Search Results (291)

Background: Hemoglobin Rothschild (Hb Rothschild), NM_000518.5(HBB):c.112T>C, is an ultra-rare low-oxygen-affinity hemoglobin variant that persistently causes reduced peripheral oxygen saturation on pulse oximetry despite normal arterial oxygenation. Fewer than ten cases have been reported worldwide, and only one involved a child—an asymptomatic carrier identified incidentally. Methods: The patient underwent clinical examination, growth assessment, blood tests, hemoglobin electrophoresis, chest CT, abdominal ultrasound, echocardiography, and pulmonary perfusion scintigraphy. Whole genome sequencing (WGS) of the proband and parents was performed, followed by bioinformatic analysis and ACMG-based variant interpretation. A PRISMA-guided PubMed literature review was conducted. Results: We report on the first pediatric case exhibiting a symptomatic clinical course. A 4-year-old boy was referred for chronically low peripheral oxygen saturation (SpO₂), 78–86%, on pulse oximetry and recurrent lower respiratory tract infections. Early developmental history revealed episodes of apnea in infancy, perioral cyanosis, poor exercise tolerance, and low weight gain. Repeated cardiopulmonary assessments, chest computed tomography (CT), echocardiography, and pulmonary perfusion scintigraphy yielded unremarkable findings. Arterial blood gas analysis consistently showed normal arterial partial pressure of oxygen (PaO₂), excluding true hypoxemia. Hemoglobin electrophoresis revealed an abnormal HbD fraction; WGS identified a heterozygous variant NM_000518.5(HBB):c.112T>C inherited from the patient’s asymptomatic father. This variant increases the partial pressure of oxygen at which hemoglobin is 50% saturated (p50), thereby decreasing hemoglobin’s oxygen affinity and shifting the oxyhemoglobin dissociation curve to the right. These alterations explain the discordance between low peripheral oxygen saturation (SpO₂) and preserved oxygen delivery to tissues. Conclusions: This case expands the clinical spectrum of Hb Rothschild and demonstrates that symptomatic presentation may occur in early childhood. Awareness of low-affinity hemoglobin variants is essential to avoid misdiagnosis and unnecessary cardiopulmonary interventions. Early genetic testing facilitates accurate diagnosis and appropriate counseling. Full article

Background/Objectives: Glioblastoma is the most common and aggressive primary brain tumor in adults, with patient prognosis remaining poor. Treatment resistance and tumor recurrence are frequent, primarily due to the high intra- and inter-tumoral heterogeneity and the existence of glioma stem cells. Thus, there is an urgent need for novel and more effective therapeutic strategies. Multitarget small molecules (MSMs) are emerging as a novel therapeutic strategy for the treatment of complex diseases such as cancer. Methods: In the present work, we have generated a novel family of indole-based MSMs with pharmacophoric moieties combining the parent compounds Contilisant and the HDAC inhibitor Tubastatin A. Thus, the MSMs were designed to inhibit monoamine oxidases (MAOs), cholinesterases (ChEs) and histone deacetylases (HDACs), while acting as histamine H3 receptor (H3R) antagonists and sigma 1 receptor (S1R) agonists. We generated four different molecules and evaluated in detail the activity of the two most efficient MSM compounds in vitro and in vivo. Results: These molecules induced potent cytotoxic effects in vitro in patient-derived glioma stem cells and glioblastoma cell lines and significantly impaired tumor growth in vivo. OMIC analyses further revealed that the compounds induce dysregulation of the cell cycle in glioma stem cells. Moreover, in silico analyses indicated that these compounds are theoretically capable of crossing the blood–brain barrier, while exhibiting low toxicity in healthy cells. Conclusions: In conclusion, our findings demonstrate the potential antitumor activity of a novel family of MSMs in preclinical models of glioblastoma. Full article

The cultivation of aesthetic appreciation through engagement with exemplary artworks constitutes a fundamental pillar in fostering children’s cognitive and emotional development, while simultaneously facilitating multidimensional learning experiences across diverse perceptual domains. However, children in early stages of cognitive development frequently encounter substantial challenges when attempting to comprehend and internalize complex visual narratives and abstract artistic concepts inherent in sophisticated artworks. This study presents an innovative methodological framework designed to enhance children’s artwork comprehension capabilities by systematically leveraging the theoretical foundations of audio-visual cross-modal integration. Through investigation of cross-modal correspondences between visual and auditory perceptual systems, we developed a sophisticated methodology that extracts and interprets musical elements based on gaze behavior patterns derived from prior pilot studies when observing artworks. Utilizing state-of-the-art deep learning techniques, specifically Recurrent Neural Networks (RNNs), these extracted visual–musical correspondences are subsequently transformed into cohesive, aesthetically pleasing musical compositions that maintain semantic and emotional congruence with the observed visual content. The efficacy and practical applicability of our proposed method were validated through empirical evaluation involving 96 children (analyzed through objective behavioral assessments using eye-tracking technology), complemented by qualitative evaluations from 16 parents and 5 experienced preschool educators. Our findings show statistically significant improvements in children’s sustained engagement and attentional focus under AI-generated, artwork-matched audiovisual support, potentially scaffolding deeper processing and informing future developments in aesthetic education. The results demonstrate statistically significant improvements in children’s sustained engagement (fixation duration: 58.82 ± 7.38 s vs. 41.29 ± 6.92 s, p < 0.001, Cohen’s d ≈ 1.29), attentional focus (AOI gaze frequency increased 73%, p < 0.001), and subjective evaluations from parents (mean ratings 4.56–4.81/5) when visual experiences are augmented by AI-generated, personalized audio-visual experiences. Full article

Background/Objectives: In the treatment of autism spectrum disorders, families express the need for dedicated clinical spaces to manage emotional overload and to develop effective relational skills. Parent training addresses this need by supporting the parent–child relationship and fostering the child’s development. This study proposes a clinical protocol designed for psychotherapists and behavior analysts, based on the Autism Open Clinical Model (A.-O.C.M.), which integrates the rigor of Applied Behavior Analysis (ABA) with a phenomenological and embodied perspective. The model acknowledges technology—particularly artificial intelligence—as an opportunity to structure adaptive and personalized intervention tools. Methods: A multi-level prompt design system was developed, grounded in the principles of the A.-O.C.M. and integrated with generative AI. The tool employs clinical questions, semantic constraints, and levels of analysis to support the clinician’s reasoning and phenomenologically informed observation of behavior. Results: Recurrent relational patterns emerged in therapist–caregiver dynamics, allowing the identification of structural elements of the intersubjective field that are useful for personalizing interventions. In particular, prompt analysis highlighted how the quality of bodily and emotional attunement influences readiness for change, suggesting that intervention effectiveness increases when the clinician can adapt their style according to emerging phenomenological resonances. Conclusions: The design of clinical prompts rooted in embodied cognition and supported by AI represents a new frontier for psychotherapy that is more attuned to subjectivity. The A.-O.C.M. stands as a theoretical–clinical framework that integrates phenomenology and intelligent systems. Full article

Kernel row number (KRN) is a pivotal determinant for yield in maize breeding programs. However, the genetic basis underlying KRN remains largely elusive. To identify candidate genes regulating KRN, a population of 318 BC₄F₄ chromosomal segment substitution lines (CSSLs) was developed via backcrossing, with Baimaya (BMY) as the donor parent and B73 as the recurrent parent. Furthermore, a high-density genetic linkage map containing 2859 high-quality single-nucleotide polymorphism (SNP) markers was constructed for quantitative trait locus (QTL) mapping of KRN. Notably, 19 QTLs controlling KRN were detected across three environments and in the Best Linear Unbiased Prediction (BLUP) values; among these, a major-effect QTL (qKRN4.09-1) was consistently identified across all three environments and BLUP. Then, the integration of linkage mapping and transcriptome analysis of 5 mm immature ears from near-isogenic lines (NILs) uncovered a candidate gene, Zm00001eb205550. This gene exhibited significant downregulation in qKRN4.09-1^BMY, and two missense variants were detected between qKRN4.09-1^BMY and qKRN4.09-1^B73. Zm00001eb205550 exhibited preferential expression in developing ears. Moreover, the pyramiding of favorable alleles from the five stable QTLs significantly increased KRN in maize. These findings advance our genetic understanding of maize ear development and provide valuable genetic targets for improving KRN in maize breeding. Full article

Background/Objectives: Disorders of gut–brain interaction (DGBI) include a spectrum of disorders with chronic/recurrent gastrointestinal symptoms, caused by dysregulation of microbiota–gut–brain interaction. Early-life events have been suggested as the main factors influencing the microbiota–gut–brain axis. We aimed to evaluate the prevalence of DGBI in 3-year-old children and its relationship with early-life events. Methods: The parents of children aged 3 years, who had been followed up in a well-baby clinic since they were 2 months old, were asked about any GI symptoms their child had experienced during the check-up visits between September 2023 and June 2024. The final diagnosis of DGBI was based on ROME IV criteria. Demographic data, including early-life factors, were collected. Results: Overall, 568 children (48.6% boys) were included, of whom 139 (24.5%) had symptoms consistent with at least one DGBI diagnosis. The most prevalent DGBI was functional constipation (20.4%), followed by colic (4.6%), infant regurgitation (2.8%), and dyschezia (1.6%). Approximately 48% of the children were breastfed for ≥6 months, and 21% were exposed to ≥1 antibiotic/antiviral drugs in the first year of life. DGBI prevalence was significantly higher in girls than in boys (28.1% vs. 20.7%; p = 0.041). Exclusive breastfeeding was the most significant protective factor against DGBI, particularly if performed for ≥3 months. Conclusions: Sex was the most significant factor affecting DGBI prevalence in children aged ≤3 years; breastfeeding offers the most effective protection against DGBI development. Full article

Breaking the maize yield plateau necessitates the development of density-tolerant varieties, for which recurrent selection is a key breeding strategy. However, a systematic understanding of how the interaction between selection density (parental screening environment) and evaluation density (variety testing environment) modulates genetic gain remains a critical knowledge gap. This study aimed to systematically elucidate this interaction and its impact on genetic gain and combining ability. We established two F2 base populations from distinct heterotic groups: Zheng 58 × LH196 (Stiff Stalk, SS) and Chang 7-2 × MBUB (Non-Stiff Stalk, NSS). Through bulk selection, we advanced populations for three cycles (C0, C2, C4) under three selection densities: low (60,000 plants/ha), medium (90,000 plants/ha), and high (120,000 plants/ha). Hybrids were generated using a double tester design and evaluated in multi-environment trials at Shijiazhuang in Hebei province and Xinxiang in Henan province in 2023 across matching density gradients. We employed analysis of variance (ANOVA) and general combining-ability (GCA) estimates to assess the genetic gains for yield and combining ability across 14 parental materials and 28 hybrids. Our results demonstrate that density compatibility between selection and evaluation environments is paramount. Genetic gain decreased by 0.89–26.52% with a density discrepancy of >30,000 plants/ha and plummeted by 19.71–77.44% when the discrepancy exceeded 60,000 plants/ha, underscoring the necessity of aligning selection density with the target environment. Under matched densities, population yield increased significantly with escalating density, with the high-density selection regime showing a maximum yield improvement of 53.78% from C0 to C4. Materials selected under high density exhibited superior performance and significantly higher combining ability (averaging a 238.35% increase) and genetic gain (averaging a 263.39% improvement) in medium-to-high-density environments, confirming strong positive selection pressure. Conversely, materials from low-density selection processes were better adapted to environments of ≤60,000 plants/ha. This study provides a crucial theoretical and practical foundation for establishing density-optimized recurrent breeding systems to directionally enhance genetic gain in maize. Full article

Background/Objectives: Transient neonatal diabetes mellitus (TNDM) is a form of neonatal diabetes mellitus (NDM) arising in the first weeks of life and remitting in infancy. Epigenetic aberrations at the imprinted 6q24 locus (overexpression of PLAGL1/HYMAI) are the most common causes of TNDM. The aim of this study was a retrospective clinical and genetic analysis of a Polish pediatric cohort, emphasizing the role of methylation-specific MLPA (MS-MLPA) in the diagnosis of TNDM. Methods: We conducted a retrospective analysis of the medical records of 22 patients with diabetes diagnosed at 1 year of age. The molecular studies included an analysis of the NDM gene panel by a targeted NGS and MS-MLPA for the 6q24 imprinting region. Results: 6q24-TNDM was confirmed in five patients, with a median age of diabetes remission of 4 months (IQR: 3–6 months). The MS-MLPA identified paternal UPD6 or isolated maternal hypomethylation of PLAGL1 in three patients, and two had a paternal 6q24 duplication. Conclusions: In our group, changes in the 6q24 region were confirmed in 22.7% of NDM patients, indicating the usefulness of the MS-MLPA technique in the diagnosis and detection of imprinting defects. We acknowledge key limitations, including diagnostic delays and incomplete parental testing, which precluded trio-based confirmation of paternal UPD6 versus epimutation in some cases; future diagnostic workflows should incorporate an early trio-based SNP array or STR confirmation. A methylation analysis should be included early in the NDM genetic diagnosis process to provide genetic counseling and monitor patients for diabetes recurrence. Full article

Saccharum spontaneum L. (wild sugarcane) possesses advantages such as strong perenniality, high stress resistance, and broad adaptability, making it the most successfully utilized wild species in sugarcane hybrid breeding. However, previous exploitation of S. spontaneum has been limited. To further explore its breeding potential, this study employed recurrent selection to improve the population of S. spontaneum (S0) before its application in germplasm innovation. Subsequently, S1 (containing two S. spontaneum bloodlines) were developed and optimized. Using S1 as dual parents, S2 (containing three or more S. spontaneum bloodlines) were further created and selected. Genetic diversity among 199 materials from seven populations (S0, S1 and S2) was evaluated using simple sequence repeat (SSR) markers. The results showed that an unweighted pair-group method with arithmetic means (UPGMA) cluster analysis based on genetic distance classified the 199 S. spontaneum materials into seven groups, largely consistent with their original population divisions. Compared to their parents, the S1 population generated an average of 18.79 novel loci (mutation rate: 25.00%), while the S2 population produced an average of 15.40 novel loci (mutation rate: 19.00%). The polymer of S. spontaneum exhibited rich genetic diversity, with Nei’s gene diversity index of 0.3390 and Shannon information index of 0.5082. Due to the increased number of original parents and trait pyramiding, the polymer of S. spontaneum demonstrated expanded genetic backgrounds and enhanced heterogeneity. Furthermore, hybridization and recombination generated novel elite loci compared to their parents, further enriching the overall genetic background and diversity of the polymer of S. spontaneum. Full article

Gene duplications are considered to be the major evolutionary resource of novel functions. The gene family Esf2/ABP1 is conserved in metazoan organisms from yeast to humans. Here we performed a search and characterization of Esf2/ABP1 homologs in the Drosophila genus. Whereas in the majority of Drosophila species this gene family is represented by only a single gene, in the melanogaster and suzukii subgroups recurrent gene duplications arose, providing 47 homologous genes located on the X chromosome. To study the evolutionary history of duplicates, we performed phylogenetic, functional domain, and tissue-specific expression analyses. We revealed a male-specific and testis-biased transcription pattern of duplicated copies in Drosophila melanogaster and Drosophila sechellia compared to ubiquitous expression of the parental gene. The amplification of 21 repeated paralogs within the heterochromatic piRNA cluster resulted in the ovarian-specific transformation of these repeats into piRNAs in D. melanogaster. In three species of the suzukii subgroup, Esf2/ABP1 genes evolved with domain diversification: in addition to RNA-binding ABT1-like domain preservation, all homologous proteins acquired expanded intrinsically disordered regions. By studying the duplicated copies of the Esf2/ABP1 family in Drosophila, we offer insight into how novel gene functions emerge and are maintained, contributing to life’s diversity and complexity. Full article

Maturity-Onset Diabetes of the Young Type 5 (MODY5) is caused by heterozygous pathogenic variants in the HNF1B gene, encoding the transcription factor hepatocyte nuclear factor-1β. HNF1B haploinsufficiency typically leads to young-onset non-immune diabetes and highly variable renal involvement, whose more frequent features are bilateral kidney cysts and renal hypodysplasia. Kidney cysts or echogenic kidneys can be identified by ultrasonography in the prenatal period, but the renal involvement can also start in childhood or later. Notably, a recurrent microdeletion syndrome at 17q12 (deleting HNF1B plus ~15 neighboring genes) accounts for ~40–50% of cases. The 17q12 deletion is a contiguous gene syndrome and affected individuals present with a complex phenotype, including neurodevelopmental disorders, liver and pancreas abnormalities, and other congenital defects. When counseling the patient and the parents, the clinician must consider multiple factors, including the molecular defect and the age of onset of the symptoms, with particular attention to prenatal diagnosis. A multidisciplinary approach and an early diagnosis are essential for the management of these conditions. Full article

Acute human alpha-herpesvirus 1 (HSV-1) infection culminates in a latent infection of neurons in trigeminal ganglia (TG) and the central nervous system. Following infection of mucosal epithelial cells, certain neurons survive infection and life-long latency is established. Periodically, stressful stimuli trigger reactivation from latency, which result in virus shedding, transmission to other people, and, occasionally, recurrent disease. The glucocorticoid receptor (GR) and Krüppel-like factor 15 (KLF15) comprise a feed-forward transcriptional loop that cooperatively transactivate key HSV-1 promoters that drive expression of infected cell protein 0 (ICP0), ICP4, and ICP27. Silencing KLF15 significantly reduces HSV-1 replication in cultured mouse neuroblastoma cells. Consequently, we hypothesized that KLF15 mediates certain aspects of reactivation from latency. To test this hypothesis, we compared HSV-1 replication in KLF15^−/− mice versus wild-type (wt) parental C57BL/6 mice. Virus shedding during acute infection was reduced in KLF15^−/− mice. Male KLF15^−/− mice shed higher titers of virus during late stages of reactivation from latency compared to KLF15^−/− females and wt mice regardless of sex. At 15 d after explant-induced reactivation, virus shedding was higher in male KLF15^−/− mice relative to wt mice and female KLF15^−/− mice. These studies confirm KLF15 expression enhances viral replication during acute infection and reactivation from latency. Full article

The fungal pathogen Puccinia striiformis f. sp. tritici, which causes yellow rust disease, poses a significant economic threat to wheat production not only in Uzbekistan but also globally, leading to substantial reductions in grain yield. This study aimed to develop yellow rust-resistance wheat lines by introgressing Yr10 and Yr15 genes into high-yielding cultivar Grom using the marker-assisted backcrossing (MABC) method. Grom was crossed with donor genotypes Yr10/6*Avocet S and Yr15/6*Avocet S, resulting in the development of F₁ generations. In the following years, the F₁ hybrids were advanced to the BC₂F₁ and BC₂F₂ generations using the MABC approach. Foreground and background selection using microsatellite markers (Xpsp3000 and Barc008) were employed to identify homozygous Yr10- and Yr15-containing genotypes. The resulting BC₂F₂ lines, designated as Grom-Yr10 and Grom-Yr15, retained key agronomic traits of the recurrent parent cv. Grom, such as spike length (13.0–11.9 cm) and spike weight (3.23–2.92 g). Under artificial infection conditions, the selected lines showed complete resistance to yellow rust (infection type 0). The most promising BC₂F₂ plants were subsequently advanced to homozygous BC₂F₃ lines harboring the introgressed resistance genes through marker-assisted selection. This study demonstrates the effectiveness of integrating molecular marker-assisted selection with conventional breeding methods to enhance disease resistance while preserving high-yielding traits. The newly developed lines offer valuable material for future wheat improvement and contribute to sustainable agriculture and food security. Full article

Background/Objectives: Leukemia is associated with high recurrence rates and cancer vaccines are emerging as a promising immunotherapy against the disease. Here, we investigate the mechanism of action by which a personalized vaccine made from leukemia cells infected with an oncolytic virus (ICV) induces anti-tumor immunity. Methods: Using the L1210 murine model, leukemia cells were infected and irradiated to create the ICV. The CRISPR-Cas9 system was used to engineer knockout cells to test in treatment efficacy studies. Results: We found that pro-inflammatory interferons (IFNs) that are produced by infected vaccine cells induce the immunoproteasome (ImP), a specialized proteasome subtype that is found in immune cells. Interestingly, we show that while a vaccine using the oncolytic vesicular stomatitis virus (oVSV) completely protects against tumor challenge, the wild-type (wt) virus, which does not induce the ImP, is not as effective. To delineate the contribution of the ImP for vaccine efficacy, we generated ImP-knockout cell lines and found no differences in treatment efficacy compared to wild-type cells. Furthermore, an ICV using another murine leukemia model that expresses the ImP only when infected by an IFN gamma-encoding variant of the virus demonstrated similar efficacy as the parental virus. Conclusions: Taken together, our data show that ImP expression by vaccine cells was not required for the efficacy of leukemia ICVs. Full article

Downy mildew caused by Plasmopara viticola is an important disease in grape production, particularly in the highly susceptible, widely cultivated Vitis vinifera L. Breeding for disease resistance is an effective solution, and V. vinifera intraspecific crosses can yield progeny with both disease resistance and high quality. To assess the potential of intraspecific recurrent selection in V. vinifera (IRSV) in improving grapevine resistance to downy mildew and to analyze the pattern of disease resistance inheritance, the disease-resistant variety Ecolly was selected as one of the parents and crossed with Cabernet Sauvignon, Marselan, and Dunkelfelder, respectively, creating three reciprocal combinations, resulting in 1657 hybrid F1 progenies. The primary results are as follows: (1) significant differences in disease resistance among grape varieties and, significant differences in disease resistance between different vintages of the same variety were found; (2) the leaf downy mildew resistance levels of F1 progeny of different hybrid combinations conformed to a skewed normal distribution and showed some maternal dominance; (3) the degree of leaf bulbous elevation was negatively correlated with the level of leaf downy mildew resistance, and the correlation coefficient with the level of field resistance was higher; (4) five progenies with higher levels of both field and in vitro disease resistance were obtained. Intraspecific hybridization can improve the disease resistance of offspring through super-parent genetic effects, and Ecolly can be used as breeding material for recurrent hybridization to obtain highly resistant varieties. Full article