Search Results (1,043)

The Arabidopsis thaliana Heat Shock Protein-Related (AtHSPR) gene participates in plant growth and abiotic stress tolerance, while its role in biotic stress resistance remains unclear. Here, we report that the athspr mutant is sensitive to Pseudomonas syringae pv. tomato (Pst) DC3000, whereas over-expression of AtHSPR enhances the defense of Arabidopsis against the pathogen. AtHSPR expression was induced by treatment with Pst DC3000, flg22, or salicylic acid (SA). Transcriptome analysis showed that mutation of AtHSPR changed the expression patterns of genes associated with defense response, oxidation–reduction, and SA responses, as well as transcription factors. The biochemical evidence revealed that AtHSPR interacted with Thimet Oligopeptidase 1 (TOP1), which modulated the SA-mediated immune response. Co-expression of AtHSPR and TOP1 showed that the TOP1 protein, normally located in the chloroplasts, gathered around the nucleus in response to a pathogen. After pathogen treatment, dynamic tubular projections (stromules) were present, extending from the chloroplasts toward the nucleus, and TOP1 was observed in the nucleus, together with AtHSPR. The top1athspr double mutant had lower SA levels and was more sensitive to pathogens than the top1 and athspr single mutants. Taken together, our results demonstrated that the interaction between AtHSPR and TOP1 plays a positive role in SA-mediated plant resistance against Pst DC3000. Full article

With the construction of transportation networks in mountainous areas under the Western Development Strategy, double-row pile foundations on slopes have been widely applied. However, due to the distortion of the soil stress field, their load distribution mechanism under bidirectional loading is extremely complex. To investigate the internal force distribution laws and deformation and failure modes, a systematic study was conducted utilizing theoretical derivation: 60 scale indoor physical model tests, and 3D refined finite element numerical simulations. The results show that the force distribution of double-row piles in slope environments differs significantly: the upper-row piles, affected by active earth pressure and sliding thrust, bear significantly higher load than the lower-row piles; meanwhile, the lower-row piles, constrained by stronger deep soil, can more fully utilize their vertical bearing capacity. Parametric analysis indicates that the terrain slope has a nonlinear amplification effect on the displacement difference at the pile top, with 50° being the critical mutation slope that triggers the failure of connection joints. In addition, the deformation mode of double-row piles undergoes a change when the pile spacing exceeds 5 times the pile diameter. Therefore, in practical engineering design, the traditional concept of symmetrical reinforcement should be abandoned in favor of differentiated bending reinforcement targeting the shallow surface layer of the upper-row piles and the deep inflection point of the lower-row piles. For working conditions with a slope greater than 50°, additional measures such as prestressed anchor cables must be applied to reduce the sliding load. Meanwhile, the row spacing should be strictly controlled within 5 times the pile diameter to fully ensure the diaphragm effect and the overall synergistic stability of the structure. Full article

Background: Benzimidazole (BZ) resistance in the gastrointestinal nematode Haemonchus contortus is a major constraint to sheep production worldwide. However, data on the prevalence and molecular mechanisms of resistance in Yili Prefecture, Xinjiang—a key livestock region in Northwestern China—remain limited. This study aimed to determine the frequency of BZ resistance-associated single nucleotide polymorphisms (SNPs) in H. contortus populations from Zhaosu and Tekesi counties. Methods: Adult male worms (n = 150) were collected from naturally infected sheep at local abattoirs. Species identity was confirmed morphologically by sequencing the internal transcribed spacer 2 (ITS-2) region. A 385 bp fragment of the isotype-1 β-tubulin gene was amplified and sequenced to detect SNPs at codons 167 (F167Y), 198 (E198A), and 200 (F200Y). Results: The F167Y mutation was absent in all individuals. In contrast, the E198A mutation occurred at exceptionally high frequencies, with resistant allele frequencies (RAF) of 64.7% in Zhaosu and 52.7% in Tekesi. The F200Y mutation showed clear geographical variation: it remained low in Zhaosu (RAF = 9.3%) but was substantially higher in Tekesi (RAF = 33.3%). Haplotype analysis revealed that resistance in Zhaosu was driven primarily by the E198A mutation, whereas the Tekesi population exhibited complex patterns of co-selection of both E198A and F200Y, with a high proportion of double-heterozygous individuals (29.3%). Conclusions: This study provides comprehensive molecular evidence of severe BZ resistance in H. contortus populations from Zhaosu and Tekesi counties, Yili Prefecture. The marked predominance of the E198A mutation, together with the emergence of multi-locus resistance in Tekesi, indicates a rapid escalation of resistance beyond historical levels. These findings suggest that benzimidazoles are likely ineffective in this region and highlight the urgent need to revise local parasite control strategies. Full article

The CRISPR/Cas9 system has been widely used for gene editing in various species; however, mosaicism remains a significant challenge. This study aimed to improve gene editing efficiency and reduce mosaicism in porcine embryos by exploring double electroporation pre- and post-in vitro fertilization combined with zona pellucida (ZP) removal. We evaluated the effects of these treatments on the development and mutation rates of oocytes/zygotes edited with guide RNAs (gRNAs) targeting GGTA1, CMAH, or B4GALNT2 genes. Double electroporation significantly increased the total and biallelic mutation rates in ZP-intact zygotes but not in ZP-free zygotes edited using GGTA1-targeted gRNAs. All blastocysts from ZP-free zygotes exhibited biallelic mutations following double electroporation. For the CMAH gene, all blastocysts exhibited mutations (biallelic mutations ≥ 80%); however, double electroporation and ZP removal did not affect their mutation rates or efficiency. For the B4GALNT2 gene, double electroporation significantly increased total mutation rates in ZP-intact zygotes, whereas all blastocysts from ZP-free zygotes showed biallelic mutation. These findings suggest that double electroporation, particularly with ZP removal, may enhance gene-editing efficiency, reduce mosaicism and improve the success of genetic modifications. Full article

Low-temperature-induced fertility restoration in thermo-sensitive genic male sterile (TGMS) lines severely impairs hybrid seed purity, which is a major bottleneck for two-line hybrid rice production. Most commercial TGMS lines rely on the single tms5 locus, leading to high climatic vulnerability. In this study, we developed a dual-locus strategy by target genome editing of TMS5 and MS1 in indica rice GH89. Adenine base editing at the MS1 locus exhibited a high editing efficiency of 93.5%. Transgene-free homozygous single mutants (GH89-tms5 and GH89-MS1) and double mutant (GH89-tms5 + MS1) were generated for phenotypic analysis. The double mutant GH89-tms5 + MS1 remained completely sterile for 5 and 10 days under controlled low temperature (23.5 °C), with only minimal fertility restoration after 15 days. In the field, it maintained complete sterility for 84 consecutive days and was fully insensitive to short-term low temperature fluctuations, outperforming single mutants and commercial control Y58S. Moreover, the double mutant retained most key yield-related agronomic traits of the wild type with only minor variations. This dual mutation forms a “double-lock” fertility regulatory system, significantly increasing the low-temperature duration threshold for fertility restoration. The GH89-tms5 + MS1 line exhibits promising potential for future rice breeding applications. Full article

Ataxia–telangiectasia is a rare, autosomal recessive primary immunodeficiency caused by mutations in the ATM gene on chromosome 11, which encodes a serine–threonine kinase essential for the recognition and repair of DNA double-strand breaks. The disease is characterized by progressive neurological impairment, immunological dysfunction, and an increased susceptibility to recurrent infections and malignancies. Pulmonary involvement represents a major source of morbidity and frequently arises from chronic infections, aspiration, and impaired airway clearance, ultimately leading to the development of bronchiectasis. The case of a 15-year-old adolescent with a history of recurrent aspiration pneumonias, neuropsychomotor developmental delay, and severe malnutrition is reported, who was admitted for evaluation of chronic productive cough, fever, and dysphagia. Comprehensive clinical assessment and ancillary investigations revealed recurrent respiratory infections, gastroesophageal reflux, and typical features of ataxia–telangiectasia, including cerebellar ataxia, oculomotor apraxia, and conjunctival telangiectasias. Additionally, bronchiectasis was identified as a secondary consequence of the underlying neurological and immunological impairment. This case highlights the diagnostic challenges posed by ataxia–telangiectasia in pediatric patients presenting with chronic respiratory symptoms and emphasizes the importance of early recognition of the underlying systemic disorder. A multidisciplinary approach is essential for accurate diagnosis and optimized management, aiming to address both the primary disease and its pulmonary complications. Full article

Background: Type 2 diabetes is projected to affect millions of people annually as the number of cases rises year on year. This includes children. Treating diabetes and its related comorbidities has a huge economic impact and puts pressure on healthcare providers. Understanding the disease at a molecular level is key for developing better therapeutics. The protein Islet Amyloid Polypeptide (IAPP) or amylin is important for glucose regulation; however, it is also instrumental in type 2 diabetes pathology. Human IAPP can misfold into oligomers and amyloid fibrillar aggregates within pancreatic islets, promoting β-cell dysfunction and death, contributing to progressive insulin deficiency and worsening hyperglycaemia. Methods: Based on previous studies on mutations at residues 18, 28 and 31,we have designed three novel IAPP analogues (two double and one triple mutant) to assess whether the combined amino acid substitutions impact fibril formation, solubility and toxicity. Results: All three of our analogues show a reduced propensity to aggregate and are more soluble than wild type IAPP. Compared with pramlintide, a clinically prescribed synthetic analogue of human amylin, all of our analogues appeared to have similarly reduced toxicity and improved solubility relative to human IAPP. Additionally, two of our analogues exhibited a markedly slower rate of fibril formation. Conclusions: Our results highlight the importance of targeting multiple residues as a promising strategy for developing improved diabetes therapeutics in the future. Full article

Radiation-induced biological responses emerge through complex interactions across multiple biological scales, ranging from molecular damage to tissue remodeling and organism-level outcomes. Although traditional radiobiology has primarily focused on DNA damage and linear dose–response relationships, increasing evidence suggests that radiation responses are highly context-dependent and cannot be fully explained by genomic alterations alone. In particular, low-dose and chronic radiation exposures often induce biological effects that involve dynamic regulatory processes beyond direct mutational burden. The narrative review proposes a conceptual multiscale framework for predictive radiobiology that integrates genomic damage, post-transcriptional regulation, network rewiring, and tissue microenvironmental interactions. Within this framework, “predictive radiobiology” refers to the integrative prediction of radiation-induced outcomes, including radiosensitivity, tissue remodeling, fibrosis progression, therapeutic response, and long-term carcinogenic risk. We discuss how radiation-induced signaling extends beyond DNA double-strand breaks to include RNA-binding protein-mediated regulation, adaptive network responses, and extracellular matrix-dependent cellular plasticity. Recent advances in multi-omics, single-cell analysis, spatial biology, and three-dimensional organotypic models have revealed that radiation responses are governed by interconnected molecular and tissue-level processes. Furthermore, artificial intelligence and systems-level computational approaches provide new opportunities for modeling non-linear and context-dependent radiation effects across biological scales. We further discuss current limitations, including data integration challenges, reproducibility issues, and the translational gap between experimental models and clinical applications. Collectively, this conceptual framework highlights the need for integrative and multiscale approaches to improve mechanistic understanding and predictive modeling in modern radiobiology. Full article

Background/Objectives: Staphylococcus haemolyticus is a common skin commensal that has emerged as a multidrug-resistant nosocomial pathogen, with sequence type 42 frequently implicated in clinical settings. The genetic basis of fusidic acid (FA) resistance mediated by mutations in elongation factor-G (fusA/EF-G) has not been systematically characterized in S. haemolyticus. Methods: Five representative FA-susceptible S. haemolyticus isolates were selected. In vitro FA resistance was induced by incubating each isolate on Mueller–Hinton agar containing 4 µg/mL FA at 37 °C for 48 h. Resistant colonies were recovered and fusA was sequenced by Sanger sequencing to identify mutations. Growth doubling times of EF-G mutant isolates were measured and compared with those of the parental susceptible strains. Potential fitness-compensatory changes in fusA were assessed by serial passage of selected mutants for ten successive passages and re-sequencing of fusA. Results: A total of 28 FA-resistant colonies were recovered. Sequencing identified mutations at seven nucleotide loci corresponding to ten distinct amino acid substitutions in EF-G: Q115L, L430S, E433G, G452C, H457Y, H457N, H457L, H457Q, R464L, and A655G. The mean doubling time of EF-G mutant isolates was significantly longer than that of the wild-type parental strains (mutants: 55.75 ± 7.78 min, n = 28; wild type: 40.78 ± 4.13 min, n = 5; Welch’s two-sample t test: t = −6.34, df ≈ 10.0, two-tailed p < 0.0001). Following ten serial passages, we did not detect compensatory mutations in fusA that restored the ancestral growth rate. Conclusions: FA resistance in S. haemolyticus can be rapidly induced in vitro through mutations in EF-G/fusA. Compared with previously reported EF-G mutations in other staphylococci, we identified two novel substitution sites (L430S, E433G) and previously unreported substitutions at established resistance positions (H457N, H457L, A655G). Mutations in EF-G (encoded by fusA) were associated with a measurable in vitro fitness cost; following ten serial passages, compensatory mutation was not detected in fusA. These findings support systematic surveillance of EF-G/fusA mutations in clinical S. haemolyticus isolates. Further studies should address their prevalence, stability, transmissibility, and clinical impact, particularly where FA use is increasing and patient populations are vulnerable. Full article

Nicolás Guillén Landrián (1938–2003) is often described as one of the most formally daring documentary filmmakers to emerge from Cuba’s Instituto Cubano del Arte e Industria Cinematográficos (ICAIC), yet decades of institutional censorship, including imprisonment, forced psychiatric treatment, and the quiet burial of his films in archives, pushed him into a kind of official nonexistence. His work resurfaced unexpectedly during a 2003 screening in Havana, an event that seemed to reveal just how much had been missing from the historical record. This article examines the systematic relationship between the revolutionary Cuban censorship apparatus and the aesthetic strategies Guillén Landrián developed, from his early ICAIC shorts to his final exile film, Inside Downtown (2001). Drawing on archival materials, published interviews, critical theory (Foucault, Agamben, Bourdieu, Scott, de Certeau), and close readings of key films such as Coffea Arábiga (1968), Desde La Habana ¡1969! Recordar (1969–1971), and Taller de Línea y 18 (1971), we argue that censorship did not simply constrain his filmmaking but shaped it in ways that opened unexpected formal paths. We describe these strategies as a “poetics of obliqueness”—a mode of working that embeds critique within intermedial collage, uneasy juxtapositions, ellipsis, allegory, and double coding. These tactics exploited the gap between the apparatus’s strict monitoring of explicit ideological statements and its difficulty policing ambiguous or formally inventive gestures. Although grounded in the Cuban case, this framework speaks to broader questions about how artists under authoritarian conditions convert pressure into a generative constraint, revealing how creativity can survive, and sometimes mutate, under sustained surveillance. Full article

Germline loss-of-function mutations in BRCA1 and BRCA2 markedly increase susceptibility to breast, ovarian, and other cancers. Mechanistically, BRCA2 facilitates RAD51 recruitment to sites of DNA damage, whereas BRCA1 regulates homologous recombination repair (HRR) through double-strand break resection and broader DNA damage response signaling. These insights underpin targeted therapies such as poly (ADP-ribose) polymerase inhibitors (PARPis), which induce synthetic lethality in homologous recombination-deficient tumors. Clinically, PARPis have demonstrated significant benefit in BRCA1/2-mutated breast, ovarian, pancreatic, and prostate cancers. However, resistance remains a major obstacle, with secondary intragenic BRCA1/2 mutations restoring partial protein function representing a prominent mechanism. Despite therapeutic advances, critical gaps persist in understanding how specific BRCA1/2 domains and residual protein activities contribute to tumorigenesis and treatment response. In this review, we summarize the structural and functional domains of BRCA1/2, their pathogenic mutation profiles, and therapeutic strategies targeting BRCA1/2-deficient cancers. Despite therapeutic advances, critical gaps persist in understanding how specific BRCA1/2 domains and residual protein activities contribute to tumorigenesis and treatment response. This review emphasizes the need for functional studies of BRCA1/2 variants to refine risk prediction and develop mutation-tailored therapies. Full article

Recent advances in CRISPR technology have expanded beyond traditional double-strand break–based genome editing to include base editors and prime editors, enabling precise and programmable sequence modifications. This evolution marks a shift from conventional mutation correction toward platform-based therapeutic systems capable of targeting a broad spectrum of pathogenic variants. Such versatility holds promise for addressing a substantial proportion of known disease-causing mutations in rare monogenic disorders. This review discusses the technological progression of CRISPR systems, highlighting the principles, applications, and limitations of emerging editing modalities. We will explore their translation into personalized gene therapies, emphasizing delivery challenges, off-target safety, and the need for regulatory innovation. The paper will also introduce the concept of interventional genetics, an emerging medical framework linking genomic diagnosis directly to therapeutic intervention through adaptive gene-editing platforms. Finally, we will outline strategies for establishing unified, scalable, and regulatory-ready editing platforms that can accelerate the clinical implementation of individualized therapies for rare diseases. Full article

Cancer is a complex and evolutionary disease, with the development of different types of cancers leading to various different defective gene mutations. Synthetic lethality is a genetic-level precision medical strategy. Currently, treating BRCA (BReast CAncer)-mutated breast or ovarian cancer cells with a chemical inhibitor (Poly(ADP-ribose) polymerase, PARPi) is a typical synthetic lethal application in clinical practice. However, PARPi therapy has been found to cause off-target effects and therapy-induced immune escape driven by PD-L1 upregulation, allowing for cancer cells to escape attack from the immune response. To overcome these challenges, we developed a core–shell structure comprising a hydrophobic core of quercetin (Q)-mediated PARP inhibition and iron oxide nanoparticles (IONPs), enveloped by a hydrophilic fucoidan (Fu) shell to encapsulate short hairpin RNA targeting Programmed Death Ligand 1 (shPD-L1) for efficient gene transfection (shPD-L1@QIO@Fu). Structurally, the incorporation of quercetin into the intermediate hydrophobic layer enables modulate of the PARP effect, while the inner aqueous core with shPD-L1 gene silencing can inhibit the expression of PD-L1 protein. In this study, we proved that shPD-L1@QIO@Fu demonstrated a dual therapeutic mechanism against BRCA-mutant cancer cells by inducing extensive DNA double-strand breaks and promoting apoptosis. Furthermore, the combined action of quercetin-mediated DNA damage and shPD-L1-driven PD-L1 suppression led to a significant reduction in PD-L1 mRNA to approximately 5% at 72 h and decreased surface PD-L1 below baseline by 96 h. This effectively suppresses PARPi-induced PD-L1 upregulation and enhances antitumor immunity. These findings demonstrate the therapeutic efficacy of shPD-L1@QIO@Fu nanomedicine, providing a promising foundation for advanced co-delivery strategies to synergize PARP inhibition mediated synthetic lethality with immune checkpoint blockade in next-generation precision medicine. Full article

Current treatments for choroidal neovascularization (CNV) and its associated subretinal fibrosis (SRF), major causes of vision loss, are limited by the need for frequent intravitreal injections and the emergence of drug resistance. This study evaluated the safety and efficacy of the intravitreal administration of engineered humanized anti-vascular endothelial growth factor Nanobodies, including a wild-type Nanobody (WHNb) and two mutated variants (MHNb136 and MHNb256), in a rat model of laser-induced CNV and associated SRF. Safety was assessed through in vivo electrophysiological and histopathological analyses following intravitreal injection of Nanobodies at doses of 12.5, 25, 50, and 100 µg. Efficacy was evaluated in rat models of laser-induced CNV and SRF using double immunohistochemistry for isolectin B4 and anti-collagen type I on sclerochoroidal flat mounts. Mean CNV and SRF areas in Nanobody-treated groups were compared with those in bevacizumab-treated and sham control groups. None of the Nanobodies showed retinal toxicity in safety assessments. Compared with bevacizumab, MHNb136 and MHNb256 reduced the CNV area by 1.72-fold and 1.8-fold, respectively (both p < 0.0001), whereas WHNb showed an effect nearly identical to that of bevacizumab. In addition, 12.5 µg MHNb136 and 100 µg MHNb256 reduced the SRF area by 1.3-fold (p = 0.047) and 1.6-fold (p = 0.0007), respectively, relative to bevacizumab. For CNV reduction, 12.5 µg MHNb136 was comparable to 25 µg MHNb256; both outperformed bevacizumab. For SRF reduction, 12.5 µg MHNb136 was more effective than bevacizumab and comparable to 100 µg MHNb256. These findings suggest that 12.5 µg MHNb136 may represent a cost-effective bioengineered Nanobody candidate for future clinical studies. Full article

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal degenerations with primary degeneration of rod photoreceptors followed by secondary cone loss. We investigated whether downregulating Nrl (neural retina leucine zipper), a key transcription factor specifying rod fate, can reprogram rods into a more resilient state. In a transgenic Nrl^N/N mouse in which Nrl was markedly downregulated, the rod phenotype became more like a rod precursor, particularly in the inferior retina. Crossing Nrl^N/N mice with two rod degeneration models, rd1 (Pde6b^rd1/rd1) and rhodopsin P23H knock-in (Rho^P23H/P23H) mice, showed significantly improved photoreceptor survival in double-mutant mice. In addition, AAV-mediated delivery of shRNA targeting Nrl mRNA substantially enhanced photoreceptor survival in rd10 (Pde6b^rd10/rd10) mice. These findings demonstrate that downregulation of Nrl reprograms rods and confers broad resistance to degeneration across multiple RP models. AAV-mediated Nrl knockdown represents a promising mutation-independent therapeutic strategy for autosomal recessive and dominant forms of RP. Full article