diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of plasma proteins to predict type 2 diabetes mellitus (T2DM) and related traits. Methods: Clinical, genetic, and high-throughput proteomic data from three subcohorts of UK Biobank participants were analyzed for association with dual-energy x-ray absorptiometry (DXA) derived truncal fat (in the adiposity subcohort), estimated maximum oxygen consumption (VO2max) (in the fitness subcohort), and incident T2DM (in the T2DM subcohort). We used least absolute shrinkage and selection operator (LASSO) regression to assess the relative ability of non-proteomic and proteomic variables to associate with each trait by comparing variance explained (R2) and area under the curve (AUC) statistics between data types. Stability selection with randomized LASSO regression identified the most robustly associated proteins for each trait. The benefit of proteomic signatures (PSs) over QDiabetes, a T2DM clinical risk score, was evaluated through the derivation of delta (Δ) AUC values. We also assessed the incremental gain in model performance metrics using proteomic datasets with varying numbers of proteins. A series of two-sample Mendelian randomization (MR) analyses were conducted to identify potentially causal proteins for adiposity, fitness, and T2DM. Results: Across all three subcohorts, the mean age was 56.7 years and 54.9% were female. In the T2DM subcohort, 5.8% developed incident T2DM over a median follow-up of 7.6 years. LASSO-derived PSs increased the R2 of truncal fat and VO2max over clinical and genetic factors by 0.074 and 0.057, respectively. We observed a similar improvement in T2DM prediction over the QDiabetes score [Δ AUC: 0.016 (95% CI 0.008, 0.024)] when using a robust PS derived strictly from the T2DM outcome versus a model further augmented with non-overlapping proteins associated with adiposity and fitness. A small number of proteins (29 for truncal adiposity, 18 for VO2max, and 26 for T2DM) identified by stability selection algorithms offered most of the improvement in prediction of each outcome. Filtered and clustered versions of the full proteomic dataset supplied by the UK Biobank (ranging between 600-1,500 proteins) performed comparably to the full dataset for T2DM prediction. Using MR, we identified 4 proteins as potentially causal for adiposity, 1 as potentially causal for fitness, and 4 as potentially causal for T2DM. Conclusions/Interpretation: Plasma PSs modestly improve the prediction of incident T2DM over that possible with clinical and genetic factors. Further studies are warranted to better elucidate the clinical utility of these signatures in predicting the risk of T2DM over the standard practice of using the QDiabetes score. Candidate causally associated proteins identified through MR deserve further study as potential novel therapeutic targets for T2DM.

A plasma proteomic signature for atherosclerotic cardiovascular disease risk prediction in the UK Biobank cohort.

Background: While risk stratification for atherosclerotic cardiovascular disease (ASCVD) is essential for primary prevention, current clinical risk algorithms demonstrate variability and leave room for further improvement. The plasma proteome holds promise as a future diagnostic and prognostic tool that can accurately reflect complex human traits and disease processes. We assessed the ability of plasma proteins to predict ASCVD. Method: Clinical, genetic, and high-throughput plasma proteomic data were analyzed for association with ASCVD in a cohort of 41,650 UK Biobank participants. Selected features for analysis included clinical variables such as a UK-based cardiovascular clinical risk score (QRISK3) and lipid levels, 36 polygenic risk scores (PRSs), and Olink protein expression data of 2,920 proteins. We used least absolute shrinkage and selection operator (LASSO) regression to select features and compared area under the curve (AUC) statistics between data types. Randomized LASSO regression with a stability selection algorithm identified a smaller set of more robustly associated proteins. The benefit of plasma proteins over standard clinical variables, the QRISK3 score, and PRSs was evaluated through the derivation of Δ AUC values. We also assessed the incremental gain in model performance using proteomic datasets with varying numbers of proteins. To identify potential causal proteins for ASCVD, we conducted a two-sample Mendelian randomization (MR) analysis. Result: The mean age of our cohort was 56.0 years, 60.3% were female, and 9.8% developed incident ASCVD over a median follow-up of 6.9 years. A protein-only LASSO model selected 294 proteins and returned an AUC of 0.723 (95% CI 0.708-0.737). A clinical variable and PRS-only LASSO model selected 4 clinical variables and 20 PRSs and achieved an AUC of 0.726 (95% CI 0.712-0.741). The addition of the full proteomic dataset to clinical variables and PRSs resulted in a Δ AUC of 0.010 (95% CI 0.003-0.018). Fifteen proteins selected by a stability selection algorithm offered improvement in ASCVD prediction over the QRISK3 risk score [Δ AUC: 0.013 (95% CI 0.005-0.021)]. Filtered and clustered versions of the full proteomic dataset (consisting of 600-1,500 proteins) performed comparably to the full dataset for ASCVD prediction. Using MR, we identified 11 proteins as potentially causal for ASCVD. Conclusion: A plasma proteomic signature performs well for incident ASCVD prediction but only modestly improves prediction over clinical and genetic factors. Further studies are warranted to better elucidate the clinical utility of this signature in predicting the risk of ASCVD over the standard practice of using the QRISK3 score.