Search Results (340)

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 (FOXG1) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the FOXG1 gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized Foxg1 c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous Foxg1 c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic FOXG1 variants correlated with overexpression of proteolipid protein 1 (Plp1), a gene linked to white matter disorders. Postnatal administration of Plp1-targeting antisense oligonucleotides (ASOs) in Foxg1 c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients. Full article

The aim of this work was to determine the influence of chosen biostimulants and microbiological preparations on the yield of sweet corn and the occurrence of Ostrinia nubilalis Hbn, and diseases. In both years of the study, the preparations used in this experiment did not have a statistically significant effect on marketable yield; however, in 2017, the highest weight was observed in the cobs of plants treated with Rizocore and Polyversum WP while the lowest in the cobs treated with RhizoVital 42. The biostimulant Asahi SL and the biological fungicide Serenade ASO proved to be the most effective in protecting sweet corn against cob and shoot infections by fungi of the genus Fusarium. All the preparations reduced the development of the common smut in corn, especially on the cobs. There were no statistically significant differences in cob infection by the O. nubilalis in the combinations treated with different preparations, although the lowest number of cobs damaged by pest in both years were observed on plots treated with Serenade ASO and RhizoVital 42, while the highest on plots treated with Goëmar BM. Full article

This study explored the impacts of various rainfall input types on short-term runoff simulations using the Cell2Flood model in the Waryong Reservoir Basin, South Korea. Six types of rainfall data were assessed: on-site gauge measurements, spatially interpolated data from 39 Automated Synoptic Observing System (ASOS) and 117 Automatic Weather System (AWS) stations using inverse distance weighting (IDW), and Hybrid Surface Rainfall (HSR) data from the Korea Meteorological Administration. The choice of rainfall input significantly affected model accuracy across the three rainfall events. The point-gauged ASOS (P-ASOS) data demonstrated the highest reliability in capturing the observed rainfall patterns, with Pearson’s r values of up to 0.84, whereas the radar-derived HSR data had the lowest correlations (Pearson’s r below 0.2), highlighting substantial discrepancies. For runoff simulation, the P-ASOS and ASOS-AWS combined interpolated dataset (R-AWS) achieved relatively accurate predictions, with P-ASOS and R-AWS exhibiting Normalized Peak Error (NPE) values of approximately 0.03 and Peak Time Error (PTE) within 20 min. In contrast, the HSR data produced large errors, with NPE up to 4.66 and PTE deviations exceeding 200 min, indicating poor temporal accuracy. Although input-specific calibration improved performance, significant errors persisted because of the inherent uncertainty of rainfall data. These findings underscore the importance of selecting and calibrating appropriate rainfall inputs to enhance the reliability of short-term flood modeling, particularly in ungauged and data-sparse basins. Full article

Congenitally corrected transposition of the great arteries (ccTGA) is an infrequent and complex congenital malformation, which accounts for approximately 0.5% of all congenital heart defects. This defect is characterized by both atrioventricular and ventriculoarterial discordance, with the right atrium connected to the morphological left ventricle (LV), ejecting blood into the pulmonary artery, while the left atrium is connected to the morphological right ventricle (RV), ejecting blood into the aorta. Due to this double discordance, the blood flow is physiologically normal. Most patients have coexisting cardiac abnormalities that require further treatment. Untreated natural course is often associated with progressive failure of the systemic right ventricle (RV), tricuspid valve (TV) regurgitation, arrhythmia, and sudden cardiac death, which occurs in approximately 50% of patients below the age of 40. Some patients do not require surgical intervention, but most undergo physiological repair leaving the right ventricle in the systemic position, anatomical surgery which restores the left ventricle as the systemic ventricle, or univentricular palliation. Various types of anatomic repair have been proposed for the correction of double discordance. They combine an atrial switch (Senning or Mustard procedure) with either an arterial switch operation (ASO) as a double-switch operation or, in the cases of relevant left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD), intra-ventricular rerouting by a Rastelli procedure. More recently implemented procedures, variations of aortic root translocations such as the Nikaidoh or the half-turned truncal switch/en bloc rotation, improve left ventricular outflow tract (LVOT) geometry and supposedly prevent the recurrence of LVOTO. Anatomic repair for congenitally corrected ccTGA has been shown to enable patients to survive into adulthood. Full article

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant genetic disease, which is caused by the mistaken expression of double homeobox protein 4 protein 4 (DUX4) in skeletal muscle. Patients with FSHD are usually accompanied by degenerative changes in the face, shoulders, and upper muscles, gradually accumulating in the lower limb muscles. The severity of patients is quite different, and most patients end up using wheelchairs and losing their self-care ability. At present, the exploration of treatment strategies for FSHD has shifted from relieving symptoms to gene therapy, which brings hope to the future of patients, but the current gene therapy is only in the clinical trial stage. Here, we conducted a comprehensive search of the relevant literature using the keywords FSHD, DUX4, and gene therapy methods including ASOs, CRISPR, and RNAi in the PubMed and Web of Science databases. We discussed the current advancements in treatment strategies for FSHD, as well as ongoing preclinical and clinical trials related to FSHD. Additionally, we evaluated the advantages and limitations of various gene therapy approaches targeting DUX4 aimed at correcting the underlying genetic defect. Full article

RNA splicing is an essential post-transcriptional mechanism that facilitates the excision of introns and the connection of exons to produce mature mRNA, which is essential for gene expression and proteomic diversity. In the liver, precise splicing regulation is critical for maintaining metabolic balance, detoxification, and protein synthesis. This review explores the mechanisms of RNA splicing and the role of splicing factors, particularly in the context of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). This review also highlights how RNA splicing dysregulation can lead to aberrant splicing and impact the progression of liver diseases such as MASLD, with a particular focus on Metabolic Dysfunction-Associated Steatohepatitis (MASH), which represents the advanced stage of MASLD. Recent advances in the clinical application of antisense oligonucleotides (ASOs) to correct splicing errors offer promising therapeutic strategies for restoring normal liver function. Additionally, the dysregulation of splicing observed in liver diseases may serve as a potential diagnostic marker, offering new opportunities for early identification of individuals more susceptible to disease progression. This review provides insights into the molecular mechanisms that govern splicing regulation in the liver, with a particular emphasis on MASLD, and discusses potential therapeutic approaches targeting RNA splicing to treat MASLD and related metabolic disorders. Full article

The glaciers in southeastern Tibet Plateau (SETP) influenced by oceanic climate are sensitive to global warming, and there remains a notable deficiency in accurate multitemporal change analyses of these glaciers. We conduct glacier inventories in the Yigong Zangbo River Basin (YZRB) in SETP for the years 1988, 2015, and 2023 utilizing Landsat and Sentinel-2 imagery, and analyze the glacier spatiotemporal variation incorporating the existing glacier inventory data. Since the 1970s until 2023, the glaciers significantly retreated at a rate of 0.76 ± 0.11%·a⁻¹, with the area decreasing from 2583.09 ± 88.80 km² to 1635.89 ± 71.74 km², and the ice volume reducing from 221.7017 ± 7.9618 km³ to 152.7429 ± 6.1747 km³. The most significant retreat occurred in glaciers smaller than 1 km². Additionally, glaciers on southern aspects retreated slower than the northern counterparts. The glaciers in the western YZRB witnessed a significantly greater shrinkage rate than those in the eastern section, with the most pronounced changes occurring in Aso Longbu River Basin. Furthermore, severe glacier mass deficits were observed from 2000 to 2019, averaging a loss rate of 0.57 ± 0.06 m w.e. a⁻¹. The continuous rise in air temperature has primarily induced a general widespread glacier change in the YZRB. However, diverse topography led to spatial variability in glacier changes with discrepancies as large as several times. The features of individual glaciers, such as glacier size, debris cover, and the development of ice-contact glacial lakes enhanced the local complexity of glacier change and elusive response behaviors to climate warming led by the different topographic conditions. Full article

Forestry in Japan and Austria share many similarities in their natural and social conditions. However, the Family Forest Owners (FFOs) in Japan seem not to be active and sustainable. To understand the factors affecting activeness and sustainability in family-owned forests in Japan, in 2021 and 2022, questionnaire surveys were done with members of Forest Owners’ Cooperatives (FOCs) in Aso, Japan, and Styria, Austria. Survey responses were comparatively analyzed via correlation analysis and binary logistic regression. Timber production was found to be more active in FOC Styria than in FOC Aso. One reason for this was the high-income dependence on forestry in Styria. Higher income was realized by self-harvest and the larger size of forest holdings and forest stands. The younger age of the members in FOC Styria, strongly affected by the pension system, leads to a higher self-harvest ratio. The culture of a sole child inheriting the family forest maintains the general size and scale of owned forests and stands in Styria. High distribution costs in FOC Aso reduced forestry income. As a result, sustainability was reduced in Aso because the availability of successors was low, and elderly forest owners who were once motivated by forestry tended to quit forestry. Full article

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development of treatments that precisely target specific molecules within the body. Despite the expanding landscape of therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics have emerged as a promising frontier in this realm, offering novel avenues for intervention such as RNA interference and the utilization of antisense oligonucleotides (ASOs). ASOs represent a versatile class of therapeutics capable of selectively targeting messenger RNAs (mRNAs) and silencing disease-associated proteins, thereby disrupting pathogenic processes at the molecular level. Recent advancements in chemical modification and carrier molecule design have significantly enhanced the stability, biodistribution, and intracellular uptake of ASOs, thereby bolstering their therapeutic potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, and parasitic diseases, our review manuscript focuses specifically on the application of ASOs in targeted cancer therapies. Through a comprehensive examination of the latest research findings and clinical developments, we delve into the intricacies of ASO-based approaches to cancer treatment, shedding light on their mechanisms of action, therapeutic efficacy, and prospects. Full article

Antisense technology demonstrates significant potential for addressing inherited brain diseases, with over a dozen products already available and numerous others in the development pipeline. The versatility of differentiating induced pluripotent stem cells (iPSCs) into nearly all neural cell types proves invaluable for comprehending the mechanisms behind neurological diseases, replicating cellular phenotypes, and advancing the testing and development of new therapies, including antisense oligonucleotide therapeutics. While delivering antisense oligonucleotides (ASOs) to human iPSC-based neuronal models has posed challenges, this study explores various delivery methods, including lipid-based transfection, gymnotic uptake, Ca⁽²⁺⁾-enhanced medium (CEM)-based delivery, and electroporation, in 2D and 3D hiPSC-derived neuronal models. This study reveals that CEM-based delivery exhibits efficiency and low toxicity in both 2D neuronal cultures and 3D brain organoids. Furthermore, the findings indicate that CEM is slightly more effective in neurons than in astrocytes, suggesting promising avenues for further exploration and optimization of preclinical ASO strategies in the treatment of neurological disorders. Full article

The direct acrylation of soybean oil was investigated by the activation of soybean oil’s (SO’s) internal fatty unsaturation with acidic catalysts. The effect of the catalyst and the reactant ratio with respect to the unsaturation and reaction time on the direct acrylation process were explored. ASO (acrylated soybean oil) with acrylation degrees (the number of acrylate molecules introduced in a triglyceride molecule) between 1.6 and 2.55 were obtained. The effect of the ASO acrylation degree on copolymerization processes was investigated. The resulting monomers were successfully copolymerized with meth(acrylate) monomers by the miniemulsion polymerization process, favoring the droplet nucleation mechanism and showing conversions higher than 97%. The acrylic–ASO copolymers presented lower Tg and higher hydrophobicity and oleophobicity than the acrylic copolymer. Full article

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2⁺, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic. Full article

Dextro-transposition of the great arteries (D-TGA) is the second most common cyanotic heart disease, accounting for 5–7% of all congenital heart defects (CHDs). It is characterized by ventriculoarterial (VA) connection discordance, atrioventricular (AV) concordance, and a parallel relationship with D-TGA. As a result, the pulmonary and systemic circulations are separated [the morphological right ventricle (RV) is connected to the aorta and the morphological left ventricle (LV) is connected to the pulmonary artery]. This anomaly is included in the group of developmental disorders of embryonic heart conotruncal irregularities, and their pathogenesis is multifactorial. The anomaly’s development is influenced by genetic, epigenetic, and environmental factors. It can occur either as an isolated anomaly, or in association with other cardiac defects. The typical concomitant cardiac anomalies that may occur in patients with D-TGA include ventriculoseptal defects, patent ductus arteriosus, left ventricular outflow tract obstruction (LVOTO), mitral and tricuspid valve abnormalities, and coronary artery variations. Correction of the defect during infancy is the preferred treatment for D-TGA. Balloon atrial septostomy (BAS) is necessary prior to the operation. The recommended surgical correction methods include arterial switch operation (ASO) and atrial switch operation (AtrSR), as well as the Rastelli and Nikaidoh procedures. The most common postoperative complications include coronary artery stenosis, neoaortic root dilation, neoaortic insufficiency and neopulmonic stenosis, right ventricular (RV) outflow tract obstruction (RVOTO), left ventricular (LV) dysfunction, arrhythmias, and heart failure. Early diagnosis and treatment of D-TGA is paramount to the prognosis of the patient. Improved surgical techniques have made it possible for patients with D-TGA to survive into adulthood. Full article

Vascular Ehlers–Danlos syndrome or Ehlers–Danlos syndrome type IV (vEDS) is a connective tissue disorder characterised by skin hyperextensibility, joint hypermobility and fatal vascular rupture caused by COL3A1 mutations that affect collagen III expression, homo-trimer assembly and secretion. Along with collagens I, II, V and XI, collagen III plays an important role in the extracellular matrix, particularly in the inner organs. To date, only symptomatic treatment for vEDS patients is available. Fibroblasts derived from vEDS patients carrying dominant negative and/or haploinsufficiency mutations in COL3A1 deposit reduced collagen III in the extracellular matrix. This study explored the potential of an antisense oligonucleotide (ASO)-mediated splice modulating strategy to bypass disease-causing COL3A1 mutations reported in the in-frame exons 10 and 15. Antisense oligonucleotides designed to redirect COL3A1 pre-mRNA processing and excise exons 10 or 15 were transfected into dermal fibroblasts derived from vEDS patients and a healthy control subject. Efficient exon 10 or 15 excision from the mature COL3A1 mRNA was achieved and intracellular collagen III expression was increased after treatment with ASOs; however, collagen III deposition into the extracellular matrix was reduced in patient cells. The region encoded by exon 10 includes a glycosylation site, and exon 15 encodes hydroxyproline and hydroxylysine-containing triplet repeats, predicted to be crucial for collagen III assembly. These results emphasize the importance of post-translational modification for collagen III homo-trimer assembly. In conclusion, while efficient skipping of target COL3A1 exons was achieved, the induced collagen III isoforms generated showed defects in extracellular matrix formation. While therapeutic ASO-mediated exon skipping is not indicated for the patients in this study, the observations are restricted to exons 10 and 15 and may not be applicable to other collagen III in-frame exons. Full article

Most damage to buildings across the contiguous United States of America (USA) is caused by gusts in convective events associated with thunderstorms. Design rules for structures to resist these events rely on the integrity of meteorological observations and the methods of assessment. These issues were addressed for the US Automated Surface Observation System (ASOS) in six preliminary studies published in 2022 and 2023, allowing this present study to focus on the analysis and reporting of gust events observed between 2000 and 2023 at 642 well-exposed ASOS stations distributed across the contiguous USA. It has been recently recognized that the response of buildings to convective gusts, which are non-stationary transient events, differs in character from the response to the locally stationary atmospheric boundary gusts, requiring gust events to be classified and assessed by type. This study sorts the mixture of all observed gust events exceeding 20 kn, but excluding contributions from hurricanes and tropical storms, into five classes of valid meteorological types and two classes of invalid artefacts. The valid classes are individually fitted to optimal sub-asymptotic models through extreme value analysis. Classes are recombined into a joint mixture model and compared with current design rules. Full article