Search Results (38)

Background/Objectives: DGAT1 p. K232A (rs109234250) is a well-established causal variant influencing milk fat and protein content in dairy cattle, but it is often absent from commercial genotyping arrays. PPP1R16A rs109146371 frequently appears as a top signal in genome-wide association studies (GWAS) for milk traits. This study aimed to evaluate the linkage disequilibrium (LD) between these two variants in Japanese Holsteins and assess whether rs109146371 exerts an independent effect on milk traits. Methods: A total of 256 Japanese Holstein cows were genotyped for DGAT1 p. K232A and PPP1R16A rs109146371 using TaqMan SNP assays. LD statistics (r², D′) were computed, and linear mixed-effects models were used to evaluate associations with 305-day milk yield, fat percentage, protein percentage, and solids-not-fat (SNF) percentage. Likelihood ratio tests were conducted to assess the independence of SNP effects. Results: Strong LD was observed between DGAT1 p. K232A and PPP1R16A rs109146371 (r² = 0.91, D′ = 0.9962). Both SNPs showed significant associations with all milk production traits; however, model comparisons indicated that rs109146371 did not improve model fit when K232A was included, suggesting no independent effect. Conclusions: PPP1R16A rs109146371 serves as a proxy for DGAT1 K232A rather than an independent determinant of milk traits. Full article

With the availability of multi-frequency, multi-constellation global navigation satellite system (GNSS) modules, precise transportation applications have become attainable. For transportation applications, GNSS geodetic-grade receivers can achieve an accuracy of a few centimeters to a few decimeters through differential, precise point positioning (PPP), real-time kinematic (RTK), and PPP-RTK solutions in both post-processing and real-time modes; however, these receivers are costly. Therefore, this research aims to assess the accuracy of a cost-effective multi-GNSS real-time PPP solution for transportation applications. For this purpose, the U-blox ZED-F9P module is utilized to collect dual-frequency multi-GNSS observations through a moving vehicle in a suburban area in New Aswan City, Egypt; thereafter, datasets involving different multi-GNSS combination scenarios are processed, including GPS, GPS/GLONASS, GPS/Galileo, and GPS/GLONASS/Galileo, using both RT-PPP and RTK solutions. For the RT-PPP solution, the satellite clock and orbit correction products from Bundesamt für Kartographie und Geodäsie (BKG), Centre National d’Etudes Spatiales (CNES), and the GNSS research center of Wuhan University (WHU) are applied to account for the real-time mode. Moreover, GNSS datasets from two geodetic-grade Trimble R4s receivers are collected; hence, the datasets are processed using the traditional kinematic differential solution to provide a reference solution. The results indicate that this cost-effective multi-GNSS RT-PPP solution can attain positioning accuracy within 1–3 dm, and is thus suitable for a variety of transportation applications, including intelligent transportation system (ITS), self-driving cars, and automobile navigation applications. Full article

Runs of homozygosity (ROHs) are continuous homozygous segments of genomes that can be used to infer the historical development of the population. ROH studies allow us to analyze the genetic structure of a population and identify signs of selection. The present study searched for ROH regions in the Faverolle chicken breed. DNA samples from modern individuals and museum Faverolle specimens were obtained and sent for whole-genome sequencing (WGS) with 30× coverage. The results were aligned to the reference genome and subjected to additional filtering. ROH segments were then analyzed using PLINK 1.9. As a result, 10 regions on GGA1, 2, 3, 4, and 13 were identified. A total of 19 genes associated with fat deposition and lipid metabolism (GBE1, CACNA2D1, STON1, PPP1R21, RPL21L1, ATP6V0E1, CREBRF, NKX2-2, COMMD1), fertility (LHCGR, GTF2A1L, SAMD5), muscle development and body weight (VGLL3, CACNA2D1, FOXN2, ERGIC1, RPL26L1), the shape and relative size of the skeleton (FAT4), and autophagy and apoptosis (BNIP1) were found. Developmental protein genes (PAX1, NKX2-2, NKX2-4, NKX2-5) formed a separate cluster. Probably, selection for the preservation of high flavor characteristics contributed to the consolidation of these ROH regions. The present research enhances our knowledge on the Faverolle breed’s genome and pinpoints their ROH segments that are also specific «selection traces». Full article

Background: Macrocephaly can be a component manifestation of several monogenic conditions, in association with intellectual disability/developmental delay (ID/DD) behaviour abnormalities, including autism spectrum disorders (ASD), and variable additional features. On the other hand, idiopathic ASD can present with developmental delay and macrocephaly. Methods: We carried out a retrospective analysis of a cohort of 78 patients who were tested from February 2017 to December 2024 by high-throughput sequencing of a panel of 27 genes (ABCC9, AKT1, AKT2, AKT3, BRWD3, DIS3L2, DNMT3A, EZH2, GPC3, GPC4, HERC1, MED12, MTOR, NFIA, NFIX, NSD1, PDGFRB, PIK3CA, PIK3R1, PIK3R2, PPP2R1A, PPP2R5D, PTEN, RAB39B, RNF135, SETD2, and TBC1D7) because of neurodevelopmental impairment, including ID/DD, ASD/behaviour abnormalities associated with macrocephaly, mimicking to a large extent idiopathic ASD. Results: Pathogenic variants leading to the diagnosis of monogenic conditions were detected in 22 patients (28%), including NSD1 (2), PTEN (16), and PPP2R5D (4). Distinctive of the PTEN-associated phenotype were true macrocephaly (100%), ASD or behaviour abnormalities (92%), mild/borderline ID (79%), and no facial dysmorphisms. Typical of the PPP2R5D-associated phenotype were relative macrocephaly (75%), a few unspecific peculiar facial characteristics (50%), and a more variable presentation of the neurodevelopmental phenotype. Conclusions: Pathogenic variants in PTEN and PPP2R5D are the most recurrent gene mutations in a patient-oriented procedure for the genetic diagnosis of apparently idiopathic ASD and behaviour abnormalities associated with macrocephaly. The clinical applicability of the presented diagnostic strategy is discussed. Full article

This article aims to examine the real-time precise point positioning (PPP) solution’s accuracy utilizing the low-cost dual-frequency multi-constellation U-blox ZED-F9P module and real-time GNSS orbit and clock products from five analysis centers, including Bundesamt für Kartographie und Geodäsie (BKG), Centre National d’Etudes Spatiales (CNES), International GNSS Service (IGS), Geo Forschungs Zentrum (GFZ), and GNSS research center of Wuhan University (WHU). Three-hour static quad-constellation GNSS measurements are collected from ZED-F9P modules and geodetic grade Trimble R4s receivers over a reference station in Aswan City, Egypt, for a period of three consecutive days. Since a multi-GNSS PPP processing model is applied in the majority of the previous studies, this study employs the single-constellation GNSS PPP solution to process the acquired datasets. Different single-constellation GNSS PPP scenarios are adopted, namely, GPS PPP, GLONASS PPP, Galileo PPP, and BeiDou PPP models. The obtained PPP solutions from the low-cost module are validated for the positioning and precipitable water vapor (PWV) domains. To provide a reference positioning solution, the post-processed dual-frequency geodetic-grade GNSS PPP solution is applied; additionally, as the station under investigation is not a part of the IGS reference station network, a new technique is proposed to estimate reference PWV values. The findings reveal that the GPS and Galileo 3D position’s accuracy is within the decimeter level, while it is within the meter level for both the GLONASS and BeiDou models. Additionally, millimeter-level PWV precision is obtained from the four PPP models. Full article

Cutaneous lupus erythematosus (CLE) is a chronic autoimmune skin disorder with limited therapeutic options, particularly for refractory discoid lupus (DLE), which often results in scarring and atrophy. Recent studies have identified miR-31, miR-485-3p, and miR-885-5p as key regulators of inflammation, apoptosis, and fibrosis in CLE skin lesions. This research investigates a novel topical miRNA therapy using DDC642 elastic liposomes to target these pathways in CLE. DDC642 liposomes were complexed with miRNAs (anti-miR-31, anti-miR-485-3p, pre-miR-885-5p) and characterized through dynamic light scattering and Cryo-TEM. Cytotoxicity, cellular penetration, and therapeutic efficacy were evaluated in primary keratinocytes, PBMCs, and immune 3D-skin organoids. miRNA lipoplexes were successfully synthesized with optimized particle size, surface charge, and encapsulation efficiency. These lipoplexes exhibited effective cellular penetration and low cytotoxicity. Anti-miR-31 lipoplexes reduced miR-31 and NF-κB levels while increasing STK40 and PPP6C expression. Pre-miR-885-5p lipoplexes elevated miR-885-5p levels and downregulated PSMB5 and NF-κB in keratinocytes. While anti-miR-485-3p lipoplexes reduced T-cell activation markers. Anti-miR-31 and pre-miR-885-5p lipoplexes successfully modulated inflammatory pathways in 3D-skin CLE models. miRNA lipoplexes represent promising candidates for pioneering topical genetic therapies for CLE. Further studies, including animal models, are necessary to validate and optimize these findings. Full article

Background: Houge-Janssens syndrome 1 is a condition with onset in early childhood caused by heterozygous pathogenic variants in the PPP2R5D gene, which encodes a B56 regulatory subunit of the serine/threonine protein phosphatase 2A (PP2A). There is evidence that the PP2A-PPP2R5D complex is involved in regulating the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway, which is crucial for several cellular processes, including the pathogenesis and progression of haemangiomas. Case presentation: We report the first PPP2R5D-related neurodevelopmental disorder case from Sardinia, a child with transient hypoglycaemia, facial dysmorphisms, and multiple haemangiomas. Whole Exome Sequencing analysis confirmed the clinical suspicion, detecting the presence of the de novo missense variant c.592G>A in the PPP2R5D gene. Conclusions: Haemangiomas have never been linked to the syndromic phenotype of the PPP2R5D-associated disorder. The close correlation between the PP2A enzyme and the PI3K/AKT signalling pathway suggests the possible correlation between its dysfunction and activation of haemangiogenesis. Our report highlights a possible link between the PPP2R5D-related disorder and altered angiogenesis, characterizing diffuse haemangiomas as a possible novel phenotypic trait of this condition. Full article

Meat quality is a complex trait that exhibits significant variation across pig breeds, and the regulatory mechanisms governing pork meat quality are not fully elucidated. We compared the transcriptomics and metabolomics of the longissimus dorsi (LD) muscle between the Songliao Black Pig (SBP) and Large White × Landrace Pig (LWLDP) to investigate breed-specific differences in meat quality and underlying regulatory pathways. The results showed that SBP meat had a higher marbling score and backfat thickness, a richer color, a lower shear force, and reduced drip loss. Fatty acid (FA) analysis identified 15 significant FAs in the LWLDP, with docosahexaenoic acid (DHA) in the SBP, while amino acid (AA) analysis revealed no breed-based differences. Transcriptome analysis identified 134 upregulated and 362 downregulated genes in the SBP. Protein–protein interaction (PPI) network analysis found 25 key genes, which are associated with muscle development, fat deposition, and overall meat quality, while genes in the insulin signaling pathway, such as PPP1R3B, PPARGC1A, SOCS1, EIF4E, PRKAR2A, PRKAG2, and FASN, play a crucial role in balancing fat metabolism and catabolism. Metabolomic analysis identified 89 upregulated and 10 downregulated metabolites in the SBP, primarily involved in fructose and mannose metabolism, amino acid biosynthesis, nucleotide sugar metabolism, and glucagon signaling pathways. Gene–metabolite association analysis found that the PPP1R3B gene had a strong association with Thr-Leu, Maltol, D-myo-Inositol-4-phosphate, and Fructose-6-phosphate, while MYOG correlated with Mannose-6-phosphate, Fructose-1-phosphate, Mannose-1-phosphate, and Glucose-6-phosphate. In contrast, NR4A3 and PPARGC1A showed a strong negative correlation with most upregulated metabolites. In conclusion, this study identified functional genes, elucidated the mechanisms associated with meat quality traits, and identified gene–metabolite associations involved in energy metabolism, muscle development, and fat deposition, providing valuable insights into the molecular mechanisms that regulate meat quality between pig breeds. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and memory loss. While the precise causes of AD remain unclear, emerging evidence suggests that messenger RNA (mRNA) dysregulation contributes to AD pathology and risk. This study examined exosomal mRNA expression profiles of 15 individuals diagnosed with AD and 15 healthy controls from Barranquilla, Colombia. Utilizing advanced bioinformatics and machine learning (ML) techniques, we identified differentially expressed mRNAs and assessed their predictive power for AD diagnosis and AD age of onset (ADAOO). Our results showed that ENST00000331581 (CADM1) and ENST00000382258 (TNFRSF19) were significantly upregulated in AD patients. Key predictors for AD diagnosis included ENST00000311550 (GABRB3), ENST00000278765 (GGTLC1), ENST00000331581 (CADM1), ENST00000372572 (FOXJ3), and ENST00000636358 (ACY1), achieving > 90% accuracy in both training and testing datasets. For ADAOO, ENST00000340552 (LIMK2) expression correlated with a delay of ~12.6 years, while ENST00000304677 (RNASE6), ENST00000640218 (HNRNPU), ENST00000602017 (PPP5D1), ENST00000224950 (STN1), and ENST00000322088 (PPP2R1A) emerged as the most important predictors. ENST00000304677 (RNASE6) and ENST00000602017 (PPP5D1) showed promising predictive accuracy in unseen data. These findings suggest that mRNA expression profiles may serve as effective biomarkers for AD diagnosis and ADAOO, providing a cost-efficient and minimally invasive tool for early detection and monitoring. Further research is needed to validate these results in larger, diverse cohorts and explore the biological roles of the identified mRNAs in AD pathogenesis. Full article

Uncrewed aircraft systems (UASs) and structure-from-motion/multi-view stereo (SfM/MVS) photogrammetry are efficient methods for mapping terrain at local geographic scales. Traditionally, indirect georeferencing using ground control points (GCPs) is used to georeference the UAS image locations before further processing in SfM software. However, this is a tedious practice and unsuitable for surveying remote or inaccessible areas. Direct georeferencing is a plausible alternative that requires no GCPs. It relies on global navigation satellite system (GNSS) technology to georeference the UAS image locations. This research combined field experiments and simulation to investigate GNSS-based post-processed kinematic (PPK) as a means to eliminate or reduce reliance on GCPs for shoreline mapping and charting. The study also conducted a brief comparison of real-time network (RTN) and precise point positioning (PPP) performances for the same purpose. Ancillary experiments evaluated the effects of PPK base station distance and GNSS sample rate on the accuracy of derived 3D point clouds and digital elevation models (DEMs). Vertical root mean square errors (RMSE_z), scaled to the 95% confidence interval using an assumption of normally-distributed errors, were desired to be within 0.5 m to satisfy National Oceanic and Atmospheric Administration (NOAA) requirements for nautical charting. Simulations used a Monte Carlo approach and empirical tests to examine the influence of GNSS performance on the quality of derived 3D point clouds. RTN and PPK results consistently yielded RMSE_z values within 10 cm, thus satisfying NOAA requirements for nautical charting. PPP did not meet the accuracy requirements but showed promising results that prompt further investigation. PPK experiments using higher GNSS sample rates did not always provide the best accuracies. GNSS performance and model accuracies were enhanced when using base stations located within 30 km of the survey site. Results without using GCPs observed a direct relationship between point cloud accuracy and GNSS performance, with ${\mathrm{R}}^2$ values reaching up to 0.97. Full article

Background: Reproductive performance is critical in the pig industry, and improved sow performance could lead to increased economic benefits. GWAS and ROH analyses based on SNP array data were conducted to identify the breed-specific genetic architecture underlying the variation in NBA and TNB. Methods: A total of 7488 breeding pigs with phenotypic data from 1586 Duroc, 2256 Landrace, and 3646 Yorkshire breeds, along with 76,756 SNP markers from Korean grand-grand-parent (GGP) breeding farms, were used. Results: In the Duroc breeds, SNPs on SSC 9 and 17 were found to be associated with the SIDT2 and TGM2 genes, respectively. In the Landrace breed, PPP1R9A, LMTK2, and GTF2H3 on SSCs 9, 3, and 14, respectively, were associated with both TNB and NBA. With the Yorkshire breed genome, GRID1, DLGAP2, ZZEF1, PARG, RNF17, and NDUFAF5 in SSCs 14, 15, 12, 14, 11, and 17, respectively, were associated with NBA and TNB traits. These genes have distinct functions, ranging from synaptic transmission and cytoskeletal organization to DNA repair and cellular energy production. In the Duroc breed, six genes identified in the ROH islands were associated with various biological pathways, molecular functions, and cellular components. NT5DC1 was associated with metaphyseal chondrodysplasia, CRTAC1 with ion binding, CFAP43 with spermatogenic failure, CASC3 with intracellular mRNA localization, ERC2 with cellular component organization, and FOCAD with Focadhesin. In the Landrace and Yorkshire breeds, PDE6D was associated with GTPase inhibitor activity. Conclusions: Through GWAS and ROH analyses, we identified breed-specific SNP markers associated with NBA and TNB in three breed genotypes, providing insights for improving reproductive performance efficiency and contributing to future breeding strategies. Full article

The escalation of climate-induced disasters underscores how climatic variability has become a main question in designing risk-sensitive policies in advanced and developing countries. The macroeconomic implications of Natural Hazards (NHs) are extremely significant, as they can compromise financial stability and long-term prosperity. To mitigate risks and close the knowledge, protection, and development gaps can free resources, speeding up reconstruction of infrastructure, recovering from disruption of supply chains, and returning to pre-disaster levels of activities. This is not a simple task involving different steps of a “ladder approach”, sharing the burden of cost and responsibilities across the relevant stakeholders and reducing moral hazard. This approach rests on Public–Private Partnerships (PPPs) and technological R&D public investments able to crowd private ones in and establish useful Public–Private Insurance Schemes enhancing the disaster risk management role of the state. This paper proposes leveraging innovation technology both to enhance risk assessment and reduce uncertainty for climate-related NHs such as landslides. It is an important interdisciplinary question; in fact, despite the unequivocal acknowledgment of the global warming system, the precise ramifications of global warming and associated climatic shifts on NHs like landslides remain still elusive. The advanced modeling technique implemented by our interdisciplinary PPP contributes to geographically circumscribe the areas eventually subjected to landslides and constantly monitor the vulnerability of their structures, infrastructures, economic activities, and hence population. The reliable data that we can produce through remote sensing acquisition systems are necessary inputs to contain risk exposure both physically and financially. Full article

Chronic venous disease (CVD) is a prevalent condition in adults, significantly affecting the global elderly population, with a higher incidence in women than in men. The modulation of gene expression through microRNA (miRNA) partly regulated the development of cardiovascular disease (CVD). Previous research identified a functional analysis of seven genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1, and PABPC3) as targets of miRNAs related to CVD. In this context, miRNAs emerge as essential candidates for CVD diagnosis, representing novel molecular and biological knowledge. This work aims to identify, by network analysis, the miRNAs involved in CVD as potential biomarkers, either by interacting with small molecules such as toxins and pollutants or by searching for new drugs. Our study shows an updated landscape of the signaling pathways involving miRNAs in CVD pathology. This latest research includes data found through experimental tests and uses predictions to propose both miRNAs and genes as potential biomarkers to develop diagnostic and therapeutic methods for the early detection of CVD in the clinical setting. In addition, our pharmacological network analysis has, for the first time, shown how to use these potential biomarkers to find small molecules that may regulate them. Between the small molecules in this research, toxins, pollutants, and drugs showed outstanding interactions with these miRNAs. One of them, hesperidin, a widely prescribed drug for treating CVD and modulating the gene expression associated with CVD, was used as a reference for searching for new molecules that may interact with miRNAs involved in CVD. Among the drugs that exhibit the same miRNA expression profile as hesperidin, potential candidates include desoximetasone, curcumin, flurandrenolide, trifluridine, fludrocortisone, diflorasone, gemcitabine, floxuridine, and reversine. Further investigation of these drugs is essential to improve the treatment of cardiovascular disease. Additionally, supporting the clinical use of miRNAs as biomarkers for diagnosing and predicting CVD is crucial. Full article

Dilated cardiomyopathy (DCM) is one of the major causes of heart failure. Although significant progress has been made in elucidating the underlying mechanisms, further investigation is required for clarifying molecular diagnostic and therapeutic targets. In this study, we found that the mRNA level of protein phosphatase 2 regulatory subunit B’ delta (Ppp2r5d) was altered in the peripheral blood plasma of DCM patients. Knockdown of Ppp2r5d in murine cardiomyocytes increased the intracellular levels of reactive oxygen species (ROS) and inhibited adenosine triphosphate (ATP) synthesis. In vivo knockdown of Ppp2r5d in an isoproterenol (ISO)-induced DCM mouse model aggravated the pathogenesis and ultimately led to heart failure. Mechanistically, Ppp2r5d-deficient cardiomyocytes showed an increase in phosphorylation of STAT3 at Y705 and a decrease in phosphorylation of STAT3 at S727. The elevated levels of phosphorylation at Y705 in STAT3 triggered the upregulation of interleukin 6 (IL6) expression. Moreover, the decreased phosphorylation at S727 in STAT3 disrupted mitochondrial electron transport chain function and dysregulated ATP synthesis and ROS levels. These results hereby reveal a novel role for Ppp2r5d in modulating STAT3 pathway in DCM, suggesting it as a potential target for the therapy of the disease. Full article

Background: Neurodevelopmental disorders (NDDs) are a group of diseases that severely affect the physical and mental health of children. The PPP2R5D gene encodes B56δ, the regulatory subunit of protein phosphatase 2A (PP2A). NDDs related to the PPP2R5D gene have recently been defined as Houge–Janssens syndrome 1. Methods: Clinical/whole exome sequencing was performed on approximately 3000 patients with NDDs from 2017 to 2023. In vitro experiments were performed to assess the impairment of variants to protein expression and the assembly of PP2A holoenzyme. The genetic information and phenotypes of the reported patients, as well as patients in this study, were summarized, and the genotype–phenotype relationship was analyzed. The probability of pathogenic missense variants in PPP2R5D was predicted using AlphaMissense (AM), and the relationship between certain phenotype and 3D protein structural features were analyzed. Results: Thirteen new patients carrying twelve PPP2R5D gene variants were detected, including five novel missense variants and one novel frameshift variant. In vitro experiments revealed that the frameshift variant p.H463Mfs*3 resulted in a ~50 kDa truncated protein with lower expression level. Except for E420K and T536R, other missense variants impaired holoenzyme assembly. Furthermore, we found that pathogenic/likely pathogenic (P/LP) variants that have been reported so far were all missense variants and clustered in three conserved regions, and the likelihood of P/LP mutations located in these conserved regions was extremely high. In addition, the macrocephaly phenotype was related to negatively charged residues involved in substrate recruitment. Conclusions: We reported thirteen new patients with PPP2R5D gene variants and expanded the PPP2R5D variant spectrum. We confirmed the pathogenicity of novel variants through in vitro experiments. Our findings in genotype–phenotype relationship provide inspiration for genetic counseling and interpretation of variants. We also provide directions for further research on the mechanism of macrocephaly phenotype. Full article